Head and neck cancer is the fifth most common cancer worldwide with an estimated annual global incidence of over 500 000 cases. These malignant tumours develop in the mucosal linings of the upper respiratory tract or in the salivary glands. The most common sites are in the oral cavity and larynx. Treatment modalities comprising surgery and chemoradiotherapy have improved significantly during the last 20 years, but not the long-term survival of patients. The aim of this thesis was to study the different factors affecting tumour growth in head and neck cancer that may have clinical implications in the future. Factors involving apoptosis, cell cycle activity, inflammation, and enzyme activity were of special interest. The results of the thesis indicate that patients with malignant salivary gland tumours having the lowest level of actively replicating cells have the best prognosis. The largest amount of replicating cells in tongue cancer specimens was found in the peripheral areas of tumour nests. Metallothionein, a protein that can hinder apoptosis, was found in excess in the same areas, whereas apoptosis activity was considerably lower. Taken together, these results indicate that the most aggressive cancer cells are found in the peripheral areas of tumours where apoptosis may be hindered. The expression of the death receptor Fas was higher in tongue cancer specimens than in normal mucosa. The expression of this receptor was studied further in two cell lines established from oral cancers. When a low dose of cisplatin was added to cell cultures, the Fas expression was enhanced in both cell lines and, furthermore, the Fas-induced apoptosis was increased in one of the cell lines. The results show that a common chemotherapeutic drug given in a low, less toxic dose may enhance receptor-mediated apoptosis of cancer cells. Malignant solid tumours are often distinguished by an increased proteolytic activity resulting in invasive growth, neo-angiogenesis, and metastases. This activity is conducted by enzymes that are secreted from tumour cells, or from normal cells in the tumour microenvironment. The regulation of enzyme secretion may be mediated by cytokines, small signalling molecules also present in cancer tissue. The results of this thesis show that two cytokines can synergistically induce enzyme secretion (matrix metalloproteinase-1 and -9) from oral cancer cells. Cytokine tumour necrosis factor-alpha and hepatocyte growth factor added alone to cell cultures strongly stimulated secretion of these enzymes. Thus, the tested cytokines, which are commonly secreted by fibroblasts and immune cells, may promote tumour growth. This thesis has contributed to an increased understanding of factors affecting tumour growth in head and neck cancer. The upcoming cancer therapies will be based on the increasing knowledge of these and other aberrant cellular mechanisms that may vary between different cancer forms.

Ovarian cancer is a disease with a high rate of mortality where the need for novel treatments will increase in the near future as older and populous generations reach the age where the cancer is usually diagnosed. Once treated, ovarian cancer tends to recur and display a newfound resistance against the platinum-based chemotherapeutic drugs that are used to treat the disease. Therefore, devising new methods of treatment is of utmost importance. Treatment with oncolytic viruses like LOAd703 offers an alternative treatment option that is more specific, causes immunogenic cell death in tumor cells, can stimulate the patient’s own immune system into fighting the cancer, and also has the potential to induce long term immune memory. In this project, the oncolytic and immunogenic capacity of LOAd703 in three different ovarian cancer cell lines was tested in conjunction with the standard-of-care chemotherapeutical drugs paclitaxel, cisplatin and carboplatin. The chemotherapy did not inhibit the replication, transgene expression or oncolysis of the LOAd703 virus. LOAd703 was able to effectively induce oncolysis in all three cell lines. The oncolytic capacity was generally increased when combined with chemotherapeutics. In cells resistant to chemotherapeutics, combination therapy with LOAd703 increased the killing capacity. While combination therapy proved effective, it did leave behind a small population of tumor cells that appeared to be resistant to both chemotherapy and viral oncolysis but longer culturing times may be tested to evaluate if complete killing will occur or if it is a primary resistance to these treatments in the cell lines. Further, if there is resistance to oncolysis or chemotherapy-mediated killing, employing tumor-immune cell co-cultures or in vivo studies might be necessary in order to assess whether the immunostimulatory effects of LOAd703 will lead to a complete eradication of the remaining tumor cells. The treatments also caused an increase in the expression of certain cell surface markers, like PD-L1 and CD262, which might open the door for future trials combining chemotherapy and LOAd703 with anti-PD-L1 inhibitors or soluble TRAIL.

