En kvantitativ studie har gjorts för att undersöka skillnader i konfliktstil enligt Thomas och Kilmanns-Conflict Mode Instrument (TKI) samt arbetskontrollokus mellan personal på olika organisationsnivåer. Det undersöktes även om det fanns skillnader mellan könen och om äldre respondenter hade högre inre arbetskontrollokus än yngre respondenter. 99 personer deltog i studien, varav 74 var tjänstemän och 24 var underställda. Respondenterna besvarade en enkät baserad på de teorier som låg till grund för studien, Thomas och Kilmanns-Conflict Mode samt Spectors teori om arbetskontrollokus. Resultatet visade att chefer var mer självhävdande i sin konfliktstil än underställda och män var mer konkurrerande i sin konfliktstil än kvinnor. Chefer hade högre grad inre kontrollokus än underställda. Det fanns även ett samband mellan inre arbetskontrollokus och konfliktstilen konkurrerande. Det hittades däremot inget samband mellan ålder, konfliktstilen undvikande och arbetskontrollokus. / Program: Organisations- och personalutvecklare i samhället

Responsable d'environ 30000 décès/an en France, le cancer du poumon est un problème de santé publique majeur. Un des enjeux actuels est d'adapter le traitement du cancer du poumon pour proposer des thérapeutiques ciblées plus efficaces et moins agressives. Les inhibiteurs de l'activité tyrosine kinase du récepteur de l'EGF (EGFR-TKI, gefitinib et erlotinib) constituent un réel progrès pour le traitement des cancers du poumon. Cependant, des mécanismes de résistance ont été décrits et des traitements combinés de thérapies ciblées avec des EGFR-TKI pourraient permettre de surmonter les résistances dans les cancers du poumon.Dans ce contexte, nous avons étudié les mécanismes impliqués dans la résistance à ces traitements. Nous montrons que l'activation de la voie de signalisation PI3K/AKT joue un rôle majeur dans la résistance aux EGFR-TKI, en inhibant l'apoptose par des mécanismes dépendant de l'acétylation. Les histones déacétylases (HDACs) et les sirtuines interviennent dans ces mécanismes de résistance, en modulant l'activation de la voie PI3K/AKT et l'apoptose. Ainsi l'utilisation d'inhibiteurs des HDACs (HDACi) et des sirtuines permettent de restaurer la sensibilité aux EGFR-TKI. Ces résultats confirment l'intérêt thérapeutique de l'association EGFR-TKI/HDACi et montrent le potentiel thérapeutique d'associer des inhibiteurs de l'EGFR et de la voie PI3K/AKT pour contourner la résistance aux EGFR-TKI.Les molécules thérapeutiques doivent atteindre spécifiquement le site tumoral, nécessitant parfois de les protéger contre leur dégradation, de réduire leurs effets indésirables, et de contrôler leur libération dans le temps et l'espace, à l'aide de transporteurs. Ainsi dans la deuxième partie de cette thèse, nous avons évalué les capacités de ciblage des tumeurs pulmonaires de nanoparticules à base de copolymère amphiphile, contenant une partie polysaccharidique hydrophile (le hyaluronane) et une partie polypeptidique hydrophobe (le poly(γ‐benzyl L‐glutamate, PBLG). Nos travaux mettent en évidence la capacité de ciblage tumoral de ces nanoparticules injectées par voie intraveineuse, ouvrant ainsi de nouvelles perspectives thérapeutiques. Notre objectif est de charger les combinaisons de traitements EGFR-TKI/HDACi que nous avons identifiées dans ces vecteurs, afin de traiter les tumeurs pulmonaires résistantes aux EGFR-TKI. / Responsible of 30000 deaths each year in France, lung cancer is a major public health problem. One of the current challenges is to adapt the treatment of lung cancer to offer more effective and less aggressive targeted therapies. EGFR tyrosine kinase inhibitors (EGFR-TKI, gefitinib and erlotinib) represent a real progress in lung cancer therapy. However resistance mechanisms have been described and combination of targeted therapy with EGFR-TKI could overcome resistance in lung cancer.In this context, we studied mechanisms involved in resistance to EGFR-TKI. We show that PI3K/AKT activation is a major pathway leading to EGFR-TKI resistance leading to apoptosis inhibition through acetylation-dependent