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Objective To determine the additional diagnostic value of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced imaging (DCE) in men requiring a repeat biopsy within the PICTURE study. Patients and methods PICTURE was a paired-cohort confirmatory study in which 249 men who required further risk stratification after a previous non-magnetic resonance imaging (MRI)-guided transrectal ultrasonography-guided biopsy underwent a 3-Tesla (3T) multiparametic (mp)MRI consisting of T2-weighted imaging (T2W), DWI and DCE, followed by transperineal template prostate mapping biopsy. Each mpMRI was reported using a LIKERT score in a sequential blinded manner to generate scores for T2W, T2W+DWI and T2W+DWI+DCE. Area under the receiver-operating characteristic curve (AUROC) analysis was performed to compare the diagnostic accuracy of each combination. The threshold for a positive mpMRI was set at a LIKERT score ≥3. Clinically significant prostate cancer was analysed across a range of definitions including UCL/Ahmed definition 1 (primary definition), UCL/Ahmed definition 2, any Gleason ≥3 + 4 and any Gleason ≥4 + 3. Results Of 249 men, sequential MRI reporting was available for 246. There was a higher rate of equivocal lesions (44.6%) using T2W alone compared to the addition of DWI (23.9%) and DCE (19.8%). Using the primary definition of clinically significant disease, there was no significant difference in the overall accuracy between T2W, with an AUROC of 0.74 (95% confidence interval [CI] 0.68-0.80), T2W+DWI at 0.76 (95% CI 0.71-0.82), and T2W+DWI+DCE, with an AUROC of 0.77 (95% CI 0.71-0.82; P = 0.55). The AUROC values remained comparable using other definitions of clinically significant disease including UCL/Ahmed definition 2 (P = 0.79), Gleason ≥3 + 4 (P = 0.53) and Gleason ≥4 + 3 (P = 0.53). Conclusions Using 3T MRI, a high level of diagnostic accuracy can be achieved using T2W as a single parameter in men with a prior biopsy; however, such a strategy can lead to a higher rate of equivocal lesions.

The availability of mutation-specific cystic fibrosis modulator therapies has the potential to improve the lives of children and adults with cystic fibrosis. The frequency of mutations causing defects in the cystic fibrosis transmembrane conductance regulator (CFTR) function varies between sub-groups in multi-ethnic populations. The profile of patients eligible for CFTR modulator ivacaftor/tezacaftor/elexacaftor (Kaftrio™) therapy based on ethnicity has not been reported in the United Kingdom CF population.We conducted a descriptive cross-sectional analysis of patients in the UK CF Registry who had annual review data submissions in 2019. Data analysed included demographic characteristics, spirometry, chronic Pseudomonas status, nutrition, and CF related diabetes status. The genotype data was stratified by whether there was at least one copy of F508del or no copy of F508del as current eligibility for ivacaftor/tezacaftor/elexacaftor, or projected future eligibility, is defined as having at least one copy of F508del mutation.Data from 9887 patients were reviewed, 46.7% female, mean age 22.5 years. 8.6% (n = 852) patients had no copy of F508del making them ineligible for ivacaftor/tezacaftor/elexacaftor. Overall, 93.4% of patients were of white ethnicity, with a similar proportion of those with at least one F508del being white (95.6%). This was reduced to 70.0% of those with no F508del. The proportion of people of Asian ethnicity was much higher in the no F508del group (19.2% vs 1.2%). Compared with one F508del patients, the no F508del group were older (25.2 years vs 22.2 years, p 0.001), had higher prevalence of pancreatic sufficiency (39.0% vs 14.9% p 0.001), lower prevalence of chronic Pseudomonas infection (21.1% vs. 26.6%, p 0.001), and higher best FEVPatients from black, Asian and minority ethnic backgrounds are significantly less likely to be eligible for ivacaftor/tezacaftor/elexacaftor based on the current prescribing policy in the UK. At present this is the most highly effective CF modulator therapy available to treat people with CF. The CF community should urgently address the unmet need for effective targeted therapies for patients without F508del.

Background Airway clearance techniques (ACTs) are integral to cystic fibrosis (CF) management. However, there is no consensus as to which outcome measures (OMs) are best for assessing ACT efficacy. Objectives: To summarise OMs that have been assessed for their clinimetric properties (including validity, feasibility, reliability & reproducibility) within the context of ACT research. MethodsEligibility Criteria - Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population. Information sources: Five medical databases; clinicaltrials.gov; abstracts from international CF conferences. Risk of Bias - The authors planned to independently assess study quality and risk of bias using the COSMIN risk of bias checklist with external validity assessment based upon study details (participants and study intervention).Synthesis of Results – Two review authors (GS and MJ) independently screened search results against inclusion criteria, further data extraction was planned but not required.ResultsIncluded studies - No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post-hoc secondary objective. Two ongoing trials were identified.DiscussionLimitations of evidence: The search strategy may have missed some lesser-known terms for ACT or manuscripts reporting clinimetric properties solely within text. Studies validating outcome measures for use in other aspects of CF, which may be relevant to ACT, are not included.Interpretation - High-quality RCTs are urgently needed to investigate & validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of CFTR modulator therapies, an accurate assessment of the current benefit of ACT or the effect of ACT withdrawal is a high priority for clinical practice and future research and OMs which have been validated for this purpose are essential.OtherFunding: NIHR/HEE Clinical Doctoral Fellowship grant for GS (reference CDRF-2014-05-055).Systematic review registration number - PROSPERO no.CRD42020206033

RationaleA previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results.ObjectivesTo compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences.MethodsWe used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics).ResultsWe included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK.ConclusionsChildren with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

Background Cancer stage can be missing in national cancer registry records. We explored whether missing prostate cancer stage can be imputed using specific clinical assumptions. Methods Prostate cancer patients diagnosed between 2010 and 2013 were identified in English cancer registry data and linked to administrative hospital and mortality data (n = 139,807). Missing staging items were imputed based on specific assumptions: men with recorded N-stage but missing M-stage have no distant metastases (M0); low/intermediate-risk men with missing N- and/or M-stage have no nodal disease (N0) or metastases; and high-risk men with missing M-stage have no metastases. We tested these clinical assumptions by comparing 4-year survival in men with the same recorded and imputed cancer stage. Multi-variable Cox regression was used to test the validity of the clinical assumptions and multiple imputation. Results Survival was similar for men with recorded N-stage but missing M-stage and corresponding men with M0 (89.5% vs 89.6%); for low/intermediate-risk men with missing M-stage and corresponding men with M0 (92.0% vs 93.1%); and for low/intermediate-risk men with missing N-stage and corresponding men with N0 (90.9% vs 93.7%). However, survival was different for high-risk men with missing M-stage and corresponding men with M0. Imputation based on clinical imputation performs as well as statistical multiple imputation. Conclusion Specific clinical assumptions can be used to impute missing information on nodal involvement and distant metastases in some patients with prostate cancer.

