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- Parker, C., et al.
(författare)
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Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 369:3, s. 213-223
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Tidskriftsartikel (refereegranskat)abstract
- Background Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. Methods In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. Results At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. Conclusions In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.)
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| 3. |
- Nilsson, S., et al.
(författare)
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A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer
- 2012
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Ingår i: European Journal of Cancer. - Oxford : Elsevier. - 0959-8049 .- 1879-0852. ; 48:5, s. 678-686
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Forskningsöversikt (refereegranskat)abstract
- Purpose: To investigate the dose-response relationship and pain-relieving effect of radium-223, a highly bone-targeted alpha-pharmaceutical. Methods: One hundred patients with castration-resistant prostate cancer (CRPC) and painful bone metastases were randomized to a single intravenous dose of 5, 25, 50 or 100 kBq/kg radium-223. The primary end-point was pain index (visual analogue scale [VAS] and analgesic use), also used to classify patients as responders or non-responders. Results: A significant dose response for pain index was seen at week 2 (P = .035). At week 8 there were 40%, 63%, 56% and 71% pain responders (reduced pain and stable analgesic consumption) in the 5, 25, 50 and 100 kBq/kg groups, respectively. On the daily VAS, at week 8, pain decreased by a mean of -30, -31, -27 and -28 mm, respectively (P = .008, P = .0005, P = .002, and P < .0001) in these responders (post-hoc analysis). There was also a significant improvement in the brief pain inventory functional index for all dose-groups (P = .04, .01, .002 and .02, Wilcoxon signed rank test). Furthermore, a decrease in bone alkaline phosphatase in the highest dose-group was demonstrated (P = .0067). All doses were safe and well tolerated. Conclusion: Pain response was seen in up to 71% of the patients with a dose response observed 2 weeks after administration. The highly tolerable side-effect profile of radium-223 previously reported was confirmed. (C) 2012 Elsevier Ltd. All rights reserved.
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| 6. |
- Haldorsen, K., et al.
(författare)
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No association of primary Sjogren's syndrome with Fc gamma receptor gene variants
- 2013
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 14:4, s. 234-237
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of primary Sjogren's syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcg receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fc gamma receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N = 527) and controls (N = 528) were genotyped for the Fc gamma receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fc gamma receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.
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| 8. |
- Nilsson, S., et al.
(författare)
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Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study
- 2007
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Ingår i: Lancet Oncol. - 1470-2045 .- 1474-5488. ; 8:7, s. 587-594
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The alpha-emitter radium-223 ((223)Ra) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone-refractory prostate cancer. We aimed to study mature outcomes from a randomised, multicentre, phase II study of (223)Ra. METHODS: Patients with hormone-refractory prostate cancer and bone pain needing external-beam radiotherapy were assigned to four intravenous injections of (223)Ra (50 kBq/kg, 33 patients) or placebo (31 patients), given every 4 weeks. Primary endpoints were change in bone-alkaline phosphatase (ALP) concentration and time to skeletal-related events (SREs). Secondary endpoints included toxic effects, time to prostate-specific-antigen (PSA) progression, and overall survival. All tests were done at a 5% significance level, based on intention to treat. FINDINGS: Median relative change in bone-ALP during treatment was -65.6% (95% CI -69.5 to -57.7) and 9.3% (3.8-60.9) in the (223)Ra group and placebo groups, respectively (p<0.0001, Wilcoxon ranked-sums test). Hazard ratio for time to first SRE, adjusted for baseline covariates, was 1.75 (0.96-3.19, p=0.065, Cox regression). Haematological toxic effects did not differ significantly between two groups. No patient discontinued (223)Ra because of treatment toxicity. Median time to PSA progression was 26 weeks (16-39) versus 8 weeks (4-12; p=0.048) for (223)Ra versus placebo, respectively. Median overall survival was 65.3 weeks (48.7-infinity) for (223)Ra and 46.4 weeks (32.1-77.4) for placebo (p=0.066, log rank). The hazard ratio for overall survival, adjusted for baseline covariates was 2.12 (1.13-3.98, p=0.020, Cox regression). INTERPRETATION: (223)Ra was well tolerated with minimum myelotoxicity, and had a significant effect on bone-ALP concentrations. Larger clinical trials are warranted to study (223)Ra on the prevention of SREs and on overall survival in patients with hormone-refractory prostate cancer. Bone-targeting properties of (223)Ra could also potentially be used for treating skeletal metastasis from other primary cancers.
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| 10. |
- Tjensvoll, K, et al.
(författare)
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Haplotype analysis of Norwegian and Swedish patients with acute intermittent porphyria (AIP): Extreme haplotype heterogeneity for the mutation R116W
- 2003
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Ingår i: Disease markers. - : Hindawi Limited. - 0278-0240 .- 1875-8630. ; 19:1, s. 41-46
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Tidskriftsartikel (refereegranskat)abstract
- Acute intermittent porphyria (AIP), the most common of the acute porphyrias, is caused by mutations in the gene encoding hydroxymethylbilane synthase (HMBS) also called porphobilinogen deaminase (PBGD). The mutation spectrum in the HMBS gene is characterized by a majority of family specific mutations. Among the exceptions are R116W and W198X, with high prevalence in both the Dutch and Swedish populations. These two mutations were also detected in unrelated Norwegian patients. Thus, Norwegian and Swedish patients were haplotyped using closely linked flanking microsatellites and intragenic single nucleotide polymorphisms (SNPs) to see if the high frequency of these two mutations is due to a founder effect. Twelve intragenic SNPs were determined by a method based on fluorescent restriction enzyme fingerprinting single-strand conformation polymorphism (F-REF-SSCP).W198X occurred exclusively on one haplotype in both Norwegian and Swedish patients, showing that it has originated from a common gene source. In contrast, R116W was found on three different haplotypes in three Norwegian families, and in five Swedish families on four or five haplotypes. This extreme haplotype heterogeneity indicates that R116W is a recurrent mutation, maybe explained by the high mutability of CpG dinucleotides. This can also explain why it is the only AIP mutation reported to occur in seven different populations (Norway, Sweden, Finland, Netherlands, France, Spain and South Africa).
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| 11. |
- Haugarvoll, K., et al.
(författare)
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GBA2 Mutations Cause a Marinesco-Sjogren-Like Syndrome: Genetic and Biochemical Studies
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background With the advent new sequencing technologies, we now have the tools to understand the phenotypic diversity and the common occurrence of phenocopies. We used these techniques to investigate two Norwegian families with an autosomal recessive cerebellar ataxia with cataracts and mental retardation. Single nucleotide polymorphism (SNP) chip analysis followed by Exome sequencing identified a 2 bp homozygous deletion in GBA2 in both families, c.1528_1529de1 [p.Met510Valfs*17]. Furthermore, we report the biochemical characterization of GBA2 in these patients. Our studies show that a reduced activity of GBA2 is sufficient to elevate the levels of glucosylceramide to similar levels as seen in Gaucher disease. Furthermore, leucocytes seem to be the proper enzyme source for in vitro analysis of GBA2 activity. We report GBA2 mutations causing a Marinesco-Sjogren-like syndrome in two Norwegian families. One of the families was originally diagnosed with Marinesco-Sjogren syndrome based on an autosomal recessive cerebellar ataxia with cataracts and mental retardation. Our findings highlight the phenotypic variability associated with GBA2 mutations, and suggest that patients with Marinesco-Sjogren-like syndromes should be tested for mutations in this gene.
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