Breast cancer is the most common cancer among women in Sweden and globally. Socio-demographic, genetic and productive factors together with some endogenous and exogenous hormones and lifestyle are some of the risk factors that can cause this type of cancer. There is no cure for metastatic breast cancer but the treatment goal is to control the disease and prolong the survival. Treatment options in metastatic breast cancer are exactly like the ones in primary breast cancer. Targeted cancer therapy is a treatment that targets either one or some specific characters of the cancer. Serine-threonine kinases called CDK4/6 inhibitors like Ibrance with chemical name palbociclib, Kisqali with chemical name ribociclib and Verzenios with chemical name abemaciclib are used for target therapy against metastatic breast cancer. CDK4/6 inhibitors in combination with aromatase inhibitors, estrogen receptor down regulators or selective receptor modulators are also used to address the treatment resistant metastatic breast cancers. The aim of this thesis is to investigate the role and the effect of CDK4/6 inhibitors in the treatment of metastatic breast cancer. Six randomized controlled trial studies were selected from the PubMed data base. Results from the trial analysis showed equal effects and relative same adverse event profiles between those three mentioned CDK4/6 inhibitors. The primary endpoint, progression free survival and secondary endpoints including overall survival, clinical benefit rate, overall response rate and safety were investigated in these studies. The duration of progression free survival (PFS) and overall response rate (ORR) was longer and improved in most studies however improvement in overall survival (OS) was not achieved. More research studies are needed to determine optimal treatment for patients with metastatic breast cancer who are medicated by CDK4/6 inhibitors. / Bröstcancer är den vanligaste cancerformen bland kvinnor i Sverige och globalt. Sociodemografiska, genetiska och reproduktiva faktorer samt vissa endogena och exogena hormoner och livsstil är några riskfaktorer som kan orsaka denna typ av cancer. Metastatisk bröstcancer innebär att cancer har spridit sig bland andra organ i kroppen bland annat ben, hjärna, lever och lungor. Det finns inget botemedel mot metastatisk bröstcancer men målet är att kontrollera sjukdomen och förlänga överlevnaden och behandlingsalternativ för detta är exakt som den i den primära bröstcancern. Målspecifik cancerterapi är en behandling som riktar sig mot någon specifik karaktär hos cancercellerna. En klass av läkemedel består av en stor familj av serintreoninkinaser som kallas CDK4/6-hämmare: Ibrance (palbocilcib), Kisqali (ribocilcib) och Verzenios (abemaciclib) används mot metastaserad bröstcancer. Syftet med det här examensarbetet var att undersöka rollen samt effekten av CDK4/6 hämmare vid behandling av metastatisk bröstcancer. Sex randomiserade kliniska studier erhölls från artikelsökningar i databasen PubMed. Resultat från artikelanalyser visade likvärdiga effekter samt relativt samma biverkningsprofil mellan de tre ovannämnda CDK4/6 inhibitorerna. Den primära utfallsvariabeln var progressionsfri överlevnad och de sekundära utfallsvariablerna inkluderade total överlevnad, klinisk nytta, den totala svarsfrekvensen och säkerhet undersöktes i dessa studier. Varaktigheten av progressionsfri överlevnad (PFS) samt den totala svarsfrekvensen (ORR) var längre och förbättrades i nästan alla studier medan den totala överlevnaden (OS) kunde inte fastställas då inte tillräckligt med data kunde samlas in. Ytterligare undersökningar behövs för att förstå den fulla mekanismen bakom resistensutveckling samt utöka strategier för att minska negativa biverkningar av CDK4/6 hämmare vid behandling av patienter vid metastatisk bröstcancer.