We evaluated the detection of clinically significant prostate cancer using magnetic resonance imaging targeted biopsies and compared visual estimation to image fusion targeting in patients requiring repeat prostate biopsies.The prospective, ethics committee approved PICTURE trial (ClinicalTrials.gov NCT01492270) enrolled 249 consecutive patients from January 11, 2012 to January 29, 2014. Men underwent multiparametric magnetic resonance imaging and were blinded to the results. All underwent transperineal template prostate mapping biopsies. In 200 men with a lesion this was preceded by visual estimation and image fusion targeted biopsies. As the primary study end point clinically significant prostate cancer was defined as Gleason 4 + 3 or greater and/or any grade of cancer with a length of 6 mm or greater. Other definitions of clinically significant prostate cancer were also evaluated.Mean ± SD patient age was 62.6 ± 7 years, median prostate specific antigen was 7.17 ng/ml (IQR 5.25-10.09), mean primary lesion size was 0.37 ± 1.52 cc with a mean of 4.3 ± 2.3 targeted cores per lesion on visual estimation and image fusion combined, and a mean of 48.7 ± 12.3 transperineal template prostate mapping biopsy cores. Transperineal template prostate mapping biopsies detected 97 clinically significant prostate cancers (48.5%) and 85 insignificant cancers (42.5%). Overall multiparametric magnetic resonance imaging targeted biopsies detected 81 clinically significant prostate cancers (40.5%) and 63 insignificant cancers (31.5%). In the 18 cases (9%) of clinically significant prostate cancer on magnetic resonance imaging targeted biopsies were benign or clinically insignificant on transperineal template prostate mapping biopsy. Clinically significant prostate cancer was detected in 34 cases (17%) on transperineal template prostate mapping biopsy but not on magnetic resonance imaging targeted biopsies and approximately half was present in nontargeted areas. Clinically significant prostate cancer was found on visual estimation and image fusion in 53 (31.3%) and 48 (28.4%) of the 169 patients (McNemar test p = 0.5322). Visual estimation missed 23 clinically significant prostate cancers (13.6%) detected by image fusion. Image fusion missed 18 clinically significant prostate cancers (10.8%) detected by visual estimation.Magnetic resonance imaging targeted biopsies are accurate for detecting clinically significant prostate cancer and reducing the over diagnosis of insignificant cancers. To maximize detection visual estimation as well as image fusion targeted biopsies are required.

Introduction and Objectives Ivacaftor, a CFTR potentiator, was shown as safe and beneficial over 24 weeks in young children with CF and a gating mutation (Davies JC, et al. Lancet Respir Med. 2016;4:107–15). This prespecified interim analysis of an ongoing observational study evaluates long-term effectiveness of ivacaftor in children aged 2–5 years with gating mutations vs concurrent comparator (COMP) and historical (HIST) cohorts untreated with CFTR modulators. Methods US CF Foundation Patient Registry and UK CF Registry data were analysed; enrolment periods: 18 March 2015 to 31 December 2016 (US); 1 January to 31 December 2017 (UK). Two matched cohorts were established per registry: ivacaftor cohort, including children aged 2–5 years with a gating CFTR mutation at ivacaftor initiation; COMP cohort, including children homozygous for F508del-CFTR who were CFTR modulator therapy-naive and matched up to 5:1 to the ivacaftor cohort on age, sex and BMI z score. Cohorts are being followed up to evaluate and compare patterns in key outcomes, including pulmonary exacerbations (PEx), hospitalisations, nutritional parameters and Pseudomonas aeruginosa prevalence, among others. Interim analyses based on follow-up through December 2018 are presented; final analysis will include data through December 2022. Given the COMP cohort attrition over time due to CFTR modulator therapy initiation, HIST cohorts, including CFTR modulator-naive children aged 2–5 years with gating mutations (2005 [US] or 2008 [UK]), provide important additional context. Results US ivacaftor, COMP and HIST cohorts included 150, 728 and 112 children; UK cohorts included 52, 236 and 36 children, respectively. In the US, ivacaftor-treated children (mean exposure, 38.4 months) had significantly lower annual risk of PEx than the COMP cohort; trends were also favourable vs the HIST cohort (figure 1). Similarly, favourable trends were observed in patterns of hospitalisations (PEx and other reasons), nutritional parameters and P. aeruginosa prevalence. UK cohort findings (mean ivacaftor exposure, 20.6 months) were generally consistent with US data. No new safety concerns were identified (no discernible trends in transaminase elevations; no deaths or transplants [ivacaftor cohorts]). Conclusions Interim results show favourable trends across multiple clinical outcomes, supporting the effectiveness of ivacaftor in children aged 2–5 years at initiation. Please refer to page A239 for declarations of interest related to this abstract.

IntroductionAirway clearance techniques (ACTs) are a gold standard of cystic fibrosis management; however, the majority of research evidence for their efficacy is of low standard; often attributed to the lack of sensitivity from outcome measures (OMs) used historically. This randomised controlled trial (RCT) investigates these standard OMs (sputum weight, forced expiratory volume in 1 s) and new OMs (electrical impedance tomography (EIT), multiple breath washout (MBW) and impulse oscillometry (IOS)) to determine the most useful measures of ACT.Methods and analysisThis is a single-centre RCT with crossover design. Participants perform MBW, IOS and spirometry, and then are randomised to either rest or supervised ACT lasting 30–60 min. MBW, IOS and spirometry are repeated immediately afterwards. EIT and sputum are collected during rest/ACT. On a separate day, the OMs are performed with the other intervention. Primary endpoint is difference in change in OMs before and after ACT/rest. Sample size was calculated with 80% power and significance of 5% for each OM (target n=64).Ethics and disseminationEthics approval was gained from the London–Chelsea Research Ethics Committee (reference 16/LO/0995, project ID 154635). Dissemination will involve scientific conference presentation and publication in a peer-reviewed journal.Trial registration numbersISRCTN11220163 and NCT02721498.

As part of the risk management plan in Europe, a long-term observational study was conducted to monitor the safety of colistimethate sodium dry powder for inhalation (CMS-DPI) compared to other inhaled antibiotics.A cohort of CMS-DPI patients and a matched cohort were identified from the UK Cystic Fibrosis Registry (UKCFR) from 2014-2018. The primary outcome was a composite endpoint, defined as adverse events (AEs) or new cystic fibrosis (CF) complications. Other outcomes included pulmonary exacerbations and treatment discontinuations.Of 1466 and 3503 patients in the CMS-DPI and comparator cohorts, respectively, 82.7% and 79.4% had AEs. Among the most common new CF complications were osteopenia, CF-related diabetes, and increased liver enzymes. The adjusted event rate ratio (ERR) for the primary outcome was 1.25 (95% confidence interval [CI]: 1.18-1.33, p0.001). After excluding new CF complications, there was no difference between cohorts (ERR=1.04, 95% CI: 0.79-1.38, p=0.785). Pulmonary exacerbations were common in CMS-DPI and comparator cohorts (78.0% and 79.9% of patients, respectively), with adjusted ERR of 1.02 (95% CI: 0.95-1.10, p=0.523). Rates of discontinuation were similar in the CMS-DPI and Tobramycin inhalation powder comparator cohorts (37.8% and 39.8% of patients, respectively).There was no difference in the rate of adverse events between CMS-DPI and comparator cohorts. The safety profile of CMS-DPI is similar to those of other inhaled antibiotics, supporting its long-term safety in people with CF. The UKCFR has developed a successful model for partnership with industry to conduct long-term studies aimed at assessing drug safety.

