Jerome Wulff

Identification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use.We analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). Tumour exome sequencing identified somatic mutations and plasma was analyzed using patient-specific RaDaR™ assays with up to 48 amplicons targeting tumour-specific variants unique to each patient.ctDNA was detected before treatment in 24%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <0.01%. ctDNA detection had clinical specificity >98.5% and preceded clinical detection of recurrence of the primary tumour by a median of 212.5 days. ctDNA was detected after treatment in 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (HR: 5.48, P <0.0003). ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively).ctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention.

<h3>Importance</h3> A meta-analysis of outcomes during the 6 months after intensive care unit (ICU) discharge indicate a prevalence for clinically important posttraumatic stress disorder (PTSD) symptoms of 25%. <h3>Objective</h3> To determine whether a nurse-led preventive, complex psychological intervention, initiated in the ICU, reduces patient-reported PTSD symptom severity at 6 months. <h3>Design, Setting, and Participants</h3> A multicenter, parallel-group, cluster-randomized clinical trial with integrated economic and process evaluations conducted in 24 ICUs in the United Kingdom. Participants were critically ill patients who regained mental capacity following receipt of level 3 (intensive) care. A total of 2961 eligible patients were identified from September 2015 to January 2017. A total of 2048 were approached for participation in the ICU, of which 1458 provided informed consent. Follow-up was completed December 2017. <h3>Interventions</h3> Twenty four ICUs were randomized 1:1 to the intervention or control group. Intervention ICUs (n = 12; 669 participants) delivered usual care during a baseline period followed by an intervention period. The preventive, complex psychological intervention comprised promotion of a therapeutic ICU environment plus 3 stress support sessions and a relaxation and recovery program delivered by trained ICU nurses to high-risk (acutely stressed) patients. Control ICUs (n = 12; 789 participants) delivered usual care in both baseline and intervention periods. <h3>Main Outcomes and Measures</h3> The primary clinical outcome was PTSD symptom severity among survivors at 6 months measured using the PTSD Symptom Scale–Self-Report questionnaire (score range, 0-51, with higher scores indicating greater symptom severity; the minimal clinically important difference was considered to be 4.2 points). <h3>Results</h3> Among 1458 enrolled patients (mean [SD] age, 58 [16] years; 599 women [41%]), 1353 (93%) completed the study and were included in the final analysis. At 6 months, the mean PTSD Symptom Scale–Self-Report questionnaire score in intervention ICUs was 11.8 (baseline period) compared with 11.5 (intervention period) (difference, −0.40 [95% CI, −2.46 to 1.67]) and in control ICUs, 10.1 (baseline period) compared with 10.2 (intervention period) (difference, 0.06 [95% CI, −1.74 to 1.85]) between periods. There was no significant difference in PTSD symptom severity at 6 months (treatment effect estimate [difference in differences] of −0.03 [95% CI, −2.58 to 2.52];<i>P</i> = .98). <h3>Conclusions and Relevance</h3> Among critically ill patients in the ICU, a nurse-led preventive, complex psychological intervention did not significantly reduce patient-reported PTSD symptom severity at 6 months. These findings do not support the use of this psychological intervention. <h3>Trial Registration</h3> ISRCTN53448131

Abstract Background Although high-flow nasal cannula therapy (HFNC) has become a popular mode of non-invasive respiratory support (NRS) in critically ill children, there are no randomised controlled trials (RCTs) comparing it with continuous positive airway pressure (CPAP). We performed a pilot RCT to explore the feasibility, and inform the design and conduct, of a future large pragmatic RCT comparing HFNC and CPAP in paediatric critical care. Methods In this multi-centre pilot RCT, eligible patients were recruited to either Group A (step-up NRS) or Group B (step-down NRS). Participants were randomised (1:1) using sealed opaque envelopes to either CPAP or HFNC as their first-line mode of NRS. Consent was sought after randomisation in emergency situations. The primary study outcomes were related to feasibility (number of eligible patients in each group, proportion of eligible patients randomised, consent rate, and measures of adherence to study algorithms). Data were collected on safety and a range of patient outcomes in order to inform the choice of a primary outcome measure for the future RCT. Results Overall, 121/254 eligible patients (47.6%) were randomised (Group A 60%, Group B 44.2%) over a 10-month period (recruitment rate for Group A, 1 patient/site/month; Group B, 2.8 patients/site/month). In Group A, consent was obtained in 29/33 parents/guardians approached (87.9%), while in Group B 84/118 consented (71.2%). Intention-to-treat analysis included 113 patients (HFNC 59, CPAP 54). Most reported adverse events were mild/moderate (HFNC 8/59, CPAP 9/54). More patients switched treatment from HFNC to CPAP (Group A: 7/16, 44%; Group B: 9/43, 21%) than from CPAP to HFNC (Group A: 3/13, 23%; Group B: 5/41, 12%). Intubation occurred within 72 h in 15/59 (25.4%) of HFNC patients and 10/54 (18.5%) of CPAP patients ( p = 0.38). HFNC patients experienced fewer ventilator-free days at day 28 (Group A: 19.6 vs. 23.5; Group B: 21.8 vs. 22.2). Conclusions Our pilot trial confirms that, following minor changes to consent procedures and treatment algorithms, it is feasible to conduct a large national RCT of non-invasive respiratory support in the paediatric critical care setting in both step-up and step-down NRS patients. Trial registration clinicaltrials.gov, NCT02612415 . Registered on 23 November 2015.