Bakgrund: Det är 50-75% av kvinnorna i Sverige som lider av klimakteriebesvär. Vanligt förekommande är vasomotoriska symtom som värmevallningar, svettningar och hjärtklappning, men även urogenital atrofi, osteoporos, urinträngningar och depression. En tredjedel av alla menopausala kvinnor är i behov av behandling för att upprätthålla sin livskvalitet. Hormonbehandling med östrogen av menopausala kvinnor började användas i USA 1942. Internationella riktlinjer idag är att östrogen ska användas ihop med en progestagen om kvinnan har intakt livmoder för att östrogenets stimulering av endometriet ska hämmas. En stor randomiserad studie, Women’s Health Initiative, visade på att konventionella hormoner ökar risken för bröstcancer och den stoppades därför i förtid 2002. Efter det steg efterfrågan på bioidentiska hormoner då dessa av många anses säkrare, men åsikterna är kontroversiella. Studier har visat att bioidentiskt progesteron kan innebära en lägre risk för bröstcancer än syntetiskt progestin när det ges ihop med östrogen, men det finns idag inga säkra bevis att det stämmer. Samtidigt visar studier på att progesteron ger ökad risk för endometriecancer jämfört med progestin när det kombineras med östrogen. Syfte: Syftet var att undersöka risken för bröst- respektive endometriecancer vid behandling av menopausala kvinnor med bioidentiska hormoner i jämförelse med konventionell hormonbehandling. Metod: En litteraturundersökning genomfördes där sex vetenskapliga artiklar granskades. Artiklarna hämtades från databasen PubMed och var alla randomiserade och inte äldre än 10 år. De analyserade alla behandling med bioidentiska eller konventionella hormoner av menopausala kvinnor. Resultat: Konventionella hormoner visade på ökad risk för bröstcancer jämfört med placebo och bioidentiska hormoner, medan de gav minskad risk för endometriecancer i jämförelse med placebo. Bioidentiska hormoner gav ökad risk för endometriecancer i jämförelse med placebo i en studie, medan en annan studie visade på att ingen ökad risk förelåg. Slutsats: De studier som har studerats i detta examensarbete visar entydigt på att bioidentiska hormoner ger lägre risk för bröstcancer än konventionella. Risken för endometriecancer kan dock öka med bioidentiska hormoner jämfört med de konventionella, men resultaten går isär. Uppföljningsstudier för bioidentiska hormoner saknas idag och behövs för att kunna fastställa effekten de har på längre sikt på bröst och endometrium. En kvinna i valet av hormonbehandling bör noga överväga balansen mellan nytta och risker. / Background: It is 50-75% of the women in Sweden who suffer from menopausal problems. Common problems include vasomotor symptoms such as hot flashes, sweating and palpitations, but also urogenital atrophy, osteoporosis, urination and depression. A third of all menopausal women are in need of treatment to maintain their quality of life. Hormone therapy with estrogen of menopausal women started in the United States in 1942. International guidelines today are that estrogen should be used in conjunction with a progestagen if the woman has an intact uterus in order for the estrogen's stimulation of the endometrium to be inhibited. A large randomized study, the Women's Health Initiative, showed that conventional hormones increase the risk of breast cancer and it was therefore stopped prematurely in 2002. After that, the demand for bioidentical hormones rose as these are considered safer by many, but opinions are controversial. Studies have shown that bioidentical progesterone may be associated with a lower risk of breast cancer than synthetic progestin when given together with estrogen, but there is currently no conclusive evidence that this is true. On the other hand, studies show that progesterone increases the risk of endometrial cancer compared to progestin when combined with estrogen. Aim: The aim of the present work was to investigate the risk of breast and endometrial cancer during treatment with bioidentical hormones of menopausal women in comparison to conventional hormone therapy.  Method: A literature study was conducted in which six scientific articles were reviewed. The articles were retrieved from the PubMed database and were all randomised and not older than 10 years. They all investigated treatment with bioidentical or conventional hormones of menopausal women.  Results: Conventional hormones showed an increased risk of breast cancer compared to placebo and bioidentical hormones, while they reduced the risk of endometrial cancer compared to placebo. Bioidentical hormones increased the risk of endometrial cancer compared to placebo in one study, while another study showed that there was no increased risk.  Conclusion: The studies analyzed in this thesis show clearly that bioidentical hormones are associated with a lower risk of breast cancer than conventional ones. However, the risk of endometrial cancer may increase with bioidentical hormones compared to the conventional ones, but the results are inconclusive. Follow-up studies for bioidentical hormones are currently lacking and are needed to determine the long-term effect they have on breasts and endometrium. In conclusion, a woman in the choice of hormone therapy should be carefully considered with the benefit of risks.

