| 1. |
- Carlsson, Maria, 1958-
(författare)
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Informational support for patients with gynaecological cancer and their families
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main purpose of the present thesis was to gain a deeper knowledge and understanding of the informational need by women with gynaecological cancer and their families. The studies evaluate the experience of different kind of information giving; a telephone-help line; a 3 years educational group support programme; and information givings in ordinary care.There was a significant correlation to interest in an educational supportive group in the prestudy depending on age, legal status, educational level. Younger individuals, couples and people with a higher formal education were generally more interesting in participating (p<0.05). Patients who actively chose to participate m a an educational support group differed from the unselected control group even prior the intervention, they with a higher formal education were generally more interesting in participating, they felt more confused and angry than the control group. After intervention, the patients in the interventional group reported a significant improved level of knowledge about cancer.Both patients and next-of-kin request information about medical- and psychological aspects of the disease and its treatment. The evaluation of the questions in the educational supportive group show that patients and their relatives asked questions of a general nature, related to basic knowledge of cancer and treatment principles, and not directly related to their own illness. There was no general difference in knowledge level between cancer patients and the controls of healthy women. The length of formal education was the most important determinator of correct answers (p<0.01).Two main themes were revealed at the interviews about the patients informations preferences. These were to actively address questions and the right to receive honest information;It is concluded that differential information giving techniques are required to satisfy the patients' different preferences. The patients express an active role in the information giving process. They preferred information with numerous opportunities to address questions, that the staff have time for questions and that the questions are honestly answered.
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| 2. |
- Jernström, Helena
(författare)
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Effects of Oral Contraceptives on Endogenous Hormones, Body Constitution, and Breast Epithelium in Healthy, Young Women
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns the effects of low-dose oral contraceptives (OCs) on endogenous hormones, insulin-like growth-factor-1 (IGF-1), sexual hormone binding globulin (SHBG), and body constitution in two groups of healthy women aged 1925 who had never been pregnant. Prolactin concentrations were elevated in a subgroup of present and former users. IGF-1 concentrations were significantly decreased during menstrual cycle days 1823 in present OC users compared with never users, while no effect was seen during cycle days 510. Former users had significantly higher follicle-stimulating hormone (FSH) concentrations than never users. This rebound-like phenomenon peaked one year after cessation of use. High FSH concentrations could increase the number of ovulations and thereby the ovarian cancer risk, especially among intermittent users who may experience repeated rebound peaks. Among present and former users SHBG concentrations were significantly correlated with reported weight gain in connection with OC start. SHBG was not related to the same hormonal and constitutional parameters in former users as in never users. Breast size was significantly larger in present users than in former and never users, and approximately half of the ever users reported breast tenderness or enlargement in connection with OC start. Breast epithelial proliferation rate was studied by means of a new monoclonal antibody, Ki-S5, in 58 women who had undergone reduction mammoplasties and who were born 1940 or later. There was no significant difference in breast tissue proliferation between present, former and never users. Women who had used OCs before the first full-term pregnancy had a significantly higher proliferation rate in the breast tissue than other women, regardless of present OC status. Women who used exogenous hormones and who had a first and/or second degree relative relative with breast cancer had a significantly higher proliferation rate in the breast tissue than other women. A high proliferation rate may increase the risk of developing breast cancer.
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| 3. |
- Johansson, Maria C
(författare)
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Improvements of the Bromodeoxyuridine-DNA Flow Cytometry Method for the Study of Cell Proliferation
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Potential doubling time (Tpot), DNA synthesis time (TS), and labelling index (LI) are fundamental growth kinetics parameters in clinical and experimental cancer research, which may be of further practical importance regarding prognosis and treatment prediction of cancer. They can be measured by bromodeoxyuridine(BrdUrd)/flow cytometry (FCM) methods, where BrdUrd, an analogue of thymidine, is incorporated into DNA and quantified simultaneously with the DNA content. However, this method requires improvements. Since in many applications only a single sample is available, the method must be reproducible, accurate, and independent of the time of sample collection in relation to BrdUrd pulse-labelling. With the modifications we describe, growth kinetic data could be obtained in response to the demands, both in vitro and in vivo and they were in agreement with those obtained with the [3H]thymidine/autoradiography method. Thus, the BrdUrd/FCM method can replace traditional [3H]thymidine-based methods. The modifications included new mathematic formulas for the calculation of LI and TS. They were compared with various other formulas, in several cell lines and experimental tumours. Our formulas did show sampling time independence in several cell lines studied. The labelling time should be kept as short as possible. The proposed TS formula is used preferable in more slowly growing cell populations. Tpot values based on our formulas did not depend on sampling time. In conclusion, with our modified BrdUrd/FCM method for growth kinetic studies, experimentally and/or clinically, it is possible to obtain reproducible and sampling time independent data from only one sampling, an advantage of great importance when clinical applications are concerned.
