Melanie Irvin-Sellers

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: ), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

Background and Purpose— Information on what effect disability before stroke can have on stroke outcome is lacking. We assessed prestroke disability in relation to poststroke hospital outcome. Methods— Analysis of prospectively collected data from the Sentinel Stroke National Audit Programme. A total of 1656 men (mean age ±SD =73.1±13.2 years) and 1653 women (79.3±13.0 years) were admitted to hyperacute stroke units with acute stroke in 4 major UK between 2014 and 2016. Prestroke disability, assessed by modified Rankin Scale (mRS), was tested against poststroke adverse outcomes, adjusted for age, sex, and coexisting morbidities. Results— Compared with patients with prestroke mRS score =0, individuals with prestroke mRS scores =3, 4, or 5 had greater adjusted risks of moderately severe or severe stroke on arrival (4.4% versus 16.7%; odds ratio [OR], 3.2 [95% CI, 2.3–4.6] P <0.001); urinary tract infection or pneumonia within 7 days of admission (9.6% versus 35.9%; OR, 3.7 [95% CI, 2.8–4.8] P <0.001); mortality (7.2% versus 37.1%; OR, 4.9 [95% CI, 3.7–6.5] P <0.001); requiring help with activities of daily living on discharge (12.3% versus 26.7%; OR, 3.1 [95% CI, 2.3–4.1] P <0.001); and transferred to new care home (2.4% versus 9.4%; OR, 2.1 [95% CI, 1.3–3.3] P =0.002). Patients with mRS scores =1 or 2 had intermediate risk of adverse outcomes. Overall, those with a mRS score =1 or 2 had length of stay on hyperacute stroke units extended by 5.3 days (95% CI, 2.8–7.7; P <0.001) and mRS score =3, 4 or 5 by 7.2 days (95% CI, 4.0–10.5; P <0.001). Conclusions— Individuals with evidence of prestroke disability, assessed by mRS, had significantly increased risk of poststroke adverse outcomes and longer length of stay on hyperacute stroke units and higher level of care on discharge.

BACKGROUND: Tiotropium and ipratropium bromide are both recognised treatments in the management of people with stable chronic obstructive pulmonary disease (COPD). There are new studies which have compared tiotropium with ipratropium bromide, making an update necessary. OBJECTIVES: To compare the relative effects of tiotropium to ipratropium bromide on markers of quality of life, exacerbations, symptoms, lung function and serious adverse events in patients with COPD using available randomised controlled trial (RCT) data. SEARCH METHODS: We identified RCTs from the Cochrane Airways Group Specialised Register of trials (CAGR) and ClinicalTrials.gov up to August 2015. SELECTION CRITERIA: We included parallel group RCTs of 12 weeks duration or longer comparing treatment with tiotropium with ipratropium bromide for patients with stable COPD. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and then extracted data on study quality and outcome results. We contacted trial sponsors for additional information. We analysed the data using Cochrane Review Manager. MAIN RESULTS: This review included two studies of good methodological quality that enrolled 1073 participants with COPD. The studies used a similar design and inclusion criteria and were of at least 12 weeks duration; the participants had a mean forced expiratory volume in one second (FEV1) of 40% predicted value at baseline. One study used tiotropium via the HandiHaler (18 µg) for 12 months and the other via the Respimat device (5 µg and 10 µg) for 12 weeks. In general, the treatment groups were well matched at baseline but not all outcomes were reported for both studies. Overall the risk of bias across the included RCTs was low.For primary outcomes this review found that at the three months trough (the lowest level measured before treatment) FEV1 significantly increased with tiotropium compared to ipratropium bromide (mean difference (MD) 109 mL; 95% confidence interval (CI) 81 to 137, moderate quality evidence, I(2) = 62%). There were fewer people experiencing one or more non-fatal serious adverse events on tiotropium compared to ipratropium (odds ratio (OR) 0.5; 95% CI 0.34 to 0.73, high quality evidence). This represents an absolute reduction in risk from 176 to 97 per 1000 people over three to 12 months. Concerning disease specific adverse events, the tiotropium group were also less likely to experience a COPD-related serious adverse event when compared to ipratropium bromide (OR 0.59; 95% CI 0.41 to 0.85, moderate quality evidence).For secondary outcomes, both studies reported fewer hospital admissions in the tiotropium group (OR 0.34; 95% CI 0.15 to 0.70, moderate quality evidence); as well as fewer patients experiencing one or more exacerbations leading to hospitalisation in the people on tiotropium in both studies (OR 0.56; 95% CI 0.31 to 0.99, moderate quality evidence). There was no significant difference in mortality between the treatments (OR 1.39; 95% CI 0.44 to 4.39, moderate quality evidence). One study measured quality of life using the St George's Respiratory Questionnaire (SGRQ); the mean SGRQ score at 52 weeks was lower in the tiotropium group than the ipratropium group (lower on the scale is favourable) (MD -3.30; 95% CI -5.63 to -0.97, moderate quality evidence). There were fewer participants suffering one of more exacerbations in the tiotropium arm (OR 0.71; 95% CI 0.52 to 0.95, high quality evidence) and there was also a reported difference in the mean number of exacerbations per person per year which reached statistical significance (MD -0.23; 95% CI -0.39 to -0.07, P = 0.006, moderate quality evidence). From the 1073 participants there were significantly fewer withdrawals from the tiotropium group (OR 0.58; 95% CI 0.41 to 0.83, high quality evidence). AUTHORS' CONCLUSIONS: This review shows that tiotropium treatment, when compared with ipratropium bromide, was associated with improved lung function, fewer hospital admissions (including those for exacerbations of COPD), fewer exacerbations of COPD and improved quality of life. There were both fewer serious adverse events and disease specific events in the tiotropium group, but no significant difference in deaths with ipratropium bromide when compared to tiotropium. Thus, tiotropium appears to be a reasonable choice (instead of ipratropium bromide) for patients with stable COPD, as proposed in guidelines. A recent large double-blind trial of the two delivery devices found no substantial difference in mortality using 2.5 µg or 5 µg of tiotropium via Respimat in comparison to 18 µg via Handihaler.