| 1. |
- Wennstig, Anna-Karin, 1973-
(författare)
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Long-term side effects of radiotherapy in breast cancer : studies in ischemic heart disease and lung cancer
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer (BC) is the most common cancer in women worldwide. Due to early detection and advances in adjuvant therapies, most women diagnosed with early BC will be cured of their disease, and issues of survivorship are of great importance. Adjuvant radiotherapy (RT) in BC is well established and significantly reduces local recurrences and BC mortality. Still, it usually involves some accidental irradiation to the heart and lungs, which may lead to long-term side effects, mainly ischemic heart disease (IHD) and lung cancer (LC). The overall aim with this thesis was to study IHD and radiation-induced LC in women receiving RT for BC from the early 1990s until recently.In paper I and paper II a cohort of women (n=182) receiving computed tomography (CT)-based RT (3DCRT) for BC during 1992 to 2012, who subsequently were referred to a coronary angiography and treated for coronary stenosis, was studied. Paper I was a reproducibility study with the aim to examine the inter-observer variation in delineation of the coronary arteries (CAs) in CT scans used for 3DCRT planning. All patients treated at one of the participating RT departments (n=32), were selected from the larger cohort, and the CAs were delineated in the patients’ CT-scans by three oncologists independently, with a validated CT-based heart atlas as guideline. Spatial difference between the different delineations, and variance in radiation dose was calculated. The median distance between the centers of the arteries was 2-8 mm for the right coronary artery (RCA), and 1-4 mm for the left main coronary artery (LMCA) and the left anterior descending artery (LAD). The intraclass correlation coefficient (ICC) was derived to quantify the variance in estimated doses. The ICC for mean doses varied from 0.76 to 0.98 for LMCA-LAD, and from 0.73 to 0.92 for RCA, indicating that variation in radiation doses was mainly due to interpatient variation. In conclusion, the study showed high consistency in contouring the CAs in the patients’ planning CTs, in particular the LMCA-LAD. In paper II, the aim was to examine the relationship between radiation dose to the CAs and subsequent coronary stenosis that required a coronary intervention at this location. The CAs were delineated and divided into segments in the 182 patients’ planning-CTs and doses were recalculated based on the dose distribution of the original RT plans. The location of the CA stenosis was identified from the Swedish Coronary Angiography and Angioplasty Register (SCAAR). Mean doses to the heart and the LAD were substantially higher in women receiving left-sided RT compared to right-sided RT. Segment-wise analyses were performed to assess the risk of developing a coronary stenosis that required an intervention at a certain radiation dose. Segments receiving radiation doses < 1 Gray (Gy) were used as reference. The main finding was a five-fold increase in risk of a clinically relevant coronary stenosis in the mid LAD at mean doses over 20 Gy, compared to doses of 0-1 Gy (odds ratio 5.23; 95 % CI (confidence interval) 2.01-13.6). There were iv too few events to calculate increase in risk per Gy. Still, the result of this study supports that the radiation dose to the LAD should be considered at RT planning and kept as low as possible.In paper III and IV, the BcBaSe cohort was used to examine risk of IHD, and radiation-induced LC after adjuvant RT for BC. The BCBaSe consists of 68089 women diagnosed with BC during 1992 to 2012, and 340352 age-matched women without BC diagnosis. In paper III, Cox regression analyses were performed to estimate risk of IHD, by comparing women with BC to women without BC diagnosis, and by comparing left-sided BC to right-sided BC. Kaplan-Meier analysis was performed to assess cumulative incidence of IHD. Women with BC had a lower risk of IHD compared to women without BC diagnosis at follow-up (hazard ratio (HR) 0.91; 95 % CI 0.88-0.95). Women irradiated for left-sided BC had a higher risk of IHD compared to women irradiated for right-sided BC (HR 1.18; 95 % CI 1.06-1.31). The HRs increased with more extensive lymph node involvement and with addition of systemic therapy. The cumulative IHD incidence was increased