| 11. |
- Hauffman, Anna
(author)
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Internet-based Psychosocial Support : Design, Effects and User Experience in the Cancer Setting
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Background and Aim Being diagnosed with cancer is often described as a major loss of control leading to severe psychological distress and symptoms of anxiety and depression can continue to affect the individual in the long term. The cancer and its treatment may influence all dimensions of health, thus the psychosocial support provided needs to be multifaceted and easy accessed. Internet-based interventions may be one way to provide such support, but evidence is limited. This thesis aimed to investigate the design, effects, and experiences of internet-based psychosocial support in cancer.Methods and Results Study 1 encompassed a co-creation development process resulting in the interactive support provided as the first step in an internet-based stepped care intervention (iCAN-DO). The effects of iCAN-DO were investigated in a randomised controlled trial, targeting individuals newly diagnosed with cancer and concurrent self-reported symptoms of anxiety and depression (according to the Hospital Anxiety and Depression Scale). Step 1 had a psycho-educative content involving self-care strategies and was available to the intervention group during the ten-month study period. Step 2 comprised a guided internet-based cognitive behavior therapy (iCBT) program and was offered those without improvement in anxiety and depression after using Step 1. The results showed that iCAN-DO improved symptoms of depression compared with standard care, while symptoms of anxiety were largely unaffected. Most participants used Step 1, while only a few used Step 2.In Study 2, aspects of usefulness, relevance, and usability in iCAN-DO were explored through qualitative interviews, analysed using content analysis. Results showed that standard healthcare did not meet the individuals' needs and iCAN-DO was used as complement, providing access to relevant, trustworthy information and support. Usability was affected by the perceived usefulness and ease of use of the intervention, as well as by the user´s circumstances in life and consequences of the cancer. The co-creation process in the development of Step 1 added relevance, but both steps 1 and 2 would have gained from being provided earlier, integrated into standard healthcare and more adaptable to the individual.Conclusion The thesis concluded that the internet-based intervention had positive effects on symptoms of depression in individuals newly diagnosed with cancer. Individuals with cancer experience several unmet needs in standard healthcare and since psycho-educative support including self-care advice seems feasible in this group, efforts are needed to incorporate internet-based support in regular oncology care. Since the intervention did not target all symptoms (i.e. anxiety) further research is needed on how to enhance efficacy and how to make iCBT more feasible for this group.
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| 12. |
- Laryea, Daniel
(author)
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Preclinical Characterization in vivo and in vitro of Novel Agents for Cancer Chemotherapy : Studies on Benomyl, Carbendazim, Cryptolepine and Acriflavine
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Preclinical methods for the identification and characterization of molecules for development into new cancer drugs were investigated. Based on repurposing, i.e. the exploration of currently prescribed drugs for new indications, and as a result of a new high throughput screening (HTS) approach, the benzimidazoles benomyl and carbendazim, the alkaloid cryptolepine and the acridine acriflavine were found interesting to characterize using these methods. In mice the benzimidazoles inhibited 3H-thymidine incorporation in tissues with high cell renewal, with benomyl being more active than carbendazim. They were rapidly absorbed with highest amounts seen in the liver, kidneys and gastro-intestinal lumen as evidenced from distribution of 14C-labeled drugs. In human tumour cell lines, the benzimidazoles showed a similar activity pattern but benomyl was more potent. This was true also in tumour cells from patients but carbendazim was relatively more active against solid tumours. Analyses of drug activity cross-resistance patterns and of drug activity – gene expression correlations in a cell line panel suggested multiple mechanisms of action for the benzimidazoles. Cryptolepine was widely distributed to tissues in vivo in the mice. It was more potent than the benzimidazoles in tumour cells, with highest activity in haematological malignancies but some patient samples of breast, colon and non small-cell lung cancer were sensitive. Cross-resistance analysis indicated cryptolepine to be a topoisomerase II inhibitor whereas drug activity – gene expression correlations suggested additional mechanisms of action. HTS on 2 000 molecules in colon cancer cell lines and normal cells identified acriflavine as a hit molecule, subsequently shown to have unprecedented activity against colorectal cancer tumour cells in patient tumour samples. Connectivity map analysis, based on drug induced gene expression perturbation patterns in a tumour cell line, indicated acriflavine to be a topoisomerase inhibitor, subsequently confirmed in a plasmid relaxation assay. In conclusion, repurposing of drugs and HTS using stringent activity criteria followed by preclinical characterization might contribute to more efficient development of new cancer drugs.
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| 13. |
- Lindman, Henrik, 1963-
(author)
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Individually Tailored Toxicity-based Chemotherapy : Studies on Patients with Primary and Metastatic Breast Cancer
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect.Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases.Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases.In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.