Introduction Diagnosing prostate cancer routinely involves tissue biopsy and increasingly image guided biopsy using multiparametric MRI (mpMRI). Excess tissue after diagnosis can be used for research to improve the diagnostic pathway and the vertical assembly of prostate needle biopsy cores into tissue microarrays (TMAs) allows the parallel immunohistochemical (IHC) validation of cancer biomarkers in routine diagnostic specimens. However, tissue within a biopsy core is often heterogeneous and cancer is not uniformly present, resulting in needle biopsy TMAs that suffer from highly variable cancer detection rates that complicate parallel biomarker validation. Materials and methods The prostate cores with the highest tumor burden (in terms of Gleason score and/or maximum cancer core length) were obtained from 249 patients in the PICTURE trial who underwent transperineal template prostate mapping (TPM) biopsy at 5 mm intervals preceded by mpMRI. From each core, 2 mm segments containing tumor or benign tissue (as assessed on H&E pathology) were selected, excised and embedded vertically into a new TMA block. TMA sections were then IHC-stained for the routinely used prostate cancer biomarkers PSA, PSMA, AMACR, p63, and MSMB and assessed using the h-score method. H-scores in patient matched malignant and benign tissue were correlated with the Gleason grade of the original core and the MRI Likert score for the sampled prostate area. Results A total of 2240 TMA cores were stained and IHC h-scores were assigned to 1790. There was a statistically significant difference in h-scores between patient matched malignant and adjacent benign tissue that is independent of Likert score. There was no association between the h-scores and Gleason grade or Likert score within each of the benign or malignant groups. Conclusion The construction of highly selective TMAs from prostate needle biopsy cores is possible. IHC data obtained through this method are highly reliable and can be correlated with imaging. IHC expression patterns for PSA, PSMA, AMACR, p63, and MSMB are distinct in malignant and adjacent benign tissue but did not correlate with mpMRI Likert score.

Background and purpose In the post-prostatectomy setting the value of Intensity-modulated (IMRT) relative to 3D-conformal radiotherapy (3D-CRT) in reducing toxicity remains unclear. We compared genitourinary (GU) and gastrointestinal (GI) toxicity after post-prostatectomy IMRT or 3D-CRT. Materials and methods A population-based study of all patients treated with post-prostatectomy 3D-CRT (n = 2422) and IMRT (n = 603) was conducted between January 1 2010 and December 31 2013 in the English National Health Service. We identified severe GI and GU toxicity using a validated coding-framework and compared IMRT and 3D-CRT using a competing-risks proportional hazards regression analysis. Results There was no difference in GI toxicity between patients who received IMRT and 3D-CRT (3D-CRT: 5.8 events/100 person-years; IMRT: 5.5 events/100 person-years; adjusted HR: 0.85, 95%CI: 0.63–1.13; p = 0.26). The GU toxicity rate was lower with IMRT but this effect was not statistically significant (3D-CRT: 5.4 events/100 person-years; IMRT: 3.8 events/100 person-years; adjusted HR: 0.76, 95%CI: 0.55–1.03; p = 0.08). Conclusions The use of post-prostatectomy IMRT compared to 3D-CRT is not associated with a statistically significant reduction in rates of severe GU and GI toxicity, although there is some evidence that GU toxicity is lower with IMRT. We would caution against rapid transition to post-prostatectomy IMRT until further evidence is available supporting its superiority.

There is uncertainty regarding the optimal sequence of surgery for patients with colorectal cancer (CRC) and synchronous liver metastases. This study was designed to describe temporal trends and inter-hospital variation in surgical strategy, and to compare long-term survival in a propensity score-matched analysis. The National Bowel Cancer Audit dataset was used to identify patients diagnosed with primary CRC between 1st January 2010 and 31st December 2015 who underwent CRC resection in the English National Health Service. Hospital Episode Statistics data was used to identify those with synchronous liver-limited metastases who underwent liver resection. Survival outcomes of propensity score-matched groups were compared. Of 1830 patients, 270 (14.8%) patients underwent a liver-first approach, 259 (14.2%) a simultaneous approach and 1301 (71.1%) a bowel-first approach. The proportion of patients undergoing either a liver-first or simultaneous approach increased over the study period, from 26.8% in 2010 to 35.6% in 2015 (P

OBJECTIVE: To compare the proportion of clinically significant prostate cancers (PCa) found in lesions detected by multiparametric MRI (mpMRI) with that found in lesions detected by multiparametric ultrasound (mpUSS), in men at risk. PATIENTS AND METHODS: CADMUS (Cancer Detection by Multiparametric Ultrasound of the prostate) is a prospective, multi-centre paired cohort diagnostic utility study with built-in randomisation of order of biopsies. The trial is registered ISRCTN38541912. All patients will undergo the index test under evaluation (mpUSS±biopsies), as well as the standard test (mpMRI±biopsies). Eligible men will be those at risk of harbouring prostate cancer usually recommended for prostate biopsy, either for the first time or as a repeat, who have not had any prior treatment for prostate cancer. Men in need of repeat biopsy will include those with prior negative results but ongoing suspicion, and those with an existing prostate cancer diagnosis but a need for accurate risk stratification. Both scans will be reported blind to the results of the other and the order in which the targeted biopsies derived from the two different imaging modalities are taken will be randomised. Comparison will be drawn between biopsy results of lesions detected by mpUSS with those lesions detected by mpMRI. Agreement over position between the two imaging modalities will be studied. DISCUSSION: CADMUS will provide level one evidence on the performance of mpUSS derived targeted biopsies in the identification of clinically significant prostate cancer in comparison to mpMRI targeted biopsies. Recruitment is underway and expected to complete in 2018.

Purpose To compare, in a national population-based study, severe genitourinary (GU) and gastrointestinal (GI) toxicity in patients with prostate cancer who were treated with radical intensity modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT). Methods and Materials Patients treated with IMRT (n=6933) or 3D-CRT (n=16,289) between January 1, 2010 and December 31, 2013 in the English National Health Service were identified using cancer registry data, the National Radiotherapy Dataset, and Hospital Episodes Statistics, the administrative database of care episodes in National Health Service hospitals. We developed a coding system that identifies severe toxicity (at least grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events scoring system) according to the presence of a procedure and a corresponding diagnostic code in patients' Hospital Episodes Statistics records after radiation therapy. A competing risks regression analysis was used to estimate hazard ratios (HRs), comparing the incidence of severe GI and GU complications after IMRT and 3D-CRT, adjusting for patient, disease, and treatment characteristics. Results The use of IMRT, as opposed to 3D-CRT, increased from 3.1% in 2010 to 64.7% in 2013. Patients who received IMRT were less likely than those receiving 3D-CRT to experience severe GI toxicity (4.9 vs 6.5 per 100 person-years; adjusted HR 0.66; 95% confidence interval 0.61-0.72) but had similar levels of GU toxicity (2.3 vs 2.4 per 100 person-years; adjusted HR 0.94; 95% confidence interval 0.84-1.06). Conclusions Prostate cancer patients who received radical radiation therapy using IMRT were less likely to experience severe GI toxicity, and they had similar GU toxicity compared with those who received 3D-CRT. These findings in an unselected “real-world” population support the use of IMRT, but further cost-effectiveness studies are urgently required.

Objectives Despite the rapid adoption of robot-assisted radical prostatectomy (RARP), there is little evidence about the occurrence of medium-term urinary complications with this type of surgery compared to laparoscopic (LRP) or retropubic open radical prostatectomy (ORP). The aim of this study was to evaluate the occurrence of severe urinary complications within two years of surgery in men undergoing RARP, LRP or ORP. Patients and Methods Population-based cohort study of men who underwent RARP (n=4,947), LRP (n= 5,479), or ORP (n=6,873) between 2008 and 2012 in the English National Health Service (NHS) using national cancer registry records linked to Hospital Episodes Statistics – an administrative database of admissions to NHS hospitals. We identified the occurrence of any severe urinary or severe stricture-related complication within two years of surgery using a validated tool. Multi-level regression modelling was used to determine the association between the type of surgery and occurrence of complications with adjustment for patient and surgical factors. Results Men undergoing RARP were least likely to experience any urinary complication (10.5%) or a stricture-related complication (3.3%) compared to those who had LRP (15.8% any or 5.7% stricture-related) or ORP (19.1% any or 6.9% stricture-related). The impact of the type of surgery on the occurrence of any urinary or stricture-related complications remained statistically significant with adjustment for patient and surgical factors (p < 0.01). Conclusion Men who underwent RARP have the lowest risk of developing severe urinary complications within two years of surgery. This article is protected by copyright. All rights reserved.