mechanisms. Histone deacetylase (HADCs) and sirtuin are involved in these mechanisms and modulate PI3K/AKT activation and apoptosis. The use of HDACs inhibitors (HDACi) and sirtuins inhibitors thus restores the sensitivity to EGFR-TKI. Altogether these results confirm the therapeutic effect of the EGFR-TKI/HDACi combination and show the therapeutic potential of the association of EGFR and PI3K/AKT inhibitors to overcome EGFR-TKI resistance.Therapeutic molecules must specifically reach the tumor site, sometimes requiring to protect them against degradation, to reduce their side effects, and to control their release in time and space, using transporters. In the second part of this thesis, we have thus evaluated the lung tumors targeting capabilities of amphiphilic copolymer-based nanoparticles, containing an hydrophilic polysaccharidic block (hyaluronan) and an hydrophobic polypeptidic block (the poly(γ‐benzyl L‐glutamate PBLG). Our work highlights the tumor targeting capability of these nanoparticles injected intravenously, offering new lung cancer therapy perspectives. Our aim is to load the drugs combination (EGFR-TKI/HDACi) in these vectors, to treat the lung tumors resistant to EGFR-TKI.

Despite the wide availability of computers to teachers throughout New Zealand, and despite the strong philosophy supporting Internet use for teacher development, the actual use of Internet websites aiming to enhance teacher professional development is not high. The New Zealand website Te Kete Ipurangi (TKI) was developed with the aim of connecting teachers to a wide range of materials and information. Professional development of this kind is well supported by many theorists as being able to break down teacher isolation and build a supportive teaching and learning community. Websites for teachers, such as this one, are beginning to develop on the Internet, and their availability to all teachers is of no dispute. The extent to which they are able to be easily employed by teachers as the resources they were intended is, however, a matter only a few have investigated. This research studies some of the navigation aspects of TKI and the usability issues which influence the overall use of this website. Usability tests and a questionnaire were utilised to examine the degree to which this website was usable for teachers and the extent to which there were navigation issues for its intended users. It found that use of TKI was constrained by teachers' own lack of confidence and feelings of inability, as well as several navigation issues. These issues centered on the language used in the website - particularly in the headings; the search facility; the layout of the site; and the speed of use.

Background: Lung cancer is the leading cause of cancer-related death and one of the most common cancer types worldwide. Epidermal growth factor receptor (EGFR) has been shown to be an important therapeutic target in non-small cell lung cancer. Kirsten rat sarcoma viral oncogene homologue (KRAS) is a downstream signalling molecule in the EGFR pathway. Lung cancer patients with EGFR mutations respond to tyrosine EGFR inhibitor therapy, in contrast, patients with KRAS mutations do not benefit of such treatment. Methods: This study investigates the frequency of EGFR and KRAS mutations in non-small cell lung cancer patients. Fifty-one lung cancer patients with primary non-small cell lung cancer diagnosed between 1995 and 2005 in the Uppsala-Örebro region were analysed by Sanger sequencing and Pyrosequencing to determine the mutation status of these genes. Results: Five EGFR mutations were found in four patients (8%), two deletions in exon 19, one point mutation in exon 20 and two point mutations in exon 21. KRAS mutations were found in 12 patients (24%), ten codon 12 mutations and two codon 61 mutations. Conclusions: This study confirms previous observations regarding the frequency of EGFR and KRAS mutations in non-small cell lung cancer. Mutations in EGFR and KRAS were mutually exclusive, indicating that both mutations present relevant tumorigenic genomic aberrations.

