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  • Baselga, J, et al. (författare)
  • Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types
  • 2002
  • Ingår i: Journal of Clinical Oncology. - American Society of Clinical Oncology. - 1527-7755. ; 20:21, s. 4292-4302
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non-small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for >or= 3 months; seven of these patients remained on study drug for >or= 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.
  • Benhamou, S, et al. (författare)
  • Meta- and pooled analyses of the effects of glutathione S-transferase M1 polymorphisms and smoking on lung cancer risk
  • 2002
  • Ingår i: Carcinogenesis. - Oxford University Press. - 0143-3334. ; 23:8, s. 1343-1350
  • Tidskriftsartikel (refereegranskat)abstract
    • Susceptibility to lung cancer may in part be attributable to inter-individual variability in metabolic activation or detoxification of tobacco carcinogens. The glutathione S-transferase M1 (GSTM1) genetic polymorphism has been extensively studied in this context; two recent meta-analyses of case-control studies suggested an association between GSTM1 deletion and lung cancer. At least 15 studies have been published after these overviews. We undertook a new meta-analysis to summarize the results of 43 published case-control studies including >18 000 individuals. A slight excess of risk of lung cancer for individuals with the GSTM1 null genotype was found (odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.07-1.27). No evidence of publication bias was found (P = 0.4), however, it is not easy to estimate the extent of such bias and we cannot rule out some degree of publication bias in our results. A pooled analysis of the original data of about 9500 subjects involved in 21 case-control studies from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC) data set was performed to assess the role of GSTM1 genotype as a modifier of the effect of smoking on lung cancer risk with adequate power. Analyses revealed no evidence of increased risk of lung cancer among carriers of the GSTM1 null genotype (age-, gender- and center-adjusted OR = 1.08, 95% CI 0.98-1.18) and no evidence of interaction between GSTM1 genotype and either smoking status or cumulative tobacco consumption.
  • Beral, V, et al. (författare)
  • Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease
  • 2002
  • Ingår i: British Journal of Cancer. - Nature Publishing Group. - 1532-1827. ; 87:11, s. 1234-1245
  • Tidskriftsartikel (refereegranskat)abstract
    • Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58515 women with invasive breast cancer and 95067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 - 1.45, P < 0.00001) for an intake of 35 - 44 g per day alcohol, and 1.46 (1.33 - 1.61, P < 0.00001) for greater than or equal to 45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1 % per 10 g per day, P < 0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers= 1.03, 95% CI 0.98 - 1.07, and for current smokers=0.99, 0.92 - 1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver. (C) 2002 Cancer Research UK.
  • Berg, Gertrud, 1944-, et al. (författare)
  • Radioiodine ablation and therapy in differentiated thyroid cancer under stimulation with recombinant human thyroid-stimulating hormone
  • 2002
  • Ingår i: J Endocrinol Invest. - 0391-4097 (Print). ; 25:1, s. 44-52
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated whether recombinant human TSH (rhTSH) safely and effectively induces uptake of high-dose 131-iodine (131I) to ablate thyroid remnant or treat disease, in patients with well-differentiated thyroid carcinoma. Eleven consecutive patients unable to tolerate thyroid hormone withdrawal received one im injection of 0.9 mg rhTSH on 2 consecutive days before receiving 4000 MBq (approximately 108 mCi) radioiodine orally. Eight patients received one, and 3 patients 2 courses. Our series comprised 7 women and 4 men (mean age, 78 yr, range: 56-87 yr). Ten patients had undergone total or near-total thyroidectomy up to 19 yr earlier. rhTSH-stimulated single course radioiodine with the intention to ablate thyroid remnant was performed in 3 patients, with following estimation of radioiodine uptake and TG measurements. Of another 8 patients given this treatment palliatively, 5 had radiological, clinical and/or laboratory response, including: 80% decreased pathological uptake between treatment courses; pronounced decrease in bone pain; diminished symptoms; improved physical condition and quality of life; lower serum TG concentration; and/or normalization of TG recovery test. Two patients with small lung metastases on computed tomography had no detectable radioiodine uptake or other response; they also lacked uptake after withdrawal-stimulated radioiodine treatment. Despite being elderly and frail, patients generally tolerated treatment well; rhTSH caused nausea in one patient and transiently increased pain in bone and soft tissue lesions in another. We conclude that rhTSH-stimulated high-dose radioiodine for remnant ablation or tumor treatment is safe, feasible and seemingly effective, enhancing quality of life and offering reasonable palliation in patients with advanced disease.
