Le mélanome est le cancer de la peau le plus dangereux : il est capable de métastaser rapidement vers les ganglions et les viscères, et est réfractaire aux chimio/radiothérapies. De nouvelles thérapies ciblant la kinase BRAFV600 retrouvée dans 60% des mélanomes ont montré des effets spectaculaires en termes de survie globale et sans progression de la maladie. L’efficacité de ces thérapies est compromise par l’apparition fréquente de résistances. Les cellules cancéreuses sont ancrées au sein d’un microenvironnement avec lequel elles interagissent. Elles profitent de facteurs solubles du stroma et de l’adhésion à la matrice extracellulaire (MEC) pour survivre face aux thérapies. La protéine matricellulaire SPARC orchestre les interactions entre les cellules saines ou cancéreuses et leur microenvironnement. Absente dans les mélanocytes, son expression est initiée et augmentée dans les mélanomes, corrélée à la progression tumorale et à un mauvais pronostic clinique. Lorsqu’elle est sécrétée par les cellules de mélanome, elle active la kinase AKT, déstabilise le suppresseur de tumeur p53 et favorise la prolifération/survie tumorale. Nous avons montré que le module SPARC/AKT est un nouveau déterminant de la résistance innée ou acquise des mélanomes mutés BRAFV600 aux anti-BRAF, et mis en évidence l’intérêt du ciblage de SPARC en combinaison avec des anti-BRAF ou -MEK pour optimiser/restaurer la sensibilité des mélanomes à ces inhibiteurs. Nous avons aussi montré que les fibroblastes ganglionnaires ont des caractéristiques de fibroblastes activés, et confèrent une résistance aux anti-BRAF aux cellules de mélanomes en générant une MEC permissive à laquelle elles adhérent. / Melanoma is the most dangerous form of skin cancer due to its high metastatic potential and its resistance to both classical chemo- and radiotherapies. New targeted therapies directed against the V600E oncogenic form of BRAF found in about 60% of patients have demonstrated spectacular efficacy both in terms of progression free and overall survival. However most patients invariably relapse after a few months due to resistance mechanisms. Cancer cells are anchored and interact constantly with their microenvironment. Both soluble factors and the extracellular matrix produced by stromal cells have been shown to contribute to cancer cell resistance to therapies. SPARC is a matricellular protein that orchestrates interactions between normal and/or cancer cells and their microenvironment. While it is absent in melanocytes, SPARC expression increases in melanoma and is correlated with both tumoral progression and a bad prognosis. When SPARC is secreted by melanoma cells, it activates the AKT kinase, destabilizes the p53 tumor suppressor and promotes proliferation and survival. Here we identify the couple SPARC/AKT as a new actor contributing to both innate and acquired resistance to BRAFV600E inhibitors. In addition, we demonstrate that targeting SPARC in melanoma cells increases their sensitivity to both BRAF and MEK inhibitors. Finally we show that lymph node fibroblasts share features of activated fibroblasts and confer resistance to BRAF inhibitors to melanoma cells through the production of a permissive extracellular matrix.