Oxygen saturation monitoring for children receiving respiratory support is standard worldwide. No randomised clinical trials have compared peripheral oxygen saturation (SpO2) targets for critically ill children. The harm of interventions to raise SpO2 to > 94% may exceed their benefits. We undertook an open, parallel-group randomised trial of children > 38 weeks completed gestation and < 16 years of age receiving invasive or non-invasive respiratory support and supplemental oxygen who were admitted urgently to one of three paediatric intensive care units. A ‘research without prior consent’ approach was employed. Children were randomly assigned to a liberal oxygenation group (SpO2 targets > 94%) or a conservative oxygenation group (SpO2 = 88–92% inclusive). Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between-group separation of SpO2 and safety. The Oxy-PICU trial was registered before recruitment: ClinicalTrials.gov identifier NCT03040570. A total of 159 children met the inclusion criteria, of whom 119 (75%) were randomised between April and July 2017, representing a rate of 10 patients per month per site. The mean time to randomisation from first contact with an intensive care team was 1.9 (SD 2.2) h. Consent to continue in the study was obtained in 107 cases (90%); the children’s parents/legal representatives were supportive of the consent process. The median (interquartile range, IQR) of time-weighted individual mean SpO2 was 94.9% (92.6–97.1) in the conservative oxygenation group and 97.5% (96.2–98.4) in the liberal group [difference 2.7%, 95% confidence interval (95% CI) 1.3–4.0%, p < 0.001]. Median (IQR) time-weighted individual mean FiO2 was 0.28 (0.24–0.37) in the conservative group and 0.37 (0.30–0.42) in the liberal group (difference 0.08, 95% CI 0.03–0.13, p < 0.001). There were no significant between-group differences in length of stay, duration of organ support or mortality. Two prespecified serious adverse events (cardiac arrests) occurred, both in the liberal oxygenation group. A definitive clinical trial of peripheral oxygen saturation targets is feasible in critically ill children.

Fever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection. An open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety. One hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2–38.6) in the restrictive group and 38.8 °C (38.6–39.1) in the permissive group, a mean difference of 0.5 °C (0.2–0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation. Uncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone. ISRCTN16022198 . Registered on 14 August 2017.

Background BRAF+MEK inhibitors extend life expectancy of patients with BRAF V600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen. Methods Patients with BRAFV600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of >1% as the detection threshold. Results 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65% AJCC (7th ed) stage IV M1c, 29% had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95%CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95%CI 0.87-3.28, p = 0.121), ORR 57% vs 77%. INT patients experienced fewer treatment-related AEs (76% vs 88%), but more grade >3 AEs (53% vs 42%). QoL favoured CONT. Detection of BRAFV600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95%CI 1.25-5.21, p=0.01) in both arms. A change to undetected during treatment did not significantly predict better OS. Conclusion INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors.

