Clinimetric analysis of outcome measures for airway clearance in people with cystic fibrosis: a systematic review.

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, and reproducibility) within the context of ACT research in CF. DESIGN AND METHODS: A systematic review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) standards. Any parallel or cross-over randomised controlled trial (RCT) investigating outcome measures for ACT in the CF population were eligible for inclusion. The search was performed in five medical databases, clinicaltrials.gov, and abstracts from international CF conferences. The authors planned to independently assess study quality and risk of bias using the COnsensus-based Standards for the selection of health status Measurement InstrumeNts (COSMIN) risk of bias checklist with external validity assessment based upon study details (participants and study intervention). Two review authors (GS and MJ) independently screened search results against inclusion criteria, and further data extraction were planned but not required. RESULTS: No completed RCTs from the 187 studies identified met inclusion criteria for the primary or post hoc secondary objective. Two ongoing trials were identified. DISCUSSION AND CONCLUSION: This empty systematic review highlights that high-quality RCTs are urgently needed to investigate and validate the clinimetric properties of OMs used to assess ACT efficacy. With the changing demographics of CF combined with the introduction of cystic fibrosis transmembrane conductance regulator (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; OMs which have been validated for this purpose are essential. REGISTRATION: This systematic review was registered on the PROSPERO database (CRD42020206033).

Who are the 10%? - Non eligibility of cystic fibrosis (CF) patients for highly effective modulator therapies.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 FEV1 from the previous year (proportion with greater than 70% FEV1 predicted, 66.1% vs 63.0%, p = 0.005). CONCLUSION: Patients 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.

Lung function in children with cystic fibrosis in the USA and UK: a comparative longitudinal analysis of national registry data.

RATIONALE: A 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. OBJECTIVES: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences. METHODS: We 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). RESULTS: We 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. CONCLUSIONS: Children 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.

Long-term safety study of colistimethate sodium (Colobreathe®): Findings from the UK Cystic Fibrosis Registry.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, p<0.001). 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). CONCLUSIONS: 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.

Patient-Reported Functional Outcomes After Hypofractionated or Conventionally Fractionated Radiation for Prostate Cancer: A National Cohort Study in England.

PURPOSE: The aim of the current study was to determine patient-reported functional outcomes in men with prostate cancer (PCa) undergoing moderately hypofractionated (H-RT) or conventionally fractionated radiation therapy (C-RT) in a national cohort study. PATIENDS AND METHODS: All men diagnosed with PCa between April 2014 and September 2016 in the English National Health Service undergoing C-RT or H-RT were identified in the National Prostate Cancer Audit and mailed a questionnaire at least 18 months after diagnosis. We estimated differences in patient-reported urinary, bowel, sexual, and hormonal function-Expanded Prostate Cancer Index Composite short-form 26 domain scores on a 0 to 100 scale-and health-related quality of life-EQ-5D-5L on a 0 to 1 scale-using linear regression with adjustment for patient, tumor, and treatment-related factors in addition to GI and genitourinary baseline function, with higher scores representing better outcomes. RESULTS: Of the 17,058 men in the cohort, 77% responded: 8,432 men received C-RT (64.2%) and 4,699 H-RT (35.8%). Men in the H-RT group were older (age ≥ 70 years: 67.5% v 60.9%), fewer men had locally advanced disease (56.5% v 71.3%), were less likely to receive androgen-deprivation therapy (79.5% v 87.8%), and slightly more men had pretreatment genitourinary procedures (24.2% v 21.2%). H-RT was associated with small increases in adjusted mean Expanded Prostate Cancer Index Composite short-form 26 sexual (3.3 points; 95% CI, 2.1 to 4.5; P < .001) and hormonal function scores (3.2 points; 95% CI, 1.8 to 4.6; P < .001). These differences failed to meet established thresholds for a clinically meaningful change. There were no statistically significant differences in urinary or bowel function and quality of life. CONCLUSION: This is the first national cohort study comparing functional outcomes after H-RT and C-RT reported by patients. These real-world results further support the use of H-RT as the standard for radiation therapy in men with nonmetastatic PCa.

Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries.

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.

Added value of diffusion-weighted images and dynamic contrast enhancement in multiparametric magnetic resonance imaging for the detection of clinically significant prostate cancer in the PICTURE trial.

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.

Ivacaftor Is Associated with Reduced Lung Infection by Key Cystic Fibrosis Pathogens. A Cohort Study Using National Registry Data.

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 outcomes of treatment are unknown.Objectives: To investigate changes in respiratory microbiology associated with long-term ivacaftor use.Methods: This was a retrospective cohort study using data from the UK CF Registry 2011-2016. Primary outcome was the annual prevalence ratios for key CF pathogens between ivacaftor users and their contemporaneous comparators. Multivariable log-binomial regression models were designed to adjust for confounders. Changes in Pseudomonas aeruginosa status were compared between groups using nonparametric maximum likelihood estimate for the purposes of Kaplan-Meier approximation.Results: Ivacaftor use was associated with early and sustained reduction in P. aeruginosa rates (2016 adjusted prevalence ratio, 0.68; 95% confidence interval, 0.58-0.79; P < 0.001) via a combination of increased clearance in those with infection (ivacaftor: 33/87 [37.9%] vs. nonivacaftor: 432/1,872 [22.8%]; P < 0.001) and reduced acquisition in those without infection (49/134 [36.6%] vs. 1,157/2,382 [48.6%]; P = 0.01). The improved prevalence of P. aeruginosa infection was independent of reduced sampling in the ivacaftor cohort. Ivacaftor was also associated with reduced prevalence of Staphylococcus aureus and Aspergillus spp. but not Burkholderia cepacia complex.Conclusions: In this study, long-term ivacaftor use was associated with reduced infection with important CF pathogens including P. aeruginosa. These findings have implications for antibiotic stewardship and the need for ongoing chronic antimicrobial therapy in this cohort.