Responsable de 1,6 million de décès par an dans le monde, le cancer du poumon constitue aujourd’hui la première cause de mortalité par cancer. Les cancers bronchiques non-à-petites cellules représentent 85% des cancers du poumon et ont un pronostic vital très mauvais. Les EGFR-TKI (inhibiteurs de l’activité tyrosine kinase de l’EGFR, gefitinib) constituent un réel progrès thérapeutique pour le traitement des cancers du poumon. Cependant, ces traitements ne sont efficaces que dans un petit sous-groupe de patients. Un des enjeux actuels est donc d’identifier les mécanismes de résistance primaire mis en jeu par les tumeurs.Les récepteurs à activité tyrosine kinase (RTK) activent des voies de signalisation intracellulaires depuis la membrane plasmique. Ces dernières années, une translocation nucléaire des RTK a également été mise en évidence. Ces travaux récents suggèrent que la signalisation nucléaire des RTK pourrait contribuer à la résistance des tumeurs en réponse aux thérapies anti-cancéreuses.Dans l’équipe, il a été montré que l’activation de l’IGF-1R est associée à la progression tumorale des adénocarcinomes pulmonaires et que le gefitinib induit une accumulation nucléaire de l’IGF-1R dans un modèle d’adénocarcinome mucineux. Sur la base de ces résultats, nous avons émis l’hypothèse que l’IGF-1R nucléaire pourrait jouer un rôle dans la résistance aux EGFR-TKI des adénocarcinomes pulmonaires mucineux.Nos résultats indiquent que plus de 70% des adénocarcinomes pulmonaires présentent un marquage nucléaire de l’IGF-1R. A l’aide de différents modèles cellulaires résistants aux EGFR-TKI, nous montrons que le gefitinib induit l’accumulation nucléaire de l’IGF-1R dans les adénocarcinomes pulmonaires mucineux. Cette translocation nucléaire implique l’endocytose clathrines-dépendante de l’IGF-1R et la formation d’un complexe entre l’IGF-1R, l’importine β1 et la pro-amphiréguline. La neutralisation de l’amphiréguline prévient le transport nucléaire de l’IGF-1R et resensibilise les cellules à l’apoptose induite par le gefitinib in vitro et in vivo. L’ensemble de ces résultats identifient le trafic intracellulaire de l’IGF-1R comme un nouveau composant de la réponse aux EGFR-TKI et suggèrent que la signalisation nucléaire IGF-1R/Areg contribue à la progression des adénocarcinomes mucineux sous EGFR-TKI. / Responsible of 1.6 million deaths each year worldwide, lung cancer is today the leading cause of cancer mortality in the world. Non-small-cell lung cancers account for about 85% of lung cancer and have a very bad prognosis (5-year survival rate inferior to 10%). EGFR-TKI (EGFR tyrosine kinase inhibitors, gefitinib) are a real medical advance for lung cancers treatment. However, these treatments are efficient in a small subgroup of patients. So, one of the current issues is to identify primary resistance mechanisms involved in tumors.Tyrosine kinase receptors (RTK) activate intracellular signaling pathways from the plasma membrane. These last years, a nuclear translocation of the RTK was shown. Recent works suggest that RTK nuclear signaling could contribute to tumors resistance in response to anti-cancerous therapies.In our team, it was shown that activation of IGF-1R signaling is associated with lung adenocarcinoma progression and that gefitinib induces IGF-1R nuclear accumulation in a mucinous adenocarcinoma cell line. On the basis of these results, we hypothesize that nuclear IGF-1R could play a role in the resistance of mucinous lung adenocarcinoma to EGFR-TKI.Our results indicate that more than 70% lung adenocarcinoma tumors present a positive IGF-1R nuclear staining. Thanks to EGFR-TKI-resistant cell lines, we show that gefitinib induces the nuclear accumulation of IGF-1R in mucinous adenocarcinoma. This nuclear translocation involves clathrin-mediated endocytosis and a complex between IGF-1R, importin β1 and pro-amphiregulin. Amphiregulin silencing prevents IGF-1R nuclear translocation in response to gefitinib and restores gefitinib-induced apoptosis in vitro and in vivo. Our whole results identify that IGF-1R intracellular trafficking is a new component of response to EGFR-TKI and strongly suggest that a nuclear IGF-1R/amphiregulin signaling contributes to mucinous lung adenocarcinoma progression in response to EGFR-TKI.