  • Berglund, Åke, 1961- (författare)
  • Optimisation of Chemotherapy Treatment in Advanced Colorectal Cancer
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Colorectal cancer is one of the most common malignant diseases in Sweden – more than 5000 new cases are diagnosed each year. The overall five-year survival is about 60% and in cases of recurrence the prognosis is poor.</p><p>In a phase III study in advanced colorectal cancer the response rate was doubled when 5-FU was given as a bolus injection versus as a short infusion. The toxicity was similar and time to progression was longer in the injection group. However, overall survival was not significantly different. Dose-effect relationships of 5-FU were studied in another phase III study recruiting 312 patients. A decrease from 500 mg/m<sup>2</sup> to 400 mg/m<sup>2</sup> worsened the treatment results. A low incidence of severe toxicity was seen in both groups. An increase to 600 mg/m<sup>2</sup> worsened the toxicity without any improvement of the results.</p><p>A cytotoxic drug sensitivity test in different tumour types, mainly gastrointestinal cancer, poorly predicted treatment outcome in a phase II study.</p><p>The conventional Nordic Flv regimen was split in a phase I/II trial. An escalation of dose was possible and the response rate was 20%.</p><p>Thymidylate synthase (TS) and the gene expression of p53 were investigated by immunohistochemical technique in the primary tumours of 132 patients. None of the markers predicted the later palliative chemotherapy result. However, TS significantly predicted time to recurrence.</p><p>Serum markers were analysed before and during FLv treatment to early predict outcomes among 87 patients. TPS is promising, both as a predictive marker before start of treatment and after a short period of treatment. In the same setting, CEA had lower predictive value. S-VEGF and S-bFGF did not yield any prognostic information of later outcome. In all studies B-haemoglobin values, performance status and subjective response were strong markers, both for prediction of objective response and for survival.</p>
  • Bergqvist, Michael, 1971- (författare)
  • Radiosensitivity in lung cancer with focus on p53
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>In Sweden approximately 2800 new lung cancer patients are diagnosed every year. Radiotherapy is used with curative intention in certain groups of patients. The aim of this thesis is to study the basis of differences in radioresistance and the possibility to predict response to radiotherapy.</p><p>In the first study we investigated, using the comet assay, four lung cancer cell lines with different sensitivity towards radiation. A clear dose-response relationship for radiation-induced DNA single strand and double strand breaks were found. All cell lines showed a remarkably efficient repair of both the DNA single strand and double strand breaks one hour after irradiation. However, further studies in one radioresistant and one radiosensitive cell line demonstrated that repair during the first 15 min had the best accordance with radiosensitivity measured as surviving fraction.</p><p>In the second and third study, sequencing studies of the p53 gene were performed on cell lines as well as on tumour material. Cell lines that were expressing a mutation in exon 7 were associated with increased radiosensitivity compared with tumor cell lines with mutations in other exons. In the clinical study, 10 patients were found to be mutated in the p53 gene whereas the other 10 patients were not. No correlation to clinical parameters could be drawn.</p><p>In the fourth study, serum from 67 patients with a confirmed diagnosis of non-small cell lung cancer was investigated for the presence of p53 antibodies. P53 antibodies in sera, taken prior to radiation treatment, were associated with increased survival.</p><p>The summary of this thesis indicates that the p53 gene has an impact on the effect of radiotherapy in lung cancer. The presence of p53 antibodies might be of clinical interest for predicting survival after radiotherapy. Further studies on the importance of the p53 gene on early repair are of interest. </p>
  • Bjerner, J, et al. (författare)
  • Protein epitopes in carcinoembryonic antigen. Report of the ISOBM TD8 workshop.
