| 1. |
- Bäcklund, Magnus
(författare)
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The epidemiology, biology and genetics of human astrocytic tumours
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden > 1000 primary central nervous system (CNS) tumours are diagnosed each year. The majority are malignant and in adults astrocytic gliomas dominate. These are classified into four malignancy grades according to WHO criteria, including Glioblastoma (GB), which is the most common and most malignant of all CNS tumours (malignancy grade IV), Anaplastic Astrocytoma (AA; malignancy grade Ill) and Astrocytoma (All; malignancy grade II). Prognosis is generally poor but varies markedly between the malignancy grades and even between individuals with the same malignancy grade. While numerous studies have addressed the issue of genetic prognostic markers in astrocytic tumours, little of clinical value has been established despite all the genetic information accumulated during the last two decades. From 1987 to 1997 we collected >700 primary CNS tumours for molecular genetic analysis and the patients were followed-up clinically regarding age, sex, date of death and therapy received. We also collected blood samples from the patients, making it possible to pair-wise compare tumour DNA with normal DNA. The number of astrocytic glioma patients included in Paper I-III was 246 (172 GB, 54 AA and 20 All). The data was used for correlation analysis with the primary endpoint to identify associations between gene abnormalities and patient survival. We analyzed 129 GB and 37 AA for loss of six tumour suppressor genes (PTEN, RB1, CDKN2A, CDKN2B, p 14ARF and TP53) and amplification of three proto-oncogenes (CDK4, MDM2, and EGFR). These are the most commonly altered genes in astrocytic tumours. We found that abnormalities in any of the four genes coding for components of the Rb1 pathway (i.e. CDKN2A, CDKN2B, RB1 and CDK4), were associated with shorter survival (p=0.002) in GB. In combination with loss of wild-type PTEN the association was even stronger (p<0.001). The survival difference (median survival in the two groups was 166 days compared to 437 days) was statistically significant in bivariate analysis adjusting for age (p=0.012). In AA we found that defects in any of the four Rb1 pathway-related genes were significantly associated with short survival (median survival 1.7 years compared to 9.9 years) in univariate (p=0.009) and multivariate analysis (p=0.013). The Epidermal Growth Factor Receptor (EGFR) gene is frequently amplified and/or rearranged in astrocytic tumours, particularly in "primary" GB. The reported results on the prognostic impact of this have so far been contradictory and few reports have correlated both amplification and rearrangements with survival. We analyzed 221 astrocytic tumours for the presence of EGFR amplification and expression of the aberrant EGFRvIII transcript. In 160 "primary" GB patients we found no significant associations between EGFR abnormalities and survival. In 41 AA we found a tendency towards shorter survival in patients with tumours expressing the EGFRvIII transcript (p=0.069). These patients were significantly older than those with no EGFRvIII present (p=0.023). As the aetiology of benign and malignant CNS tumours is largely unknown we performed an epidemiological study exploring if an association between CNS tumours and parathyroid adenomas exists (Paper IV). Known hereditary factors explain only a few percent of the incidence, as do the best characterized exogenous factors. We used the Swedish Cancer Registry (SCR) to identify all individuals operated for parathyroid adenomas between 1958 and 1999 (n=12,468) and using the SCR they were followed-up for the subsequent development of CNS tumours. There were 70 such cases observed. Compared to the 35 expected, the standard incidence ratio (SIR) was 2.0. This increased risk was independent of duration of follow-up and was confined to meningiomas (SIR=2.4), the most common type of benign tumour of the CNS, and neurinomas (SIR=3.4). For astrocytic tumours, after excluding the first year, the observed number was close to the expected (SIR=0.8). With the studies included in this thesis, and the conclusions drawn, I hope to add something to the understanding of what causes CNS tumours as well as what dictates their prognosis.