background: Transrectal prostate biopsy has limited diagnostic accuracy. Prostate Imaging Compared to Transperineal Ultrasound-guided biopsy for significant prostate cancer Risk Evaluation (PICTURE) was a paired-cohort confirmatory study designed to assess diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) in men requiring a repeat biopsy. methods: All underwent 3 T mpMRI and transperineal template prostate mapping biopsies (TTPM biopsies). Multiparametric MRI was reported using Likert scores and radiologists were blinded to initial biopsies. Men were blinded to mpMRI results. Clinically significant prostate cancer was defined as Gleason greater than or equal to4+3 and/or cancer core length greater than or equal to6 mm. results: Two hundred and forty-nine had both tests with mean (s.d.) age was 62 (7) years, median (IQR) PSA 6.8 ng ml (4.98–9.50), median (IQR) number of previous biopsies 1 (1–2) and mean (s.d.) gland size 37 ml (15.5). On TTPM biopsies, 103 (41%) had clinically significant prostate cancer. Two hundred and fourteen (86%) had a positive prostate mpMRI using Likert score greater than or equal to3; sensitivity was 97.1% (95% confidence interval (CI): 92–99), specificity 21.9% (15.5–29.5), negative predictive value (NPV) 91.4% (76.9–98.1) and positive predictive value (PPV) 46.7% (35.2–47.8). One hundred and twenty-nine (51.8%) had a positive mpMRI using Likert score greater than or equal to4; sensitivity was 80.6% (71.6–87.7), specificity 68.5% (60.3–75.9), NPV 83.3% (75.4–89.5) and PPV 64.3% (55.4–72.6). conclusions: In men advised to have a repeat prostate biopsy, prostate mpMRI could be used to safely avoid a repeat biopsy with high sensitivity for clinically significant cancers. However, such a strategy can miss some significant cancers and overdiagnose insignificant cancers depending on the mpMRI score threshold used to define which men should be biopsied.

Rationale: Ivacaftor can greatly improve clinical outcomes in people with cystic fibrosis (CF) and has been shown to have in vitro antibacterial properties, yet the long-term microbiological outcom...

Background Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years. Methods Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity. Results US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012–2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV1, −0.7 percentage points with ivacaftor vs −8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m2 with ivacaftor vs +1.6 kg/m2 in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings. Conclusions This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor.

Background High-intensity focused ultrasound (HIFU) is a minimally-invasive treatment for nonmetastatic prostate cancer. Objective To report medium-term outcomes in men receiving primary whole-gland HIFU from a national multi-centre registry cohort. Design, setting, and participants Five-hundred and sixty-nine patients at eight hospitals were entered into an academic registry. Intervention Whole-gland HIFU (Sonablate 500) for primary nonmetastatic prostate cancer. Redo-HIFU was permitted as part of the intervention. Outcome measurements and statistical analysis Our primary failure-free survival outcome incorporated no transition to any of the following: (1) local salvage therapy (surgery or radiotherapy), (2) systemic therapy, (3) metastases, or (4) prostate cancer-specific mortality. Secondary outcomes included adverse events and genitourinary function. Results and limitations Mean age was 65 yr (47–87 yr). Median prostate-specific antigen was 7.0 ng/ml (interquartile range 4.4–10.2). National Comprehensive Cancer Network low-, intermediate-, and high-risk disease was 161 (28%), 321 (56%), and 81 (14%), respectively. One hundred and sixty three of 569 (29%) required a total of 185 redo-HIFU procedures. Median follow-up was 46 (interquartile range 23–61) mo. Failure-free survival at 5 yr after first HIFU was 70% (95% confidence interval [CI]: 64–74). This was 87% (95% CI: 78–93), 63% (95% CI: 56–70), and 58% (95% CI: 32–77) for National Comprehensive Cancer Network low-, intermediate-, and high-risk groups, respectively. Fifty eight of 754 (7.7%) had one urinary tract infection, 22/574 (2.9%) a recurrent urinary tract infection, 22/754 (3%) epididymo-orchitis, 227/754 (30%) endoscopic interventions, 1/754 (0.13%) recto-urethral fistula, and 1/754 (0.13%) osteitis pubis. Of 206 known to be pad-free pre-HIFU, 183/206 (88%) remained pad free, and of 236 with good baseline erectile function, 91/236 (39%) maintained good function. The main limitation is lack of long-term data. Conclusions Whole-gland HIFU is a repeatable day-case treatment that confers low rates of urinary incontinence. Disease control at a median of just under 5 yr of follow-up demonstrates its potential as a treatment for nonmetastatic prostate cancer. Endoscopic interventions and erectile dysfunction rates are similar to other whole-gland treatments. Patient summary In this report we looked at the 5-yr outcomes following whole-gland high-intensity focused ultrasound treatment for prostate cancer and found that cancer control was acceptable with a low risk of urine leakage. However, risk of erectile dysfunction and further operations was similar to other whole-gland treatments like surgery and radiotherapy.

Men with negative prostate biopsies or those diagnosed with low-risk or low-volume intermediate-risk prostate cancers often require a second prostate biopsy prior to a treatment decision. Prostate HistoScanning (PHS) is an ultrasound imaging test that might inform prostate biopsy in such men. PICTURE was a prospective, paired-cohort validating trial to assess the diagnostic accuracy of imaging in men requiring a further biopsy (clinicaltrials.gov, NCT01492270) (11 January 2012–29 January 2014). We enrolled 330 men who had undergone a prior TRUS biopsy but where diagnostic uncertainty remained. All eligible men underwent PHS and transperineal template prostate mapping (TTPM) biopsy (reference standard). Men were blinded to the imaging results until after undergoing TTPM biopsies. We primarily assessed the ability of PHS to rule out clinically significant prostate (negative predictive value [NPV] and sensitivity) for a target histological condition of Gleason ≥4+3 and/or a cancer core length (MCCL) ≥6 mm. We also assessed the role of visually estimated PHS-targeted biopsies. Of the 330 men enrolled, 249 underwent both PHS and TTPM biopsy. Mean (SD) age was 62 (7) years, median (IQR) PSA 6.8 (4.98–9.50) ng/ml, median (IQR) number of previous biopsies 1 (1–2) and mean (SD) gland size 37 (15.5) ml. One hundred and forty six (59%) had no clinically significant cancer. PHS classified 174 (70%) as suspicious. Sensitivity was 70.3% (95% CI 59.8–79.5) and NPV 41.3% (95% CI 27.0–56.8). Specificity and positive predictive value (PPV) were 14.7% (95% CI 9.1–22.0) and 36.8% (95% CI 29.6–44.4), respectively. In all, 213/220 had PHS suspicious areas targeted with targeting sensitivity 13.6% (95% CI 7.3–22.6), specificity 97.6% (95% CI 93.1–99.5), NPV 61.6% (95% CI 54.5–68.4) and PPV 80.0% (95% CI 51.9–95.7). PHS is not a useful test in men seeking risk stratification following initial prostate biopsy.