Environ 5% des patientes sont diagnostiquées chaque année avec un cancer du sein d’emblée métastatique et 20 à 30% des cancers du sein localisés évoluent vers un stade secondairement métastatique. Les bénéfices de l’activité physique pendant les traitements chez les patientes avec un cancer du sein localisé ont largement été démontrés mais la littérature est limitée dans le cancer du sein métastatique. Ce travail de thèse a permis d’évaluer les effets potentiels de l’activité physique chez des patientes atteintes d’un cancer du sein métastatique à travers trois études.L’étude observationnelle StoRM a montré une association du niveau d’activité physique recueilli par questionnaire à une meilleure survie des patientes HER2. L’étude interventionnelle ABLE a mis en évidence la faisabilité d’une intervention en activité physique avec une montre connectée dans cette population avec un excellent taux d’adhérence (96%), l’intérêt et la volonté des patientes pour les programmes d’activité physique ainsi qu’une amélioration fonctionnelle. L’intervention a contribué au un maintien de la qualité de vie, de la fatigue et du niveau d’activité physique malgré les traitements et l’avancée de la maladie. De potentiels biomarqueurs prédictifs d’une progression tumorale ont été identiés. L’étude MUST a montré que l’antioxydant SOD et de la force isométrique d’extension du quadriceps semblent prévenir la sarcopénie et une association entre le statut sarcopénie et le risque de toxicités a été confirmé. Ce travail de thèse représente une première étape dans l’analyse des effets de l’activité physique auprès de patientes atteintes d’un cancer du sein métastatique. L’activité physique semble être bénéfique dans cette population, mais ces résultats nécessitent d’être confirmés dans une étude à plus grande échelle. Ces résultats préliminaires soulignent l’importance de proposer des interventions adaptées en activité physique aux patientes atteintes d’un cancer du sein métastatique dès le diagnostic pour poursuivre un mode de vie actif le plus longtemps possible / Approximately 5% of patients are diagnosed with metastatic breast cancer each year and 20 to 30% of localized breast cancers become secondarily metastatic. Benefits of physical activity during treatment in patients with localized breast cancer have been widely demonstrated, but the literature is limited in metastatic breast cancer. This thesis work assessed the potential effects of physical activity in patients with metastatic breast cancer through three studies.The StoRM observational study showed an association between the level of physical activity collected by questionnaire with an improvement of survival for HER2 patients. The ABLE intervention study highlighted the feasibility of a physical activity intervention with an activity tracker in this population with an excellent adherence rate (96%), patients' interest and willingness to participate in physical activity programs and functional improvements. The intervention contributed to maintaining quality of life, fatigue and physical activity levels despite treatment and disease progression. Potential biomarkers predictive of tumor progression have been identified. The MUST study showed that the antioxidant SOD and quadriceps isometric extension force appear to prevent sarcopenia and an association between sarcopenia status and toxicity risk was confirmed. This thesis work represents a first step in analyzing the effects of physical activity on patients with metastatic breast cancer. Physical activity appears to be beneficial in this population, but these results need to be confirmed in a larger scale study. These preliminary results highlight the importance of providing appropriate physical activity interventions for patients with metastatic breast cancer at the time of diagnosis in order to maintain an active lifestyle as long as possible

INTRODUÇÃO: A insuficiência respiratória acomete grande parte dos pacientes oncológicos levando a altos índices de mortalidade. A ventilação não invasiva (VNI) pode auxiliar seu manejo, mas seus efeitos ainda são pouco conhecidos sobre os mecanismos de defesa pulmonar. OBJETIVOS: Observar o efeito da VNI com máscara facial usando-se geradores de fluxo com pressão positiva contínua (CPAP) e ventilador microprocessado no modo pressão de suporte + pressão positiva ao final da expiração (PSV + PEEP), a fim de verificar impacto nas propriedades viscoelásticas do muco respiratório e o conforto proporcionado ao paciente. MÉTODOS: A VNI foi instalada após diagnóstico de insuficiência respiratória em dezenove