Chronic myeloid leukemia is a clonal haematopoietic disease, with characteristic BCR-ABL1 fusion gene. Despite the significant improvement in patient treated with tyrosine kinase inhibitors (TKI), 20-30 % of patients develop resistance. One of the main causes of treatment failure are mutations in the BCR-ABL1 kinase domain (KD). The aim of this work was to elucidate the molecular mechanisms of resistance and mutagenesis development in CML using an in vitro CML model KCL-22. The main part of this work was focused on the identification of genes involved in DNA damage response and repair, that could play a role in the process of mutagenesis of BCR-ABL1. We used the RT2 Profiler PCR Arrays method for the group of selected genes regulating DNA damage response and repair. We identified the genes XRCC6 and PARP1 whose gene expression was significantly and specifically decreased during KD BCR-ABL1 mutagenesis. Products of these genes are involved in repairing DNA double-strand breaks through non-homologous end joining (NHEJ). During study of the KD BCR-ABL1 mutagenesis we also found that clones, which developed mutations, did not show the increased BCR-ABL1 expression in the beginning of the culture compared to the clones in which mutations have not evolved. Key words: myeloid leukemia, mutation,...

Hintergrund Die chronische myeloische Leukämie (CML) ist eine myeloproliferative Er- krankung, die aufgrund ihres Modellcharakters unter der Behandlung mit Tyrosin-Kinase- Inhibitoren (TKI) gut für eine Beschreibung mittels computerbasierter Modelle geeignet ist. Grundlage für die Entstehung einer CML ist die Bildung eines Philadelphia-Chromosoms durch eine Translokation der Chromosomen 9 und 22. Es resultiert das Onkogen BCR- ABL1, welches für eine konstitutiv aktive Tyrosinkinase codiert. Diese führt zu ungeregelter Proliferation der betroffen Zellen und zur Verdrängung der gesunden Blutbildung. Das überaktivierte Protein kann durch TKIs gezielt gehemmt werden. Damit ist es möglich, die Tumorlast erheblich zu senken und das Fortschreiten der Erkrankung aufzuhalten. Aktuell werden in der klinischen Anwendung außerhalb von Studien TKIs für die gesamte Lebensdauer der Patienten eingesetzt. Absetzstudien zeigten, dass circa 50% der Patienten nach einer über zwei Jahren nicht nachweisbaren BCR-ABL1-Last nach Behandlungsstopp kein erneutes Anwachsen der Tumorlast aufwiesen. Die Anwendung von computergestützten Modellsimulationen hilft, Zugriff auf die klinisch nur schwer zu messenden leukämischen Stammzellen zu bekommen und darüber Vorhersagen über den weiteren Therapieverlauf zu treffen. Aufgabenstellung Im Rahmen der vorliegenden Arbeit sollen Möglichkeiten der Übertragung von Patientendaten auf das etablierte Modell nach Roeder und Loeffler (2002) verbessert werden. Die vom Modell vorhergesagten Stammzellkinetiken sollen abschließend auf Praxistauglichkeit geprüft werden. Material und Methoden Aufgrund der Vergleichbarkeit zu früheren Untersuchungen erfolgte die Auswahl von 51 Patienten des deutsches Armes der IRIS-Studie. Deren Therapieverläufe wurden analysiert und können über eine biphasische exponentielle (biexponentielle) bzw. über eine stückweise lineare Funktion beschreiben werden. Als Erweiterung der Arbeiten von Horn et al. (2013) wurden alle Parameter der biexponentiellen Funktion in die Entwicklung neuer Methoden einbezogen. Zusätzlich wurde untersucht, ob die Einbeziehung von zensierten Messpunkte die Form der biexponentiellen Funktion verändert. Basierend auf den Therapiedaten der IRIS-Patienten erfolgte die Ermittlung eines Para meterraumes für Eingangsparameter der Modellsimulation (Modellparameter), welcher in 270.400 individuelle Paramterkombinationen unterteilt wurde. Es erfolgten anschließend die Simulation und Auswertung nach der biexponentiellen Beschreibung. Auf Basis dieser erheblich größeren Datengrundlage konnten zwei neue Verfahren der Modellparameteridentifikation für individuelle Patienten entwickelt werden. Einerseits wurde in Anlehnung an die Arbeit von Horn