| 1. |
|
|
| 2. |
- Munthe, Christian, 1962
(författare)
-
The magic word? Ethical experience of prioritizing cancer-related health action in a Swedish context
- 2018
-
Ingår i: What is so Special about Cancer? Perspectives from Clinical Research, Philosophy and Social Sciences, University of Cambridge, April 5-6, 2018.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Across health systems and the history of modern welfare societies, the experience of cancer as a privileged diagnostic category in the prioritizing of resources for different health actions is commonplace, although there are notable exceptions to be found in low resource settings. While this situation can often be criticised from an ethical standpoint, health resource allocation also has a political pragmatic side that may, if not justify, so at least partly excuse the way in which measures related to cancer are being given privileged access to healthcare and public health resources. This since democratically elected political representatives cannot completely ignore the iconic status of cancer in the public mind. I describe some of this dynamic based on the Swedish experience of introducing screening and testing programs, as well as new drugs for cancer treatment. While Sweden is certainly not immune to the privileged standing of cancer in health resource allocation, there is a development in public and popular attitude towards a more egalitarian conception of cancer disease compared to other diseases. Parts that explain this development have to do with a new and more systematic focus on assessing the effectiveness of and evidence for suggested health actions according to generic models, such as HTA, standardised rules how priority setting arguments must be shaped in order to have political validity, and a broader awareness of the phenomenon of opportunity cost in policy making generally. In addition, political agendas increasingly focused on cost cutting in public expenditure in spite of ever greater levels of societal wealth has certainly also contributed, albeit that mechanism may probably also be properly criticised from an ethical standpoint.
|
|
| 3. |
- Mayrhofer, Markus, 1981-
(författare)
-
Copy Number Analysis of Cancer
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- By accurately describing cancer genomes, we may link genomic mutations to phenotypic effects and eventually treat cancer patients based on the molecular cause of their disease, rather than generalizing treatment based on cell morphology or tissue of origin.Alteration of DNA copy number is a driving mutational process in the formation and progression of cancer. Deletions and amplifications of specific chromosomal regions are important for cancer diagnosis and prognosis, and copy number analysis has become standard practice for many clinicians and researchers. In this thesis we describe the development of two computational methods, TAPS and Patchwork, for analysis of genome-wide absolute allele-specific copy number per cell in tumour samples. TAPS is used with SNP microarray data and Patchwork with whole genome sequencing data. Both are suitable for unknown average ploidy of the tumour cells, are robust to admixture of genetically normal cells, and may be used to detect genetic heterogeneity in the tumour cell population. We also present two studies where TAPS was used to find copy number alterations associated with risk of recurrence after surgery, in ovarian cancer and colon cancer. We discuss the potential of such prognostic markers and the use of allele-specific copy number analysis in research and diagnostics.
|
|
| 4. |
- Malmström, Annika, 1957-
(författare)
-
Studies for Better Treatment of Patients with Glioma
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older.The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally.The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated).The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed by SRT to patients randomized to neoadjuvant treatment and was compared to postoperative SRT alone. Although this trial could not illustrate any advantage of delaying the start of SRT while administering TMZ for the study cohort in general, for those included as astrocytoma grade III the median survival was found to be superior by 5 years when randomized to neoadjuvant TMZ. This trial also confirmed the importance of MGMT promoter methylation for the efficacy of TMZ.The third study (paper III) investigated international practices for analyzing tumor MGMT promoter methylation status. MGMT analysis can be conducted by various laboratory methods, which in some cases can provide opposing results regarding the MGMT methylation status of the patient´s tumor. This can lead to incorrect treatment recommendations. To establish which methods and cut-offs that are regularly used to determine tumor MGMT status in the clinic, an international survey was provided to those working in the field. We also inquired about opinions regarding an international consensus on how MGMT should be tested. The 152 respondents reported several methodologies and different cut-off levels also for the same method. A majority of respondents warrant international guidelines.In conclusion, the results of the 2 randomized trials contribute to individualized treatment recommendations for patients affected by GBM or astrocytoma grade III. The results of the survey regarding analyses of MGMT clarify the current problematic situation. The request of the respondents regarding international guidelines might contribute to their future development, so that personalized treatment recommendations can be improved.
