Colorectal cancer is the second leading cause of cancer-related deaths worldwide as of 2020. Early detection and diagnosis of colorectal cancer can greatly increase the chances of successful treatment and can also reduce the cost of care including treatment. It’s shown in recent years that the colorectal cancer screening rates have slowed nationwide which impacts the new diagnoses of colorectal cancer (CRC) and the ability to treat it at an early stage to avoid increase in mortality rate. The purpose of this research is to examine the impact of the Affordable Care Act 2010 ‘s policy to remove colorectal cancer screening fee for adults aged 50-75 on screening, incidence, and mortality rate of colorectal cancer using panel data model and employing sequential recursive system of equations method. Since a decision to get screened is an individual’s choice, this study explores methods to increase colorectal cancer screening rate with the help of behavioral economics theories. Results of the study show that Affordable Care Act’s policy to remove colorectal cancer screening fee has a significant impact on both colorectal cancer screening and incidence rates. The ACA’s policy is associated with an increase in colorectal cancer screening rate while associating with a decrease in cancer incidence rate. Relating to the colorectal cancer mortality rate, an effort was made to examine the effect of the Affordable Care Act's policy to remove colorectal cancer screening fee on the overall cost savings resulting from lives saved. However, since this study found no significant impact of the ACA's policy on the mortality rate of colorectal cancer, further exploration in this regard was not pursued. On the other hand, studies conducted to increase colorectal cancer screening rate by applying behavioral economics methods have shown that default method with an opt-out choice and financial incentive with a loss-framed messaging methods are proven effective. Therefore, these methods can be investigated to design and implement a nationwide initiative.

Bakgrund: Bröstcancer är ett folkhälsoproblem som i Sverige drabbar cirka 9000 kvinnor årligen. Mastektomi är en behandling mot bröstcancer som orsakar stress, sorg och ångest vilket kan leda till en negativ självbild och minskad livskvalitet. Sexuell hälsa har betydelse på kvinnors generella livskvalitet och bör uppmärksammas. Syfte: Syftet var att belysa den sexuella hälsan hos kvinnor som har genomgått mastektomi efter en bröstcancerdiagnos. Metod: En litteraturstudie med en induktiv ansats, där fem artiklar var kvalitativa och sex var kvantitativa. Resultat: Tre kategorier identifierades: Kroppsuppfattningens betydelse för sexuell hälsa efter mastektomi, värdet av en förtroendefull intim relation för att återfå och bibehålla sexuell hälsa efter mastektomi och betydelsen av stöd för återhämtning från sexuell ohälsa efter mastektomi. Kvinnor som genomfört en mastektomi upplevde sexuell ohälsa i förhållande till en förändrad kroppsbild. Minskad vaginal lubrikation, smärta vid samlag och minskad sexuell lust var några av flertal problem som kvinnorna upplevde. Stöd från anhöriga och vården var väsentligt för en snabbare återhämtning. Konklusion: Kvinnor upplevde att kroppen förändrades, vilket leder till sexuell dysfunktion och sexuell ohälsa. Kvinnorna behövde ensamtid för återhämtning samtidigt som stödet från anhöriga var avgörande för läkningsprocessen. Forskning och kunskap kring sexuell ohälsa är bristande och bör uppmärksammas av hälso- och sjukvårdspersonal. / Background: Breast cancer is a public health problem that in Sweden affects approximately 9,000 women annually. Mastectomy is a treatment for breast cancer that causes stress, sadness and anxiety, which can lead to a negative self-image and reduced quality of life. Sexual health has meaning on women’s general quality of lifeand should be paid attention to. Aim: The aim was to shed light on the sexual health of women who have undergone mastectomy after a breast cancer diagnosis. Method: A literature study with an inductive approach, where five articles were qualitative andsix were quantitative. Results: Three categories were identified: The meaning of body image for sexual health after mastectomy, the value of a trustful intimate relationship to regain and maintain sexual health after a mastectomy and the importance of support for recovery from sexual ill- health after a mastectomy. Women who underwent a mastectomy experienced sexual discomfort in relation to a changed body image. Decreased vaginal lubrication, pain during intercourse and decreased sexual desire are some of many problems the women experienced. Support from relatives and care was felt to be essential for a faster healing process. Conclusion: Women experienced that the body changes in connection with mastectomy, which leads to sexual dysfunction and sexual illness. The women need time alone to recover, while the support of relatives is crucial in the healing process. Research and knowledge about sexual ill-health is lacking and should be paid attention to by healthcare professionals.