et al. (2013) ein Verfahren unter Nutzung der Regression vorgestellt. Andererseits konnte über den Vergleich der Abstände zwischen simulierten und realen Therapieverläufen eine Suche (lookup-table) etabliert werden. Die Berechnung des Abstandes zwischen Therapieverläufen ermöglicht gleichzeitig den Vergleich der verschiedenen Verfahren und damit eine Aussage über deren Anpassungsgüte. Zum Schluss wurde beispielhaft für einen Patienten das Verfahren der lookup-table angewendet und die resultierende Stammzellkinetik weiter analysiert. Ergebnisse Einführend erfolgte die Analyse der resultierenden biexponentiellen Funktion mit und ohne Einbeziehung von Messunsicherheiten. Es zeigte sich, dass der Verlauf dieser Funktion besonders in Bereichen, die von einbezogenen Messunsicherheiten betroffen sind, abweichend ist. Die Beschreibung des Langzeitverlaufs erfolgt jedoch annähernd gleich. Anschließend erfolgte die Validierung der Größe des vorsimulierten Datenpool anhand eines Vergleichs der statistischen Parameter von Patienten und Simulationen. Dieser zeigte sich dabei für die weiteren Untersuchungen geeignet. Die Nutzung der lookup-table zur Identifikation der am besten zu einem Patienten passenden Therapiesimulation ist überlegen sowohl gegenüber von der Horn et al. (2013) beschriebenen als auch in dieser Arbeit neu entwickelten Regressionsverfahren. Diese ergeben deutliche Abweichungen zwischen Patientendaten und Simulation. Eine Analyse des vorhergesagten Therapieverlaufes im Stammzellkompartiment ergibt jedoch, dass ähnliche Therapieverläufe im peripheren Blut durch stark unterschiedliche Stammzellkonfigurationen beschrieben werden können. Es resultiert eine starke Streuung der vorhergesagten Zeitpunkte eines möglichen Therapieendes. Schlussfolgerungen Die Nutzung der lookup-table zu Identifikation einer passenden Therapiesimulation ist hoch effektiv und anderen Verfahren, die auf Regression basieren, überlegen. Die etablierte Computersimulation nach Roeder und Loeffler (2002) bietet Zugriff auf die Therapie in der Ebene der Stammzellen. Die in weiteren Analysen gezeigten Streuungen der vorhergesagten Therapieverläufe im Stammzellkompartiment lassen den Schluss zu, dass Methoden zur Eingrenzung der Stammzellverläufe entwickelt werden müssen, um die Vorhersagen klinisch nutzbar zu machen. Weiterhin muss anhand von Messungen an Knochenmarkproben von realen Patienten geprüft werden, ob die von der Simulation postulierten Verläufe der Tumorlast im Stammzellkompartiment der realen Behandlung entsprechen. Ausblick Die in aktuellen Arbeiten beschriebene Rolle des Immunsystems im Therapieverlauf der CML (Saussele et al. 2016; Clapp et al. 2016) sollte in eine Verbesserung des Stammzellmodells nach Roeder und Loeffler (2002) einfließen. Weiterhin kann die Validierung der im Rahmen der Individualmedizin zu treffenden Absetzvorhersagen letztendlich nur über klinische Absetzuntersuchungen ermöglicht werden. / Background Chronic myeloic leukaemia (CML) is a myeloproliferative disease, which is well suited for modelling approaches. It is characterized by the oncogenic BCR-ABL1 fusion gene originating from an inverse translocation of the chromosomes 9 and 22 leading to the Philadelphia chromosome. The result is a constitutively activated tyrosine-kinase. This is followed by an extensive proliferation of leukaemic stem cells leading to a displacement of normal haematopoesis. The molecular specificity of CML forms the basis of a highly efficient, targeted therapy by tyrosine kinase inhibitors (TKIs). TKIs can decrease the tumour burden and slow down or eventually stop progressing of the disease. Currently, in clinical applications drugs are administered for the remaining life span. Interestingly, in recent treatment cessation trials patients were stopped after two years of non-detectable tumour burden and about 50% remained without relapse. The application of computer-based modelling helps to gain access to stem cell counts being difficult to measure clinically. This forms the basis for predictions