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| 2. |
- Eklund, Magnus, 1976-
(författare)
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Adoption of the Innovation System Concept in Sweden
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In 2001 Sweden founded the government agency of VINNOVA, named after the OECD-endorsed innovation system concept. Criticising the common assumption that countries are passive and uncritical recipients of the approaches promoted by the OECD, this dissertation tries to show that Swedish actors were in fact very active and strategic as they contributed to the national adoption of the concept. With inspiration from conceptual history and Quentin Skinner’s analysis of the rhetorical use of concepts, this study focuses on the research funding reform process between 1995 and 2001, investigating how actors trying to defend the contested institution of sectoral research used the innovation system concept to rhetorically legitimise their project. To compare these uses with earlier ways of discussing innovation in Sweden, the innovation debate that arose in relation to the industrial crises of the 1970s and 1990s has also been studied. It was found that the early Swedish innovation debate had paid little attention to the university sector. When Research 2000 in 1998 proposed that researcher-dominated research councils should be given control over sectoral research funding, a coalition in favour of industrially relevant research mobilised to protect its influence over research funding. The concept was now appropriated and used to rhetorically reframe the universities as part of a system with the main function of promoting innovations. By using the concept it was also possible to draw on the legitimacy offered by the OECD and science.
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| 3. |
- Eriksson, Mikael, et al.
(författare)
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Low-Dose Tamoxifen for Mammographic Density Reduction : A Randomized Controlled Trial
- 2021
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 39:17, s. 1899-
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms.PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis.RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.
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| 4. |
- Funke, Michael, 1966-
(författare)
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Regulating a Controversy : Inside Stakeholder Strategies and Regime Transition in the Self-Regulation of Swedish Advertising 1950–1971
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns the development of the self-regulation of advertising in Sweden from 1950 until 1971. Self-regulation was initiated in the 1930s due to a business desire to regulate fair competition in marketing, and while it initially was a minor operation, the 1950s and 1960s were characterized by extensive development. When self-regulation was overtaken by state policies in 1971, it included several interlocking systems, of which parts survived the introduction of the state regime. The thesis’ aim has been to analyze how the rapid regime transitions in the self-regulation regime can be understood.The existing literature identifies four major transitions that occurred during the studied time period. To understand them, the thesis has studied the policy processes leading up to these transitions. Focus has been on the business interest organizations that controlled the regime and their regulatory strategies. Theoretically, the analysis has departed from the hypothesis that tensions between these organizations, due to their members’ different market interests and varying levels of exposure to regulation and public badwill, to a significant degree informed their strategic choices as well as policy outcomes.The results show that the policy processes preceding the regime transitions were characterized by internal tensions, whereby organizations representing advertisers, and to a lesser degree media carriers, due to their members’ higher level of exposure to regulation and public badwill, successfully supported stronger market policing, while ad agencies, being less exposed, as well as a peak industry organization for the proliferation of marketing largely opposed such measures, preferring a more lenient regulation. However, due to increased exposure to regulation and bad will, the ad agencies finally abandoned their opposition and took the lead in regulatory innovation through the introduction of an extensive clearance program that survived the launch of the state regime, becoming a key component in the co-regulatory structure that followed.
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| 5. |
- Gabrielson, Marike, et al.
(författare)
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Effects of tamoxifen on normal breast tissue histological composition : Results from a randomised six-arm placebo-controlled trial in healthy women
- 2023
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 152:11, s. 2362-2372
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Tidskriftsartikel (refereegranskat)abstract
- Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.
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| 6. |
- Hammarström, Mattias, et al.
(författare)
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Side effects of low-dose tamoxifen : results from a six-armed randomised controlled trial in healthy women
- 2023
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Ingår i: British Journal of Cancer. - 0007-0920 .- 1532-1827. ; 129:1, s. 61-71
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Tidskriftsartikel (refereegranskat)abstract
- Background: Adherence to adjuvant tamoxifen therapy is suboptimal, and acceptance of tamoxifen for primary prevention is poor. Published results indicate effect of low-dose tamoxifen therapy. Using questionnaire data from a randomised controlled trial, we describe side effects of standard and low-dose tamoxifen in healthy women. Methods: In the KARISMA trial, 1440 healthy women were randomised to 6 months of daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. Participants completed a 48-item, five-graded Likert score symptom questionnaire at baseline and follow-up. Linear regression models were used to identify significant changes in severity levels across doses and by menopausal status. Results: Out of 48 predefined symptoms, five were associated with tamoxifen exposure (hot flashes, night sweats, cold sweats, vaginal discharge and muscle cramps). When comparing these side effects in premenopausal women randomised to low doses (2.5, 5 mg) versus high doses (10, 20 mg), the mean change was 34% lower in the low-dose group. No dose-dependent difference was seen in postmenopausal women. Conclusions: Symptoms related to tamoxifen therapy are influenced by menopausal status. Low-dose tamoxifen, in contrast to high-dose, was associated with less pronounced side effects, a finding restricted to premenopausal women. Our findings give new insights which may influence future dosing strategies of tamoxifen in both the adjuvant and preventive settings. Trial registration: ClinicalTrials.gov ID: NCT03346200.