Background Osteoarthritis (OA) is the most common long-term condition managed in UK general practice. However, care is suboptimal despite evidence that primary care and community-based interventions can reduce OA pain and disability. Objectives The overall aim was to improve primary care management of OA and the health of patients with OA. Four parallel linked workstreams aimed to (1) develop a health economic decision model for estimating the potential for cost-effective delivery of primary care OA interventions to improve population health, (2) develop and evaluate new health-care models for delivery of core treatments and support for self-management among primary care consulters with OA, and to investigate prioritisation and implementation of OA care among the public, patients, doctors, health-care professionals and NHS trusts, (3) determine the effectiveness of strategies to optimise specific components of core OA treatment using the example of exercise and (4) investigate the effect of interventions to tackle barriers to core OA treatment, using the example of comorbid anxiety and depression in persons with OA. Data sources The North Staffordshire Osteoarthritis Project database, held by Keele University, was the source of data for secondary analyses in workstream 1. Methods Workstream 1 used meta-analysis and synthesis of published evidence about effectiveness of primary care treatments, combined with secondary analysis of existing longitudinal population-based cohort data, to identify predictors of poor long-term outcome (prognostic factors) and design a health economic decision model to estimate cost-effectiveness of different hypothetical strategies for implementing optimal primary care for patients with OA. Workstream 2 used mixed methods to (1) develop and test a ‘model OA consultation’ for primary care health-care professionals (qualitative interviews, consensus, training and evaluation) and (2) evaluate the combined effect of a computerised ‘pop-up’ guideline for general practitioners (GPs) in the consultation and implementing the model OA consultation on practice and patient outcomes (parallel group intervention study). Workstream 3 developed and investigated in a randomised controlled trial (RCT) how to optimise the effect of exercise in persons with knee OA by tailoring it to the individual and improving adherence. Workstream 4 developed and investigated in a cluster RCT the extent to which screening patients for comorbid anxiety and depression can improve OA outcomes. Public and patient involvement included proposal development, project steering and analysis. An OA forum involved public, patient, health professional, social care and researcher representatives to debate the results and formulate proposals for wider implementation and dissemination. Results This programme provides evidence (1) that economic modelling can be used in OA to extrapolate findings of cost-effectiveness beyond the short-term outcomes of clinical trials, (2) about ways of implementing support for self-management and models of optimal primary care informed by National Institute for Health and Care Excellence recommendations, including the beneficial effects of training in a model OA consultation on GP behaviour and of pop-up screens in GP consultations on the quality of prescribing, (3) against adding enhanced interventions to current effective physiotherapy-led exercise for knee OA and (4) against screening for anxiety and depression in patients with musculoskeletal pain as an addition to current best practice for OA. Conclusions Implementation of evidence-based care for patients with OA is feasible in general practice and has an immediate impact on improving the quality of care delivered to patients. However, improved levels of quality of care, changes to current best practice physiotherapy and successful introduction of psychological screening, as achieved by this programme, did not substantially reduce patients’ pain and disability. This poses important challenges for clinical practice and OA research. Limitations The key limitation in this work is the lack of improvement in patient-reported pain and disability despite clear evidence of enhanced delivery of evidence-based care. Future work recommendations (1) New thinking and research is needed into the achievable and desirable long-term goals of care for people with OA, (2) continuing investigation into the resources needed to properly implement clinical guidelines for management of OA as a long-term condition, such as regular monitoring to maintain exercise and physical activity and (3) new research to identify subgroups of patients with OA as a basis for stratified primary care including (i) those with good prognosis who can self-manage with minimal investigation or specialist treatment, (ii) those who will respond to, and benefit from, specific interventions in primary care, such as physiotherapy-led exercise, and (iii) develop research into effective identification and treatment of clinically important anxiety and depression in patients with OA and into the effects of pain management on psychological outcomes in patients with OA. Trial registration Current Controlled Trials ISRCTN06984617, ISRCTN93634563 and ISRCTN40721988. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme and will be published in full in Programme Grants for Applied Research Programme ; Vol. 6, No. 4. See the NIHR Journals Library website for further project information.

Background Unchecked patient deterioration can lead to in-hospital cardiac arrest (IHCA) and avoidable death. The National Cardiac Arrest Audit (NCAA) has found fourfold variation in IHCA rates and survival between English hospitals. Key to reducing IHCA is both the identification of patients at risk of deterioration and prompt response. A range of targeted interventions have been introduced but implementation varies between hospitals. These differences are likely to contribute to the observed variation between and within hospitals over time. Objective To determine how interventions aimed at identification and management of deteriorating patients are associated with IHCA rates and outcomes. Design A mixed-methods study involving a systematic literature review, semistructured interviews with 60 NHS staff, an organisational survey in 171 hospitals and interrupted time series and difference-in-difference analyses (106 hospitals). Setting English hospitals participating in the NCAA audit. Participants NHS staff (approximately 300) and patients (13 million). Interventions Education, track-and-trigger systems (TTSs), standardised handover tools and outreach teams. Main outcome measures IHCA rates, survival and hospital-wide mortality. Data sources NCAA, Hospital Episode Statistics, Office for National Statistics Mortality Statistics. Methods A literature review and qualitative interviews were used to design an organisational survey that determined how interventions have been implemented in practice and across time. Associations between variations in services and IHCA rates and survival were determined using cross-sectional, interrupted time series and difference-in-difference analyses over the index study period (2009/10 to 2014/15). Results Across NCAA hospitals, IHCAs fell by 6.4% per year and survival increased by 5% per year, with hospital mortality decreasing by a similar amount. A national, standard TTS [the National Early Warning Score (NEWS)], introduced in 2012, was adopted by 70% of hospitals by 2015. By 2015, one-third of hospitals had converted from paper-based TTSs to electronic TTSs, and there had been an increase in the number of hospitals with an outreach team and an increase in the number with a team available at all times. The extent of variation in the uses of educational courses and structured handover tools was limited, with 90% of hospitals reporting use of standardised communication tools, such as situation, background, assessment and recommendation, in 2015. Introduction of the NEWS was associated with an additional 8.4% decrease in IHCA rates and, separately, a conversion from paper to electronic TTS use was associated with an additional 7.6% decrease. However, there was no associated change in IHCA survival or hospital mortality. Outreach teams were not associated with a change in IHCA rates, survival or hospital mortality. A sensitivity analysis restricted to ward-based IHCAs did not alter the findings but did identify an association between increased outreach team intensity in 2015 and IHCA survival. Limitations The organisational survey was not able to explore all aspects of the interventions and the contextual factors that influenced them. Changes over time were dependent on respondents’ recall. Conclusions Standardisation of TTSs and introduction of electronic TTSs are associated with a reduction in IHCAs. The apparent lack of impact of outreach teams may reflect their mode of introduction, that their effect is through providing support for implementation of TTS or that the organisation of the response to deterioration is not critical, as long as it is timely. Their role in end-of-life decision-making may account for the observed association with IHCA survival. Future work To assess the potential impact of outreach teams at hospital level and patient level, and to establish which component of the TTS has the greatest effect on outcomes. Funding The National Institute for Health Research Health Services and Delivery Research programme.

