| 1. |
- Heggebo, L. C., et al.
(författare)
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Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden
- 2023
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Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThe use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life.Methods and analysisPRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints.Ethics and disseminationTo implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums.Trial registration numberClinicalTrials.gov Registry (NCT05190172).
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| 2. |
- Shin, J. H., et al.
(författare)
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IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5
- 2007
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Ingår i: Genes Immun. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 8:6, s. 503-12
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Tidskriftsartikel (refereegranskat)abstract
- In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.
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| 3. |
- Borgegard, Tomas, et al.
(författare)
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Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.
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| 4. |
- Gruber, A, et al.
(författare)
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A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia
- 2003
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Ingår i: Leukemia Research. - 0145-2126 .- 1873-5835. ; 27, s. 323-
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Tidskriftsartikel (refereegranskat)abstract
- The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate. Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10mg/kg per 24h in combination with daunorubicin 45mg/m2 for 3 days and cytarabine 1g/m2 twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients. ⌐ 2002 Elsevier Science Ltd. All rights reserved.
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| 5. |
- Gustavsson, Anders, et al.
(författare)
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Clinical trial : colectomy after rescue therapy in ulcerative colitis-3-year follow-up of the Swedish-Danish controlled infliximab study
- 2010
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley. - 0269-2813 .- 1365-2036. ; 32:8, s. 984-989
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Tidskriftsartikel (refereegranskat)abstract
- Background The long-term efficacy of infliximab as rescue therapy in steroid-refractory ulcerative colitis is not well described. Aim To examine the long-term efficacy of infliximab as a rescue therapy through a 3-year follow-up of a previous placebo-controlled trial of infliximab in acute steroid-refractory ulcerative colitis. Method In the original study, 45 patients were randomized to a single infusion of infliximab 5 mg/kg or placebo, and at 3 months, 7/24 patients given infliximab were operated vs. 14/21 patients given placebo. Three years or later, patients were asked to participate in a clinical follow-up. Results Another seven patients underwent colectomy during follow-up: five in the infliximab group and two in the placebo group. After 3 years, a total of 12/24 (50%) patients given infliximab and 16/21 (76%) given placebo (P = 0.012) had a colectomy. None of eight patients in endoscopic remission at 3 months later had a colectomy compared with 7/14 (50%) patients who were not in remission (P = 0.02). There was no mortality. Conclusion The benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years. The main advantage of infliximab treatment occurred during the first 3 months, whereas subsequent colectomy rates were similar in the two groups. Mucosal healing at 3 months influenced later risk of colectomy.
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| 6. |
- Lindehammer, Sabina, et al.
(författare)
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Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk
- 2008
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 45:4, s. 231-5
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.
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| 7. |
- Sedimbi, S. K., et al.
(författare)
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SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients
- 2007
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Ingår i: Genes Immun. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 8:6, s. 518-21
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Tidskriftsartikel (refereegranskat)abstract
- SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.
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| 8. |
- Åkesson, K, et al.
(författare)
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The non-inherited maternal HLA haplotype affects the risk for type 1 diabetes
- 2009
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Ingår i: International journal of immunogenetics. - 1744-3121 .- 1744-313X. ; 36:1, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to test the hypothesis that the human leucocyte antigen (HLA) haplotype that is not inherited from the mother, that is, the non-inherited maternal antigen (NIMA) affects the risk for type 1 diabetes (T1D). A total of 563 children with T1D and 286 non-diabetic control children from Sweden were genotyped for DRB1, DQA1 and DQB1 alleles. The frequency of positively (DR4-DQA1*0301-B1*0302 and DR3-DQA1*0501-B1*0201), negatively (DR15-DQ A1*0102-B1*0602) or neutrally (all other) T1D associated HLA haplotypes were compared between NIMA and non-inherited paternal antigen (NIPA). All comparisons were carried out between HLA-matched patients and controls. The frequency of positively associated NIMA was higher among both DR4/X-positive healthy individuals compared wit DR4/X-positive patients (P < 0.00003) and DR3/X-positive healthy individuals compared with DR3/X-positive patients (P < 0.009). No such difference was observed for NIPA. High-risk NIMA was increased compared to NIPA among healthy DR3/X- and DR4/X-positive children (P < 0.05). There was no difference in frequency of positively associated haplotypes between patient NIMA and NIPA. The NIMA but not the NIPA affects the risk for T1D, suggesting that not only the inherited but also non-inherited maternal HLA haplotypes, perhaps through microchimerism or other mechanisms, may influence the risk for the disease.
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