Glioblastoma is the fastest-growing, and the most common malignant brain tumour in adults. It is normally treated with surgery and radio- or chemotherapy, but the approximate life expectancy is of 15 months with a high probability of cancer recurring. Therefore, there is a need for decreasing its severity. Bulk and single-cell RNA sequencing allow the identification of cellular states in tumours affected by cell-intrinsic and extrinsic factors. Four different cellular states have been identified in glioblastoma: neural progenitor-like, oligodendrocyte progenitor-like, astrocyte-like, and mesenchymal-like. As glioblastoma is an immunosuppressive tumour, it can alter the immune system and increase the tumour's immune escaping by segregating immunosuppressive factors or interacting with the brain microenvironment.Two datasets were used in this study to explore if the localization of the tumour in the brain microenvironment and the tendency of glioblastomas to activate microglial cells are due to particular ligand-receptor interactions. Data quality control was applied to both datasets and SingleCellSignalR and CellphoneDB packages were used to predict the possible interactions. A total of seven experiments were designed for this study. The first dataset, GBmap, allowed us to do a comparison between tumour cells and microglia, tumour cells and other cell types in the brain, and the four cellular states of glioblastoma with microglia and macrophages. Next, healthy microglia from GBmap was used to compare with the tumour bulk data from the second dataset, HGCC. The bootstrap technique was performed to compare bulk data vs single-cell data, and a comparison between tumour cells and microglia or other cell types was analysed.Results showed specific and shared interactions between cell types or cellular states, revealing the different localization of the tumour cells depends on the expressed ligand-receptor pairs. Also, a total of four patterns of interactions were found in the 50 samples to have a different tendency to activate microglial cells, which are promising results to further explore drugs to interfere with or how these interactions are related to patient survival. Furthermore, even if glioblastoma is a heterogenous disease, more interactions were predicted with microglial/macrophage cells without a uniform pattern between patients, and therefore, this study is a starting point upon which further in vitro studies would be needed to study the predicted interactions as potential targets to stop the progression of this type of cancer.

Background: Cervical cancer is a global health problem, by year 2020 around 600,000 women were suffering from cervical cancer. The contagious infection Human Papillomavirus causes the majority of cervical cancers worldwide. The impact of cervical cancer on women contributes to changes in their social and sexual relations in which women finds themselves.  Aim: The aim was to describe women's experiences of living with cervical cancer. Method:The method used in this study was literature-based. Friberg's five-step model was used to analyze the selected scientific articles used for the result. Results: Based on the analysis work, three themes emerged: the intimate relationship, being affected by cervical cancer and a second chance. Seven subthemes were compiled in coding: the experience of changed sexuality and femininity, to feel loneliness in the disease, to find support in the environment, to feel bad about what is to be cured, a constant worry, see life with new eyes, find comfort in religion and faith, there is a future. Conclusion: Women's lives after suffering from cervical cancer changed drastically and affected their health.

This thesis explored symptom clusters in patients with lung cancer before, during and after oncological treatment. A literature review and an interview study was used to explore the symptom cluster experience from the patients’ perspective. A large diversity of symptom cluster constellations were identified, in which fatigue was the most commonly occurring symptom, followed by dyspnea, pain, depression, cough and nutritional impact symptoms. Many symptom assessment instruments were identified, measuring mostly the intensity-dimension alone or in combination with timing. The results also stress that living with symptom clusters during treatment is more about survival than actually living. Patients’ symptom management strategies were shaped by impacting conditions such as knowledge and earlier experience of symptoms. Symptoms were often regarded as unavoidable by the patients and something to accept. How symptoms were recognized by health care professionals further added to the normalization of symptom clusters. Subsequently, patients would not always ask for support, and their quality of life was negatively affected. Holistic person-centered care including multi-dimensional symptom assessment is considered essential to ensure adequate symptom cluster management for patients with lung cancer.