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| 4. |
- Lundin, Catarina
(författare)
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Cytogenetic studies of benign breast lesions
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In the present thesis benign breast lesions of various histologies, i.e., fibrocystic lesions from women with and without a known hereditary predisposition to breast cancer, fibroadenomas, phyllodes tumors, and papillomas were cytogenetically investigated with the aim to characterize the chromosomal patterns, and to relate the findings with those in breast carcinomas. No lesion-specific aberration was detected; on the contrary, changes repeatedly encountered in short-term cultures from breast cancer samples were found in these benign entities as well, e.g., gain of 1q, interstitial deletion of 3p, and trisomies 7, 18, and 20, and some cases even displayed cytogenetic polyclonality. Especially intriguing is the prevalence of rearrangements of the short arm of chromosome 3, with the minimally deleted bands 3p13-14, in proliferative lesions from prophylactic mastectomies in breast cancer families. The potential tumor suppressor gene(s) in this region remains, however, to be identified. In general, the frequency of benign cases with chromosome abnormalities is lower compared to breast cancer, and seems to correlate with the histologic features of the tissue, and the corresponding risk of developing invasive mammary carcinoma. The anomalies are generally less complex than those detected in invasive carcinoma, and more often involve balanced rearrangements. Furthermore, the degree of cytogenetic complexity seems to correlate with the description of a phyllodes tumor as benign or malignant: malignant phyllodes tumors have a more complex karyotype.
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| 5. |
- Cwikiel, Magdalena
(författare)
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Pathophysiology of 5-fluorouracil induced cardiotoxicity : a clinical and experimental study
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis concerns the pathophysiology of 5-fluorouracil (5-FU) induced cardiotoxicity. The aim of the clinical studies was to determine whether hemorheological factors might explain 5-FU cardiotoxicity (I) and if the syndrome was associated with free radical (FR) generation and lipid peroxidation (II). Changes in blood and plasma viscosity, fibrinogen, hematocrit, and thiobarbituric acid-reactive substances (TBARS) were studied in patients with esophageal or head and neck carcinoma during treatment with 5-FU. The study showed a decrease in blood and plasma viscosity, probably caused by a decrease in fibrinogen. Study of TBARS did not support the hypothesis that FRs could be involved in the cardiotoxicity of 5-FU. In the experimental studies in rabbits (III,IV) we examined the early and late, local and systemic effect of 5-FU on endothelium, using scanning and transmission electron microscopic evaluation of small arteries, after in vivo treatment with 5-FU. Perfusion fixation was used. The following parameters were evaluated: vessel wall and endothelial cell (EC) contraction, EC edema, cytolysis, denuded areas, platelet accumulation, fibrin formation. The studies showed severe damage to ECs with accompanying thrombus formation, supporting the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on the endothelium is the pathophysiological mechanism of 5-FU cardiotoxicity. The influence of 5-FU on endothelial cell lines in a cell culture model was studied with regard to DNA synthesis, cell death and release of prostacyclin (V). Methotrexate (MTX), an antimetabolite without cardiotoxic properties, was tested in the same way. (3H)thymidine incorporation, total cellular protein, loss of (3H)thymidine from prelabelled cells, 6-keto-prostaglandin F1* were measured. DNA synthesis decreased significantly and the release of prostacyclin by ECs increased significantly when incubated with 5-FU; this effect was not seen for MTX. The study indicate specific susceptibility of benign EC for 5-FU.