Radiotherapy is a common and useful method for treating prostate cancer, often using gold fiducial markers in the prostate as guidance. However, when there is a high risk of lymph node involvement, the independent motion of volumes causes complications in patient positioning since there is a choice between position against the gold fiducial markers or the bone anatomy. This leads to expansion of margins for either the prostate or the pelvic lymph nodes. In this thesis two different treatment strategies were performed and compared against given treatment plans. The purpose was to evaluate the standard treatment and to be able to recommend a new clinical approach for treatment of high-risk prostate cancer. Nine high-risk prostate cancer patients with their given treatment plans were used as a baseline. The patients underwent a planning CT and five CBCTs during the treatment. Two new treatment plan setups were done, a robust treatment and a sequential treatment with three and nine different plans respectively. The baseline and the robust treatment used gold fiducial markers as reference, with a prescribed dose of 2.20 Gy over 35 fractions with a VMAT. The sequential treatment used both gold fiducial markers and bone anatomy as reference, done by 35 fractions with a prescribed dose of 0.6 Gy with a single arc and 1.6 Gy with a dual arc respectively. A total of thirteen different treatment plan setups for each patient were simulated 100 times each, resulting in 11700 simulated treatments in total. The resulting simulated treatments were evaluated by the percentage passing nine different clinical goals, as well as dose and percentage volume averages for these goals. The results from the simulated robust treatments showed a decrease in percentage passing and D98 for the prostate and an increase in percentage passing and D98 for the lymph nodes and vesicles compared to the baseline. An increase in percentage passing and D98 was seen in the sequential treatment strategy for both targets compared to the baseline. The rectum had a larger percentage passing the clinical goals and a lower V69, V74 and V59 for both the robust and sequential treatment strategies. The D2 for the external were lower in the robust treatment strategy but higher in the sequential treatment strategy, while the D2 to the femoral heads were lower for both compared to the baseline treatment strategy. In conclusion, an improved dose coverage was seen in the sequential strategy with good sparing of risk organs. The robust treatment strategy showed promising results for sparing risk organs, but with a less robust dose coverage of the prostate.

Background: Breast cancer (BC), the most common cancer affecting women, has consequences on physical and psychological health. Recent studies highlighted selfcompassions’-, and fear of receiving compassion's protective respectively detrimental effects on psychological health. This study explored the moderating role of fear of receiving compassion from others on the associations between self-compassion and psychological distress. Methods: Participants were 78 Portuguese women with non-metastatic BC. Participants completed self-report measures of self-compassion, fear of receiving compassion from others, and psychological distress. Moderation analyzes through PROCESS Macro in SPSS was conducted. Results: Fear of receiving compassion from others moderated the association between self-compassion and depressive symptoms. At moderate and high levels of the moderator, the association was significant, at low levels the association was nonsignificant. The associations of self-compassion with anxiety, and with stress were not moderated by fear of receiving compassion from others. Conclusions: To our knowledge this study is solitary in examining fear of receiving compassion from others as moderator of the associations between self-compassion and psychological distress. This study contributes to increased understanding of psychological distress among women with BC. The findings should direct future research towards longitudinal, intervention-based studies, targeting fear of receiving compassion, and self-compassion, through compassion-focused therapies. / Bakgrund: Bröstcancer (BC), den vanligaste cancerformen hos kvinnor, har konsekvenser för fysisk och psykologisk hälsa. Tidigare studier har belyst självmedkänsla och rädsla för att ta emot medkänslas skyddande, respektive skadliga effekter på psykologisk hälsa. Den här studien undersökte den modererande rollen av rädsla för att ta emot medkänsla från andra på sambandet mellan självmedkänsla och psykologiska besvär. Metod: Deltagarna var 78 portugisiska kvinnor med icke-metastaserad BC. Deltagarna genomförde självskattningar avseende självmedkänsla, rädsla för att ta emot medkänsla från andra och psykologiska besvär. Moderationsanalyser genomfördes i PROCESS Macro i SPSS. Resultat: Rädsla för att ta emot medkänsla från andra modererade sambandet mellan självmedkänsla och depressiva symtom. Vid moderata och höga nivåer av moderatorn var associationen signifikant, vid låga nivåer var associationen inte signifikant. Associationerna mellan självmedkänsla och ångest eller stress modererades inte av rädsla för att ta emot medkänsla från andra. Slutsatser: Såvitt vi vet är denna studie ensam att undersöka rädsla för att ta emot medkänsla från andra som moderator på sambandet mellan självmedkänsla och psykologiska besvär. Denna studie bidrar till ökad förståelse för psykologiska besvär hos kvinnor med BC. Resultaten bör rikta framtida forskning mot longitudinella, interventionsbaserade studier, inriktade på rädsla för att ta emot medkänsla och självmedkänsla genom compassionfokuserade terapier.