Bakgrund: Bröstcancer är den vanligaste cancerformen bland kvinnor både i Sverige och globalt. Mastektomi är en av behandlingsformerna för bröstcancer, vilket innebär att en del eller hela bröstet tas bort. Kvinnobrösten har utöver den fysiologiska funktionen en sexuell, samt kulturell betydelse. I vårt samhälle är brösten en symbol för femininitet samt sexualitet, vilket gör förlusten av ett bröst till en av de orsaker som ändrar kvinnors kroppsbild. Sjuksköterskan har en central roll i omvårdnadsarbetet och att hjälpa patienten att acceptera och förstå att kroppen har ändrats samt ge stöd. Syfte: Syftet med denna litteraturstudie var att beskriva upplevd självbild och behov av stöd hos kvinnor som genomgått mastektomi. Metod: Den valda metoden är en litteraturstudie med inriktning på kvalitativa studier. Informationssökningen gjordes i databaserna PubMed, CINAHL och Psycinfo. Relevanta studier kvalitetsgranskades med hjälp av SBU:s granskningsmall för kvalitativ forskningsmetodik. Studiernas data analyserades och nyckelord samt meningsenheter identifierades. Resultat: Bearbetning av data gav tre huvudteman; Faktorer som påverkar kvinnans sjukdomsförlopp, upplevelser av förändrad kropp och livet efter mastektomin. I dessa tre teman framkom sex subteman; Stöd från olika parter i kvinnas liv, information & förberedelse, bröstensbetydelse och den emotionella påverkan, mastektomins inverkan på när relationer, bli vän med sin nya förändrade kropp, återfå livskvalitet. Konklusion: Mastektomi påverkade kvinnors fysiska samt psykosociala välbefinnande och ett behov av stöd uppstod. Stöd från sjuksköterskan behövdes innan, under och efter behandlingen. Ett personcentrerat arbetssätt var av vikt för att en anpassad vård skulle kunna ges där varje individs behov var i fokus. Trots att mastektomin innebar en förändring i vardagen utvecklade majoriteten av kvinnorna en acceptans gentemot den nya kroppsbilden. Livet var det som var betydelsefullt och ett förlorat bröst var obetydligt sett till helheten. / Background: Breast cancer is the most common form of cancer among women both in Sweden and globally. Mastectomy is one of the treatments for breast cancer, where a part or all of the breast is removed. In addition to the physiological function, the female breast has a sexual and cultural significans. In our society, the breasts are a symbol of femininity and sexuality, which makes the loss of a breast one of the reasons that women's body image changes. The nurse has a central role in the nursing work, helping the patient to accept and understand that the body has changed and provide support. Aim: The aim of this literature study was to describe perceived self-image and need for support in women who have undergone mastectomy. Method: The chosen method is a literature study with focus on qualitative studies. The information search was performed in the databases PubMed, CINAHL and Psycinfo. Relevant studies were quality reviewed using SBU's review template for qualitative research. The data from the studies were analyzed and keywords as well as units of meaning were identified. Results: The data process yielded three main themes; factors that influence women around the mastectomy, experiences of an altered body and the life after mastectomy. In these three themes, six sub themes emerged; Support from different parties in women's lives, information & preparation, the meaning of the breast and the emotional impact, the impact of mastectomy on relationships, becoming friends with their new changed body, regain quality of life. Conclusion: Mastectomy affected women's physical and psychosocial well-being and a need for support arose. Nursing support was needed before, during and after treatment. A person-centered approach was important so that adapted care could be provided where everyone’s needs were in focus. Even though mastectomy meant a change in everyday life, most women developed an acceptance of the new body. The loss of a breast was insignificant, what mattered was being alive.