of long-term therapy outcomes. Aim of this work This work aims on identifying a suitable algorithm to efficiently identify model simulations that optimally decribe individual patient kinetics. Furthermore, the clinical usability of the new methods was investigated. Material and methods The analysed group of patients was chosen out of the German cohort of the IRIS trial to ensure comparability to former investigations. It consists of 51 individuals. The course of leukaemic burden , i. e. leukaemic vs. non-leukaemic cells on a single patient level can be described as a biphasic exponential (bi-exponential) or a piecewise linear function. As an extension to former methods described by Horn et al. (2013) all parameters are included into further method development. Additionally, an investigation was conducted whether censored data points change the functional behaviour of a bi-exponential fit based on patients’ data. According to therapy data of all patients an input parameter space for the model simulation was delimited, such that all observed patient kinetics can be mimicked by the model. This parameter space was uniformly divided into 270.400 discrete parameter combinations. The therapy simulation of each combination was conducted and described by a bi-exponential function likewise to the patients’ fit. With the help of these huge variety of in silico therapies two new methods of model parameter identification for individual patients were developed. The first one is an advanced approach based on a regression model proposed by Horn et al. (2013). The second one by comparing distances between the patients’ and the models’ bi-exponential functions (lookup table). The comparison of the distances between different therapy courses (either simulated or patients’ data) was also used to compare the quality of different methods. As an example, for one patient the stem cell kinetics from the model were analysed in more detail and checked for robustness. Such a strategy, which might build the basis for clinical applications. Results A comparison between the different bi-exponential functions with and without censored data points revealed differences especially in the area in which censoring was performed. However, for the long-term tumour burden censored data had no influence. Secondly, an investigation was performed showing the sufficiency of the pre-simulated therapy courses for the new methods, i. e. lookup-table and regression models. The lookup- table turns out to be superior to identify a therapy simulation for a unique patient, since the complexity of linear regression models lead to increased deviations between patients’ therapy courses and the simulations. Unfortunately, distinct stem cell configurations lead to similar therapy descriptions in peripheral blood, assuming the correctness of the model. As a result, the prediction of a safe treatment cessation is often widely spread. Conclusions The new developed lookup-table to identify model simulations suitable for an individual patient is highly effective and superior to other methods using regression models. The simulation of the TKI treatment using the agent-based model of Roeder und Loeffler (2002) gives easy access to therapy courses on the level of leukaemic stem cells. Unfortunately, the finding of a well fitting simulation within the peripheral blood is not enough to provide a point of safe treatment cessation, since different stem cell configurations can lead to similar therapy courses. Additionally, it is necessary to check which of the assumed therapy courses on the stem cell level is appropriate. This could be done by gathering more information from bone-marrow punctures during the course of treatment. Outlook Investigations of new data showed the important role of the immune system in CML treatment (Saussele et al. 2016; Clapp et al. 2016). This should be taken into account by improving the model of Roeder und Loeffler (2002). Additionally, data from cessation trials can be used to validate the model assumptions.

