| 1. |
- Sjöholm, H, et al.
(författare)
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Necrosis of malignant gliomas after intratumoral injection of 201Tl in vivo in the rat
- 1995
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Ingår i: Anti-Cancer Drugs. - 0959-4973. ; 6:1, s. 109-114
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Tidskriftsartikel (refereegranskat)abstract
- Fourteen adult Fischer 344 rats were inoculated in vivo unilaterally in the caudate nucleus in the brain with malignant RG 2 glioma cells. By 3 weeks a tumor with a diameter of 3-6 mm normally develops. Ten animals which survived the repeated periods of anesthesia and thallium (Tl) injections (intratumorally three times of 201Tl, 15-23 days after inoculation) showed a prolonged retention of radioactivity at the site of injection with no uptake in other organs except for the kidneys. Singular circumscribed necroses were found post-mortem at the site of injection, comprising malignant glioma tumor tissue, which in six animals was absent, in three animals was markedly reduced in size compared with controls and in one animal had the expected size. In four animals metastases were found in distant locations in the brain; in three of these cases there was a retention of radioactivity in the tumor. The selective necrotizing effect on the tumor cells is interpreted as mainly due to emission of Auger electrons from intracellularly accumulated 201Tl, giving rise to very high energy deposition in the vicinity of the cell nucleus. The results should also have implications for the treatment of human malignant gliomas.
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| 2. |
- 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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| 3. |
- Kjellén, Elisabeth, et al.
(författare)
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A Phase I/II Evaluation of Metoclopramide as a Radiosensitiser in Patients with Inoperable Squamous Cell Carcinoma of the Lung
- 1995
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 31:13-14, s. 2196-2202
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Tidskriftsartikel (refereegranskat)abstract
- The feasibility of administering metoclopramide (MCA) as a radiosensitizer has been evaluated in 23 patients with a pathological or cytological diagnosis of a squamous cell carcinoma of the lung, clinically evaluated as inoperable. All patients received 40-60 Gy radiotherapy fractionated into 1.8 Gy fractions 5 times per week (Monday-Friday). Two MCA treatment regimens were used: (i) MCA at 2 mg/kg administered by intravenous infusion 1-2 h prior to radiotherapy 3 times per week (Monday, Wednesday, Friday); and (ii) MCA at 1 mg/kg administered by intravenous infusion 1-2 h prior to radiotherapy 5 times per week (Monday-Friday). 11 of the 23 patients treated with radiotherapy and MCA had none to mild pneumonitis or fibrosis and another 8 of the 23 had moderate levels. No patient had their therapy interrupted due to radiation-related side-effects. The MCA-related side-effects were as expected, i.e. 78% of the patients experienced sedation/tiredness and 48% expressed restlessness/anxiety symptoms. Both the total dose and serum levels of MCA were significantly associated to the MCA side-effect profile. Tumour response, duration of tumour response and survival were significantly positively correlated to the total and weekly doses of MCA administered to the patients during their radiotherapy treatment. These favourable phase II data have justified the initiation of a phase II/III randomised multicentred trial being carried out in Europe to evaluate MCA as a radiosensitiser.
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| 4. |
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| 5. |
- Sundgren, P, et al.
(författare)
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Paragangliomas of the spinal canal
- 1999
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Ingår i: Neuroradiology. - : Springer Science and Business Media LLC. - 1432-1920 .- 0028-3940. ; 41:10, s. 788-794
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Tidskriftsartikel (refereegranskat)abstract
- We report the clinical MRI and histopathological features of five consecutive cases of spinal paraganglioma. Three intradural tumours were found in the typical location (two at the L4, one at the S2 level); one intradural extramedullary tumour arose at an unusual level, from the ventral C2 root, and one extradural tumour growing along the L5 nerve root sheath had an aggressive growth pattern with early, local paraspinal recurrence and, eventually, intradural metastatic spread. This type of growth pattern has not been described previously. Paragangliomas of the spinal canal are more common than previously thought and can be located anywhere along the spine, although the lumbosacral level is the most common. Their appearance on MRI can not distinguish them from other tumours in the spinal canal. Even though paragangliomas in general are benign and slowly growing their growth pattern can vary and be more aggressive, to the point of metastatic spread.
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| 6. |
- Berglund, Jan, et al.
(författare)
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Rapid increase in volume of the remnant after hemithyroidectomy does not correlate with serum concentration of thyroid stimulating hormone
- 1998
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Ingår i: European Journal of Surgery. - : Oxford University Press (OUP). - 1102-4151 .- 1741-9271. ; 164:4, s. 257-262
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To study the effect of postoperative thyroxine on the volume of the thyroid remnant after lobectomy for benign nontoxic goitre. DESIGN: Prospective, randomised study. SETTING: University hospital, Sweden. SUBJECTS: 50 consecutive patients who underwent lobectomy for benign non-toxic goitre. INTERVENTIONS: Patients were randomised postoperatively to take thyroxine 0.1 mg or placebo daily. MAIN OUTCOME MEASURES: The median volume of the remaining thyroid lobe measured by ultrasound. Serum concentrations of thyroxine, triiodothyronine (T3) and thyroid stimulating hormone (TSH) were measured preoperatively and 1, 3, 6, 12 months postoperatively. RESULTS: The median volume of the remaining lobe had increased significantly compared with preoperatively by 1 month postoperatively by 30% in the thyroxine group and 25% in the placebo group (p < 0.01). The difference between the groups was not significant. After the first month the volume did not change significantly. In the thyroxine group, the TSH concentration was unchanged and the thyroxine concentration increased significantly throughout the study. In the placebo group there was a significant increase in TSH concentration and a significant decrease in that of thyroxine at all follow-up examinations. CONCLUSIONS: There is a significant increase in the volume of the remaining thyroid 1 month after lobectomy that persisted throughout the first year. Thyroxine given in a dose that kept the serum TSH concentration at the same level as preoperatively did not seem to influence volume changes; consequently we consider that these are caused by factors other than TSH.
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| 7. |
- 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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| 8. |
- 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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| 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. |
- 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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