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| 6. |
- Garkavij, Michael
(författare)
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Improving radioimmunotargeting of tumors : the impact of extracorporeal immunoadsorption and preload in rats
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In radioimmunotherapy of tumors, uptake of the monoclonal antibody (MAb) used is often too low in relation to its uptake in normal tissues. The purpose of these studies was to improve experimental tumor radioimmunotargeting with (a) extracorporeal immunoadsorption (ECIA), where excess of radiolabeled MAbs circulating in blood is removed, (b) or by preload with unlabeled MAb prior to injection of radiolabeled MAb, (c) or by a combination of these. ECIA based on the avidin-biotin concept enables direct adsorption of radiolabeled and biotinylated MAb from blood and increases the tumor-to-normal tissue (T/N) uptake ratio by reducing background radioactivity in radiosensitive organs. 267 rats (athymic or Brown Norwegian) grafted with human adenocarcinoma or rat colon adenocarcinoma tumors intramuscularly, and beneath the kidney or liver capsule were included in the studies. Of these rats, 82 were subjected to ECIA. Two radioiodinated and biotinylated MAbs, murine L6 or chimeric BR96, were used and evaluated. (I) Using 50 µg dosage of L6, ECIA reduced whole body and plasma activity as well as improved the detectability of subrenal capsule tumors. T/N uptake ratios were increased on average 3 times. (II) The efficacy of ECIA in removing different injected amounts of L6 from plasma was similar. The highest T/N ratios persisting 24h after start of the ECIA were obtained by using 10 µg of 125I-L6-biotin. (III) The efficacy of preload in enhancing tumor uptake and simultaneously decreasing uptake in normal tissues was obtained with 250µg of 125I-L6 preceded by a preload of 50µg unlabeled L6 only. (IV) The effects on radioimmunotargeting of preload and ECIA in combination were synergistic and improved T/N uptake ratios up to 17 times. (V) As compared with ECIA, a new method of whole blood immunoadsorption (WBIA) was technically easier to perform, safer and more reliable, but of approx. comparable efficiency. (VI) WBIA was even applicable on the internalizing and highly tumor selective 125I-BR96-biotin MAb, resulting in manifestly improved T/N ratios.
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| 7. |
- Hugosson, Claes
(författare)
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Diagnosis of solid abdomino-pelvic tumours in children : A retrospective radiological study
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Problems and Aims: Solid abdomino-pelvic tumours (APTs) in children constitute a heterogeneous group of masses which may originate from the retroperitoneum, the abdominal or pelvic cavities or any adjacent structure. They have different histological features, growth patterns and prognoses.The aim of the present investigation was to study the potential of modern imaging to assess the location, size and type of tumour, the extent of the disease and, if possible, the tumour stage in order to provide information to guide therapy.Materials and Methods: Imaging was performed in 92 children and adolescents with a primary APT using conventional radiography, radionuclide scintigraphy, US, CT and MR imaging for pre-treatment assessment, US-guided biopsies were performed in 61 children: the results were analysed retrospectively for yield and complications.Results: In pelvic bone tumours, all imaging modalities contributed to the evaluation of the primary tumour. Conventional radiography and bone scintigraphy were necessary for an initial diagnosis and CT for further evaluation. MR imaging and/or dynamic contrast-enhanced CT were mandatory prior to surgical resection.In primary kidney tumours contrast-enhanced CT and non-enhanced MR imaging were equally accurate in determining the size and origin of the tumours but were inadequate in assessment of tumour staging. MR imaging findings varied somewhat between Wilms' tumours and non-Wilms' tumours.In solid pelvic tumours compartmental localization was equally assessed with CT and MR and, together with gender, was found to correlate with the type of tumour.In abdominal neuroplastoma, evaluation of the local disease was equally accurate with CT and MR imaging, while assessment of invasion and lymphadenopathy was not possible regardless of imaging modality. Metastatic disease needed imaging with CT, MR, scintigraphy and bone marrow aspiration for assessment. Staging accuracy improved if an increased number of imaging methods were used.Needle core biopsy provided significantly better results than fine needle aspiration biopsy without an increase in complications.Conclusions: Assessment of APT in children requires the use of several different yet complementary imaging modalities in defining location, extent and tissue characteristics of the tumour. The choice of imaging modality depends on history, clinical findings, presumed location and available techniques. Pre-treatment assessment with imaging constitutes the basis for presentation of a staging protocol.