Studies have demonstrated an association between height and weight and mortality among patients in the Intensive Care Unit (ICU) and the optimal body mass index (BMI) might be well above the optimal values in the general population. Most of these studies have relied on estimated values, the validity of which is not known. Admissions to adult general ICUs from 1 April 2009 to 31 March 2016 in the Case Mix Programme (CMP) Database were described by height and weight assessment methods (measured or estimated). A multilevel logistic regression model was built, which had acute hospital mortality as the outcome and included standard case mix adjustment, BMI, the assessment method and the interactions between BMI and assessment method. There were 690,405 eligible admissions and most patients (59.7%) had estimates of height and/or weight recorded. Patients with both height and weight measured had lower severity and mortality. The association between BMI and mortality was reverse J-shaped with the lowest mortality at BMI 34.3 kg/m2. Whether height and weight were measured or estimated did not influence the association between BMI and mortality. For epidemiological comparisons of mortality among critically ill adults, estimated values of height and weight appear valid.

Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile infections declined across the UK National Health Service in the decade that followed implementation of an infection control campaign. The national impact on intensive care unit (ICU)-acquired infections has not been documented. Methods Data on MRSA, C. difficile, vancomycin-resistant Enterococcus (VRE), and ICU–acquired bloodstream infections (UABSIs) for 1 189 142 patients from 2007 to 2016 were analyzed. Initial coverage was 139 ICUs increasing to 276 ICUs, representing 100% of general adult UK ICUs. Results ICU MRSA and C. difficile acquisitions per 1000 patients decreased between 2007 and 2016 (MRSA acquisitions, 25.4 to 4.1; and C. difficile acquisitions, 11.1 to 3.5), whereas VRE acquisitions increased from 1.5 to 5.9. There were 13 114 UABSIs in 1.8% of patients who stayed longer than 48 hours on ICU. UABSIs fell from 7.3 (95% confidence interval [CI], 6.9–7.6) to 1.6 (95% CI, 1.5–1.7)/1000 bed days. Adjusting for patient factors, the incidence rate ratio was 0.21 (95% CI, 0.19–0.23, P &amp;lt; .001) from 2007 to 2016. The greatest reduction, comparing rates in 2007/08 and 2015/16, was for MRSA (97%), followed by P. aeruginosa (81%), S. aureus (79%) and Candida spp (72%), with lower reductions for the coliforms (E. coli 57% and Klebsiella 49%). Conclusions Large decreases in ICU-acquired infections occurred across the UK ICU network linked with the first few years of a national infection control campaign, but rates have since been static. Further reductions will likely require a new intervention framework.

