| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- Isacsson, Ulf
(författare)
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Comparative treatment planning in external radiotherapy of malignant tumours : Potential gains using protons
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is well known that protons have physical characteristics superior to conventional radiation qualities in external beam radiotherapy. The primary aim of this work is to determine if the physical advantages also may lead to clinical advantages. A second aim is to evaluate the treatment planning algorithms incorporated into a 3D treatment planning system, used in the prediction, Helax-TMSTM. The potential benefits of using protons instead of conventional radiation qualities is evaluated by comparing treatment plans. Dose-response models of tumour control probability (TCP) and normal tissue complication probability (NTCP) were used to predict the treatment outcome for the different plans. Uncertainties in the results were studied in sensitivity analyses.Comparative studies were performed in four different tumour types, locally advanced rectal cancer, a paraspinal tumour, oesophageal cancer and left-sided node-positive breast cancer. Advantages with protons were seen in all cases, but the advantages were of different size.Proton therapy in patients with oesophageal carcinoma increases the TCP from 6 to 49% if a risk of 1% in the spinal cord and a total NTCP for the two lungs equivalent to a one-sided pulmectomy is allowed. This gain is relatively insensitive to variations, within reasonable limits, in the dose-response parameters.Proton therapy reduces the risk for cardiac mortality and radiation pneumonitis to almost zero when treating node-positive left-sided breast cancer after breast-conserving surgery.The evaluation of the treatment planning algorithms shows that pencil kernel algorithms are required in order to accurately calculate dose distributions in heterogeneous patient volumes. The scattering phenomenon in the vicinity of interfaces between different materials is modelled. The magnitude of the effect is underestimated (less than 1%) due to the inherent approximations.
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| 9. |
- 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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| 10. |
- Ahlman, Håkan, 1947, et al.
(författare)
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The relevance of somatostatin receptors in thyroid neoplasia.
- 1997
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Ingår i: The Yale journal of biology and medicine. - 0044-0086. ; 70:5-6, s. 523-33
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 111In-octreotide scintigraphy in patients with persistent medullary thyroid carcinoma (MTC) visualized tumors in about half of the surgically explored sites. Tumor visualization correlated with rapid tumor growth and large tumor volume as judged from calcitonin levels. The 111In concentration ratio between tumor (T) and blood (B) in surgically excised lymph node metastases of MTC showed a large variation, with low values for microscopic and high values for macroscopic metastases in individual patients. Three cases of MTC, Hürthle cell adenoma and papillary thyroid cancer are reported with preoperative scintigraphy, T/B ratios and Northern analyses of the surgical biopsies. Visualization of tumors was possible in the absence of sstr2 (the high affinity receptor for octreotide) with the exception of microscopic tumor growth. T/B values in the patient with Hürthle cell adenoma were similar to those found in the contralateral thyroid lobe with goitre. The relatively high uptake of 111In in benign thyroid conditions probably limits the use of octreotide scintigraphy in the diagnosis of primary tumors. The technique has certain advantages over radioiodine scintigraphy after the surgical treatment of thyroid tumors: no need for withdrawal of thyroxin substitution; a possibility to diagnose metastases of tumors that do not concentrate radioiodine (MTC, Hürthle cell cancer); and complementary information about metastatic sites of non-medullary thyroid cancer (papillary and follicular tumors).
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