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| 14. |
- Lövborg, Henrik, 1974-
(author)
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Cellular Pharmacology of the Novel Antitumoural Cyanoguanidine CHS 828
- 2004
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Doctoral thesis (other academic/artistic)abstract
- The antitumoural cyanoguanidine CHS 828 has shown promising activity in a number of preclinical and clinical studies. However, the mechanisms underlying the cell death induced by CHS 828 has not been clarified. This thesis describes in vitro studies of the cellular pharmacology of CHS 828.CHS 828 induced cell death with necrosis like features in the lymphoma cell line U-937 GTB. Addition of 3-aminobenzamide, an inhibitor of ADP-ribosylation, resulted in a decreased sensitivity to CHS 828 and a shift in the mode of cell death towards apoptosis. Mouse fibroblasts lacking the enzyme PARP-1 were more sensitive to CHS 828 compared to normal fibroblasts. CHS 828 was able to induce p53 in normal fibroblasts but this effect does not seem to be necessary to induce cell death.Characterization of two CHS 828 resistant cell lines indicated that they were selectively resistant to cyanoguanidines. Known mechanisms of anticancer drug resistance did not seem to account for the cyanoguanidine resistance. One possible resistance mediating protein, which was upregulated in the resistant cells, was epidermal fatty acid binding protein.A novel high content screening assay was also developed. The assay was shown to be suitable both for screening of potential novel antitumoural substances as well for mechanistic studies. In the assay, CHS 828 induced caspase-3 activity and reduction in mitochondrial membrane potential, both signs of apoptosis, in U-937 GTB cells. However, nuclei in exposed cells did not show nuclear fragmentation, one of the hallmarks of apoptosis.CHS 828 was also shown to indirectly inhibit the proteasome activity in U-937 GTB cells. In conclusion, the results presented provide new insights into the metabolic and molecular events involved in cell death induced by CHS 828.
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| 15. |
- Nygren, Christer, et al.
(author)
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Dilemmas in service transformation : a service strategy implementation case
- 2018
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In: The 28th International RESER Conference – Services in the age of contested globalization RESER2018.
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Conference paper (peer-reviewed)abstract
- This paper study a service strategy implementation case using an inductive method to catch informant-centric perspectives and create theory-centric categories leading to the findings of three dilemmas: not really service but only services, waste of potential value and no one owns services. These dilemmas can be used in servitization implementation work from a practical viewpoint and can be of value for the discussion around service strategy implementation within an industrial organisation, working with software development apart from more traditional manufacturing.
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| 16. |
- Rickardson, Linda, 1980-
(author)
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New Methods to Screen for Cancer Drugs and to Evaluate their Mechanism of Action
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Cancer is a common disease and due to problems with resistance against cancer drugs and the limited benefit from chemotherapy in many diagnoses, there is a need to develop new cancer drugs. In this thesis new methods to screen for cancer drugs and to evaluate their mechanism of action are discussed. In Paper I, it was found that by studying the gene expression of a cell line panel and combining the data with sensitivity data of a number of cytotoxic drugs, it was possible to cluster compounds according to mechanism of action as well as identifying genes associated with chemosensitivity. In Paper II, studies of compounds with selective activity in drug-resistant cell lines revealed the glucocorticoids as a group of interesting compounds. The glucocorticoid receptor was overexpressed in 8226/Dox40 and the difference in sensitivity was abolished when the cells were treated with a glucocorticoid receptor antagonist. In Paper III, an image-based screening method for new proteasome inhibitors was successfully developed and the compounds disulfiram, PDTC and NSC 95397 were identified as inhibitors of the proteasome. In Paper IV, disulfiram and PDTC were shown to induce cytotoxic activity, to inhibit the activation of the transcription factor NFkappaB and to inhibit the degradation of proteins normally degraded by the proteasome. In Paper V, NSC 95397 was shown to be cytotoxic to all cells in the resistance-based cell line panel as well as to patient samples from a variety of cancer diagnoses. Connectivity Map was successfully used as a tool to propose a new mechanism of action of NSC 95397. The gene expression induced by NSC 95397-treatment was similar to that induced by several proteasome inhibitors not present in the Connectivity Map.
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| 17. |
- von Heideman, Anne, 1956-
(author)
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Exploring Cancer Drugs In Vitro and In Vivo : With Special Reference to Chemosensitivity Testing and Early Clinical Development
- 2011
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Doctoral thesis (other academic/artistic)abstract
- The aims of this thesis were to investigate the utility of in vitro drug sensitivity testing to optimize the use of cancer chemotherapy and to assess the properties of a new cancer drug in a phase I clinical trial. Tumour cells from patients were analysed with the short-term Fluorometric Microculture Cytotoxicity Assay (FMCA). In samples from a wide spectrum of tumour types, the effect of the drug combination FEC (5Fu-epirubicin-cyclophosphamide) was generally appropriately predicted from the effect of the best component drug. However, of samples intermediately sensitive to the best single drug, 45% converted to sensitive when testing the combination. Thus, combination testing may identify advantageous interactions and improve in vitro test performance. In tumour samples from peritoneal carcinomatosis, significant differences in drug sensitivity between diagnoses were observed, cross-resistance between most drugs was modest or absent, and the concentration-effect relationships for two drugs in individual samples varied considerably. Thus, for optimal selection of drugs for intraperitoneal chemotherapy, differences in drug sensitivity at the diagnosis and individual patient level should be considered. In samples from patients with ovarian carcinoma, drug sensitivity was related to tumour grade, histologic subtype and patient treatment status. In a homogeneous subset of patients, the FMCA predicted individual patient tumour response with high sensitivity and specificity. Thus, if carefully interpreted in the context of important clinical variables, in vitro testing could be of value for individualizing chemotherapy in ovarian cancer. Employing a once weekly dosing schedule in a phase I trial, the mechanistically new and preclinically promising NAD depleting drug CHS 828 produced dose limiting thrombocytopenia and gastrointestinal toxicity without clear evidence of anti-tumour efficacy. It is concluded that in vitro drug sensitivity testing could be a way to optimize the use of chemotherapy and that successful development of new cancer drugs needs improved strategies.
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