Background Ventilator-associated pneumonia (VAP) is common and costly. In a recent randomized controlled trial, the Venner-PneuX (VPX) endotracheal tube system (Qualitech Healthcare Limited, Maidenhead, United Kingdom) was found to be superior to standard endotracheal tubes (SET) in preventing VAP. However, VPX is considerably more expensive. We evaluated the costs and benefits of VPX to determine whether replacing SET with VPX is a cost-effective option for intensive care units. Methods We developed a decision analytic model to compare intubation with VPX or SET for patients requiring mechanical ventilation after cardiac operations. The model was populated with existing evidence on costs, effectiveness, and quality of life. Cost-effectiveness and cost-utility analyses were conducted from a National Health Service hospital perspective. Uncertainty was assessed through deterministic and probabilistic sensitivity analyses. Results Compared with SET, VPX is associated with an expected cost saving of £738 per patient. VPX led to a small increase in quality-adjusted life years, indicating that the device is overall less costly and more effective than SET. The probability of VPX being cost-effective at £30,000 per quality-adjusted life year is 97%. VPX would cease to be cost-effective if (1) it led to a risk reduction smaller than 0.02 compared with SET, (2) the acquisition cost of VPX was as high as £890, or (3) the cost of treating a case of VAP was lower than £1,450. Conclusions VPX resulted in improved outcomes and savings that far offset the cost of the device, suggesting that replacing SET with VPX is overall beneficial. Findings were robust to extreme values of key variables.

Background: Robot-assisted radical prostatectomy (RARP) has been rapidly adopted without robust evidence comparing its functional outcomes against laparoscopic radical prostatectomy (LRP) or open retropubic radical prostatectomy (ORP) approaches. This study compared patient-reported functional outcomes following RARP, LRP or ORP. Methods: All men diagnosed with prostate cancer in England during April – October 2014 who underwent radical prostatectomy were identified from the National Prostate Cancer Audit and mailed a questionnaire 18 months after diagnosis. Group differences in patient-reported sexual, urinary, bowel and hormonal function (EPIC-26 domain scores) and generic health-related quality of life (HRQoL; EQ-5D-5L scores), with adjustment for patient and tumour characteristics, were estimated using linear regression. Results: In all, 2219 men (77.0%) responded; 1310 (59.0%) had RARP, 487 (21.9%) LRP and 422 (19.0%) ORP. RARP was associated with slightly higher adjusted mean EPIC-26 sexual function scores compared with LRP (3·5 point difference; 95% CI: 1.1–5.9, P=0.004) or ORP (4.0 point difference; 95% CI: 1.5–6.5, P=0.002), which did not meet the threshold for a minimal clinically important difference (10–12 points). There were no significant differences in other EPIC-26 domain scores or HRQoL. Conclusions: It is unlikely that the rapid adoption of RARP in the English NHS has produced substantial improvements in functional outcomes for patients.

Background The nipple-areola complex (NAC) is important aesthetically and functionally for both sexes. Methods for positioning the NAC in males are less well established in the literature compared to females but are just as important. Objectives This study aims to determine the normal parameters for the male NAC, to review literature, and to present a reliable method for preoperative placement. Methods Normal male patients, with no prior chest wall conditions, were prospectively recruited to participate. General demographics and chest wall dimensions were recorded-sternal notch to nipple (SNND), internipple (IND), anterior axillary folds distances (AFD), NAC, and chest circumference were measured. Comparisons were made using t test and ANOVA. Results One hundred and fifty-eight patients were recruited (age range, 18-90 years); mostly (86.7%) with normal or overweight BMI. The IND averaged 249.4 mm, the SNND averaged 204.2 mm, and the AFD averaged 383.8 mm. Areola diameter averaged 26.6 mm and for the nipple, 6.9 mm. The IND:AFD ratio was 0.65. There was no statistical difference in the IND:AFD ratio, SNND, or NAC parameters comparing different ethnic groups. The SNND increased with greater BMI (P ≤ 0.001). Using these data, we suggest ideal NAC dimensions and devised a simple method for positioning of the NAC on the male chest wall. Conclusions This is the largest study, with the widest range in age and BMI, to date on this topic. Although fewer men than women undergo surgery to the breast, there is a growing awareness for enhancing the appearance of the male chest wall. Level of Evidence 4

Background: Patients who receive a liver transplant for hepatocellular carcinoma (HCC) are in better physical condition than other liver transplant recipients. However, HCC patients often receive poorer quality livers. Tumour recurrence also has a negative effect on post-transplant outcomes. We compared mortality of HCC and non-HCC recipients in different post-transplant time periods ('epochs') to separate the impact of these different risk factors on short and longer term post-transplant survival. Methods: We identified a population-based cohort of first-time liver transplant recipients (aged = 16 years) between 2008 and 2016 in the UK. We used Cox regression to estimate hazard ratios (HR) comparing post-transplant mortality between HCC and non-HCC patients in three post-transplant epochs: 0 to 90 days, 90 days to 2 years, and 2 to 5 years, with adjustment first for recipient and later also for donor characteristics. Findings: 1 270 HCC and 3 657 non-HCC transplant recipients were included. 5-year post-transplant survival was 74.5% (95%CI 71.2% to 77.5%) in HCC patients and 84.6% (83.0% to 86.1%) in non-HCC patients. With adjustment for recipient characteristics only, mortality was lower but not statistically significantly different in the first 90-days (HR 0.76, 95% CI 0.53-1.09, p=0.11), but HCC recipients had significantly higher 90-day mortality (90 days to 2 years: 1.99, 1.48-2.66, P

Background Ventilator-associated pneumonia is associated with significant morbidity, mortality and healthcare costs. Most of the cost data that are available relate to general intensive care patients in privately remunerated institutions. This study assessed the cost of managing ventilator-associated pneumonia in a cardiac intensive care unit in the National Health Service in the United Kingdom. Methods Propensity-matched study of prospectively collected data from the cardiac surgical database between April 2011 and December 2014 in all patients undergoing cardiac surgery (n = 3416). Patients who were diagnosed as developing ventilator-associated pneumonia, as per the surveillance definition for ventilator-associated pneumonia (n = 338), were propensity score matched with those who did not (n = 338). Costs of treating post-op cardiac surgery patients in intensive care and cost difference if ventilator-associated pneumonia occurred based on Healthcare Resource Group categories were assessed. Secondary outcomes included differences in morbidity, mortality and cardiac intensive care unit and in-hospital length of stay. Results There were no significant differences in the pre-operative characteristics or procedures between the groups. Ventilator-associated pneumonia developed in 10% of post-cardiac surgery patients. Post-operatively, the ventilator-associated pneumonia group required longer ventilation (p Conclusion Ventilator-associated pneumonia was associated with significant morbidity to the patients, generating significant costs. This cost was nearer to the lower end for the cost for general intensive care unit patients in privately reimbursed systems.

ObjectivesWe used national data to study differences in academic achievement between 5-year-old children with an isolated oral cleft and the general population. We also assessed differences by cleft type.MethodsChildren born in England with an oral cleft were identified in a national cleft registry. Their records were linked to databases of hospital admissions (to identify additional anomalies) and educational outcomes. Z-scores (signed number of SD actual score is above national average) were calculated to make outcome scores comparable across school years and across six assessed areas (personal development, communication and language, maths, knowledge of world, physical developmentandcreative development).Results2802 children without additional anomalies, 5 years old between 2006 and 2012, were included. Academic achievement was significantly below national average for all six assessed areas with z-scores ranging from −0.24 (95% CI −0.32 to −0.16) forknowledge of worldto −0.31 (−0.38 to −0.23) forpersonal development. Differences were small with only a cleft lip but considerably larger with clefts involving the palate. 29.4% of children were documented as having special education needs (national rate 9.7%), which varied according to cleft type from 13.2% with cleft lip to 47.6% with bilateral cleft lip and palate.ConclusionsCompared with national average, 5-year-old children with an isolated oral cleft, especially those involving the palate, have significantly poorer academic achievement across all areas of learning. These outcomes reflect results of modern surgical techniques and multidisciplinary approach. Children with a cleft may benefit from extra academic support when starting school.

