| 1. |
- Su, Zhan, et al.
(författare)
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Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
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Tidskriftsartikel (refereegranskat)abstract
- Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.
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| 3. |
- Gillies, Mark C., et al.
(författare)
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Triamcinolone-induced cataract in eyes with diabetic macular oedema: 3-year prospective data from a randomized clinical trial
- 2010
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Ingår i: Clinical and Experimental Ophthalmology. - : Wiley. - 1442-6404. ; 38:6, s. 605-612
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Tidskriftsartikel (refereegranskat)abstract
- P>Purpose: To describe the 3-year risk of cataract after intravitreal triamcinolone (IVTA) injections for diabetic macular oedema and the outcomes of cataract surgery. Methods: Prospective data from a randomized clinical trial were analysed. At baseline, 27 phakic eyes with diabetic macular oedema were randomized to receive IVTA and 25 to receive sham injection. After 2 years, initial sham-treated eyes were eligible to receive IVTA as the study became open label for the third year. The cumulative incidence of cataract surgery was the primary outcome of the study. Other outcomes assessed included progression of cataract, best-corrected logarithm of the minimal angle of resolution visual acuity before and after surgery and central macular thickness. Results: Over the 3 years of the study, 15/27 (56%) phakic eyes in the IVTA treated group underwent cataract surgery as compared with 2/25 (8%) initial sham-treated eyes (P < 0.001). Mean visual acuity 6 months after cataract surgery was better than at entry into the trial. Two (15%) of the eyes in the IVTA-treated group undergoing cataract surgery had a loss of > 15 letters. In the IVTA-treated group, 10/15 (67%) eyes that had three or more injections had progression of posterior subcapsular cataract by >= 2 grades as compared with only 2/12 (17%) eyes that had fewer than three injections (P = 0.009). Conclusions: Over half of the eyes receiving IVTA injections for diabetic macular oedema required cataract surgery within 3 years. In eyes with three or more IVTA injections, two-thirds had progression of posterior subcapsular cataract. Visual outcomes after cataract surgery were generally good, although a small proportion of eyes lost greater than 15 letters over the course of the study.
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| 4. |
- Higgins, Geoff S, et al.
(författare)
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Overexpression Of POLQ Confers a Poor Prognosis In Early Breast Cancer Patients.
- 2010
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Ingår i: Oncotarget. - 1949-2553. ; 1:3, s. 175-184
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Tidskriftsartikel (refereegranskat)abstract
- Depletion of POLQ (DNA polymerase theta) has recently been shown to render tumour cells more sensitive to radiotherapy whilst having little or no effect on normal tissues. This finding led us to investigate whether tumours that overexpress POLQ are associated with an adverse outcome. We therefore correlated the clinical outcomes of two retrospective series of patients with early breast cancer with the expression levels of POLQ, as determined by microarray gene expression analysis. We found that a significant number of tumours overexpressed POLQ and that overexpression was correlated with ER negative disease (p=0.047) and high tumour grade (p=0.004), both of which are associated with poor clinical outcomes. POLQ overexpression was associated with poor relapse free survival rates on both univariate (HR 5.80; 95% CI, 2.220 to 15.159; p<0.001) and multivariate analysis (HR 8.086; 95% CI 2.340 to 27.948 p=0.001). Analysis of other published clinical series confirmed that POLQ overexpression is associated with adverse clinical outcomes. The poor prognosis associated with POLQ is independent of other clinical or pathological features. The mechanism that causes this adverse outcome remains to be elucidated but may in part arise from resistance to adjuvant treatment. These findings, combined with the limited normal tissue expression of POLQ, make it a very appealing target for possible clinical exploitation.
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| 6. |
- Sartor, Oliver, et al.
(författare)
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Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases : results from a phase 3, double-blind, randomised trial
- 2014
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Ingår i: The Lancet Oncology. - 1470-2045 .- 1474-5488. ; 15:7, s. 738-746
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Tidskriftsartikel (refereegranskat)abstract
- Background Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range a-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases. Methods In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2: 1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751. Findings Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15.6 months [95% CI 13.5-18.0] vs 9.8 months [7.3-23.7]; hazard ratio [HR] = 0.66, 95% CI 0.52-0.83; p = 0.00037). The risks of external beam radiation therapy for bone pain (HR 0.67, 95% CI 0.53-0.85) and spinal cord compression (HR = 0.52, 95% CI 0.29-0.93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0.62, 95% CI 0.35-1.09), or the need for tumour-related orthopaedic surgical intervention (HR 0.72, 95% CI 0.28-1.82). Interpretation Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.
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