  • 2002
  • Ingår i: Tumor Biology. - 1010-4283 .- 1423-0380. ; 23:4, s. 249-62
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>To characterize antigenic sites in carcinoembryonic antigen (CEA) further and to investigate whether there are differences between colon tumor CEA and meconium CEA (NCA-2) that can be detected by anti-CEA monoclonal antibodies (MAb), 19 new anti-CEA MAb were analyzed with respect to specificity, epitope reactivity and affinity. Their reactivities were compared with 10 anti-CEA MAb with known CEA-domain binding specificity that have previously been classified into five nonoverlapping epitope groups, GOLD 1-5. Cross-inhibition assays with antigen-coated microtiter plates and immunoradiometric assays were performed in almost all combinations of MAbs, using conventionally purified CEA (domain structure: N-A1B1-A2B2-A3B3-C) from liver metastasis of colorectal carcinomas, recombinant CEA, meconium CEA (NCA-2), truncated forms of CEA and NCA (CEACAM6) as the antigens. The affinity of the MAbs for CEA was also determined. The new MAbs were generally of high affinity and suitable for immunoassays. Three new MAbs were assigned to GOLD epitope group 5 (N-domain binding), 3 MAbs to group 4 (A1B1 domain), 1 to group 3 (A3B3 domain), 3 to group 2 (A2B2 domain) and 3 to group 1 (also the A3B3 domain). Three MAbs formed a separate group related to group 4, they were classified as GOLD 4' (A1B1 domain binding). The remaining 3 MAbs appear to represent new subspecificities with some relationship to GOLD groups 1, 2 or 4, respectively. Five MAbs, all belonging to epitope group 1 and 3, reacted strongly with tumor CEA but only weakly or not at all with meconium CEA, demonstrating that the two products of the CEA gene differ from each other, probably due to different posttranslational modifications.</p>
  • Bjornstrom, K, et al. (författare)
  • A tyrosine kinase regulates propofol-induced modulation of the beta-subunit of the GABA(A) receptor and release of intracellular calcium in cortical rat neurones
  • 2002
  • Ingår i: Acta Physiologica Scandinavica. - Wiley-Blackwell. - 0001-6772. ; 175:3, s. 227-235
  • Tidskriftsartikel (refereegranskat)abstract
    • Propofol, an intravenous anaesthetic, has been shown to interact with the beta -subunit of the gamma -amino butyric acid(A) (GABA(A) ) receptor and also to cause changes in [Ca2+ ](i) . The GABA(A) receptor, a suggested target for anaesthetics, is known to be regulated by kinases. We have investigated if tyrosine kinase is involved in the intracellular signal system used by propofol to cause anaesthesia. We used primary cell cultured neurones from newborn rats, pre-incubated with or without a tyrosine kinase inhibitor before propofol stimulation. The effect of propofol on tyrosine phosphorylation and changes in [Ca2+ ](i) were investigated. Propofol (3 mu g mL(-1) , 16.8 mu M) increased intracellular calcium levels by 122 +/- 34% (mean +/- SEM) when applied to neurones in calcium free medium. This rise in [Ca2+ ](i) was lowered by 68% when the cells were pre-incubated with the tyrosine kinase inhibitor herbimycin A before exposure to propofol (P < 0.05). Propofol caused an increase (33 +/- 10%) in tyrosine phosphorylation, with maximum at 120 s, of the beta -subunit of the GABA(A) -receptor. This tyrosine phosphorylation was decreased after pre-treatment with herbimycin A (44 +/- 7%, P < 0.05), and was not affected by the absence of exogenous calcium in the medium. Tyrosine kinase participates in the propofol signalling system by inducing the release of calcium from intracellular stores and by modulating the beta -subunit of the GABA(A) -receptor.