pacientes, admitidos nas unidades de tratamento intensivo do Hospital A. C. Camargo, sendo nove submetidos ao CPAP e dez com PSV + PEEP. Foram colhidos antes e após uma hora de VNI: os dados clínicos, secreção nasal, gasometria, e o grau de conforto através de uma escala visual. As propriedades físicas do muco (transportabilidade in vitro, adesividade e wettabilidade ou hidrofobicidade) foram avaliadas respectivamente no palato de rã, máquina da tosse e ângulo de contato. RESULTADOS: Os grupos eram homogêneos entre si em relação à idade, sexo, tipo e estadiamento do tumor e SAPS II. Em relação às propriedades físicas do muco, houve um aumento da transportabilidade in vitro do muco nasal com o sistema PSV + PEEP (p = 0,04) e um aumento na wettabilidade no grupo CPAP (p = 0,06). Os dois sistemas foram eficazes em melhorar significativamente os sinais vitais, a PaO2/FiO2, o padrão e o conforto respiratório e em evitar a intubação traqueal nas primeiras 24 horas (p < 0,05). Entretanto, independentemente do tipo de sistema de VNI usado, foram encontrados altos índices de intubação endotraqueal e mortalidade no seguimento destes pacientes. CONCLUSÃO: As propriedades físicas do muco (transportabilidade in vitro e wettabilidade) se alteraram após uma hora de uso da VNI e parecem ser dependentes da temperatura e umidificação dentro da máscara. A VNI mostrou-se útil em reverter a insuficiência respiratória em pacientes selecionados, ou pelo menos em trazer conforto para pacientes hipoxêmicos que a princípio recusam a intubação endotraqueal / INTRODUCTION: Respiratory failure is a common situation among cancer patients leading to high rates of mortality. Noninvasive ventilation (NIV) can help its management, but its effects are still unknown regarding the pulmonary defense mechanisms. OBJECTIVES: Observe the effect of NIV with facial mask using a flow generator with continuous positive pressure (CPAP) and standard intensive care unit ventilator using pressure support ventilation + positive end expiratory pressure (PSV + PEEP), to verify impact on the physical properties of respiratory mucus and the comfort provided to the patient. METHODS: NIV was started after diagnosis of respiratory failure in nineteen patients, admitted in the intensive care unit of the A. C. Camargo Hospital. Nine patients were submitted to CPAP and ten to PSV + PEEP. Nasal mucus, blood gases, and the degree of comfort through a visual scale were accessed before and after one hour. The physical properties of nasal mucus (transportabilility in vitro, adhesivity and wettability or hydrofobicity) were evaluated respectively by frog palate, cough machine and contact angle. RESULTS: Groups had similar characteristics about age, sex, tumor and SAPS II score. Regarding the physical properties of the mucus, there was an increase in mucus transportability (by the frog palate model) with the system PSV + PEEP (p = 0.04) and an increase in the contact angle in the CPAP groupo (p = 0.06). The two systems were effective in improving the vital signs, the PaO2/FiO2, the respiratory pattern and comfort and avoiding endotracheal intubation in the first 24 hours (p < 0.05). However, regardless of the type of NIV system used, high rates of endotracheal intubation and mortality were found. CONCLUSION: The physical properties of the mucus (transportability in vitro and wettability) changed after an hour of use of the NIV as a result of temperature and humidification into the mask. NIV was useful in reversing the respiratory failure in selected patients, or at least in bringing comfort for those who refuse endotracheal intubation

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-08-08T20:45:16Z No. of bitstreams: 1 daniellezacaronsantos.pdf: 1089910 bytes, checksum: c826630c6083dd96be8ff3a550b429b6 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-09T11:43:27Z (GMT) No. of bitstreams: 1 daniellezacaronsantos.pdf: 1089910 bytes, checksum: c826630c6083dd96be8ff3a550b429b6 (MD5) / Made available in DSpace on 2017-08-09T11:43:27Z (GMT). No. of bitstreams: 1 daniellezacaronsantos.pdf: 1089910 bytes, checksum: c826630c6083dd96be8ff3a550b429b6 (MD5) Previous issue date: 2017-03-28 / A síndrome de compressão medular metastática (SCMM) é uma urgência oncológica. A independência funcional é uma das maiores preocupações dos indivíduos que enfrentam o processo de morrer. O nível funcional é um dos itens do índice prognóstico de Tokuhashi (IPT) que é uma ferramenta utilizada para nortear o tipo de tratamento para a SCMM de acordo com a sobrevida. O objetivo deste estudo é avaliar a sobrevida, a funcionalidade