Author: Jason Curtis

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol (2018)

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Type of publication:
Journal article

Author(s):
Sydes, M R; Spears, M R; Mason, M D; Clarke, N W; Dearnaley, D P; de Bono, J S; Attard, G; Chowdhury, S; Cross, W; Gillessen, S; Malik, Z I; Jones, R; Parker, C C; Ritchie, A W S; Russell, J M; Millman, R; Matheson, D; Amos, C; Gilson, C; Birtle, A; Brock, S; Capaldi, L; Chakraborti, P; Choudhury, A; Evans, L; Ford, D; Gale, J; Gibbs, S; Gilbert, D C; Hughes, R; McLaren, D; Lester, J F; Nikapota, A; O'Sullivan, J; Parikh, O; Peedell, C; Protheroe, A; Rudman, S M; Shaffer, R; Sheehan, D; Simms, M; *Srihari, N; Strebel, R; Sundar, S; Tolan, S; Tsang, D; Varughese, M; Wagstaff, J; Parmar, M K B; James, N D; STAMPEDE Investigators

Citation:
Annals of Oncology : Official Journal of the European Society for Medical Oncology; May 2018; vol. 29 (no. 5); p. 1235-1248

Abstract:
 Background Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP versus SOC+DocP. Method Recruitment to SOC+DocP and SOC+AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for≥2years and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly×6+prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg+prednisolone 5mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC+AAP, and HR>1 favours SOC+DocP. Results A total of 566 consenting patients were contemporaneously randomised: 189 SOC+DocP and 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66years and median PSA 56ng/ml. With median follow-up 4years, 149 deaths were reported. For overall survival, HR=1.16 (95% CI 0.82-1.65); failure-free survival HR=0.51 (95% CI 0.39-0.67); progression-free survival HR=0.65 (95% CI 0.48-0.88); metastasis-free survival HR=0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR=1.02 (0.70-1.49); and symptomatic skeletal events HR=0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, and 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.Trial registration Clinicaltrials.gov: NCT00268476.

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Giant Circumflex Artery Aneurysm with a Coronary Sinus Fistula (2018)

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Type of publication:
Journal article

Author(s):
Libertini, Richard; *Walbridge, David; Jones, Hefin R; Gunning, Mark; Satur, Christopher Mr

Citation:
The Annals of Thoracic Surgery; May 2018 [online]

Abstract:
Giant coronary artery aneurysms (GCCAA) are extremely rare entities, and of the circumflex artery we are aware of only 13 case reports. We therefore provide this case report to add evidence of the natural history and pathophysiology and describe successful surgical treatment of the condition.

Design and implementation of a custom next generation sequencing panel for selected vitamin D associated genes (2017)

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Type of publication:
Journal article

Author(s):
Benson K.A.; Maxwell A.P.; Smyth L.J.; Kilner J.; McKnight A.J.; *Chand S. ; Borrows R.

Citation:
BMC Research Notes; Jul 2017; vol. 10 (no. 1); p. 348

Abstract:
 BACKGROUND: Biologically active vitamin D has an important regulatory role within the genome. It binds the vitamin D receptor (VDR) in order to control the expression of a wide range of genes as well as interacting with the epigenome to modify chromatin and methylation status. Vitamin D deficiency is associated with several human diseases including end-stage renal disease.METHODS: This article describes the design and testing of a custom, targeted next generation sequencing (NGS) panel for selected vitamin D associated genes. Sequencing runs were used to determine the effectiveness of the panel for variant calling, to compare efficiency and data across different sequencers, and to perform representative, proof of principle association analyses. These analyses were underpowered for significance testing. Amplicons were designed in two pools (163 and 166 fragments respectively) and used to sequence two cohorts of renal transplant recipients on the Ion Personal Genome Machine (PGM)TM and Ion S5TM XL desktop sequencers.RESULTS: Coverage was provided for 43.8 kilobases across seven vitamin D associated genes (CYP24A1, CUBN, VDR, GC, NADSYN1, CYP27B1, CYP2R1) as well as 38 prioritised SNPs. Sequencing runs provided sufficient sequencing quality, data output and validated the effective library preparation and panel design.CONCLUSIONS: This novel, custom-designed, validated panel provides a fast, cost effective, and specific approach for the analysis of vitamin D associated genes in a wide range of patient cohorts. This article does not report results from a controlled health-care intervention.