8517 Background: Liquid biopsies based on circulating tumor DNA (ctDNA) analysis are being investigated for detection of residual disease and recurrence. Conclusive evidence for utility of ctDNA in early-stage non-small cell lung cancer (NSCLC) is awaited. Due to low ctDNA levels in early-stage disease or post-treatment, effective methods require high analytical sensitivity to detect mutant allele fractions (MAF) below 0.01%. Methods: We analysed 363 plasma samples from 88 patients with NSCLC recruited to the LUng cancer CIrculating tumour DNA (LUCID) study, with disease stage I (49%), II (28%) and III (23%). 62% were adenocarcinomas. Plasma was collected before and after treatment, and at 3, 6 and 9 months after surgery (N = 69) or chemoradiotherapy (N = 19). Additional plasma was collected at disease relapse for 17 patients. Median follow-up was 3 years, and 40 patients progressed or died of any cause. We employed the RaDaR™ assay, a highly sensitive personalized assay using deep sequencing of up to 48 tumor-specific variants. Variants identified by tumor exome analysis were tested by deep sequencing of tumor tissue and buffy coat DNA to verify somatic mutations and exclude clonal hematopoiesis. The RaDaR assay demonstrated 90% sensitivity at 0.001% MAF in analytical validation studies. Results: ctDNA was detected in 26% of samples, at median MAF of 0.047% (range: 0.0007% to &gt; 2%), and prior to treatment in 87%, 77% and 24% for disease stage III, II and I respectively. For 62 patients, plasma was collected at a landmark timepoint, between 2 weeks and 4 months after initial treatment. ctDNA detection at the landmark timepoint was strongly predictive of clinical disease relapse, with Hazard Ratio of 20.7 (CI: 7.7-55.5, p-value &lt; 0.0001). All 11 cases with ctDNA detected at landmark had disease progression, a median of 121 days after detection, and these included all 8 patients that relapsed within 300 days of treatment. Across 27 patients whose disease progressed during the study, ctDNA was detected at any timepoint post-treatment in 17 cases, with a median lead time of 203 days, and up to 741 days prior to clinical progression. ctDNA was detected post-treatment, in 13 of the 15 patients that progressed and had ctDNA detected prior to treatment. Conclusions: Our results support an emerging paradigm shift, by demonstrating that liquid biopsies can reliably detect recurrence of NSCLC at a preclinical stage, many months before clinical progression, thereby offering the opportunity for earlier therapeutic intervention. Clinical trial information: NCT04153526.

TPS619 Background: Triple negative breast cancers (TNBCs) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination-deficient tumors, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Methods: This is a 3-stage open-label randomized phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. The aim is to establish whether the addition of olaparib to neoadjuvant platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. In stages 1 and 2, all patients receive 4 cycles of 3-weekly carboplatin AUC5/weekly paclitaxel 80mg/m 2 . They are randomly assigned 1:1:1 to a control arm, or to one of two research arms. These research arms include different treatment schedules of olaparib 150 mg BD for 12 days. In stage 3, patients are randomly assigned 1:1 to either the control or research arm chosen following stage 2. The primary endpoints are: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. Key eligibility criteria are age 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by combining olaparib with platinum-based chemotherapy. This trial includes an optional pathway called PARTNERING for patients with residual disease after six chemotherapy cycles. This aims to establish if adding new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Each cohort will consist of 15 patients. Since May 2016, 756 patients from 30 sites have been enrolled. An IDSMC review following stages 1 and 2 identified no safety concerns and Research Arm 2 was selected (olaparib administration on days 3-14). Stage 3 phase I (recruitment of non-gBRCA and gBRCA patients) completed December 2021. Stage 3 phase II (recruitment of gBRCA patients) remains open to patients in the U.K. and internationally. 5 patients have enrolled in PARTNERING. Follow-up duration is 10 years. Clinical trial information: NCT03150576.

Optimal targets for systemic oxygenation in paediatric critical illness are unknown. Observational data indicate that high levels of arterial oxygenation are associated with poor outcomes in resuscitation of the newborn and in adult critical illness. Within paediatric intensive care units (PICUs), staff prevent severe hypoxia wherever possible, but beyond this there is no consensus. Practice varies widely with age, diagnosis, treating doctor and local or national guidelines followed, though peripheral blood oxygen saturations (SpO2) of >95% are often targeted. The overall aim of this pilot study is to determine the feasibility of performing a randomised trial in critically ill children comparing current practice of liberal SpO2 targets with a more conservative target.Oxy-PICU is a pragmatic, open, pilot randomised controlled trial in infants and children requiring mechanical ventilation and receiving supplemental oxygen for abnormal gas exchange accepted for emergency admission to one of three participating UK PICUs. The study groups will be either a conservative SpO2 target of 88%-92% (inclusive) or a liberal SpO2 target of >94%. Infants and children who fulfil all inclusion criteria and none of the exclusion criteria will be randomised 1:1 by a secure web-based system to one of the two groups. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support. Discharge outcomes will also be recorded. In addition to observational data, blood and urine samples will be taken to identify biochemical markers of oxidative stress. Outcomes are targeted at assessing study feasibility with a primary outcome of adequate study recruitment (target: 120 participants).The trial received Health Research Authority approval on 1 June 2017 (16/SC/0617). Study findings will be disseminated in national and international conferences and peer-reviewed journals.NCT03040570.

