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The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer
No full textPARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer(1,2), who were germline BRCA1 and BRCA2 wild type(3). Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)(4), and secondary end points included event-free survival (EFS) and overall survival (OS)(5). pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .Accepted version (6 month embargo), submitted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial
No full textBACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided a of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.Published version, accepted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Genetic modifiers of rare variants in monogenic developmental disorder loci
No full textRare damaging variants in a large number of genes are known to cause monogenic developmental disorders (DDs) and have also been shown to cause milder subclinical phenotypes in population cohorts. Here, we show that carrying multiple (2-5) rare damaging variants across 599 dominant DD genes has an additive adverse effect on numerous cognitive and socioeconomic traits in UK Biobank, which can be partially counterbalanced by a higher educational attainment polygenic score (EA-PGS). Phenotypic deviators from expected EA-PGS could be partly explained by the enrichment or depletion of rare DD variants. Among carriers of rare DD variants, those with a DD-related clinical diagnosis had a substantially lower EA-PGS and more severe phenotype than those without a clinical diagnosis. Our results suggest that the overall burden of both rare and common variants can modify the expressivity of a phenotype, which may then influence whether an individual reaches the threshold for clinical disease.Accepted version (6 months embargo), submitted versionJournal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Cyanoacrylate venous closure - Untold story or unjustified alarm?
No full textPublished version, accepted versionRDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Clinical utility of anti-Müllerian hormone in female children and adolescents
No full textAnti-Müllerian hormone (AMH) is a dimeric glycoprotein that belongs to the transforming growth factor beta superfamily and plays essential roles in sexual differentiation and folliculogenesis. In the male embryo, AMH is produced by the Sertoli cells and induces the involution of the Müllerian ducts. In females, AMH is predominately produced by the granulosa cells of growing preantral and small antral follicles and regulates follicular maturation. Many recent studies have highlighted the significant role of this hormone in the diagnostic approach to female children and adolescents with various disorders that affect ovarian development and function. AMH is considered a valuable diagnostic tool in the management of female pediatric patients with conditions such as polycystic ovary syndrome, precocious puberty, ovarian tumors, differences in sex development, and premature ovarian insufficiency. Standardization of AMH assays, internationally approved reference values based on age and pubertal stage, and widespread availability of the test could further upgrade the clinical utility of AMH, rendering it a valuable tool in the armamentarium of physicians involved in the care of female children and adolescents, and promote future research.Not hel
Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of the Phase 2 RAIDER Randomised Controlled Trial
No full textBACKGROUND AND OBJECTIVE: Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule. METHODS: RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART. KEY FINDINGS AND LIMITATIONS: A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy. CONCLUSIONS AND CLINICAL IMPLICATIONS: Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial
No full textBACKGROUND: The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation. METHODS: We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7-14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing. FINDINGS: Between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI -0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (p(non-inferiority)=0·0003). Superiority was not identified (p(superiority)=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, -0·004 to 0·006; p=0·78). INTERPRETATION: Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation. FUNDING: British Heart Foundation.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Air Pollution and Myocardial Infarction-A New Smoker's Paradox?
No full textBackground/Objectives: Ambient air pollution is a significant public health concern, known to affect cardiovascular health adversely. Research has identified both long-term and short-term cardiovascular risks associated with various air pollutants, including those linked to acute coronary syndromes. However, the observed effects are rather small, with most data sourced from highly polluted regions. Methods: This study utilized a prospective registry database, documenting 12,581 myocardial infarction (MI) events in Styria, Austria from January 2007 to December 2015. Pollutants analyzed included particulate matter (PM(2.5), PM(10)) and gases, such as NO(2), CO, SO(2), O(3) and NOx. We employed generalized linear models to examine the interaction of each of these pollutants on the daily incidence of MI. Additionally, we conducted separate analyses for patients with specific comorbidities: diabetes mellitus (DM), arterial hypertension (HTN), heart failure with reduced ejection fraction (HFrEF), chronic obstructive pulmonary disease (COPD) and current smokers. Results: No significant associations were identified between any of the pollutants and MI incidence, both in the overall cohort and in patient subgroups with DM, HTN, HFrEF or COPD. However, among active smokers, we observed a decreased relative risk of MI associated with elevated levels of NO(2), CO, SO(2) and NOx on the day of MI (p < 0.01 for all pollutants). Conversely, an increased MI risk was associated with rising ozone levels (p = 0.0027). This counterintuitive finding aligns with previously published data and may suggest a new dimension to the smoker's paradox". Conclusions: In regions with low pollution levels, air pollutants pose only minor or insignificant short-term risks for myocardial infarction. Active smokers exhibit an altered response to ambient air pollution."Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
Frequencies and causes of ABO-incompatible red cell transfusions in France, Germany and the United Kingdom
No full textPrevention of ABO-incompatible red cell transfusions (ABO-it) requires accurate donor and patient identification and correct application of processes for transfusion safety. In France and Germany, a bedside identity check and ABO compatibility test are performed. In the UK, an identity check, often structured as a bedside checklist, is performed with or without electronic patient identification (ePID). To compare the efficacy of ABO-it bedside preventive measures, frequencies and causes of ABO-it between 2013 and 2022 were investigated in all three countries. Despite differing bedside safety measures, similar average ABO-it frequencies were observed in France (0.19 [SD:0.09]/100 000 issued red cell units) and in the UK (0.28 [SD:0.17]/100 000), whereas a higher frequency (0.71 [SD:0.23]/100 000) was observed in Germany which has similar bedside safety measures to France. ABO-it resulted mostly from erroneous patient identification and transfusion of a red cell unit intended for another patient. In France and Germany, all ABO-it were associated with incorrectly performed identity check and ABO compatibility test. In the UK, most ABO-it were associated with incorrectly performed identity checks. Current measures to prevent ABO-it are not fully effective. Further development and implementation of effective patient identification systems, including electronic information systems, across the entire transfusion process, should be considered.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
Technological advances in diabetes
No full textFull Text unavailable for 1 year from time of publication