| 41. |
- Bethke, Lara, et al.
(författare)
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CASP8 D302H and meningioma risk : an analysis of five case-control series
- 2009
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Ingår i: Cancer Letters. - Clare : Elsevier. - 0304-3835 .- 1872-7980. ; 273:2, s. 312-315
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Tidskriftsartikel (refereegranskat)abstract
- Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.
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| 42. |
- Bethke, Lara, et al.
(författare)
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Comprehensive analysis of DNA repair gene variants and risk of meningioma
- 2008
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:4, s. 270-276
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility.Methods: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case–control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided.Results: The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1–interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; Ptrend = 8.95 × 10−6; P = .009 after adjusting for multiple testing).Conclusions: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.
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| 43. |
- Bethke, Lara, et al.
(författare)
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Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 17:6, s. 800-805
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Tidskriftsartikel (refereegranskat)abstract
- Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case–control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case–control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14–1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.
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| 44. |
- Bethke, Lara, et al.
(författare)
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Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma
- 2008
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 17:5, s. 1195-1202
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Tidskriftsartikel (refereegranskat)abstract
- Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.
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| 45. |
- Bethke, Lara, et al.
(författare)
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The Common D302H Variant of CASP8 Is Associated with Risk of Glioma
- 2008
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 17:4, s. 987-989
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Tidskriftsartikel (refereegranskat)abstract
- Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor.
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| 46. |
- Borgå, Olof, et al.
(författare)
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Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours : A Dose-Escalation Study
- 2019
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Ingår i: Advances in Therapy. - : Springer. - 0741-238X .- 1865-8652. ; 36:5, s. 1150-1163
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: A water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK).Methods: This was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model.Results: Thirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m2. MTD was established as 250 mg/m2. Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m2 with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration–time curve to infinite time (AUCinf), respectively.Conclusion: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf showed a tendency to increase linearly with dose within the 150–275 mg/m2dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy.Trial Registration: EudraCT no: 2004-001821-54.
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| 47. |
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| 48. |
- Brendle, Annika, et al.
(författare)
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Polymorphisms in predicted microRNA-binding sites in integrin genes and breast cancer ITGB4 as prognostic marker.
- 2008
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 29:7, s. 1394-1399
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Tidskriftsartikel (refereegranskat)abstract
- Integrins control the cell attachment to the extracellular matrix and play an important role in mediating cell proliferation, migration and survival. A number of important cancer-associated integrin genes can be regulated by microRNAs (miRNAs) that bind to their target sites in the 3' untranslated regions. We examined the effect of single-nucleotide polymorphisms (SNPs) in predicted miRNA target sites of six integrin genes (ITGA3, ITGA6, ITGAv, ITGB3, ITGB4 and ITGB5) on breast cancer (BC) risk and clinical outcome. Six SNPs were genotyped in 749 Swedish incident BC cases with detailed clinical data and up to 15 years of follow-up together with 1493 matched controls. We evaluated associations between genotypes and BC risk and clinical tumour characteristics. Survival probabilities were compared between different subgroups. As a novel finding, several SNPs seemed to associate with the hormone receptor status. The strongest association was observed between the A allele of the SNP rs743554 in the ITGB4 gene and oestrogen receptor-negative tumours [odds ratio 2.09, 95% confidence intervals (CIs) 1.19-3.67]. The same SNP was associated with survival. The A allele carriers had a worse survival compared with the wild-type genotype carriers (hazard ratio 2.11, 95% CIs 1.21-3.68). The poor survival was significantly associated with the aggressive tumour characteristics: high grade, lymph node metastasis and high stage. None of the SNPs was significantly associated with BC risk. As the ITGB4 SNP seems to influence tumour aggressiveness and survival, it may have prognostic value in the clinic.
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| 49. |
- Bruhn, Helena, et al.
(författare)
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Do presenting symptoms predict treatment decisions and survival in glioblastoma? Real-world data from 1458 patients in the Swedish brain tumor registry
- 2024
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Ingår i: Neuro-Oncology Practice. - : OXFORD UNIV PRESS. - 2054-2577 .- 2054-2585.
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Tidskriftsartikel (refereegranskat)abstract
- Background Glioblastoma is the most common malignant brain tumor in adults. Non-invasive clinical parameters could play a crucial role in treatment planning and serve as predictors of patient survival. Our register-based real-life study aimed to investigate the prognostic value of presenting symptoms. Methods Data on presenting symptoms and survival, as well as known prognostic factors, were retrieved for all glioblastoma patients in Sweden registered in the Swedish Brain Tumor Registry between 2018 and 2021. The prognostic impact of different presenting symptoms was calculated using the Cox proportional hazard model. Results Data from 1458 adults with pathologically verified IDH wild-type glioblastoma were analyzed. Median survival time was 345 days. The 2-year survival rate was 21.5%. Registered presenting symptoms were focal neurological deficits, cognitive dysfunction, headache, epilepsy, signs of raised intracranial pressure, and cranial nerve symptoms, with some patients having multiple symptoms. Patients with initial cognitive dysfunction had significantly shorter survival than patients without; 265 days (245-285) vs. 409 days (365-453; P < .001). The reduced survival remained after Cox regression adjusting for known prognostic factors. Patients presenting with seizures and patients with headaches had significantly longer overall survival compared to patients without these symptoms, but the difference was not retained in multivariate analysis. Patients with cognitive deficits were less likely to have radical surgery and to receive extensive anti-neoplastic nonsurgical treatment. Conclusions This extensive real-life study reveals that initial cognitive impairment acts as an independent negative predictive factor for treatment decisions and adversely affects survival outcomes in glioblastoma patients.
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| 50. |
- Bruhn, Helena, et al.
(författare)
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Initial cognitive impairment predicts shorter survival of patients with glioblastoma
- 2022
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Ingår i: Acta Neurologica Scandinavica. - : Wiley. - 0001-6314 .- 1600-0404. ; 145:1, s. 94-101
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Seizures as presenting symptom of glioblastoma (GBM) are known to predict prolonged survival, whereas the clinical impact of other initial symptoms is less known. Our main objective was to evaluate the influence of different presenting symptoms on survival in a clinical setting. We also assessed lead times, tumour size and localization. Methods Medical records of 189 GBM patients were reviewed regarding the first medical appointment, presenting symptom/s, date of diagnostic radiology and survival. Tumour size, localization and treatment data were retrieved. Overall survival was calculated using Kaplan-Meier and Mann-Whitney U test. Cox regression was used for risk estimation. Results Cognitive impairment as the initial symptom was often misinterpreted in primary health care leading to a delayed diagnosis. Initial global symptoms (66% of all patients) were associated with reduced survival compared to no global symptoms (median 8.4 months vs. 12.6 months). Those with the most common cognitive dysfunctions: change of behaviour, memory impairment and/or disorientation had a reduced median survival to 6.4 months. In contrast, seizures (32%) were associated with longer survival (median 11.2 months vs. 8.3 months). Global symptoms were associated with larger tumours than seizures, but tumour size had no linear association with survival. The setting of the first medical appointment was evenly distributed between primary health care and emergency units. Conclusion Patients with GBM presenting with cognitive symptoms are challenging to identify, have larger tumours and reduced survival. In contrast, epileptic seizures as the first symptom are associated with longer survival and smaller tumours.
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