e os seus fatores associados em pacientes com SCMM de uma unidade de referência oncológica na cidade do Rio de Janeiro, Brasil. O recrutamento dos casos foi através de busca ativa nas enfermarias das unidades hospitalares do serviço de referência em oncologia e/ou pesquisa no banco de dados dos atendimentos realizados pela equipe de fisioterapia, parte do sistema de prontuário e informação médica do serviço. Foi analisada a sobrevida de 163 pacientes e foi efetuada avaliação da capacidade funcional em até 48 horas após o diagnóstico da SCMM para 47 pacientes. A correlação entre ASIA e grau de dependência funcional foi calculada através do teste da correlação de Sperman. A diferença na pontuação da MIF de acordo com ASIA foi avaliada pelo teste de Kruskall-Wallis. As funções de sobrevida foram estimadas pelo método de Kaplan-Meier e o modelo de riscos proporcionais de Cox foi utilizado para avaliação prognóstica. A concordância entre o tempo de sobrevida observado e o estimado pelo IPT foi avaliada pelo coeficiente de Choen'sKappa. O tempo de sobrevida global foi de 4,54 meses (IC95%: 2,60-6,64). Os fatores prognósticos associados à sobrevida foram o estadiamento do câncer IV (HR:2,20; IC95%: 1,3-3,72) e III (HR:2,50; IC95%: 1,47-4,25), o atendimento de urgência (HR=1,7; IC95%: 1,18-2,26) e o KPS:80-100% (HR: 0,55; IC95%: 0,38-0,80) e 5070% (HR: 0,53; IC95%: 0,36-0,78). O valor preditivo positivo total do IPT foi de 55,8% e a concordância entre os tempos de sobrevida foi de 0,24 (p< 0,01). O grau de dependência funcional foi associado ao KPS, a ASIA, à capacidade de deambular, ao tempo de sobrevida e à cor da pele (p<0,05). Houve diferença na MIF (p= 0,04) e MIFmotor (p=0,01) segundo ASIA. A correlação entre MIF e ASIA foi de 0,35 (p<0,02) e entre esta e MIFmotor foi de 0,40 (p<0,01). O IPT pode auxiliar no manejo terapêutico da SCMM, considerando também o estadiamento o tipo do primeiro atendimento e o KPS apesar de necessária revisão dos seus parâmetros, além de auxiliar no planejamento da reabilitação. A MIF é apropriada para avaliar a funcionalidade na SCMM A reabilitação paliativa é indicada para esses pacientes e as estratégias devem estar aliadas ao prognóstico de sobrevida. / Metastatic spinal cord compression syndrome (MSCC) is an oncology emergency. Functional independence is a major concern for individuals facing the process of dying. The functional level is an item of Tokuhashi Prognostic Index (TPI), which is a tool used to guide the type of treatment for MSCC in accordance with survival. The aim of this study is to evaluate the survival, function and its associated factors patients with MSCC of an oncology reference unit in the city of Rio de Janeiro, Brazil. The recruitment of cases on the search for diseases of hospital units of reference service in oncology and / or research without database of the consultations performed by physiotherapy team, part of the system of medical records and information of the service. The survival of 163 patients was analyzed and functional capacity evaluation was performed within 48 hours after the diagnosis of SCMM for 47 patients. The correlation between ASIA and functional dependence degree was calculated using the Sperman correlation test. The difference in FIM scores according to ASIA was assessed by the Kruskall-Wallis test. Survival functions were estimated using the Kaplan-Meier method and the Cox proportional hazards model was used for prognostic evaluation. The agreement between the observed survival time and the estimated TPI was evaluated by the Choen'sKappa coefficient. The overall survival time was 4.54 months (95% CI: 2.60-6.64). The prognostic factors associated with survival were cancer staging IV (HR: 2.20, 95% CI: 1.3-3.72) and III (HR: 2.50, 95% CI: 1.47-4.25) (HR = 1.7, 95% CI: 1.18-2.26) and KPS: 80-100% (HR: 0.55; 95% CI: 0.38-0.80) and 50-70% (HR: 0.53, 95% CI: 0.36-0.78). The total positive predictive value of the TPI was 55.8% and the agreement between the survival times was 0.24 (p <0.01). The degree of functional dependence was associated with KPS, ASIA, gait ability, survival time and skin color (p <0.05). There was difference in FIM (p = 0.04) and FIM motor (p = 0.01) according to ASIA. IPT can help in the therapeutic management of MSCC, also considering staging the type of first care and KPS despite the necessary revision of its parameters, besides assisting in rehabilitation planning. MIF is appropriate for assessing functionality in MSCC Palliative rehabilitation is indicated for these patients and strategies should be combined with the prognosis of survival.