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| 8. |
- Johannsson, Oskar Thor
(författare)
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Hereditary Breast Cancer in South Sweden. Early findings from studies on the role of BRCA1
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The thesis presents the results from investigations into the role of BRCA1 in hereditary cancer in South Sweden. Loss of heterozygosity (LOH) studies found loss of the wildtype allele of BRCA1 to be common in BRCA1 associated breast cancer, but due to the high degree of LOH on chr. 17q in sporadic breast cancer not to be indicative of the presence of a BRCA1 mutation. Seventeen different germline BRCA1 mutations have been found in 34 separate breast and breast-ovarian cancer families. Five founder mutations were identified. If silent and suspected polymorphism mutations are excluded, frameshift, nonsense and splice mutations account for 93% in our material. mRNA in situ hybridization of BRCA1 was found to be able to identify BRCA1 and sporadic tumors with 95% specificity and sensitivity. The histology and tumor biological features of BRCA1 associated breast cancers was found to be predominantly of the ductal type, histological grade III, non-diploid with a high S-phase, predominantly TP53 positive and E
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| 9. |
- Johnsson, Anders
(författare)
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Pharmacokinetic and pharmacodynamic studies on cisplatin in mice and men
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Methodological tools for studies of the cytostatic agen cisplatin (CDDP) were explored and applied to elucidate various aspects of pharmacokinetics, drug distribution, chemomodulation and pharmacodynamics. An immunohistochemical assay for analysis of CDDP-DNA adducts, i.e. the drug in its probable target position, was modified to allow quantitation with computerized image analysis. The methodological sources of error were estimated. We found the method to be feasible for comparing samples of the same tissue type, stained in the same batch and preferrably measured by one observer on one occasion. The pharmacokinetics were studied as platinum (Pt) and CDDP-DNA adducts in nude mice. The highest tissue concentration was noted in kidney at 15 min. A biphasic elimination of Pt was observed in most sample types and the terminal half-life was similar (55h-76h) in whole-blood, serum, kidney, liver and testis. In brain the pharmacokinetics differed with a gradual accumulation during the study period of 7 days. Peak adduct levels were reached between 30 min and 4h. Each tissue type had its specific adduct staining pattern. With escalating CDDP doses there was a linear increase in both Pt concentrations and CDDP-DNA adducts including tumor. There were also good correlations between serum-Pt, tissue levels of Pt and adducts, respectively. Heterogeneities in the intratumoral drug distribution were described and a model was presented for investigating the potential influence of vascularization and cell proliferation on intratumoral adduct distribution by using different immunohistochemical stainings of parallel sections. A weak correlation was found between adducts and proliferation, which might indicate that drug uptake and adduct formation is increased in proliferating cells. The antifungal agent amphotericin B was given to glioma-bearing rats with the purpose of enhancing the cytotoxicity of CDDP. The combined treatment resulted in excessive nephrotoxicity and in increase levels of CDDP-DNA adducts on kidneys. This indicates that nephrotoxicity is related to adduct formation in kidneys. It also shows that adduct analysis can be a valuable tool for assessing the mechanisms of interaction between CDDP and modulation agents. Ten patients were studies during the first cycle of CDDP-based chemotherapy. With limited-sampling and a population approach useful pharmacokinetic information was obtained. CDDP-DNA adducts in lymphocytes and buccal cells showed different kinetic profiles, possibly due to differences in cell turn-over. Renal damage, studied in terms of urinary protein excretion, was first displayed as tubular damge and later as impaired glomerular barrier function. Significant correlations were found between tubular dysfunction and pharmacokinetic parameters. These results could be the basis for further pharmacodynamic studies aiming towards individualized dose adaptation for cancer chemotherapy.
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| 10. |
- Knutson, Folke
(författare)
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The quality of red blood cells and platelets intended for transfusion : Opportunities for improvements
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A new, automated technique for collection and instant preparation of blood components has been developed. The device enables the combined collection of red cells (250 mL) and plasma (475 mL). No adverse effects were seen in the donors. The blood components were of good quality. The impact of the pre-separation temperature on whole blood was studied in two studies. In the first study blood was collected and put into stoppered test tubes. The test tubes were then put into water bath at 15,20,25 and 30 °C. Samples were taken at intervals during 24 hours. The lactate concentration increased and 2,3-DPG concentrations decreased during storage and at a higher rate with higher temperature. In the second study blood was collected and dived into half units. One half unit was actively cooled to 20 °C the other half kept at 28 °C. Blood component preparation was done after 6 hours. There were a significant change in 2,3-DPG, pH and lactate already after two hours hold of the whole blood. The differences were maintained for one week and for 2,3-DPG throughout 28 days storage. Myeloperoxidase levels in plasma were lower in the cooled units. The leucocytes reduction properties of BAT procedure were improved by addition of mannitol in the anticoagulant. The contents of leucocytes in RBC units were in the test group 32x106 and in the control group 573x106. In vitro storage data showed no significant difference between the two groups during 42 days of storage of the red cells. A photochemical treatment (PCT) process has been used in decontamination of buffy-coat derived platelets (BC-PCs). Different strains of bacteria known to be associated with bacterial contamination's of blood components were added to two pooled ABO matched BC-PCs. After mixing the BC-PCs were divided. One BC-PC underwent PCT and the other did not. All bacterial experiments were made in duplicates. In all experiments, the bacteria were killed except in one with Bacillus cereus, a known spore former. PCT conditions similar to those used in the bacterial inactivation experiment were efficacious to inactivate HIV-1. In a second study a number of in vitro parameters known to be related to viability or function of stored platelets were tested. No physiologically relevant differences were found between the test and the control BC-PCs during 7 days of storage.
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