Natriuretic peptide-based screening and collaborative care for heart failure:the STOP-HF randomized trial

IMPORTANCE: Prevention strategies for heart failure are needed.

OBJECTIVE: To determine the efficacy of a screening program using brain-type natriuretic peptide (BNP) and collaborative care in an at-risk population in reducing newly diagnosed heart failure and prevalence of significant left ventricular (LV) systolic and/or diastolic dysfunction.

DESIGN, SETTING, AND PARTICIPANTS: The St Vincent's Screening to Prevent Heart Failure Study, a parallel-group randomized trial involving 1374 participants with cardiovascular risk factors (mean age, 64.8 [SD, 10.2] years) recruited from 39 primary care practices in Ireland between January 2005 and December 2009 and followed up until December 2011 (mean follow-up, 4.2 [SD, 1.2] years).

INTERVENTION: Patients were randomly assigned to receive usual primary care (control condition; n=677) or screening with BNP testing (n=697). Intervention-group participants with BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative care between their primary care physician and specialist cardiovascular service.

MAIN OUTCOMES AND MEASURES: The primary end point was prevalence of asymptomatic LV dysfunction with or without newly diagnosed heart failure. Secondary end points included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure.

RESULTS: A total of 263 patients (41.6%) in the intervention group had at least 1 BNP reading of 50 pg/mL or higher. The intervention group underwent more cardiovascular investigations (control, 496 per 1000 patient-years vs intervention, 850 per 1000 patient-years; incidence rate ratio, 1.71; 95% CI, 1.61-1.83; P<.001) and received more renin-angiotensin-aldosterone system-based therapy at follow-up (control, 49.6%; intervention, 56.5%; P=.01). The primary end point of LV dysfunction with or without heart failure was met in 59 (8.7%) of 677 in the control group and 37 (5.3%) of 697 in the intervention group (odds ratio [OR], 0.55; 95% CI, 0.37-0.82; P = .003). Asymptomatic LV dysfunction was found in 45 (6.6%) of 677 control-group patients and 30 (4.3%) of 697 intervention-group patients (OR, 0.57; 95% CI, 0.37-0.88; P = .01). Heart failure occurred in 14 (2.1%) of 677 control-group patients and 7 (1.0%) of 697 intervention-group patients (OR, 0.48; 95% CI, 0.20-1.20; P = .12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; 95% CI, 0.45-0.81; P = .002).

CONCLUSION AND RELEVANCE: Among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and heart failure.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00921960.

RAS mutations and cetuximab in locally advanced rectal cancer: results of the EXPERT-C trial.

Background: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial.

Methods: Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed.

Results: Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n = 40; CAPOX-C, n = 38). In this population, after a median follow-up of 63.8 months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p = 0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p = 0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p = 0.20).

Conclusions: RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

The prognostic impact of clinical and molecular features in hairy cell leukaemia variant and splenic marginal zone lymphoma.

Hairy cell leukaemia variant (HCL-variant) and splenic marginal zone lymphoma (SMZL) are disorders with overlapping features. We investigated the prognostic impact in these disorders of clinical and molecular features including IGH VDJ rearrangements, IGHV gene usage and TP 53 mutations. Clinical and laboratory data were collected before therapy from 35 HCL-variant and 68 SMZL cases. End-points were the need for treatment and overall survival. 97% of HCL-variant and 77% of SMZL cases required treatment (P = 0·009). Survival at 5 years was significantly worse in HCL-variant [57% (95% confidence interval 38-73%)] compared with SMZL [84% (71-91%); Hazard Ratio 2·25 (1·20-4·25), P = 0·01]. In HCL-variant, adverse prognostic factors for survival were older age (P = 0·04), anaemia (P = 0·01) and TP 53 mutations (P = 0·02). In SMZL, splenomegaly, anaemia and IGHV genes with >98% homology to the germline predicted the need for treatment; older age, anaemia and IGHV unmutated genes (100% homology) predicted shorter survival. IGHV gene usage had no impact on clinical outcome in either disease. The combination of unfavourable factors allowed patients to be stratified into risk groups with significant differences in survival. Although HCL-variant and SMZL share some features, they have different outcomes, influenced by clinical and biological factors.

Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C).