Breast cancer is the most common form of cancer in women worldwide and the second leading cause of cancer death. It is a heterogeneous disease and is subdivided into different subtypes, all with different treatment responses and survival outcomes. Luminal breast cancers are characterised by the expression of oestrogen receptor and generally have a good prognosis. More aggressive tumours are marked by the presence of growth stimulating receptor tyrosine kinase HER2 (HER2-like breast cancer) or the absence of oestrogen receptor, progesterone receptor, and HER2 (triple-negative breast cancer,TNBC). The latter is the most aggressive form and is difficult to treat due to lack of treatment targets. This thesis aimed to explore possible prognostic and predictive biomarkers in different subtypes and study their role in breast cancer. To this aid, breast cancer tumours of pre- and post-menopausal patients enrolled in two cohorts were analysed for gene copy numbers and expression of proteins involved in cell proliferation. Gene copy numbers of receptor tyrosine kinases MET and EGFR, Met’s ligand HGF, and protein tyrosine phosphatase PTPN2 were determined by droplet digital PCR or quantitative PCR in both cohorts. Met, phosphorylated Met (pMet), HGF, and PTPN2 protein expression levels were analysed with immunohistochemical staining in the pre-menopausal cohort. Moreover,the role of the aforementioned proteins was investigated in breast cancer cell lines. Amplification of MET, HGF, and EGFR in breast tissues was found to be low (5-8%). These three genes, all located on chromosome 7, were found to be strongly correlated with eachother and to be associated with shortened distant recurrence-free survival. High protein expression of Met, pMet, and HGF was found in 33%, 53%, and 49% of the breast tumours. MET and EGFR were found to be more often amplified in TNBC disease, correlating with worse survival. Moreover, stromal expression of HGF was associated with shorter survival in TNBC. EGF stimulation in TNBC cell line MDA-MB-468 led to inhibited cell proliferation and migration. Partial knockdown of EGFR caused TNBC cells to proliferate and migrate more upon EGF treatment, mirroring EGFR inhibitor resistance. Knockdown of Met had in part the opposite effects, indicating that Met inhibitors might be useful in the treatment of TNBC. The increase in proliferation and migration upon EGFR depletion could be counteracted with simultaneous knockdown of EGFR and Met, indicating that dual inhibition of these proteins might be a future treatment option in TNBC. Copy loss of PTPN2 was reported in 15% of the cases in both pre- and post-menopausal cohorts. Low cytoplasmic PTPN2 protein expression was found in half of the cases. Loss of PTPN2 gene or protein was associated with a shorter distant recurrence-free survival in Luminal A and HER2-positive tumours, not in TNBC, suggesting a subtype-related prognostic value of PTPN2. Subtype relevance of PTPN2 was further implied by in vitro analyses. Whereas PTPN2 knockdown had no observed effect on TNBC cell lines, knockdown in the Luminal A cell line MCF7 inhibited Met phosphorylation and promoted phosphorylation of Akt, a key regulator of cellular proliferation and survival. The cell growth and survival regulating RAS/MAPK pathway remained unaffected. Knockdown in the HER2-positive cell line SKBR3 led to increased Met phosphorylation and decreased RAS/MAPK-related Erk phosphorylation as well as EGF-mediated transcription factor STAT3 phosphorylation. These results indicate that the role of PTPN2 in breast cancer is subtype-related and needs to be further investigated for future treatment options.

Pancreatic cancer is characterized by its desmoplastic tumor microenvironment and the infiltration of immunosuppressive cells. It is a devastating disease where most patients are diagnosed at a late stage and the treatment options are few. The development of new treatments is surly needed. One treatment option explored is the use of immunotherapy with the intent to activate the immune system and change the balance from pro-tumor to anti-tumor. This thesis presents the idea of using oncolytic adenoviruses called LOAd-viruses that are armed with immunostimulatory- and microenvironment-modulating transgenes. For effective treatment of pancreatic cancer, the virus needs to be able to be given in addition to standard therapy, the chemotherapy gemcitabine. In paper I, the immunomodulatory effect of gemcitabine was evaluated in blood from pancreatic cancer patients receiving their first 28-day cycle of treatment with infusions day 1, 8 and 15 followed by a resting period. Gemcitabine reduced the level of immunosup-pressive cells and molecules but the effect did not last throughout the resting period. On the other hand, gemcitabine did not affect the level or proliferative function of effector T cells indicating that gemcitabine could be combined with immunotherapy. The LOAd700 virus expresses a novel membrane-bound trimerized form of CD40L (TMZ-CD40L). In paper II, LOAd700 showed to be oncolytic in pancreatic cancer cell lines as well as being immunostimulatory as shown by its capacity to activate dendritic cells (DCs), myeloid cells, endothelium, and to promote expansion of antigen-specific T cells. In paper III, LOAd703 armed with both 4-1BBL and TMZ-CD40L was evaluated. LOAd703 gave a more profound effect than LOAd700 on activation of DCs and the virus was also capable of reducing factors in stellate cells connected to the desmo-plastic and immunosuppressive microenvironment. In paper IV, LOAd713 armed with TMZ-CD40L in combination with a single-chain variable fragment against IL-6R was evaluated. The virus could kill pancreatic cancer cells lines through oncolysis and could also reduce factors involved in desmoplasia in stellate cells. Most interestingly, LOAd713 could reduce the up-regulation of PD-1/PD-L1 in DCs after CD40 activation. Taken together, LOAd703 and LOAd713 seem to have interesting features with their combination of immunostimulation and microenvironment modulation. At present, LOAd703 is evaluated in a clinical trial for pancreatic cancer (NCT02705196).