Background Fever accelerates host immune system control of pathogens but at a high metabolic cost. The optimal approach to fever management and the optimal temperature thresholds used for treatment in critically ill children are unknown. Objectives To determine the feasibility of conducting a definitive randomised controlled trial (RCT) to evaluate the clinical effectiveness and cost-effectiveness of different temperature thresholds for antipyretic management. Design A mixed-methods feasibility study comprising three linked studies – (1) a qualitative study exploring parent and clinician views, (2) an observational study of the epidemiology of fever in children with infection in paediatric intensive care units (PICUs) and (3) a pilot RCT with an integrated-perspectives study. Setting Participants were recruited from (1) four hospitals in England via social media (for the FEVER qualitative study), (2) 22 PICUs in the UK (for the FEVER observational study) and (3) four PICUs in England (for the FEVER pilot RCT). Participants (1) Parents of children with relevant experience were recruited to the FEVER qualitative study, (2) patients who were unplanned admissions to PICUs were recruited to the FEVER observational study and (3) children admitted with infection requiring mechanical ventilation were recruited to the FEVER pilot RCT. Parents of children and clinicians involved in the pilot RCT. Interventions The FEVER qualitative study and the FEVER observational study had no interventions. In the FEVER pilot RCT, children were randomly allocated (1 : 1) using research without prior consent (RWPC) to permissive (39.5 °C) or restrictive (37.5 °C) temperature thresholds for antipyretics during their PICU stay while mechanically ventilated. Main outcome measures (1) The acceptability of FEVER, RWPC and potential outcomes (in the FEVER qualitative study), (2) the size of the potentially eligible population and the temperature thresholds used (in the FEVER observational study) and (3) recruitment and retention rates, protocol adherence and separation between groups and distribution of potential outcomes (in the FEVER pilot RCT). Results In the FEVER qualitative study, 25 parents were interviewed and 56 clinicians took part in focus groups. Both the parents and the clinicians found the study acceptable. Clinicians raised concerns regarding temperature thresholds and not using paracetamol for pain/discomfort. In the FEVER observational study, 1853 children with unplanned admissions and infection were admitted to 22 PICUs between March and August 2017. The recruitment rate was 10.9 per site per month. The majority of critically ill children with a maximum temperature of &gt; 37.5 °C received antipyretics. In the FEVER pilot RCT, 100 eligible patients were randomised between September and December 2017 at a recruitment rate of 11.1 per site per month. Consent was provided for 49 out of 51 participants in the restrictive temperature group, but only for 38 out of 49 participants in the permissive temperature group. A separation of 0.5 °C (95% confidence interval 0.2 °C to 0.8 °C) between groups was achieved. A high completeness of outcome measures was achieved. Sixty parents of 57 children took part in interviews and/or completed questionnaires and 98 clinicians took part in focus groups or completed a survey. Parents and clinicians found the pilot RCT and RWPC acceptable. Concerns about children being in pain/discomfort were cited as reasons for withdrawal and non-consent by parents and non-adherence to the protocol by clinicians. Limitations Different recruitment periods for observational and pilot studies may not fully reflect the population that is eligible for a definitive RCT. Conclusions The results identified barriers to delivering the definitive FEVER RCT, including acceptability of the permissive temperature threshold. The findings also provided insight into how these barriers may be overcome, such as by limiting the patient inclusion criteria to invasive ventilation only and by improved site training. A definitive FEVER RCT using a modified protocol should be conducted, but further work is required to agree important outcome measures for clinical trials among critically ill children. Trial registration The FEVER observational study is registered as NCT03028818 and the FEVER pilot RCT is registered as Current Controlled Trials ISRCTN16022198. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 5. See the NIHR Journals Library website for further project information.