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Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register (2018)

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Type of publication:
Journal article

Author(s):
Humphries S.E.; Cooper J.A.; Seed M.; *Capps N.; Durrington P.N.; Jones B.; McDowell I.F.W.; Soran H.; Neil H.A.W.

Citation:
Atherosclerosis; Jul 2018; vol. 274 ; p. 41-46

Abstract:
 Background and aims: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992-2008 and 2008-2016. Methods: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20-79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). Results: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3%-76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32-8.89) pre-1992 to 4.66 (3.46-6.14) in 1992-2008 and 2.51 (1.01-5.17) post-2008, while in women the corresponding values were 7.23 (2.65-15.73), 4.42 (2.70-6.82) and 6.34 (2.06-14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29-2.08)), although in women the excess persisted (post-2008 3.65 (1.75-6.72)). Conclusions: The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately.

Approaches to alcohol screening in secondary care: a review and meta-analysis (2017)

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Type of publication:
Conference abstract

Author(s):
*Walsh S.; Haroon S.; Nirantharakumar K.; Bhala N.

Citation:
The Lancet; Nov 2017; vol. 390

Abstract:
Background Alcohol misuse is common among patients accessing secondary care and an important cause of premature disability and death. The objective of this review was to summarise approaches to alcohol screening in secondary care, including the diagnostic accuracy, uptake, yield, and implementation challenges. Methods Search terms for alcohol, screening, and secondary care were combined in Medline, EMBASE, and other bibliographic databases for English language studies published from Jan 1, 2000, to Sept 4, 2015. We included studies and reviews of any design that evaluated alcohol screening with questionnaires or biochemical tests among adolescents and adults in secondary care. The primary outcomes were the diagnostic accuracy, uptake, and yield of alcohol screening. A random-effects proportion meta-analysis summarised screening uptake and yield, stratified by clinical setting. Findings 97 articles met the inclusion criteria and were included, with data from 1 213 761 screened patients. The Alcohol Use Disorders Identification Test (AUDIT) and AUDITConsumption (AUDIT-C) were the most widely validated screening tests and demonstrated high diagnostic accuracy and uptake. Overall, uptake for alcohol screening in secondary care was 79% (95% CI 74-84; n=45 studies, 477 533 of 604 471 screened patients) and the highest uptake was in outpatient clinics at 91% (82-96; n=8, 208 245 of 228 841). Overall, the proportion of patients screening positive for alcohol misuse was 28% (23-32, n=44; 135 741 of 484 788) with the highest yield in outpatient clinics of 31% (22-41; n=7, 72 270 of 233 128). However, there was significant heterogeneity in estimates of both uptake and yield of alcohol screening (I2>90%). Interpretation Alcohol screening in secondary care is likely to have a high uptake and yield, particularly in outpatient clinics. AUDIT and AUDIT-C are the most widely validated screening tools for alcohol misuse in secondary care and have high diagnostic accuracy and uptake. The review included a large number of studies, and a range of clinical settings and patient groups, strengthening the generalisability of the findings. However, a systematic assessment of risk of bias was not conducted and study selection was performed by one reviewer. Further research is needed to evaluate the cost-effectiveness of alcohol screening in secondary care.

How accurate is glycated haemoglobin in patients with liver cirrhosis? A case series (2018)

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Type of publication:
Conference abstract