Cette thèse propose une modélisation aussi générique que possible de la combustion dans les moteurs automobiles dans un cadre de simulation aux grandes échelles. Une première étude aborde la fermeture du terme de transport non résolu pour la flamme de prémélange. Par la suite, un couplage entre les modèles ecfm-les et pcm-fpi est proposé et validé pour intégrer les effets de chimie complexe à la simulation de la flamme de prémélange. Ce travail est étendu par l'adjonction de modélisations spécifiques à l'allumage par bougie et de l'auto-inflammation, toujours en intégrant les effets de chimie détaillée. Des calculs d'application aux combustions anormales dans les moteurs à allumage commandé concluent ce travail. / This work proposes a modeling as generic as possible of the combustion in automotive engines in the framework of large-eddy simulation. A first study addresses the closure of the non resolved transport term for the premixed flame. Then, a coupling between the models pcm-fpi and ecfm-les is proposed and validated to account for the detailed chemistry effects in the premixed flame modeling. This work is extended adding specific models for spark-ignition and auto-ignition, still integrating detailed chemistry effects. This work is ended by computations of abnormal combustions occurring in spark-ignition engines.

Bakgrund: Vid kronisk myeolid leukemi (KML) överproducerar blodstamceller omogna granulocyter som kan öka risken för infektioner, anemi och lätta blödningar. Ifall sjukdomen inte åtgärdas i tidigt skede så kan cancercellerna konkrurera ut friska blodceller vilket kan leda till ett livshotande tillstånd. KML drabbar främst vuxna över 55 år. Orsaken till KML är nästan alltid en somatisk mutation i blodcellerna som leder till förändring i karyotypen, den abnormala kromosomen kallas för Philadelphia kromosomen. De olika behandlingalternativ som finns mot KML inkluderar kemoterapi (låg dos/hög dos med stamcellstransplantation), interferon alfa, donator lymfocytinfusion och tyrosinkinasinhibitor (TKI). TKI är standardbehandling vid KML och TKIs inlkluderar imatinib, dasatinib, nilotinib, bosutinib och ponatinib. Studier har visat att TKI administrerat på friska råttor och möss har en teratogen effekt. Syfte: Syftet med arbetet var att utvärdera risker och fördelar vid behandling av kronisk myeloid leukemi med tyrosinkinasinhibitor i samband med graviditet. Metod: Arbetet är en litteraturstudie baserat på 13 caserapporter därav 4 studier om imatinib, 4 om nilotinib, 4 om dasatinib och 1 studie om imatinib, nilotinib och dasatinib. Bosutinib och ponatinib exkluderades eftersom det fanns inga studier om exponering av dessa läkemedel under graviditet. Resultat: Från studierna om imatinib var det totalt 23 av 163 patienter som fick missfall och 14 av 90 födsel slutade med foster abnormiteter. Totalt hade 49 fall rapporterats om exponering med nilotinib under graviditet därav 46 fall resulterade i normal födsel och 3 spädbarn fick fetala abnormiteter som resulterade till dödlighet. Av de fyra fall som rapporterades om Dasatinib var det ett som slutade med abort efter vecka 17 på grund av fostrets dåliga perinatala prognos. Alla patienter behandlades inte med TKIs under graviditeten. Vissa patienter hade kombinationer av läkemedel. Slutsats: Det finns fortfarande inte bekräftade risker med TKI behandling i samband med graviditet då statistiskt underlag saknas. Fördelen med att behandlas med TKI under graviditet är att risken för återfall och försämrad sjukdomprognos förminskas. Läkaren ska alltid diskutera med patienten om eventuella risker och möjligheter. Behandling för varje patient individualiseras utifrån patienens önskemål. / Background Chronic myeloid leukemia (CML) is a type of leukemia that affects bone marrow and blood cells. In CML, the blood stem cells produce an excessive number of immature granulocytes which leads to a high count of white blood cells in patients. Consequently, the risk of acquiring infections, anemia