PURPOSE: To evaluate the addition of cetuximab to neoadjuvant chemotherapy before chemoradiotherapy in high-risk rectal cancer. PATIENTS AND METHODS: Patients with operable magnetic resonance imaging-defined high-risk rectal cancer received four cycles of capecitabine/oxaliplatin (CAPOX) followed by capecitabine chemoradiotherapy, surgery, and adjuvant CAPOX (four cycles) or the same regimen plus weekly cetuximab (CAPOX+C). The primary end point was complete response (CR; pathologic CR or, in patients not undergoing surgery, radiologic CR) in patients with KRAS/BRAF wild-type tumors. Secondary end points were radiologic response (RR), progression-free survival (PFS), overall survival (OS), and safety in the wild-type and overall populations and a molecular biomarker analysis. RESULTS: One hundred sixty-five eligible patients were randomly assigned. Ninety (60%) of 149 assessable tumors were KRAS or BRAF wild type (CAPOX, n = 44; CAPOX+C, n = 46), and in these patients, the addition of cetuximab did not improve the primary end point of CR (9% v 11%, respectively; P = 1.0; odds ratio, 1.22) or PFS (hazard ratio [HR], 0.65; P = .363). Cetuximab significantly improved RR (CAPOX v CAPOX+C: after chemotherapy, 51% v 71%, respectively; P = .038; after chemoradiation, 75% v 93%, respectively; P = .028) and OS (HR, 0.27; P = .034). Skin toxicity and diarrhea were more frequent in the CAPOX+C arm. CONCLUSION: Cetuximab led to a significant increase in RR and OS in patients with KRAS/BRAF wild-type rectal cancer, but the primary end point of improved CR was not met.

Systematic evaluation of patient-reported outcome (PRO) protocol content and reporting in UK cancer clinical trials: the EPiC study protocol

Introduction Emerging evidence suggests that patient-reported outcome (PRO)-specific information may be omitted in trial protocols and that PRO results are poorly reported, limiting the use of PRO data to inform cancer care. This study aims to evaluate the standards of PRO-specific content in UK cancer trial protocols and their arising publications and to highlight examples of best-practice PRO protocol content and reporting where they occur. The objective of this study is to determine if these early findings are generalisable to UK cancer trials, and if so, how best we can bring about future improvements in clinical trials methodology to enhance the way PROs are assessed, managed and reported. Hypothesis: Trials in which the primary end point is based on a PRO will have more complete PRO protocol and publication components than trials in which PROs are secondary end points.

Methods and analysis Completed National Institute for Health Research (NIHR) Portfolio Cancer clinical trials (all cancer specialities/age-groups) will be included if they contain a primary/secondary PRO end point. The NIHR portfolio includes cancer trials, supported by a range of funders, adjudged as high-quality clinical research studies. The sample will be drawn from studies completed between 31 December 2000 and 1 March 2014 (n=1141) to allow sufficient time for completion of the final trial report and publication. Two reviewers will then review the protocols and arising publications of included trials to: (1) determine the completeness of their PRO-specific protocol content; (2) determine the proportion and completeness of PRO reporting in UK Cancer trials and (3) model factors associated with PRO protocol and reporting completeness and with PRO reporting proportion.

Ethics and dissemination The study was approved by the ethics committee at University of Birmingham (ERN_15-0311). Trial findings will be disseminated via presentations at local, national and international conferences, peer-reviewed journals and social media including the CPROR twitter account and UOB departmental website (http://www.birmingham.ac.uk/cpro0r).

Effective end wall profiling rules for a highly loaded compressor cascade

This paper presents a numerical study of a linear compressor cascade to investigate the effective end wall profiling rules for highly-loaded axial compressors. The first step in the research applies a correlation analysis for the different flow field parameters by a data mining over 600 profiling samples to quantify how variations of loss, secondary flow and passage vortex interact with each other under the influence of a profiled end wall. The result identifies the dominant role of corner separation for control of total pressure loss, providing a principle that only in the flow field with serious corner separation does the does the profiled end wall change total pressure loss, secondary flow and passage vortex in the same direction. Then in the second step, a multi-objective optimization of a profiled end wall is performed to reduce loss at design point and near stall point. The development of effective end wall profiling rules is based on the manner of secondary flow control rather than the geometry features of the end wall. Using the optimum end wall cases from the Pareto front, a quantitative tool for analyzing secondary flow control is employed. The driving force induced by a profiled end wall on different regions of end wall flow are subjected to a detailed analysis and identified for their positive/negative influences in relieving corner separation, from which the effective profiling rules are further confirmed. It is found that the profiling rules on a cascade show distinct differences at design point and near stall point, thus loss control of different operating points is generally independent.