  • Bjørnerud, Atle, 1962- (författare)
  • Proton Relaxation Properties of a Particulate Iron Oxide MR Contrast Agent in Different Tissue Systems Implications for Imaging
  • 2002
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Knowledge of the relationship between <i>in vivo</i> contrast agent concentration and magnetic resonance (MR) signal response is an important requirement in contrast enhanced MR imaging in general and in MR based perfusion imaging in particular. This relationship is a complex function of the properties of the contrast agent as well as the structure of the target tissue. The aim of the present work was to quantify the effects of the iron oxide nanoparticle based intravascular contrast agent, NC100150 Injection, on proton relaxation rates in different tissue systems <i>in vivo</i> in a pig model and <i>ex vivo</i> in phantoms containing whole blood. Methods that enabled accurate relaxation rate measurements in these organs were developed, and validated. From these measurements, trans-compartmental water exchange rates and blood volume could be estimated and the MR signal response could be predicted as a function of contrast agent concentration under relevant imaging conditions. </p><p>Using a 1.5 Tesla clinical MR system, the longitudinal (R<sub>1</sub>=1/T<sub>1</sub>) proton relaxation rates in blood, renal cortex, paraspinal muscle and myocardium were measured <i>in vivo</i> as a function of plasma concentration (C<sub>p</sub>) of NC100150 Injection. The transverse (R<sub>2</sub><sup>*</sup> = 1/T<sub>2</sub><sup>*</sup>) relaxation rates were measured <i>in vivo</i> in blood, renal cortex and muscle as a function of C<sub>p</sub> and <i>ex vivo</i> in blood as a function of C<sub>p</sub> and blood oxygenation tension. The proton nuclear MR (NMR) linewidth and lineshape were analysed as a function of C<sub>p</sub> and blood oxygen tension <i>ex vivo</i> at 7.05 T. </p><p>In muscle and renal cortex, there was a linear correlation between R<sub>2</sub><sup>*</sup> and C<sub>p</sub> whereas R<sub>2</sub><sup>*</sup> increased as a quadratic function of C<sub>p </sub>in blood. The NMR linewidth increased linearly with C<sub>p</sub> in fully oxygenated blood whereas in deoxygenated blood the linewidth initially decreased with increasing Cp, reaching a minimum and then increasing again with further increase in C<sub>p</sub>. R<sub>1</sub> increased linearly with C<sub>p</sub> in blood and from the slope of R<sub>1</sub> vs. C<sub>p</sub> the T<sub>1</sub>-relaxivity (r<sub>1</sub>) of NC100150 Injection in blood at 1.5 T was estimated to be (mean ± SD) 13.9 ± 0.9 s<sup>-1</sup>mM<sup>-1</sup>. In tissue, the maximum increase in R<sub>1</sub> was limited by the rate of water exchange between the intravascular and interstitial tissue compartments. Using a two-compartment exchange-limited relaxation model, the permeability surface area (PS) product was estimated to be 61.9 ± 2.9 mL/min/g in renal cortex and 10.1 ± 1.5 mL/min/g in muscle and the total myocardial water exchange rate, <i>k</i><i>t</i>, was 13.5 ± 6.4 s<sup>-1</sup>. The estimated blood volumes obtained from the same model were 19.1 ± 1.4 mL/100 g, 2.4 ± 1.4 mL/100 g and 11.2 ± 2.1 mL/100 g, respectively in renal cortex, muscle and myocardium.</p><p>Current T<sub>2</sub><sup>*</sup> based first-pass MR perfusion methods assume a linear correlation between R<sub>2</sub><sup>*</sup> and C<sub>p</sub> both in blood and tissue and our results therefore suggest that quantitative perfusion values can not easily be obtained with existing tracer kinetic models. The correlation between MR signal response and C<sub>p</sub> is further complicated in the kidney by a significant first-pass increase in R<sub>1</sub> which may lead to an underestimation of C<sub>p</sub>. In T<sub>1</sub>-based perfusion methods, low concentrations of NC100150 Injection must be used in order to maintain a linear dose-response relationship between R<sub>1</sub> and C<sub>p</sub>. The effect of blood oxygenation on the NMR linewidth in the presence of NC100150 Injection enabled accurate estimation of magnetic susceptibility of deoxyhemoglobin and the effect can potentially be used to determine blood oxygenation status.</p><p>In conclusion, NC100150 Injection is well suited as a T<sub>2</sub><sup>*</sup> perfusion agent due to the large magnetisation and intravascular biodistribution of this agent. T<sub>1</sub>-based perfusion imaging with this agent is limited by water exchange effects and large T<sub>2</sub><sup>*</sup> effects at higher contrast agent concentrations. Quantitative perfusion assessment is unlikely to be feasible with any of these approaches due to the non-linear dose response.</p>
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