Le mélanome métastatique reste un enjeu majeur de santé publique. Les avancées fulgurantes de ces dernières années ont permis d’améliorer la prise en charge thérapeutique, notamment avec l’arrivée des anticorps bloquant ou agonistiques ciblant les molécules de co-inhibition ou de co-stimulation. Cependant, certains patients sont réfractaires à tout traitement. Il est donc nécessaire de mettre en évidence l’importance de certains paramètres immunologiques permettant d’améliorer le suivi des patients de stade III à haut risque de récidive. De plus, il est primordial de découvrir des marqueurs prédictifs associés à la réponse à ces différents traitements immunomodulateurs. Nous avons identifié une association entre une fréquence élevée de CD45RA+CD4+ et de CD3-CD56- au sein des métastases ganglionnaires avec la survenue d’une récidive anticipée.Une forte expression de NKG2D à la surface des lymphocytes T CD8+, une faible proportion de Tregs ou une faible expression de PD-L1 à la surface des T circulants sont associées à une meilleure survie. Aussi, la mise en place d’un test in-vitro étudiant les réactivités fonctionnelles des lymphocytes infiltrant les tumeurs a permis de dégager l’importance de l’expression de CD95/Fas sur les T CD4+ circulants et de CD137/4-1BB sur les T CD8+ circulants dans la prédiction de la réponse à l’ipilimumab (anti-CTLA-4) et à la combinaison ipilimumab + nivolumab (anti-PD-1). Par ailleurs, le pattern d’expression des récepteurs de chimiokines à la surface des lymphocytes T périphériques permet de détecter les localisations métastatiques de mélanome. Cette étude a révélé également l’importance biologique de l’axe CCR9/CCL25 dans l’immunosurveillance naturelle anti-tumorale. / Metastatic melanoma (MM) is an unmet medical need. The development of immune checkpoint blockers (ICB) improved patient’s clinical outcomes. However, some patients still do not respond to these therapies. To adress these issues, we must find some immunological parameters which predict the relapse of high risk resected stage III melanoma patients. Moreover, it is an urgent need to identify some predicting parameters to these ICB. In our studies, high frequencies of CD45RA+CD4+ and CD3-CD56- in metastatic lymph nodes are associated with a short relapse-free survival. Higher expression of NKG2D on CD8 T cells, low Tregs and low PD-L1 expression on circulating T cells are associated with a prolonged overall survival.Furthermore, we designed an in-vitro test to assess intratumor lymphocytes reactivities to ICB and cytokines (IL-2 and IFNα2a). Low expression of CD95/Fas on CD4+ circulating T cells and high expression of CD137/4-1BB on circulating CD8+ T cells are associated with the response to ipilimumab (anti-CTLA-4) and to the combination ipilimumab + nivolumab (anti-PD-1), respectively. In addition, the chemokine receptor pattern expressed at the surface of circulating lymphocytes could predict the metastatic spreading of melanoma. In this last study, we demonstrated the critical role of CCR9/CCL25 pathway in the natural anti-cancer immune surveillance.

As a life-limiting illness mediated by rapid advancements in biomedical technologies, metastatic breast cancer (MBC) now presents in increasingly unexpected ways where women are living longer. These women’s lives may not fit well with established healthcare and societal understandings of an advanced breast cancer, including disease progression and prognosis. This qualitative inquiry aims to think differently about women’s daily lives with an ongoing MBC. While also considering the underexplored context of these women living in smaller communities. I explored communities on Central Vancouver Island, which is on the west coast of British Columbia, Canada. The research question directing my inquiry was: how are women, who are living with MBC as a life-limiting illness over an extended period, produced as both living and dying subjects? Informing this research was a feminist relational materialist approach with a healthcare practitioner orientation, primarily informed by Braidotti. I used multiple data collection methods centred around sequential interviews with 14 women who had been living relatively well with MBC for at least two years. Working with relational materialist and post qualitative principles, analysis disclosed the importance of temporal pulses and bodily transpositions in women’s lives. Temporal pulses speak to how time was laden with tensions such that a distinctive part of living with ongoing MBC was an embodied sense of fluctuating time. There was also the idea as to how, at any given moment, women could bodily know their illness and mortality through varying frequencies of the presence and/or absence of markers of living and dying, often at the same time. Bodily transpositions speak to how life-limiting illness was not so much about women moving from one set of circumstances to another as part of a clean-edged transition. Rather, the women navigated daily life with few set waymarkers. Within this context, ‘hope’ took on new forms and living with their advanced breast cancer became a kind of endurance demarcated by what I refer to as generative living. These findings call into question the ways in which MBC gets talked about in categorical terms as palliative or end of life, and/or as chronic. Findings are an opportunity for healthcare practitioners, policymakers, and interdisciplinary leaders to further understand MBC specific to our contemporary context. Project findings renew discussions of how best to support women’s needs, including the ways MBC is talked about. There is also the opportunity to direct further research into MBC as an example of today’s shifting boundaries of living and dying (which I am framing as living<=>dying). / Graduate

Circulating tumor DNA (ctDNA) in peripheral blood of patients with metastatic colorectal cancer appears to be a promising molecular marker that provides various applications. ctDNA levels vary depending on the presence, alternatively on the volume of tumor mass within patient's body, which can be used primarily for early detection of disease progression or recurrence and moreover for evaluating radicality of surgical treatment, all within long-term postoperative follow-up of the patient. Due to minimal invasivity of ctDNA analysis from peripheral blood (so-called liquid biopsy), it is possible to perform it repeatedly at relatively short time intervals. On account of very low fraction of ctDNA in total cell-free DNA (cfDNA) ranging between units and hundreds of percent, the key factor is optimal methodology covering all steps from the isolation process to a sufficiently sensitive detection technology. In this thesis I focus on an optimization of isolation process and analysis of ctDNA obtained from tumor tissue and plasma of selected patients with metastatic colorectal cancer in connection with surgical radicality and correlation with a clinical status of the patients.