Objective To evaluate the minimum disease burden of prostate cancer at which multiparametric magnetic resonance imaging (MRI) optimally performs. Methods Between 2006 and 2008, 64 men underwent multiparametric MRI imaging (index test) followed by template prostate mapping biopsy (reference test). Three radiologists independently reported each quadrant of every prostate on a scale of 1 to 5: highly likely benign, likely benign, equivocal, likely malignant, highly likely malignant (≥3 or ≥4 was considered positive). There were 256 prostate sectors; bootstrapping adjustment was used to account for nonindependence. The target condition indicating cancer on biopsies was varied by changing the maximum cancer core length (MCCL) and total cancer core length (TCCL) within each sector from 1 mm to 10 mm. The sensitivity, specificity, and positive (PPVs) and negative predictive values (PPVs) were calculated for each MCCL and TCCL. Gleason ≤3+3 and Gleason ≥3+4 cancers were analyzed separately. Results Mean age was 62 years (range, 40-76 years), and mean prostate-specific antigen level was 8.2 μg/L (range, 2.1-43 μg/L). Fifty percent of quadrants (127 of 256) had prostate cancer, of which 65% (83 of 127) were Gleason ≤3+3. For Gleason ≤3+3, multiparametric MRI had an NPV of ≥95% at an MCCL of ≥5 mm and at a TCCL of ≥7 mm (MRI score ≥3). For Gleason ≥3+4, an NPV of ≥95% was seen at an MCCL of ≥5 mm (MRI score ≥3) and TCCL ≥6 mm. Conclusion Multiparametric MRI may allow areas of the prostate which test negative to avoid biopsy. Whether multiparametric MRI can be used as a “triage” test before the first biopsy requires results from ongoing prospective validating cohort studies.

Background One-third of men may experience biochemical failure by 8 years following radical radiotherapy for localised prostate cancer. Over 90% of men are started on androgen deprivation therapy (ADT) which is non-curative and confers systemic side-effects. Focal salvage therapy (FST) limits collateral tissue damage and may improve therapeutic ratios. In order to deliver FST, distant disease must be ruled-out and intra-prostatic disease must be accurately detected, localised and characterised. Aim FORECAST – Focal Recurrent Assessment and Salvage Treatment – is a study designed to evaluate a novel imaging-based diagnostic and therapeutic complex intervention pathway for men who fail radiotherapy. Methods Men with biochemical failure following radical prostate radiotherapy, prior to salvage therapy will be recruited. They will undergo whole-body multi-parametric MRI (WB-MRI), choline PET/CT, bone-scan and pelvic-mpMRI and then MRI transperineal-targeted biopsies (MRI-TB) and Transperineal Template Prostate Mapping Biopsy (TPM). Those suitable for FST will undergo either high intensity focused ultrasound (HIFU) or cryotherapy. Results Primary outcome measures: a) the accuracy of WB-MRI to detect distant metastatic disease; b) accuracy of prostate mpMRI in local detection of radiorecurrent prostate cancer; c) detection accuracy of MRI-TB; and d) rate of urinary incontinence following FST. Conclusion Focal salvage therapy may confer lower rates of morbidity whilst retaining disease control. In order to deliver FST, intra- and extra-prostatic disease must be detected early and localised accurately. Novel diagnostic techniques including WB-MRI and MRI-TB may improve the detection of distant and local disease whilst reducing healthcare burdens compared with current imaging and biopsy strategies.

Introduction Patient choice policies have been introduced across publicly funded health systems to give patients more control over their care, and to encourage quality improvement amongst providers. To date we have no empirical evidence that patients requiring radiation treatment are prepared to travel to alternative more distant centres or the factors that influence this. Materials and Methods We present the results of a national cohort study using administrative hospital data for all 44,363 men who were diagnosed with prostate cancer and underwent radical radiotherapy in the English National Health Service between 2010 and 2014. Using geographic information systems we investigated the extent to which men choose to travel beyond (“bypass”) their nearest radiotherapy centre and conditional logistic regression to estimate the effect of hospital and patient characteristics on this mobility. Results 20.7% (n= 9,161) of men bypassed their nearest radiotherapy centre. Travel time had a very strong impact on where patients moved to for their treatment, but its effect was smaller for men who were younger, more affluent, and from rural areas (p for interaction always

Many countries have introduced policies that enable patients to select a health care provider of their choice with the aim of improving the quality of care. However, there is little information about the drivers or the impact of patient mobility. Using administrative hospital data (n=19256) we analysed the mobility of prostate cancer patients who had radical surgery in England between 2010 and 2014. Our analysis, using geographic information systems and multivariable choice modelling, found that 33·5% (n=6465) of men bypassed their nearest prostate cancer surgical centre. Travel time had a strong impact on where patients moved to but was less of a factor for men who were younger, fitter, and more affluent (p always < 0.001). Men were more likely to move to hospitals that provided robotic prostate cancer surgery (odds ratio: 1.42, p

Multiparametric magnetic resonance imaging (mpMRI) has the potential to serve as a non-invasive triage test for men at risk of prostate cancer. Our objective was to determine the performance characteristics of mpMRI in men at risk before the first biopsy using 5 mm template prostate mapping (TPM) as the reference standard. One hundred and twenty-nine consecutive men with clinical suspicion of prostate cancer, who had no prior biopsy, underwent mpMRI (T1/T2-weighted, diffusion-weighting, dynamic contrast enhancement) followed by TPM. The primary analysis used were as follows: (a) radiological scores of suspicion of ⩾3 attributed from a five-point ordinal scale, (b) a target condition on TPM of any Gleason pattern ⩾4 and/or a maximum cancer core length of ⩾4 mm and (c) two sectors of analysis per prostate (right and left prostate halves). Secondary analyses evaluated the impact of changing the mpMRI score threshold to ⩾4 and varying the target definition for clinical significance. One hundred and forty-one out of 258 (55%) sectors of analysis showed ‘any cancer’ and 77/258 (30%) had the target histological condition for the purpose of deriving the primary outcome. Median (with range) for age, PSA, gland volume and number of biopsies taken were 62 years (41–82), 5.8 ng ml−1 (1.2–20), 40 ml (16–137) and 41 cores (20–93), respectively. For the primary outcome sensitivity, specificity, positive and negative predictive values and area under the receiver-operating curve (with 95% confidence intervals) were 94% (88–99%), 23% (17–29%), 34% (28–40%), 89% (79–98%) and 0.72 (0.65–0.79), respectively. MpMRI demonstrated encouraging diagnostic performance characteristics in detecting and ruling out clinically significant prostate cancer in men at risk, who were biopsy naive.

Multiparametric magnetic resonance imaging can be used to guide prostate biopsy by targeting biopsies to areas in the prostate at high risk for cancer. We compared the detection of clinically significant and insignificant cancer by transperineal magnetic resonance imaging targeted biopsy and transperineal template guided prostate biopsy.A total of 182 men with a lesion suspicious for cancer on multiparametric magnetic resonance imaging underwent transperineal magnetic resonance imaging targeted biopsy using a cognitive registration technique, followed by systematic transperineal template guided prostate biopsy. The primary outcome was the detection rate of clinically significant prostate cancer. Clinical significance was defined using maximum cancer core length 4 mm or greater and/or Gleason grade 3 + 4 or greater (University College London definition 2). We secondarily evaluated other commonly used thresholds of clinically significant disease, including maximum cancer core length 6 mm or greater and/or Gleason grade 4 + 3 or greater, maximum cancer core length 3 mm or greater and/or Gleason grade 3 + 4 or greater, and maximum cancer core length 2 or greater mm and/or Gleason grade 3 + 4 or greater. Strategies were statistically compared with the McNemar test.Mean ± SD patient age was 63.3 ± 7.2 years. Median prostate specific antigen was 6.7 ng/ml (IQR 4.7-10.0). Clinically significant cancer was detected by magnetic resonance imaging targeted biopsy and template guided prostate biopsy in 103 (57%) and 113 of the 182 men (62%) (p = 0.174), and clinically insignificant cancer was detected in 17 (9.3%) and 31 (17.0%), respectively (p = 0.024).Prostate biopsy targeted to suspicious lesions on multiparametric magnetic resonance imaging has encouraging rates of detection of clinically significant cancer while also decreasing the detection rate of clinically insignificant cancer. This is achieved with fewer biopsy cores than for systematic template guided biopsy. Further prospective, multicenter, comparative trials of the performance of targeting strategies are needed to consider magnetic resonance imaging targeted biopsy an alternative to conventional systematic biopsy.

