Non-small cell lung cancer (NSCLC) causes most of the cancer deaths worldwide. Tyrosine kinase inhibitors (TKIs), like erlotinib and crizotinib, are commonly used as specific treatments targeting epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged NSCLC. Autophagy is a highly conserved cellular process in response to stress. Tumor microenvironment (TME) is composed of both tumor cells and stromal cells. This study aimed to investigate whether autophagy could confer intrinsic and acquired resistance to TKIs in NSCLC, and its role in the presence of TME or in animal models. In the first part of this study, the effect of EGFR TKI or ALK TKI on sensitive NSCLC cells to generate autophagy was investigated, and manipulation of autophagy in these cell lines was performed. Autophagy inhibition was shown to enhance apoptotic effect of TKIs in sensitive NSCLC cells. This part provided strong evidence that TKIs and autophagy inhibitor chloroquine (CQ) work synergistically in sensitive NSCLC cells. Autophagy induction by erlotinib treatment was observed in a HCC827 (lung adenocarcinoma, EGFR exon 19 del) xenograft model, which was in line with the in vitro observation. Correspondingly, the combination of erlotinib (12.5 mg/kg) with CQ (50 mg/kg) in the HCC827 xenograft model achieved greater tumor growth suppression, compared with single drug treatments. In the second part of this study, a model of TME was established to allow study of autophagy under such circumstances. An activated TME with cytokine production, autophagy induction and epithelial-to-mesenchymal transition (EMT) was generated by co-culturing NSCLC cells and human fibroblasts. Sensitivity to TKI under TME was not affected, and combination of chloroquine with TKI under TME remained synergistic compared with single treatments. In the third part of this study, erlotinib-resistant (ER) HCC827 cells were acquired by stepwise exposure to increasing concentrations of erlotinib in cell culture. Common acquired resistance mechanisms to EGFR TKI (EGFR T790M or c-MET amplification) were excluded in this ER HCC827 model, except EMT. Autophagy status in ER HCC827 cells was studied and autophagy manipulation was performed. It was found that CQ and erlotinib worked synergistically to induce cell death even in ER HCC827 cells. In an ER HCC827 xenograft model, significant degree of autophagy and EMT was evident. Interestingly, combining erlotinib (25 mg/kg) with CQ (50 mg/kg) showed better inhibitory effect on tumor growth compared with single treatments. In summary, TKIs induced both apoptosis and autophagy in EGFR-mutated and ALK-rearranged NSCLC cells. Autophagy inhibition by CQ enhanced TKI-induced cell death in sensitive cells. The presence of TME did not confer TKI resistance. Autophagy was highly activated in EGFR-mutated NSCLC cells with acquired resistance to erlotinib. Combination of CQ with erlotinib remained synergistic in the presence of TME and acquired resistance, both in vitro and in vivo. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Colorectal cancer is a serious health problem that has concerned people for decades. In Hong Kong, it is the most common cancer and the second leading cause of death. Among colorectal cancer patients, around 40-50% of them will develop metastatic disease. Chemotherapy is playing an important role all the time in the treatment of advanced colorectal cancer. In the past decade, the application of targeted therapies in treatment has largely improved efficacy and prolonged survival. Bevacizumab and cetuximab are two commonly used targeted agents in daily clinical practice of Hong Kong. Since multiple clinical trials have studied bevacizumab and cetuximab in combination with other chemotherapies, limited data is available in Asian patients. Therefore, we conduct three 5-year retrospective analyses based on patients received treatment in Hong Kong Queen Mary Hospital, to investigate the clinical efficacy and toxicity of those two drugs. The first study examined the use of bevacizumab in treating KRAS mutated type patients. We found the efficacy and results were consistent with historical data. In the next analysis of cetuximab, comparable data were shown which suggested the consistency with previous studies. The last study is aim to compare bevacizumab and cetuximab in previously untreated wild-type KRAS patients. Identical response rates, progression-free survival and overall survival were finally reported. / published_or_final_version / Medicine / Master / Master of Philosophy

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Background: Almost one child a day is diagnosed with cancer in Sweden. When a child is affected with cancer a whole family, not least siblings will face a new way of life. A sibling’s relationship is unique and can only be fully understood by the ones that have experienced it themselves. There are many advantages in involving family in the caring of a child and also to see the family as a unit. Aim: The aim of the study was to illuminate siblings’ experiences of living in a family with a child with cancer. Methods: This is a literature review based on the result of ten scientific articles with qualitative approach. All articles have been examined to ensure the qualitative value of them and have been textual analyzed. Included articles have qualitative approaches to seek for depth and find siblings’ experiences. Chosen theoretical framework has been used to further lift the result. Results: Four main themes emerged from the result; altered living, need of information, anxiety and grief and support interventions. What these four have in common is that the way of life was altered. Conclusion: Siblings to a child with cancer is an exposed group both physically, mentally and emotionally. There are still gaps to fill regarding what nurses can do to identify and meet siblings needs during a cancer period and altered living. Clinical significance: This literature review can contribute to enhanced knowledge about what it is like being a sibling to a child with cancer. Key words: siblings, cancer, altered living / Bakgrund: I Sverige drabbas nästan ett barn varje dag av cancer. När ett barn drabbas avcancer ställs en hel familj, inte minst syskonen inför en ny livsvärld. En syskonrelation är unikoch kan endast förstås av de som levt i en. Det finns många fördelar med att involverafamiljen i omvårdnaden av ett barn och att se familjen som en enhet. Syfte: Syftet medstudien är att belysa syskons upplevelse av att leva i en familj med ett cancersjukt barn.Metod: Detta är en litteraturstudie baserad på resultatet av tio vetenskapliga artiklar. Samtligaartiklar har kvalitetsgranskats och analyserats. Inkluderade artiklar har varit kvalitativa, dettaför att söka efter djup och finna syskonens upplevelser. Vald teoretisk referensram haranvänts för att ytterligare lyfta resultatet. Resultat: Fyra huvudteman framkom ur resultatet;förändrad vardag, behov av information, oro och sorg samt stödinsatser. Det gemensammaför dessa teman är att livsvärlden blev förändrad. Slutsats: Syskonen till barn med cancer ären utsatt grupp så väl fysiskt, psykiskt som emotionellt. Fortfarande finns kunskapsluckor omhur sjuksköterskor ska identifiera och bemöta syskonens behov under cancerperioden och ideras förändrade livsvärld. Klinisk betydelse: Denna litteraturstudie kan bidra till ökadkunskap om hur det är att vara syskon till ett barn med cancer.

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published_or_final_version / Surgery / Master / Master of Surgery

published_or_final_version / Surgery / Master / Master of Surgery

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / Surgery / Master / Master of Surgery

published_or_final_version / abstract / toc / Clinical Psychology / Master / Master of Social Sciences