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Institution

Leicester Royal Infirmary

HealthcareLeicester, United Kingdom
About: Leicester Royal Infirmary is a healthcare organization based out in Leicester, United Kingdom. It is known for research contribution in the topics: Population & Carotid endarterectomy. The organization has 5300 authors who have published 6204 publications receiving 208464 citations.


Papers
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Journal ArticleDOI
TL;DR: In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient malignant pleural mesothelioma and warrants further clinical investigation inArginine-dependent cancers.
Abstract: Importance Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. Objective To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. Design, Setting, and Participants A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. Interventions Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m 2 , weekly intramuscular) plus best supportive care (BSC) or BSC alone. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18 F-fluorodeoxyglucose positron-emission tomography. Results Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group ( P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group ( P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group ( P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. Conclusions and Relevance In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. Trial Registration clinicaltrials.gov Identifier:NCT01279967

149 citations

Journal ArticleDOI
TL;DR: Examining whether surgery before a 36h watershed improves survival and the effect of various parameters on in-patient mortality found that ultra-early surgery (within 12h) reduces risk of in-hospital mortality andeditious surgery is associated with improved patient survival.
Abstract: Background Hip fracture is a common injury with associated high mortality. Recent drives by the Department of Health have sought to prioritise these patients’ care. In April 2010, the Best Practice Tariff was introduced in England and Wales. This offers financial incentives to institutions that provide holistic care and surgery within 36 h for hip fracture patients. The England and Wales National Institute for Health and Clinical Excellence (NICE) published its first guidance on hip fracture management in June 2011, and emphasised the need for surgery on the day or day after admission. In spite of the emphasis placed on this injury, the predictors of in-hospital mortality remain ill-defined. In particular the effect of the timing of surgery remains contentious. Objective To address the issues raised by NICE around surgical timing and examine whether surgery before a 36 h watershed improves survival. In addition, to examine survival outcomes for each 12 h watershed following admission. Materials and methods Prospectively collected data on 2056 patients presenting to our unit with hip fractures between February 2008 and May 2011 were retrospectively reviewed. Multivariate regression analysis was used to correct for confounders, and so determine the effect of various parameters on in-patient mortality. Results Age ( p p p p p p p Conclusions Expeditious surgery is associated with improved patient survival. Other predictors of in-hospital mortality include age, gender, in-hospital fracture and ASA-grade. Ultra-early surgery (within 12 h) reduces risk of in-hospital mortality.

149 citations

Journal ArticleDOI
TL;DR: Hemopoietic stem cell transplantation can be performed safely in patients with RA, and initial results indicate significant responses in patientsWith severe, treatment-resistant disease.
Abstract: Objective. Evidence from animal studies, case reports, and phase I studies suggests that hemopoietic stem cell transplantation (HSCT) can be effective in the treatment of rheumatoid arthritis (RA). It is unclear, however, if depletion of T cells in the stem cell product infused after high-dose chemotherapy is beneficial in prolonging responses by reducing the number of infused autoreactive T cells. This pilot multicenter, randomized trial was undertaken to obtain feasibility data on whether CD34 selection (as a form of T cell depletion) of an autologous stem cell graft is of benefit in the HSCT procedure in patients with severe, refractory RA. Methods. Thirty-three patients with severe RA who had been treated unsuccessfully with methotrexate and at least 1 other disease-modifying agent were enrolled in the trial. The patients received high-dose immunosuppressive treatment with 200 mg/kg cyclophosphamide followed by an infusion of autologous stem cells that were CD34 selected or unmanipulated. Safety, efficacy (based on American College of Rheumatology [ACR] response criteria), and time to recurrence of disease were assessed on a monthly basis for up to 12 months. Results. All patients were living at the end of the study, with no major unexpected toxicities. Overall, on an intent-to-treat basis, ACR 20% response (ACR20) was achieved in 70% of the patients. An ACR70 response was attained in 27.7% of the 18 patients who had received CD34-selected cells and 53.3% of the 15 who had received unmanipulated cells (P = 0.20). The median time to disease recurrence was 147 days in the CD34-selected cell group and 201 days in the unmanipulated cell group (P = 0.28). There was no relationship between CD4 lymphopenia and response, but 72% of rheumatoid factor (RF)-positive patients had an increase in RF titer prior to recurrence of disease. Conclusion. HSCT can be performed safely in patients with RA, and initial results indicate significant responses in patients with severe, treatment-resistant disease. Similar outcomes were observed in patients undergoing HSCT with unmanipulated cells and those receiving CD34-selected cells. Larger studies are needed to confirm these findings.

149 citations

Journal ArticleDOI
TL;DR: Gastrin induces proliferation via the CCK(2) receptor in Barrett's mucosa and may have implications for the management of patients with Barrett's esophagus in whom gastrin is elevated by acid-suppression therapy.

148 citations

Journal ArticleDOI
TL;DR: Five antibodies directed against the whole or part of p53 protein have been used to detect the protein immunohistochemically in 70 infiltrating breast carcinomas and 10 ductal carcinomas in situ.
Abstract: Five antibodies directed against the whole or part of p53 protein have been used to detect the protein immunohistochemically in 70 infiltrating breast carcinomas and 10 ductal carcinomas in situ. Mutations are known to occur in different conserved domains, and the antibodies employed spanned the expected sites. p53 protein was identified in 53 per cent of infiltrating carcinomas using the antibodies PAb 240, PAb 1801, C19, and JG8. The antibody PAb 421 detected the protein in 31.5 per cent; all positive with the other antibodies. Well-differentiated oestrogen receptor-positive tumours had a low incidence of p53 detection. Variation in the percentage of reactivity was seen between carcinomas and in some cases between different antibodies in the same cancer. Those carcinomas with a high percentage of positive cells with all antibodies were more likely to have metastasized to nodes, be at an advanced stage, and be oestrogen receptor-negative/epidermal growth factor receptor-positive. There was no significant correlation with c-erbB-2 protein expression or retinoblastoma protein loss. p53 protein was detected in a high proportion of cells in three of the six comedo ductal carcinomas in situ studied but either not at all or at a lower level in tumours of the cribriform type. p53 mutations are common in breast carcinomas, but heterogeneity within individual tumours is frequent. Marked expression of p53 appears to relate to tumour progression.

148 citations


Authors

Showing all 5314 results

NameH-indexPapersCitations
George Davey Smith2242540248373
Nilesh J. Samani149779113545
Peter M. Rothwell13477967382
John F. Thompson132142095894
James A. Russell124102487929
Paul Bebbington11958346341
John P. Neoptolemos11264852928
Richard C. Trembath10736841128
Andrew J. Wardlaw9231133721
Melanie J. Davies8981436939
Philip Quirke8937834071
Kenneth J. O'Byrne8762939193
David R. Jones8770740501
Keith R. Abrams8635530980
Martin J. S. Dyer8537324909
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
20234
202219
2021168
2020120
2019110
2018121