|
|
| 5. |
|
|
| 6. |
- Senkowski, Wojciech
(författare)
-
High-throughput screening using multicellular tumor spheroids to reveal and exploit tumor-specific vulnerabilities
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
|
|
| 7. |
- Ulfenborg, Benjamin, 1985-
(författare)
-
Bioinformatics tools for discovery and evaluation of biomarkers : Applications in clinical assessment of cancer
- 2016
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a disease characterized by abnormal proliferation of cells in the body and ranks as the second leading cause of death worldwide. In order to improve cancer patient care, a major focus of cancer research is to discover biomarkers. A biomarker is a biological molecule found in tissues or body fluids and can be used to predict or assess disease states. The aim of this thesis is to develop bioinformatics tools for discovery and evaluation of novel biomarkers from high-throughput datasets.MicroRNAs (miRNAs) are short non-coding RNAs that function as negative regulators of gene expression. Dysregulation of miRNAs in cancer is frequently reported, making them interesting as biomarker candidates. GenoScan was developed for genome-wide discovery of miRNA-coding genes, as a first step in the identification of novel mi-RNA biomarkers.High-throughput technologies such as microarrays allow researchers to measure the expression of thousands of genes or miRNAs simultaneously. The Decision Trunk Classifier (DTC) algorithm has been developed to screen datasets from these experiments for biomarker candidates. When applied to a miRNA expression dataset for endometrial cancer (EC) samples vs. controls, a two-marker model with 98 % accuracy was generated. These miRNAs (hsa-miR-183-5p and hsa-miRPlus-C1070) are promising as biomarkers for EC screening.The miREC database was developed to store gene and miRNA data from curated expression profiling studies of EC, as well as gene-miRNA regulatory connections. Using gene-miRNA interaction networks from miREC, the roles of miRNAs in cancer hallmark acquisition can be clarified. To further support exploratory analysis of expression data, DTC was extended with partial least squares regression models. The resulting PLS-DTC algorithm can be used to gain deeper insights into the perturbation of biological processes and pathways.
|
|
| 8. |
- Forsell, Karl, 1975-
(författare)
-
Health hazards and cancer in relation to occupational exposures among Swedish seafarers
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis explores health hazards for seafarers in the Swedish merchant fleet, and occupational risks for lung cancer, mesothelioma and hematologic malignancy (HM). A special focus has been exposure to benzene and biomarker levels for work on product or chemical tankers during the mid-1990’ies.In a case report, we describe two cases of mesothelioma and two cases of lung cancer having worked in the engine room. Cumulative exposure to asbestos were up to 5 fibreyears. Other exposures were carcinogenic PAHs and nitroarenes. A web-based survey to active seafarers in the Swedish merchant fleet revealed noise, the risk of accidents, whole-body vibrations and ergonomic strain as main work environment problems. General health, work ability and safety climate were all rated high. Associations were found between lower airway symptoms and soot (PR 2.4, 95% CI 1.1-5.1) and between hearing impairment and noise exposure (PR 1.5; 95% CI 1.3–1.7). Iso-strain was especially common in the service department. Twenty-two percent of men and 45% of women had been subjected to harassments. The tanker study showed a geometric mean for benzene exposure of 0.45 mg/m3 (4hTWA) during a work shift, with a wide range (0.02-143 mg/m3). Correlations were found between exposure and benzene in alveolar air (p<0.0001), unmetabolised benzene in urine (p<0.0001) and ttMA in urine (p=0.0011). All biomarkers increased significantly during work (p<0.002). In a case-referent study with the observation period 1985 to 2014, the OR for HM was 1.32 (95% CI 0.86-2.02) if work on tankers had started before 1985 and with a cumulated tanker service of at least five years. If work on tankers had started after 1985, the OR was 0.85 (95% CI 0.51-1.43).In conclusion, health hazards in today’s seafaring relate to physical, chemical and psychosocial factors. Work on tankers with mixed open and closed cargo systems might have led to important benzene up-take. Possibly, the risk for HM for seafarers on tankers has decreased during the last decades.
|
|
| 9. |
- Johansson, Patrik
(författare)
-
Large scale integration and interactive exploration of cancer data – with applications to glioblastoma
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma is the most common malignant brain tumor, with a median survival of approximately 15 months. The standard of care treatment consists of surgical resection followed by radiotherapy and chemotherapy, where chemotherapy only prolongs survival by approximately 3 months. There is therefore an urgent need for new approaches to better understand the molecular vulnerabilities of glioblastoma. To this end, we have conducted four interdisciplinary studies.In study 1 we develop a method for efficiently constructing and exploring large integrative network models that include multiple cohorts and multiple types of molecular data. We apply this method to 8 cancers from The Cancer Genome Atlas (TCGA) and make the integrative network available for exploration and visualization through a custom web interface.In study 2 we establish a biobank of 48 patient derived glioblastoma cell cultures called the Human Glioma Cell Culture (HGCC) resource. We show that the HGCC cell cultures represent all transcriptional subtypes, carry genomic aberrations typical of glioblastoma, and initiate tumors in vivo. The HGCC is an open resource for translational glioblastoma research, made available through hgcc.se.In study 3 we extend the analysis of HGCC cell cultures both in terms of number (to over 100) and in terms of data types (adding mutation, methylation and drug response data). Large-scale drug profiling starting from over 1500 compounds identified two distinct groups of cell cultures defined by vulnerability to proteasome inhibition, p53/p21 activity, stemness and protein turnover. By applying machine learning methods to the combined drug profiling and matched genomics data we construct a first network of predictive biomarkers.In study 4 we use the methods developed in study 1 applied to the data generated in studies 2 and 3 to construct an integrative network model of HGCC and glioblastoma data from TCGA. We present an interactive method for exploring this network based on searching for network patterns representing specific hypotheses defined by the user.In conclusion, this thesis combines the development of integrative models with applications to novel data relevant for translational glioblastoma research. This work highlights several potentially therapeutically relevant aspects, and paves a path towards more comprehensive and informative models of glioblastoma.
|
|
| 10. |
- Aljabery, Firas
(författare)
-
Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
|
|