Author(s):
*Basavaraju N.; *Rangan S.; *Singh P.; *Moulik P

Citation:
Diabetic Medicine; Mar 2018; vol. 35 ; S1

Abstract:
Introduction: Glycated haemoglobin (HbA1c) is the gold standard for monitoring glycaemic control in patients with diabetes. We present three cases of chronic liver disease where HbA1c may be misleading. Case 1: A 71-year-old Caucasian woman with liver cirrhosis due to hepatitis C, Type 2 diabetes, previous bladder tuberculosis and chronic kidney disease stage 3 was evaluated in clinic. Her capillary glucose (CG) was 6 to 9 mmol/l, no hypoglycaemia. She was anaemic; HbA1c was low at 34mmol/mol. Fructosamine was elevated at 296umol/l (205 to 285). Case 2: A 38-year-old Caucasian man with alcoholic liver cirrhosis, portal hypertension, and Type 2 diabetes was admitted with haematemesis. His CG was 10 to 14 mmol/l and HbA1c 26mmol/mol. He had iron deficiency anaemia, deranged liver enzymes and renal function. Fructosamine was normal at 246umol/l. Case 3: A 65-year-old Caucasian woman with non-alcoholic steatohepatosis/cirrhosis, portal hypertension, Type 2 diabetes, iron deficiency anaemia was admitted with melena. Her CG was 12 to 14mmol/l and HbA1c 44mmol/mol. Results showed acute kidney injury, deranged liver enzymes, normal albumin but low haemoglobin. Fructosamine is awaited. All patients required insulin for management of their diabetes. Discussion: The degree of glycation (glucose binding to N-terminal valine of HbA) is dependent on glycation rate, glucose availability and lifespan of red blood cells. Reference range of HbA1c is based on normal lifespan of RBC. There are very limited studies in evaluating the accuracy of HbA1c in chronic liver disease (CLD). Multiple factors can shorten RBC survival in CLD, including anaemia, portal hypertension, hypersplenism, variceal bleeding, resulting in falsely low HbA1c. Fructosamine, glycated albumin can also be inaccurate. Capillary glucose monitoring should guide glycaemic management.

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A prospective study of hospitalised patients with diabetes and hypoglycaemia following the National Inpatient Diabetes Audit (NaDIA) (2018)

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Type of publication:
Conference abstract

Author(s):
*Htun H.; *Richardson E.; *Barton D.

Citation:
Diabetic Medicine; Mar 2018; vol. 35 ; S1

Abstract:
Background: A growing concern regarding increasing incidence of hypoglycaemia in hospitalised patients with diabetes and its association to all-cause mortality is well recognised. There has been no further study regarding the implication of appropriate management of hypoglycaemia following the NaDIA data 2016. Aims: To determine the quality of care provided to patients with diabetes with hypoglycaemia and to minimise the risk of avoidable complications and prolonged hospital stay. Methods: We prospectively identified 50 patients with diabetes who experienced one or more episodes of hypoglycaemia during their hospital stay in 2017. We assessed their clinical information regarding specific risk factors, medication and insulin prescription errors. Results: The study population identified the evidence of mild hypoglycaemic and severe hypoglycaemic episodes as 68% and 20% respectively. Recurrent hypoglycaemic episodes were highlighted as nine cases, especially in older patients aged over 65 years, with HbA1c >70mmol/mol. Their morbidity status was captured with mean prolonged hospital stay of 18 days. Regarding risk stratification, 44 cases were largely contributed to by a variety of clinical risk factors, whereas six cases (half of NaDIA 2016 figures) of those resulted from medication management errors, especially insulin prescription and administration. More than 90% of patients were seen by a member of the diabetes team following hypoglycaemic episodes. Conclusion: Our data confirm strong morbidity risk with recurrent hypoglycaemia. The study suggests much closer attention to correctable risk factors, so as to minimise avoidable complications with structured diabetes team input to ensure good quality care is to be maintained.

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A pilot experience in using a digital app to follow-up prostate cancer patients in Shropshire, UK (2018)

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Type of publication:
Conference abstract

Author(s):
*Phan Y.; *Loh A.; *Anandakumar A.; *Umranikar S.; *Elves A.

Citation:
European Urology, Supplements; Mar 2018; vol. 17 (no. 2)

Abstract:
Introduction & Objective: It is not uncommon for patients with cancer to experience physical, mental and social distress, forming a significant burden that has a negative impact on their quality of life. We have piloted a digital app called VitruCare in our hospital in order to address these issues in patients with prostate cancer. More importantly, the app also serves as a communication tool between the hospital medical team and the patients. Materials and Methods: Patients with prostate cancer were invited to use VitruCare in our pilot study. 53 users were followed prospectively. Data on various domains such as "My Goals", "My Lifestyle", "My Priorities", "My Diaries", and "How Do I Feel Today" were analysed retrospectively. Results: The users of this application have a median age of 72.5 years old. 14% have nodal or bone metastasis, and median time since treatment is 48 months. 60% have completed the lifestyle questionnaire and "How Do I Feel Today" trackers. 20% of the users who completed the lifestyle questionnaire reported anxiety. 42% have used the diary function and 47% have used the secured messaging function. Usage of the lifestyle questionnaire, "How Do I Feel Today" trackers, secured messaging and diary functions does not appear to be age related. Patients who have been treated and further away from treatment in time are more likely to be used the app. Conclusions: The level of engagement in this pilot study reflects the willingness of patients to utilize this innovative app that has the potential to monitor the well-being of patients with prostate cancer out with the constraints of a fixed clinic appointment.

Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. (2018)

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Type of publication:
Journal article

Author(s):
Hawkey, Peter M; *Warren, Roderic E; Livermore, David M; McNulty, Cliodna A M; Enoch, David A; Otter, Jonathan A; Wilson, A Peter R

Citation:
Journal of Antimicrobial Chemotherapy; Mar 2018; vol. 73 ; p. iii2

Abstract:
The Working Party makes more than 100 tabulated recommendations in antimicrobial prescribing for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) and suggest further research, and algorithms for hospital and community antimicrobial usage in urinary infection. The international definition of MDR is complex, unsatisfactory and hinders the setting and monitoring of improvement programmes. We give a new definition of multiresistance. The background information on the mechanisms, global spread and UK prevalence of antibiotic prescribing and resistance has been systematically reviewed. The treatment options available in hospitals using intravenous antibiotics and in primary care using oral agents have been reviewed, ending with a consideration of antibiotic stewardship and recommendations. The guidance has been derived from current peer-reviewed publications and expert opinion with open consultation. Methods for systematic review were NICE compliant and in accordance with the SIGN 50 Handbook; critical appraisal was applied using AGREE II. Published guidelines were used as part of the evidence base and to support expert consensus. The guidance includes recommendations for stakeholders (including prescribers) and antibiotic-specific recommendations. The clinical efficacy of different agents is critically reviewed. We found there are very few good-quality comparative randomized clinical trials to support treatment regimens, particularly for licensed older agents. Susceptibility testing of MDR GNB causing infection to guide treatment needs critical enhancements. Meropenem- or imipenem-resistant Enterobacteriaceae should have their carbapenem MICs tested urgently, and any carbapenemase class should be identified: mandatory reporting of these isolates from all anatomical sites and specimens would improve risk assessments. Broth microdilution methods should be adopted for colistin susceptibility testing. Antimicrobial stewardship programmes should be instituted in all care settings, based on resistance rates and audit of compliance with guidelines, but should be augmented by improved surveillance of outcome in Gram-negative bacteraemia, and feedback to prescribers. Local and national surveillance of antibiotic use, resistance and outcomes should be supported and antibiotic prescribing guidelines should be informed by these data. The diagnosis and treatment of both presumptive and confirmed cases of infection by GNB should be improved. This guidance, with infection control to arrest increases in MDR, should be used to improve the outcome of infections with such strains. Anticipated users include medical, scientific, nursing, antimicrobial pharmacy and paramedical staff where they can be adapted for local use.

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A rare presentation of haematuria: hip prosthesis in the bladder (2018)

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Type of publication:
Journal article

Author(s):
*Phan, Yih Chyn; *Eli, Nnaemeka; *Pillai, Praveen; *O'Dair, Jonathan

Citation:
BMJ case reports; Mar 2018; vol. 2018

Abstract:
An 80-year-old woman presented to our department with visible haematuria and stage II acute kidney injury (AKI). She had stage IIB cervical cancer, for which she received chemotherapy and external beam radiotherapy in 2003. Four years later, she had a left dynamic hip screw for an extracapsular neck of femur fracture following a fall. In 2010, she underwent a right total hip replacement owing to osteoarthritis, and it was subsequently revised in 2012 owing to a right acetabular component failure. In this admission, her AKI improved with intravenous fluid administration and her haematuria settled following catheterisation with a three-way catheter and bladder irrigation with saline. She underwent a flexible cystoscopy which revealed that a part of her right hip prosthesis was in the bladder, having eroded through the right bony pelvis. However, she declined any surgical interventions.

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