Prostate Imaging Compared to Transperineal Ultrasound-guided biopsy for significant prostate cancer Risk Evaluation (PICTURE): a prospective cohort validating study assessing Prostate HistoScanning.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: PHS is not a useful test in men seeking risk stratification following initial prostate biopsy.

Immunohistochemical biomarker validation in highly selective needle biopsy microarrays derived from mpMRI-characterized prostates.

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.

Accuracy of Transperineal Targeted Prostate Biopsies, Visual Estimation and Image Fusion in Men Needing Repeat Biopsy in the PICTURE Trial.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cost of treating ventilator-associated pneumonia post cardiac surgery in the National Health Service: Results from a propensity-matched cohort study.

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 < 0.01), more respiratory support, longer cardiac intensive care unit (8 vs 3, p < 0.001) and in-hospital stay (16 vs 9) days. The overall cost for post-operative recovery after cardiac surgery for ventilator-associated pneumonia patients was £15,124 compared to £6295 for non-ventilator-associated pneumonia (p < 0.01). The additional cost of treating patients with ventilator-associated pneumonia was £8829. 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.

Treatment-related toxicity in men who received Intensity-modulated versus 3D-conformal radiotherapy after radical prostatectomy: A national population-based study.

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.

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England.

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.

Defining Normal Parameters for the Male Nipple-Areola Complex: A Prospective Observational Study and Recommendations for Placement on the Chest Wall.

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.

Determinants of Patient Mobility for Prostate Cancer Surgery: A Population-based Study of Choice and Competition.

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<0.001) and to hospitals that employed surgeons with a strong media reputation (odds ratio: 2.18, p<0.001). Patient mobility occurred in the absence of validated measures of the quality of care, instead influenced by the adoption of robotic surgery and the reputation of individual clinicians. National policy based on patient choice and provider competition may have had a negative impact on equality of access, service capacity, and health system efficiency. PATIENT SUMMARY: In this study, we assessed the reasons why men would choose to have prostate cancer surgery at a centre other than their nearest. We found that in England men were attracted to centres that carried out robotic surgery and employed surgeons with a national reputation.

Early academic achievement in children with isolated clefts: a population-based study in England.

OBJECTIVES: We 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. METHODS: Children 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 development andcreative development). RESULTS: 2802 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) for knowledge of world to -0.31 (-0.38 to -0.23) for personal 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. CONCLUSIONS: Compared 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.

National cohort study comparing severe medium-term urinary complications after robot-assisted vs laparoscopic vs retropubic open radical prostatectomy.

OBJECTIVES: To evaluate the occurrence of severe urinary complications within 2 years of surgery in men undergoing either robot-assisted radical prostatectomy (RARP), laparoscopic radical prostatectomy (LRP) or retropubic open radical prostatectomy (ORP). PATIENTS AND METHODS: We conducted a population-based cohort study in 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 2 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 with 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 after adjustment for patient and surgical factors (P < 0.01). CONCLUSION: Men who underwent RARP had the lowest risk of developing severe urinary complications within 2 years of surgery.

Hospital Quality Factors Influencing the Mobility of Patients for Radical Prostate Cancer Radiation Therapy: A National Population-Based Study.

PURPOSE: To investigate whether patients requiring radiation treatment are prepared to travel to alternative more distant centers in response to hospital choice policies, and the factors that influence this mobility. METHODS AND MATERIALS: 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 radiation therapy 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 radiation therapy center, and we used conditional logistic regression to estimate the effect of hospital and patient characteristics on this mobility. RESULTS: In all, 20.7% of men (n=9161) bypassed their nearest radiation therapy center. 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 <.001). Men were prepared to travel further to hospitals that offered hypofractionated prostate radiation therapy as their standard schedule (odds ratio 3.19, P<.001), to large-scale radiation therapy units (odds ratio 1.56, P<.001), and to hospitals that were early adopters of intensity modulated radiation therapy (odds ratio 1.37, P<.001). CONCLUSIONS: Men with prostate cancer are prepared to bypass their nearest radiation therapy centers. They are more likely to travel to larger established centers and those that offer innovative technology and more convenient radiation therapy schedules. Indicators that accurately reflect the quality of radiation therapy delivered are needed to guide patients' choices for radiation therapy treatment. In their absence, patient mobility may negatively affect the efficiency and capacity of a regional or national radiation therapy service and offer perverse incentives for technology adoption.

National Population-Based Study Comparing Treatment-Related Toxicity in Men Who Received Intensity Modulated Versus 3-Dimensional Conformal Radical Radiation Therapy for Prostate Cancer.

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.