Inadequate metabolic conditions in solid tumors lead to the formation of quiescent cancer cells that are suspended in a transient cell cycle arrest. When conditions change, quiescent cancer cells can re-enter the cell cycle and cause recurrence. Drug screening efforts have revealed mitochondrial oxidative phosphorylation as a unique metabolic dependency in quiescent cancer cells. The anthelmintic drug nitazoxanide is an inhibitor of oxidative phosphorylation and preferentially active against quiescent cancer cells in multicellular tumor spheroids.  In this thesis, we employed current and developed new models of quiescent cancer cells and applied live cell imaging for improved preclinical evaluation of cancer drugs in hepatocellular and colorectal carcinoma cell lines. As part of this work, a new assay to measure mitochondrial membrane potential in three-dimensional cell models was developed, an application of the JC-1 assay, and we demonstrated that the preferential activity against quiescent cancer cells of nitazoxanide is shared by two kinase inhibitors: sorafenib and regorafenib. The sensitivity of quiescent cancer cells to nitazoxanide, sorafenib, and regorafenib correlated with the disruption of the mitochondrial membrane potential. Nitazoxanide and sorafenib, in combination, caused an additive decrease in viability, mitochondrial membrane potential, and colony regrowth capacity.  Furthermore, we developed a quiescent hollow fiber assay and implemented an improved analysis using live cell imaging and adenosine triphosphate analysis. Hypoxia and cancer cell quiescence were enriched in hollow fiber macrocapsules over time, and the culture conditions affected nitazoxanide sensitivity. Additionally, we used basement membrane extract gel to support cell growth in hollow fiber macrocapsules and implanted macrocapsules in mice. We observed that the in vivo environment was favorable to cell growth. Through this characterization of the quiescent hollow fiber assay, we were able to outline important paths for future research.

About 12 to 17 percent of all breast cancers are triple-negative breast cancer (TNBC). In TNBC, estrogen, progesterone, and human epidermal growth factor receptor two are not expressed, or copies of the HER2 gene are decreased (or both). This makes TNBC hard to treat in comparison with other kinds of breast cancers. New studies have made some interesting observations on how some monoclonal antibodies can help to treat TNBC. One of the monoclonal antibodies that can be useful for treating TNBC is pembrolizumab. Pembrolizumab inhibits programmed death ligand 1 (PD-1), which is located on the surface of T cells from connecting to immune checkpoint proteins such as programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) located on the surface of the cancer cell. Breaking this connection enables continued activation of T cells and attack of the cancer cells. This thesis aimed to evaluate if pembrolizumab was safe and effective as monotherapy or as a combination therapy with chemotherapy for patients with different stages of TNBC. This study was based on scientific articles identified from the database PubMed. Five randomized controlled trial studies were selected for further study in this project. Two publications were chosen from keynote-355, which studied the effect and safety of Pembrolizumab in combination with chemotherapy and compared it to chemotherapy monotherapy in patients with metastatic TNBC. The first study included patients from different countries as it was a multi-center study, and the second one focused only on patients who enrolled in Japan. One study was chosen from keynote-119 studies, which compared health-related quality of life for patients who were treated with pembrolizumab monotherapy or with monotherapy of chemotherapy. The last two articles which were chosen were about keynote-522. The first article about keynote-522 compared was a multicenter study enrolled in 21 countries. In this study, patients had early-stage TNBC and received neoadjuvant placebo chemotherapy or pembrolizumab chemotherapy. After the breast operation, either adjuvant pembrolizumab or placebo was received. The other study looked at Asian patients who enrolled in keynote-522. Results showed that monotherapy with pembrolizumab did not make a massive difference in overall survival compared to chemotherapy. Still, it led to better health- related quality of life for patients (Combined Positive Score (CPS) ≥ 10) treated with pembrolizumab. Results from keynote-355 showed that combination therapy with pembrolizumab and chemotherapy led to better and longer progression-free survival and overall survival in patients with CPS ≥ 10 treated with pembrolizumab. The analysis of Japanese patients showed even better progression-free survival and overall survival results than the global population. The study from keynote-522 showed that neoadjuvant pembrolizumab and chemotherapy followed by adjuvant pembrolizumab had a better effect than only neoadjuvant chemotherapy. The second keynote-522 study showed the same results as the global study and better results at event-free survival for the Asian population than the overall population. After reviewing the articles, it was found that pembrolizumab proves to be a safe and effective treatment for TNBC. To enhance understanding of the drug's effects, measures such as extending follow-up periods, conducting further studies to assess its effectiveness, and exploring new research methodologies are proposed.