and hemorrhage, is increased. If not successfully treated the leukemia cells will eventually crowd out platelets and healthy blood cells and ultimately lead to death. Generally, CML occurs in adults aged 55 years or older. The cause of CML is in most cases a somatic mutation that is referred to as the Philadelphia chromosome. There are various treatments for CML, I.e., chemotherapy, interferons-alpha, high-dose chemotherapy combined with a stem cell transplantation, donor lymphocyte infusion (DLI), and tyrosine kinase inhibitors (TKI). TKI are the standard treatment for CML. There are several types of TKI, namely: Imatinib, nasatinib, nilotinib, bosutinib and ponatinib. Although considered the most effective treatment for CML, there are several animal studies indicating that TKI has a teratogenic effect. Purpose The objective of this study was to evaluate the risks and benefits of TKI treatment in connection with pregnancy. Method  A literature review based on 13 case reports, among them four reports about imatinib, four reports about nilotinib, four reports about dasatinib and one report describing several patients treated with imatinib, nilotinib and dasatinib. Studies about bosutinib and ponatinib are excluded from this study due to the lack of scientific research regarding their impact on pregnant women. Result The studies about Imatinib showed that 23 of 163 patients had miscarriage. Furthermore, 14 of the 90 live births resulted in foster abnormalities. There were totally 49 cases in which Nilotinib was administered to pregnant women. In 46 cases the patients gave birth to healthy children. However, in three cases the fetuses were abnormal and in one of these cases the child was stillborn. Moreover, there were four case studies in which the patients were treated with dasatinib. In one case the treatment lead to an abortion after week 17 due do the fetus poor perinatal prognosis. All patients were not treated with TKIs during pregnancy. Some patients had combinations of drugs.  Conclusion  There are still no confirmed risks with TKI treatment in connection with pregnancy because statistical evidence is missing. The benefit of being treated with TKI during pregnancy is that the risk of relapse and impaired disease prognosis is reduced. The doctor should always discuss with the patient about risks and opportunities. Treatment for each patiens is individualized based on the patients wishes.

<p><strong>Background: </strong>Lung cancer is the leading cause of cancer-related death and one of the most common cancer types worldwide. Epidermal growth factor receptor (EGFR) has been shown to be an important therapeutic target in non-small cell lung cancer. Kirsten rat sarcoma viral oncogene homologue (KRAS) is a downstream signalling molecule in the EGFR pathway. Lung cancer patients with <em>EGFR </em>mutations respond to tyrosine EGFR inhibitor therapy, in contrast, patients with <em>KRAS </em>mutations do not benefit of such treatment.</p><p><strong>Methods: </strong>This study investigates the frequency of <em>EGFR </em>and <em>KRAS </em>mutations in non-small cell lung cancer patients. Fifty-one lung cancer patients with primary non-small cell lung cancer diagnosed between 1995 and 2005 in the Uppsala-Örebro region were analysed by Sanger sequencing and Pyrosequencing to determine the mutation status of these genes.</p><p><strong>Results: </strong>Five <em>EGFR </em>mutations were found in four patients (8%), two deletions in exon 19, one point mutation in exon 20 and two point mutations in exon 21. <em>KRAS </em>mutations were found in 12 patients (24%), ten codon 12 mutations and two codon 61 mutations.</p><p><strong>Conclusions: </strong>This study confirms previous observations regarding the frequency of <em>EGFR </em>and <em>KRAS </em>mutations in non-small cell lung cancer. Mutations in <em>EGFR </em>and <em>KRAS </em>were mutually exclusive, indicating that both mutations present relevant tumorigenic genomic aberrations.</p>