Hintergrund: Ziel der Studie war der Vergleich von Patienten mit duktalem Pankreaskarzinom (PDAC) im progressionsfreien und Gesamtüberleben sowie im Rezidivmuster in Abhängigkeit einer Resektion der Vena portae oder der Vena mesenterica superior (PV/SMV). Methoden: Es wurde eine retrospektive Analyse durchgeführt. Hierbei wurden Patienten betrachtet, die zwischen 2005 und 2015 eine pyloruserhaltende partielle Pankreatoduodenektomie (PPPD), eine klassische Pankreatoduodenektomie (kPD) oder eine totale Pankreatektomie (TP) erhielten. Diese wurden in drei Gruppen eingeteilt. Die P+I+- Gruppe bestand aus Patienten mit Venenresektion (P+), bei denen eine pathohistologische Infiltration der PV oder SMV vorlag (I+). Fand sich bei durchgeführter Venenresektion keine portalvenöse Infiltration (I-), wurden die Patienten der P+I--Gruppe zugeordnet. Als Kontrollgruppe galten Patienten ohne Venenresektion (P-I-), welche zu denen der P+I+- Gruppe gematcht wurden. Die statistischen Analysen wurden mit dem R Softwarepaket durchgeführt. Das Signifikanzlevel wurde für alle Berechnungen auf α = 0,05 festgelegt. Ergebnisse: Insgesamt wurden 179 Patienten eingeschlossen. 113 erhielten eine portalvenöse Resektion. Davon hatten 36 (31,9%) eine pathohistologische Lumeninfiltration (P+I+), bei 77 (68,1%) lag dagegen keine Infiltration vor (P+I-). 66 Patienten ohne Venenresektion wurden zu den Patienten der P+I+-Gruppe gematcht (P-I-). Zwischen den drei Gruppen waren die meisten pathohistologischen Parameter vergleichbar. 17 Patienten (9,5%) wurden neoadjuvant therapiert, davon erhielten 16 eine Venenresektion (P+). Für das Gesamtüberleben konnten signifikante Unterschiede nachgewiesen werden (11,9 Monate [P+I+] vs. 16,1 Monate [P+I-] vs. 20,1 Monate [P-I-]; p=0,01). In der univariaten Überlebensanalyse konnte für den erhöhten präoperativen CA19-9 Wert, den Resektionsstatus (R), den Lymphknotenstatus (N), das Lymphknotenverhältnis (LNR), die mikroskopische Veneninvasion (V) sowie die pathohistologisch gesicherte Infiltration der PV/SMV ein negativer Einfluss nachgewiesen werden. In der multivariaten Analyse blieb die wahre Infiltration der PV/SMV als einziger signifikanter negativer Einflussfaktor auf das Gesamtüberleben erhalten (p=0,014). Die Inzidenz an Fernmetastasen war in der P+I+- Gruppe signifikant erhöht (75% [P+I+] vs. 45,8% [P+I-] vs. 54,7% [P-I-], p=0,01). Für ein Lokalrezidiv fanden sich dagegen keine Häufigkeitsunterschiede zwischen den Gruppen (p=0,96). Das mediane progressionsfreie Überleben war für Patienten der P+I+-Gruppe signifikant verkürzt (7,4 Monate [P+I+] vs. 10,9 Monate [P+I-] vs. 11,6 Monate [P-I-]; p=0,02). Die Lumeninfiltration der PV/SMV, die mikroskopische Veneninvasion (V), der präoperative CA19-9 Wert sowie der Differenzierungsgrad (G) waren negative Einflussfaktoren auf das progressionsfreie Überleben. In der multivariaten Analyse blieben die pathohistologisch gesicherte Infiltration sowie das Grading als negative unabhängige Einflussfaktoren nachweisbar. In 25% der Fälle manifestierte sich das Rezidiv initial in der Leber. Schlussfolgerung: Die pathohistologisch gesicherte Infiltration der PV/SMV ist ein unabhängiger Risikofaktor für das progressionsfreie und das Gesamtüberleben. Die Inzidenz an Fernmetastasen ist für die Patienten der P+I+-Gruppe erhöht. Eine potentiell kurative venöse Resektion kann den Einfluss der aggressiven Tumorbiologie und des fortgeschrittenen Krankheitsbildes nicht vollständig kompensieren. / Background. The present study aims to evaluate the longterm outcome and metastatatic pattern of patients who underwent an operation for pancreatic ductal adenocarcinoma (PDAC) with portal or superior mesenteric vein (PV/SMV) resection. Methods. Patients who underwent a pylorus preserving pancreaticoduodenectomy (PPPD), Whipple procedure (kPD) or total pancreatoduodenectomy (TP) between 2005 and 2015 were retrospectively analyzed. The patients were categorized in three subgroups. Those whom received a vein resection with pathohistological tumor invasion of the PV/SMV (P+I+) those at whom underwent vein resection but without pathohistological tumor invasion (P+I-) and lastly a third group (P-I-) matched to the P+I+ included patients without vein resection. Statistical analysis was performed using the R software package. The significance level for all calculations was set at α = 0.05. Results. The study cohort included 179 patients, 113 of whom underwent simultaneous PV/SMV resection. 