Glioblastoma (GBM) is the most common high-grade brain tumor diagnosed in patients who are more than 50 years of age. The standard of care treatment is surgery, followed by radiotherapy and chemotherapy. The median life expectancy of patients is only between 12 to 15 months after receiving current treatment regimes. Hence, identification of new therapeutic compounds and gene targets are highly warranted. This thesis describes four interlinked studies to attain this goal. In study 1, we explored drug combination effects in a material of 41 patient-derived GBM cell (GC) cultures. Synergies between three compounds, pterostilbene, gefitinib, and sertraline, resulted in effective killing of GC and can be predicted by biomarkers. In study 2, we performed a large-scale screening of FDA approved compounds (n=1544) in a larger panel of GCs (n=106). By combining the large-scale drug response data with GCs genomics data, we built a novel computational model to predict the sensitivity of each compound for a given GC. A notable finding was that GCs respond very differently to proteasome inhibitors in both in-vitro and in-vivo. In study 3, we explored new gene targets by RNAi (n=1112) in a panel of GC cells. We found that loss of transcription factor ZBTB16/PLZF inhibits GC cell viability, proliferation, migration, and invasion. These effects were due to downregulation of c-MYC and Cyclin B1 after the treatment. In study 4, we tested the genomic stability of three GCs upon multiple passaging. Using molecular and mathematical analyses, we showed that the GCs undergo both systematic adaptations and sequential clonal takeovers. Such changes tend to affect a broad spectrum of pathways. Therefore, a systematic analysis of cell culture stability will be essential to make use of primary cells for translational oncology. Taken together, these studies deepen our knowledge of the weak points of GBM and provide several targets and biomarkers for further investigation. The work in this thesis can potentially facilitate the development of targeted therapies and result in more accurate tools for patient diagnostics and stratification.

High-throughput drug screening (HTS) in live cells is often a vital part of the preclinical anticancer drug discovery process. So far, two-dimensional (2D) monolayer cell cultures have been the most prevalent model in HTS endeavors. However, 2D cell cultures often fail to recapitulate the complex microenvironments of in vivo tumors. Monolayer cultures are highly proliferative and generally do not contain quiescent cells, thought to be one of the main reasons for the anticancer therapy failure in clinic. Thus, there is a need for in vitro cellular models that would increase predictive value of preclinical research results. The utilization of more complex three-dimensional (3D) cell cultures, such as multicellular tumor spheroids (MCTS), which contain both proliferating and quiescent cells, has therefore been proposed. However, difficult handling and high costs still pose significant hurdles for application of MCTS for HTS. In this work, we aimed to develop novel assays to apply MCTS for HTS and drug evaluation. We also set out to identify cellular processes that could be targeted to selectively eradicate quiescent cancer cells. In Paper I, we developed a novel MCTS-based HTS assay and found that nutrient-deprived and hypoxic cancer cells are selectively vulnerable to treatment with inhibitors of mitochondrial oxidative phosphorylation (OXPHOS). We also identified nitazoxanide, an FDA-approved anthelmintic agent, to act as an OXPHOS inhibitor and to potentiate the effects of standard chemotherapy in vivo. Subsequently, in Paper II we applied the high-throughput gene-expression profiling method for MCTS-based drug screening. This led to discovery that quiescent cells up-regulate the mevalonate pathway upon OXPHOS inhibition and that the combination of OXPHOS inhibitors and mevalonate pathway inhibitors (statins) results in synergistic toxicity in this cell population. In Paper III, we developed a novel spheroid-based drug combination-screening platform and identified a set of molecules that synergize with nitazoxanide to eradicate quiescent cancer cells. Finally, in Paper IV, we applied our MCTS-based methods to evaluate the effects of phosphodiesterase (PDE) inhibitors in PDE3A-expressing cell lines. In summary, this work illustrates how MCTS-based HTS yields potential to reveal and exploit previously unrecognized tumor-specific vulnerabilities. It also underscores the importance of cell culture conditions in preclinical drug discovery endeavors.