in women receiving left-sided RT compared to rightsided RT, starting from the first years after RT and sustained with longer followup. In paper IV, Kaplan-Meier analyses were performed to assess cumulative incidence of LC and LC-specific survival. Cox regression analyses were performed to estimate risk of LC after adjuvant RT for BC, comparing women with BC to women without BC diagnosis. Women with BC receiving RT had a higher cumulative incidence of LC compared both to women with BC not receiving RT and women without BC. This became apparent 5 years after RT and increased with longer follow-up. Women with BC receiving RT had a higher risk of LC compared to women without BC diagnosis (HR 2.35; 95 % CI 1.54-3.59). LCspecific survival was significantly higher in women with a prior BC compared to women without a prior BC diagnosis. In paper III and paper IV information on individual dosimetry data was not available. Most women likely received 3DCRT given with tangential fields and were treated before breathing adaption techniques were implemented in Sweden. The results of these studies emphasize the importance of further development and implementing of RT techniques and regimens that lower the cardiac and lung doses.In conclusion, we found that radiation doses to the LAD remained high in women receiving 3DCRT for BC between 1992 and 2012, and were associated with an increased risk of clinically relevant CA stenosis. Delineating the LAD was feasible and the results of these studies support that the LAD radiation dose should be considered in RT treatment planning. The register-based studies confirmed that the risk of IHD was significantly increased in women receiving left-sided RT and that the risk of LC after BC RT was significantly increased in this large cohort of women with BC.
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| 2. |
- Blomqvist, Carl Oliver, 1984-
(författare)
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Flerspråkighet eller språkförbistring? : Finska segment i svenska medeltidsbrev 1350–1526
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis examines fragmentary Finnish in Late Old Swedish charters (c. 1350–1526) issued in the Finnish part of the Swedish realm, the diocese of Åbo. Consisting mostly of proper names, albeit occasionally displaying Finnish inflectional and derivational morphology, these fragments have previously not generally been regarded as representing actual written Finnish, but rather as onomastic loans or transcriptions of oral language by more or less monolingual Swedish scribes. This thesis attempts a description and analysis of the Swedish–Finnish language mixture, to see to what extent the embedding of Finnish segments in these Swedish-language charters can be said to reflect scribal proficiency in Finnish or a lack thereof.The thesis relies on theoretical and empirical findings in the fields of code-switching and historical sociolinguistics. To provide a socio-historical context for the linguistic analysis, sociolinguistic conditions in medieval Finland and the textual genre of medieval charters are outlined. The bilingual segments in the data are then described and compared with models of code-switching from modern studies, to see whether their form corresponds to patterns that could be expected of more or less balanced bilinguals. The choice between Swedish and Finnish linguistic variants is also considered in the light of textual and sociolinguistic factors, and a study is made of Finnish grammatical transfer in the scribal Swedish of medieval Finland.Although the scarcity of the medieval data does not allow definite conclusions, the tentative results reveal a language mixture that is mainly well formed, though limited in scope and with some instances of scribal errors that could be due to a lack of proficiency in Finnish. On the other hand, the insertion of Finnish segments shows a stylistic patterning that suggests a linguistic awareness on the part of the scribes, and the choice of Swedish prepositions in certain constructions differs quantitatively from the norm in non-Finnish parts of medieval Sweden, in a way that can partly be attributed to the influence of Finnish locative case semantics. While it is apparent that proficiency levels in Finnish must have varied somewhat among medieval scribes in Finland, the results point to a more or less bilingual proficiency, or at least extensive passive knowledge of Finnish.