36 patients (31,9%) had pathohistological tumor infiltration (P+I+), 77 (68,1%) did not (P+I-). 66 patients without vein resection (P-I-) were balanced by the P+I+ group. Most of pathohistological tumor characteristics were comparable between groups. 17 patients (9.5%) received neoadjuvant therapy, 16 of them were in vein resection group (P+). The study revealed differences in overall median survival (11.9 months [P+I+] vs. 16.1 months [P+I-] vs. 20.1 months [P-I-]; p=0.01). Univariate survival analysis shown negative consequences for CA19-9, resection margin (R), status of nodal metastasis (N), lymph node ratio (LNR), microvascular vein invasion (V) and true invasion of the PV/SMV. Multivariate survival analysis identified true invasion of the PV/SMV as the only significant, negative prognostic factor (p= 0.01). Whereas the incidence of local tumor recurrence was comparable (p=0.96), the proportion of patients with distant metastasis showed significant differences (75% [P+I+] vs. 45.8% [P+I-] vs 54.7% [P-I-]; p=0.01). The median time to progression were significantly shorter if the PV/SMV was infiltrated (7,4 months [P+I+] vs. 10,9 months [P+I-] vs. 11,6 months [P-I-]; p=0.02). Univariate progression analysis revealed significances for true invasion of the PV/SMV, microvascular vein invasion (V), CA19-9 and histologic classification (G). Multivariate progression analysis detected pathohistological invasion of the PV/SMV and histologic classification (G) as independent factors. Initial liver metastasis occurred in 25% of the patients. Conclusions. Pathohistological invasion of the PV/SMV is an independent risk factor for overall and progression free survival. Patients of P+I+-group had a higher incidence of distant metastasis, local progression is comparable. Even radical and complete resection cannot completely compensate for aggressive tumor biology and advanced disease. Modifiziert nach Mierke et al., 2016

<p>A multitude of neurologic diseases are increasing in patients that both diminish quality and quantity of life. My dissertation research focused on unraveling the blood-brain barrier’s alterations (BBB), primarily in lung cancer brain metastases, the most common brain metastasis in patients. We optimized a reliable and reproducible mouse model for creating brain metastases using patient derived brain seeking cells of non-small lung cancer (NSCLC) using ultrasound-guided intracardiac injection. I then evaluated brain tissue with qualitative and quantitative immunofluorescence for individual components of the BBB. Using this experimental method, I was able to identify the specific shift of each BBB component over time in NSCLC brain metastases. I then used human brain metastases specimens to demonstrate the clinical relevance of my findings. These results show distinct alterations in the BBB, which have the potential for targeting therapeutic delivery to extend patient survival. I was also able to characterize a novel epithelial-mesenchymal (EMT) phenotype in vertebral metastases of NSCLC in our model, with features similar to those seen in human patients. Most recently, I analyzed patterns of paracellular permeability associated with each BBB component of NSCLC brain metastases which may provide direct passageways for therapeutic delivery. Altogether, this research offered foundational evidence for the future development of targeted novel therapeutics, including nanoparticles. Outside