Background Early definitive treatment (cholecystectomy or endoscopic sphincterotomy in the same admission or within 2 weeks after discharge) of gallstone disease after a biliary attack of acute pancreatitis is standard of care. This study investigated whether compliance with early definitive treatment for acute gallstone pancreatitis can be used as a care quality indicator for the condition. Methods A retrospective cohort study was conducted using the Hospital Episode Statistics database. All emergency admissions to National Health Service hospitals in England with a first time diagnosis of acute gallstone pancreatitis in the financial years 2008, 2009 and 2010 were examined. Trends in early definitive treatment between hospital trusts were examined and patient morbidity outcomes were determined. Results During the study interval there were 19 510 patients with an overall rate of early definitive treatment at 34·7 (range 9·4–84·7) per cent. In the 1-year follow-up period, 4661 patients (23·9 per cent) had one or more emergency readmissions for complications related to gallstone pancreatitis. Of these, 2692 (57·8 per cent) were readmissions for acute pancreatitis; 911 (33·8 per cent) were within the first 2 weeks of discharge, with the remaining 1781 (66·2 per cent) occurring after the point at which definitive treatment should have been received. Early definitive treatment resulted in a 39 per cent reduction in readmission risk (adjusted risk ratio (RR) 0·61, 95 per cent c.i. 0·58 to 0·65). The risk was further reduced for acute pancreatitis readmissions to 54 per cent in the early definitive treatment group (adjusted RR 0·46, 0·42 to 0·51). Conclusion In acute gallstone pancreatitis, compliance with recommended early definitive treatment varied considerably, with associated variation in outcomes. Compliance should be used as a quality indicator to improve care.

INTRODUCTION This paper describes, for the first time, the outcomes of patients undergoing total hip replacement for acute fractured neck of femur (#NOF) as recorded by the National Joint Registry of England and Wales (NJR). METHODS In the NJR we identified 1,302 of 157,232 Hospital Episode Statistics linked patients who had been recorded as having a total hip replacement for acute #NOF between April 2003 and November 2008. RESULTS The revision rate at five years for fully uncemented components was 4.1% (95% confidence interval [Cl]: 2.2-7.3%), for hybrid it was 2.2% (95% Cl: 0.9%-5.3%) and for fully cemented components 0.9% (95% Cl: 0.4-2.0%). Five-year revision rates were increased for those whose operations were performed via a posterior versus a lateral approach. The Kaplan-Meier estimate of 30-day mortality was 1.4% (95% Cl: 1.0-2.4%), which is over double the 30-day mortality rate for total hip replacement identified by the Office for National Statistics. The mean length of stay was also increased for those undergoing total hip replacements for #NOF compared with non-emergency indications. CONCLUSIONS Our data suggest that total hip replacements for acute #NOF give comparable results with total hip replacements for other indications.

Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping.In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease.Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification.According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

PURPOSE: To prospectively compare the diagnostic performance and time efficiency of both second and concurrent computer-aided detection (CAD) reading paradigms for retrospectively obtained computed tomographic (CT) colonography data sets by using consensus reading (three radiologists) of colonoscopic findings as a reference standard. MATERIALS AND METHODS: Ethical permission, HIPAA compliance (for U.S. institutions), and patient consent were obtained from all institutions for use of CT colonography data sets in this study. Ten radiologists each read 25 CT colonography data sets (12 men, 13 women; mean age, 61 years) containing 69 polyps (28 were 1-5 mm, 41 were >or=6 mm) by using workstations integrated with CAD software. Reading was randomized to either "second read" CAD (applied only after initial unassisted assessment) or "concurrent read" CAD (applied at the start of assessment). Data sets were reread 6 weeks later by using the opposing paradigm. Polyp sensitivity and reading times were compared by using multilevel logistic and linear regression, respectively. Receiver operating characteristic (ROC) curves were generated. RESULTS: Compared with the unassisted read, odds of improved polyp (>or=6 mm) detection were 1.5 (95% confidence interval [CI]: 1.0, 2.2) and 1.3 (95% CI: 0.9, 1.9) by using CAD as second and concurrent reader, respectively. Detection odds by using CAD concurrently were 0.87 (95% CI: 0.59, 1.3) and 0.76 (95% CI: 0.57, 1.01) those of second read CAD, excluding and including polyps 1-5 mm, respectively. The concurrent read took 2.9 minutes (95% CI: -3.8, -1.9) less than did second read. The mean areas under the ROC curve (95% CI) for the unassisted read, second read CAD, and concurrent read CAD were 0.83 (95% CI: 0.78, 0.87), 0.86 (95% CI: 0.82, 0.90), and 0.88 (95% CI: 0.83, 0.92), respectively. CONCLUSION: CAD is more time efficient when used concurrently than when used as a second reader, with similar sensitivity for polyps 6 mm or larger. However, use of second read CAD maximizes sensitivity, particularly for smaller lesions.

OBJECTIVES: To determine whether modified transperineal template prostate-mapping (TTPM) biopsy protocols, altering the template or the biopsy density, have sensitivity and negative predictive value (NPV) equal to full 5-mm TTPM. PATIENTS AND METHODS: Retrospective analysis of an institutional registry including treatment-naive men undergoing 5-mm TTPM biopsy analysed in a 20-zone fashion. The value of three modified strategies was assessed by comparing the information provided by selected zones against full 5-mm TTPM. Strategy 1, did not consider the findings of anterior areas; strategies 2 and 3 simulated a reduced biopsy density by excluding intervening zones. A bootstrapping technique was used to calculate reliable estimates of sensitivity and NPV of these three strategies for the detection of clinically significant disease (maximum cancer core length ≥4 mm and/or Gleason score ≥3 + 4). RESULTS: In all, 391 men with a median (interquartile range, IQR) age of 62 (58-67) years were included. The median (IQR) PSA level and PSA density were 6.9 (4.8-10) ng/mL and 0.17 (IQR 0.12-0.25) ng/mL/mL, respectively. A median (IQR) of 6 (2-9) cores out of 48 (33-63) taken per man were positive for prostate cancer. No cancer was detected in 67 men (17%), whilst low-, intermediate- and high-risk disease was identified in 78 (20%), 80 (21%), and 166 (42%), respectively. Strategy 1, 2 and 3 had sensitivities of 78% [95% confidence interval (CI) 73-84%], 85% (95% CI 80-90%) and 84% (95% CI 79-89%), respectively. The NPVs of the three strategies were 73% (95% CI 67-80%), 80% (95% CI 74-86%) and 79% (95% CI 72-84%), respectively. CONCLUSION: Altering the template or decreasing sampling density has a substantial negative impact on the ability of TTPM biopsy to exclude clinically significant disease. This should be considered when modified TTPM biopsy strategies are used to select men for tissue-preserving approaches, and when modified TTPM are used to validate new diagnostic tests.