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| 3. |
- Ahlin, Cecilia, 1966-
(författare)
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Cyclin A and cyclin E as prognostic factors in early breast cancer
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is one of the most common malignancies in women. Due to early detection and the use of screening programs approximately 60% of all new cases lack lymph node involvement. Today, a substantial proportion of these women will be offered adjuvant systemic chemotherapy. However, better proliferation markers are needed to predict patient outcome and to avoid overtreatment. Cyclin A, cyclin E and Ki-67 are all markers for proliferation and involved in the regulation of the cell cycle. Overexpression has been associated with disease recurrence in several studies, but the results have not been consistent. However, none of these studies has investigated aberrant expression of cyclin E (the expression of cyclin E during phases of the cell cycle other than late G1 and early S-phase). Studies have shown that aberrant cyclin E might provide additional prognostic information compared to cyclin E alone.The aims of this thesis were 1.to investigate the prognostic value of cyclin A, cyclin E and aberrant cyclin E in early breast cancer. 2.to validate the tissue microarray (TMA) technique for cyclin A and 3.to define the most optimal cut-off values for cyclin A and Ki-67.We found that the agreement of TMA and large section results was good with kappa values 0.62-0.75 and that the reproducibility of the two readers’ results was good or even very good, with kappa values 0.71 – 0.87. The optimal cut-off value for cyclin A average was 8% and for cyclin A maximum value 11%. The corresponding values for Ki-67 were 15 and 22%. Neither cyclin E nor aberrant cyclin E was a prognostic factor in low-risk node negative breast cancer patients. Finally, we conclude that cyclin A is a prognostic factor in node negative breast cancer (univariate analysis average value OR=2.9 95% CI 1.8-4.6; maximum value OR=3.7 95% CI 2.3-5.9).
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| 4. |
- Lindman, Henrik, 1963-
(författare)
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Individually Tailored Toxicity-based Chemotherapy : Studies on Patients with Primary and Metastatic Breast Cancer
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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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| 5. |
- Monazzam, Azita, 1971-
(författare)
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Multicellular Tumour Spheroids in a Translational PET Imaging Strategy
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Positron Emission Tomography (PET) has gained an important roll in clinical for diagnosis, staging and prognosis of a range of cancer types. Utilization of PET for monitoring and evaluation of cancer treatment is an attractive but almost new concept. The proper choice of PET-tracer as a biomarker for treatment follow-up is crucial. The important characteristic for a suitable tracer is its ability to reflect the response to a treatment at an early stage, before any morphologically changes occurs. It would be an advantage to screen a battery of PET tracers in a preclinical model and introduce a few potential tracers in clinical trial.The most conventional pre-clinical approach in PET-oncology utilizes xenografts in mice or rats and requires a large number of subjects. It would be a great advantage to introduce a less demanding but still reliable preclinical method for a more efficient planning of studies in animal model and then in human trials.The Multicellular Tumour Spheroid (MTS) system represents an intermediary level between cells growing as monolayer and solid tumours in experimental animals or patients. It mimics the growth of naturally occurring human tumours before neovascularization and appears to be more informative than monolayer and more economical and more ethical than animal models.The aim of this work was to establish, refine and evaluate the application of MTS model as a preclinical approach in PET oncology. The vision was to introduce a preclinical method to probe and select PET tracer for treatment monitoring of anticancer drugs, which can hopefully be applied for optimization in breast cancer treatment.In this thesis, a number of basic experiments were performed to explore the character of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) uptake in MTS. FDG as the most established PET tracer was an obvious initial option for the evaluation of the model. For further assess-ment, we studied effects on FDG uptake in MTS treated with five routinely used chemother-apy agents. For association of PET tracer uptake to size change of MTS, we developed a reliable and user-friendly method for size determination of MTS. The next step was to apply the MTS model to screen PET tracers for analysis of early response of chemotherapy in breast cancer. Finally the method was utilized for translational imaging exemplified with a new chemotherapy agent.The results were encouraging and the MTS model was introduced and evaluated as a preclini-cal tool in PET oncology. The method was implicated to in vitro quickly assess a therapy profile of existing and newly developed anticancer drugs in order to investigate the effects of candidate drugs on tumour-growth, selection of appropriate PET tracer for treatment monitor-ing and finally understanding relation between growth inhibition and biomarkers as part of translational imaging activities.
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| 6. |
- Zhou, Wenjing, 1979-
(författare)
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Aspects of Progression in Breast Carcinoma : from ductal carcinoma in situ to invasive cancer
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown.In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes.In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade.In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence.In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.
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