In most countries in the Western world, more than 50% of adults are overweight or obese putting them at increased risk of hypertension, type 2 diabetes, coronary heart disease, stroke and other chronic disorders. It is not clear what impact increasing prevalence of over-weight and obesity has on hospital admissions. The objective of this study was to examine the relationship between body mass index (BMI) and number of days spent in hospital. The study was designed as a retrospective and prospective cohort study using nationally representative Health Survey data linked to NHS hospital admissions data. The study was set in Scotland. The participants were a nationally representative sample of 6968 (45%) men and 8700 (55%) women, of 16-74 years of age, living in private households whose BMI was recorded in the 1995 and 1998 Scottish Health Surveys. The outcome measure was the number of days spent in hospital between 1981 and 2004. The results showed that the proportion of participants in both normal weight (BMI 20-24.9 kg/m(2)) and over-weight (BMI 25-29.9 kg/m(2)) categories was 37%, with 21% in the obese (BMI ≥30 kg/m(2)) and 5% in the under-weight (BMI <20 kg/m(2)) categories. The median number of days spent in hospital between 1981 and 2004 was six. The odds ratios (95% confidence intervals) for spending above the median numbers of days in hospital adjusted for age, sex, socioeconomic status and behavioural factors (i.e. smoking, alcohol drinking and physical activity) were 1.29 (1.06-1.56) for the <20 kg/m(2) group, 1.00 (0.91-1.11) for the 25-29.9 kg/m(2) group and 1.24 (1.10-1.38) for the ≥30 kg/m(2) group compared with the 20-24.9 kg/m(2) group. In conclusion, extremes of BMI category identified at a single point in time are associated with spending above the median number of days in hospital over a 20-year period after adjusting for demographic, behavioural and socioeconomic exposures.

Objectives: In the absence of EuroQol 5D data, mapping algorithms can be used to predict health-state utility values (HSUVs) for use in economic evaluation. In a placebo-controlled Phase II study of olaparib maintenance therapy (NCT00753545), health-related quality of life was measured using the Functional Assessment of Cancer Therapy – Ovarian (FACT-O) questionnaire. Our objective was to generate HSUVs from the FACT-O data using published mapping algorithms. Materials and methods: Algorithms were identified from a review of the literature. Goodness-of-fit and patient characteristics were compared to select the best-performing algorithm, and this was used to generate base-case HSUVs for the intention-to-treat population of the olaparib study and for patients with breast cancer antigen mutations. Results: Four FACT – General (the core component of FACT-O) mapping algorithms were identified and compared. Under the preferred algorithm, treatment-related adverse events had no statistically significant effect on HSU ( P >0.05). Discontinuation of the study treatment and breast cancer antigen mutation status were both associated with a reduction in HSUVs (–0.06, P =0.0009; and –0.03, P =0.0511, respectively). The mean HSUV recorded at assessment visits was 0.786. Conclusion: FACT – General mapping generated credible HSUVs for an economic evaluation of olaparib. As reported in other studies, different algorithms may produce significantly different estimates of HSUV. For this reason, it is important to test whether the choice of a specific algorithm changes the conclusions of an economic evaluation. Keywords: platinum sensitive ovarian cancer, EQ 5D, maintenance therapy, olaparib

Abstract Background Failure to recognise and respond to patient deterioration on hospital wards is a common cause of healthcare-related harm. If patients are not rescued and suffer a cardiac arrest as a result then only around 15% will survive. Track and Trigger systems have been introduced into the NHS to improve both identification and response to such patients. This study examines the association between the type of Track &amp; Trigger System (TTS) (National Early Warning Score (NEWS) versus non-NEWS) and the mode of TTS (paper TTS versus electronic TTS) and incidence of in-hospital ward-based cardiac arrests (IHCA) attended by a resuscitation team. Methods TTS type and mode was retrospectively collected at hospital level from 106 NHS acute hospitals in England between 2009 to 2015 via an organisational survey. Poisson regression and logistic regression models, adjusted for case-mix, temporal trends and seasonality were used to determine the association between TTS and hospital-level ward-based IHCA and survival rates. Results The NEWS was introduced in England in 2012 and by 2015, three-fifths of hospitals had adopted it. One fifth of hospitals had instituted an electronic TTS by 2015. Between 2009 and 2015 the incidence of IHCA fell. Introduction or use of NEWS in a hospital was associated with a reduction of 9.4% in the rate of ward-based IHCA compared to non-NEWS systems (incidence rate ratio 0.906, p &lt; 0.001). The use of an electronic TTS was also associated with a reduction of 9.8% in the rate of IHCA compared with paper-based TTS (incidence rate ratio 0.902, p = 0.009). There was no change in hospital survival. Conclusions The introduction of standardised TTS and electronic TTS have the potential to reduce ward-based IHCA. This is likely to be via a range of mechanisms from early intervention to institution of treatment limits. The lack of association with survival may reflect the complexity of response to triggering of the afferent arm of the rapid response system.