of the brain metastases field, we used an experimental framework to successfully characterize the BBB alterations in a traumatic brain injury model (bTBI). These findings provided the first description of this unique pathology and the framework for developing therapeutics in other neurologic diseases. Although my research work has focused on animal models of disease, future directions based on my research work include the developing a novel 3D BBB-on-chip device to enable high throughput novel therapeutic delivery through the BBB. Long-term, identifying targetable alterations in the restrictive BBB using <i>in vitro</i> and <i>in vivo</i> models provides a potential conduit for effective prevention and treatment of a myriad of neurologic diseases to prolong patient survival and quality of life.</p>

Pour les patients diagnostiqués avec un cancer au stade précoce, les décisions de traitement dépendent de l’évaluation du risque de rechute métastatique. Les outils de pronostic actuels sont fondés sur des approches purement statistiques, sans intégrer les connaissances disponibles sur les processus biologiques à l’oeuvre. L’objectif de cette thèse est de développer des modèles prédictifs du processus métastatique en utilisant une approche de modélisation mécaniste et la modélisation à effets mixtes. Dans la première partie, nous étendons un modèle mathématique du processus métastatique pour décrire la croissance de la tumeur primaire et de la masse métastatique totale chez des souris traitées avec le sunitinib (un inhibiteur de tyrosine kinase ayant une action anti-angiogénique) administré comme traitement néoadjuvant (i.e. avant exérèse de la tumeur primaire). Le modèle est utilisé pour tester des hypothèses expliquant les effets différentiels du sunitinib sur la tumeur primaire et les métastases. Des algorithmes d’apprentissage statistique sont utilisés pour évaluer la valeur prédictive des biomarqueurs sur les paramètres du modèle.Dans la deuxième partie de cette thèse, nous développons un modèle mécaniste pour la prédiction du temps de rechute métastatique et le validons sur des données cliniques des patientes atteintes d’un cancer du sein localisé. Ce modèle offre des prédictions personnalisées des métastases invisibles au moment du diagnostic, ainsi que des simulations de la croissance métastatique future, et il pourrait être utilisé comme un outil de prédiction individuelle pour aider à la gestion des patientes atteintes de cancer du sein. / For patients diagnosed with early-stage cancer, treatment decisions depend on the evaluation of the risk of metastatic relapse. Current prognostic tools are based on purely statistical approaches that relate predictor variables to the outcome, without integrating any available knowledge of the underlying biological processes. The purpose of this thesis is to develop predictive models of the metastatic process using an established mechanistic modelling approach and the statistical mixed-effects modelling framework.In the first part, we extend the mathematical metastatic model to describe primary tumour and metastatic dynamics in response to neoadjuvant sunitinib in clinically relevant mouse models of spontaneous metastatic breast and kidney cancers. The calibrated model is then used to test possible hypothesis for the differential effects of sunitinib on primary tumour and metastases, and machine learning algorithms are applied to assess the predictive power of biomarkers on the model parameters.In the second part of this thesis, we develop a mechanistic model for the prediction of the time to metastatic relapse and validate it on a clinical dataset of breast cancer patients. This model offers personalised predictions of the invisible metastatic burden at the time of diagnosis, as well as forward simulations of metastatic growth, and it could be used as a personalised prediction tool to assist in the routine management of breast cancer patients.