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| 7. |
- Henriksson, Tommy, 1978-
(författare)
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CONTRIBUTION TO QUANTITATIVE MICROWAVE IMAGING TECHNIQUES FOR BIOMEDICAL APPLICATIONS
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation presents a contribution to quantitative microwave imaging for breast tumor detection. The study made in the frame of a joint supervision Ph.D. thesis between University Paris-SUD 11 (France) and Mälardalen University (Sweden), has been conducted through two experimental microwave imaging setups, the existing 2.45 GHz planar camera (France) and the multi-frequency flexible robotic system, (Sweden), under development. In this context a 2D scalar flexible numerical tool based on a Newton-Kantorovich (NK) scheme, has been developed. Quantitative microwave imaging is a three dimensional vectorial nonlinear inverse scattering problem, where the complex permittivity of an object is reconstructed from the measured scattered field, produced by the object. The NK scheme is used in order to deal with the nonlinearity and the ill-posed nature of this problem. A TM polarization and a two dimensional medium configuration have been considered in order to avoid its vectorial aspect. The solution is found iteratively by minimizing the square norm of the error with respect to the scattered field data. Consequently, the convergence of such iterative process requires, at least two conditions. First, an efficient calibration of the experimental system has to be associated to the minimization of model errors. Second, the mean square difference of the scattered field introduced by the presence of the tumor has to be large enough, according to the sensitivity of the imaging system. The existing planar camera associated to a flexible 2D scalar NK code, are considered as an experimental platform for quantitative breast imaging. A preliminary numerical study shows that the multi-view planar system is quite efficient for realistic breast tumor phantoms, according to its characteristics (frequency, planar geometry and water as a coupling medium), as long as realistic noisy data are considered. Furthermore, a multi-incidence planar system, more appropriate in term of antenna-array arrangement, is proposed and its concept is numerically validated. On the other hand, an experimental work which includes a new fluid-mixture for the realization of a narrow band cylindrical breast phantom, a deep investigation in the calibration process and model error minimization, is presented. This conducts to the first quantitative reconstruction of a realistic breast phantom by using multi-view data from the planar camera. Next, both the qualitative and quantitative reconstruction of 3D inclusions into the cylindrical breast phantom, by using data from all the retina, are shown and discussed. Finally, the extended work towards the flexible robotic system is presented.
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| 8. |
- Petersson, Gustav Jakob, 1981-
(författare)
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Swedish marine insurance between the World Wars
- 2010
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present licentiate thesis analyses developments in Swedish marine insurance during the interwar period, including both direct marine insurance and marine reinsurance. This is done in order to provide insights on how companies of a highly internationalised and vulnerable line of insurance were affected by and responded to new risks during a period of far-reaching international financial and economic crises. Finally, the consequences of new risks and strategies are assessed. This thesis argues that during the interwar period Swedish maritime trade and Swedish marine insurance greatly depended on each other for marine insurance cover and marine insurance premium incomes. The business results in Swedish marine insurance partly depended on the development of Swedish trade. These business results were also vulnerable to currency risks. Swedish marine insurers faced no similar trade or currency risks during the two decades preceding World War I, and accordingly the returns on Swedish marine insurance were lower during the interwar period than during the last two pre-war decades. These factors probably bore their most severe consequences during the early 1920s when Swedish marine insurance on average induced losses to insurers. The remaining years of the period constituted a long-run recovery, and the Great Depression of the early 1930s caused no difficulties of the same order. This thesis also indicates that interwar Swedish marine insurers responded to new risks by increasing the level of cession to reinsurers. Another response was to increase the level of differentiation among insurance lines. This thesis describes the consequences of new risks and strategies in interwar Swedish marine insurance, focusing on the development of the Swedish marine insurance market structure and on the business results of Swedish marine insurers. Though this market shrunk and grew excessively, the relative importance of stock and mutual insurers showed only minor fluctuations. The importance of specialised marine reinsurance companies, however, fluctuated greatly. Also, cooperation between interwar marine insurers and the formation of insurance groups set new trends of concentration for the future. Finally, even though Swedish marine insurance during some years induced losses the Swedish marine insurers never experienced true losses on their total businesses.
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