Objective We assessed the impact of comorbidity on mortality in three periods after liver transplantation (first 90 days, 90 days–5 years and 5–10 years). Design Prospective cohort study using records from the UK Liver Transplant Audit (UKLTA) linked to Hospital Episode Statistics (HES), an administrative database of hospital admissions in the English National Health Service (NHS). Comorbidities relevant for liver transplantation were identified from the 10th revision of the International Classification of Diseases (ICD-10) codes in HES records of admissions in the year preceding their operation. Multivariable Cox regression was used to estimate HRs for three different time periods after liver transplantation. Setting All liver transplant centres in the NHS hospitals in England. Participants Adults who received a first elective liver transplant between April 1997 and March 2010 in the linked UKLTA-HES database. Outcomes Patient mortality in three different time periods after transplantation. Results Among 3837 recipients, 45.1% had comorbidities. Recipients with cardiovascular disease had statistically significantly higher mortality in all three periods after transplantation (first 90 days: HR=2.0; 95% CI 1.4 to 2.9, 90 days–5 years: 1.6; 1.2 to 2.2, beyond 5 years: 2.8; 1.7 to 4.4). Prior congestive cardiac failure (3.2; 2.1 to 4.9) significantly increased mortality only in the first 90 days. History of non-hepatic malignancy appeared to increase risk over all periods, but significantly only in the first 90 days (1.9; 1.0 to 3.6). A diagnosis of connective tissue disease, dementia, diabetes, chronic pulmonary and renal disease did not have a significant impact on mortality in any period. Conclusions The impact of comorbidities present at the time of transplantation changes with time after transplantation. Renal disease, pulmonary disease and diabetes had no impact on mortality in contrast to previous reports.

Background Positive cytomegaloviral status of the donor or of the recipient adversely affects survival and enhances the development of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. The role of ganciclovir prophylaxis in cytomegalovirus infection in respect to obliterative bronchiolitis or to BOS development is not known. Methods From the Papworth transplant database, we identified 146 patients who received organs from cytomegalovirus-positive donors. We classified patients into 3 groups as follows: Group 1 consisted of 42 patients who underwent transplantation between 1990 and 1992 when no prophylaxis was given; Group 2 consisted of 49 patients who underwent transplantation between 1992 and 1995 when 4 weeks of IV ganciclovir was given as prophylaxis; and Group 3 consisted of 55 patients who underwent transplantation between 1995 and 1998 when cytomegalovirus prophylaxis consisted of IV (1 week) followed by oral ganciclovir for a total of 3 months. Donor management, recipient management during and after surgery, and pharmacotherapy were uniform during the study period. We used survival and regression methods to compare these groups, adjusting for the transplantation type (single lung, double lung, or heart-lung) and for HLA typing. Results We found a significant difference among all 3 groups in numbers of cytomegaloviral disease episodes in the 1st year after transplantation. The number of rejection episodes in the 3 groups during the 1st post-transplant year gradually decreased from Group 1 to Group 3. We identified no statistically significant benefit in the time to BOS occurrence or in actuarial survival. Conclusion Extended prophylaxis with IV and oral ganciclovir practically abolishes cytomegaloviral disease and is related to a decreased incidence of rejection episodes. However, ganciclovir prophylaxis is not related to a decreased incidence or progression of BOS or survival.

Background According to International Society for Heart and Lung Transplantation (ISHLT) data, the 30-day survival after heart transplantation has continually improved from 84% (1979–85) to 91% (1996–2001). This has probably been achieved by better donor/recipient selection, along with improved surgical technique and immunosuppressive therapy. On the other hand, the data concerning the early causes of death after cardiac transplantation is incomplete, because in 25% of cases, an unknown cause is listed. This study investigated the incidence and causes of 30-day mortality (determined by postmortem studies) after cardiac transplantation and assessed the possibility of improvements. Methods A retrospective study of all patients who underwent heart transplantation at Papworth Hospital from 1979 to June 2001 ( n = 879) and who died within 30 days of surgery was carried out. Postmortem examination data were available for all patients. Results The mean (standard deviation) recipient and donor ages were 46 (12) and 31 (12) years, respectively. Overall, the 30-day mortality was 8.5% ( n = 75), 12.1% for the 1979 to 1985 period and 6.9% for the 1996 to 2001 period. The primary causes of death were graft failure (30.7%), acute rejection (22.7%) (1.3% for the 1996–2001 era), sepsis (18.7%) gastrointestinal problems (bowel infarction and pancreatitis; (9.3%), postoperative bleeding (6.7%), and other (12%). Conclusions Our 30-day mortality compares favorably with the data from the ISHLT registry, with great improvement in the early mortality. Acute rejection is no longer a major cause of early mortality. Further reduction may be achieved by a better protection of the donor heart against the effects of brainstem death and ischemic injuries. However, the quest to improve early outcome should not be at the expense of needy patients by being overselective.

Aims In practice, clinicians vary markedly in the amount of information they give to patients before consent for investigation or treatment is obtained. We present a study to evaluate the amount of information patients feel that they should be given. Materials and methods Between October 2001 and February 2002, 82 adults were enrolled into the study before commencing treatment with radiotherapy. Participants were interviewed with the aid of a questionnaire, and responses were analysed to detect differences related to age, sex, disease site, treatment intent and social class. Results The distribution of responses to the interview was large. For a mild side-effect, 23 patients (28%) wanted to be informed if the risk of the side-effect was as small as 0.1%, whereas 25 patients (31%) would only want to be informed if there was either a 50% or a 100% chance of it occurring. For severe side-effects, 36 (44%) wanted to be informed of a 0.1% risk, whereas 13 (16%) only wanted to be informed if the risk was either 50% or 100%. There was no association with sex, treatment intent (radical or palliative), social class or disease site. Information requirements tended to be greater in people under 60 years. This reached statistical significance ( P =0.007) for severe side-effects, where younger patients were more likely to want to be informed of a side-effect if there was a 10% or less chance of it occurring. Conclusions Information needs varied widely within our survey population. It is difficult to predict how much information patients feel they need before giving informed consent. Therefore, a patient-centred approach must involve tailoring information to individual patient requirements.

Objective Although the beneficial effect of aspirin prescription after coronary surgery has been established, the efficacy of clopidogrel has never been compared with that of aspirin in the critical early postoperative period. We therefore conducted a prospective, double-blind, randomized controlled trial to compare the efficacies of these antiplatelet regimens. Methods Patients undergoing elective primary coronary artery bypass surgery were invited to participate. After the operation, patients were randomized to receive 100 mg aspirin, 325 mg aspirin, or 75 mg clopidogrel tablets daily for 5 days. Our primary outcome measure was platelet aggregation on day 5, expressed as percentage of baseline. Assessment of platelet aggregation was undertaken with the technique of Born. Results From September 2002 to July 2003, a total of 54 patients were randomized into the study. There were 2 self-withdrawals and 2 protocol violations, leaving 50 patients for analysis, 34 in the aspirin group and 16 in the clopidogrel arm. Compared with baseline, the mean percentage aggregations with collagen on day 5 were 56% for aspirin and 99% for clopidogrel. The mean difference between the two arms was 42% (95% confidence interval 27%-56%) in favor of aspirin. At the same time point, the effective concentration to inhibit 50% aggregation in the samples from patients randomly assigned to receive clopidogrel were not raised for our entire panel of agonists (changes of −0.04 μg/L for collagen, −0.01 μmol/L for epinephrine, and −0.02 μmol/L for adenosine diphosphate). Conclusion Clopidogrel, unlike aspirin, did not inhibit platelet aggregation in the first 5 postoperative days and therefore should not be used as a sole antiplatelet agent early after coronary surgery.