Where direct or indirect estimates of health state utility values (HSUVs) are not available, mapping algorithms can be used to generate HSUVs from health related quality of life data. In a phase II randomised study of olaparib maintenance therapy in platinum-sensitive recurrent ovarian cancer, the Functional Assessment of Cancer Therapy Ovarian (FACT-O) questionnaire was used. Although no FACT-O mapping algorithms are currently available, several algorithms using FACT-General (G) domains of FACT-O have been published. In this analysis, we applied FACT-G mapping algorithms to the FACT-O data collected in the olaparib study and compared the HSUVs generated. FACT-O data were collected at scheduled visits, and on treatment discontinuation. Three algorithms mapping FACT-G to EuroQol (EQ-5D) [ (Cheung, 2009), Ordinary Least Squares (OLS) and Tobit (Longworth, 2014) ] and one from FACT-G to Time-Trade-Off (Dobrez, 2007) were applied to data from the phase II study. The agreement between HSUVs was assessed using concordance correlation coefficients (CCCs), and paired t-tests for mean HSUVs. HSUVs were generated for 93% of patients in the study. Mean predicted HSUVs using OLS and Tobit were statistically consistent (p-value=0.947), whilst Cheung and Dobrez HSUVs were different from other algorithms (p-values < 0.05). The CCCs comparing OLS to Tobit and OLS to Cheung were 0.915 and 0.851, respectively. The CCCs comparing Dobrez to the EQ-5D algorithms were 0.629 (OLS), 0.619 (Tobit) and 0.783 (Cheung). The lowest and highest mean predicted HSUVs were estimated using OLS and Dobrez, respectively. HSUVs can be estimated from FACT-O using FACT-G mapping algorithms. Comparable HSUVs were generated using OLS and Tobit algorithms, whilst Cheung and Dobrez generated distinct HSUVs profiles. Without trial data directly comparing EQ-5D to FACT-O, it is difficult to identify the optimal mapping algorithm. Instead, a range of plausible mean HSUVs can be derived for use in cost-utility analyses.

Background High numbers of patients experience severe acute stress in critical care units. Acute stress has been linked to post-critical care psychological morbidity, including post-traumatic stress disorder (PTSD). Previously, a preventive, complex psychological intervention [Psychological Outcomes following a nurse-led Preventative Psychological Intervention for critically ill patients (POPPI)] was developed by this research team, to be led by nurses, to reduce the development of PTSD symptom severity at 6 months. Objectives The objectives were to (1) standardise and refine the POPPI intervention, and, if feasible, (2) evaluate it in a cluster randomised clinical trial (RCT). Design Two designs were used – (1) two feasibility studies to test the delivery and acceptability (to patients and staff) of the intervention, education package and support tools, and to test the trial procedures (i.e. recruitment and retention), and (2) a multicentre, parallel-group, cluster RCT with a baseline period and staggered roll-out of the intervention. Setting This study was set in NHS adult, general critical care units. Participants The participants were adult patients who were &gt; 48 hours in a critical care unit, receiving level 3 care and able to consent. Interventions The intervention comprised three elements – (1) creating a therapeutic environment in critical care, (2) three stress support sessions for patients identified as acutely stressed and (3) a relaxation and recovery programme for patients identified as acutely stressed. Main outcome measures Primary outcome – patient-reported symptom severity using the PTSD Symptom Scale – Self Report (PSS-SR) questionnaire (to measure clinical effectiveness) and incremental costs, quality-adjusted life-years (QALYs) and net monetary benefit at 6 months (to measure cost-effectiveness). Secondary outcomes – days alive and free from sedation to day 30; duration of critical care unit stay; PSS-SR score of &gt; 18 points; depression, anxiety and health-related quality of life at 6 months; and lifetime cost-effectiveness. Results (1) A total of 127 participants were recruited to the intervention feasibility study from two sites and 86 were recruited to the RCT procedures feasibility study from another two sites. The education package, support tools and intervention were refined. (2) A total of 24 sites were randomised to the intervention or control arms. A total of 1458 participants were recruited. Twelve sites delivered the intervention during the intervention period: &gt; 80% of patients received two or more stress support sessions and all 12 sites achieved the target of &gt; 80% of clinical staff completing the POPPI online training. There was, however, variation in delivery across sites. There was little difference between baseline and intervention periods in the development of PTSD symptom severity (measured by mean PSS-SR score) at 6 months for surviving patients in either the intervention or the control group: treatment effect estimate −0.03, 95% confidence interval (CI) −2.58 to 2.52; p = 0.98. On average, the intervention decreased costs and slightly improved QALYs, leading to a positive incremental net benefit at 6 months (£835, 95% CI −£4322 to £5992), but with considerable statistical uncertainty surrounding these results. There were no significant differences between the groups in any of the secondary outcomes or in the prespecified subgroup analyses. Limitations There was a risk of bias because different consent processes were used and as a result of the lack of blinding, which was mitigated as far as possible within the study design. The intervention started later than anticipated. Patients were not routinely monitored for delirium. Conclusions Among level 3 patients who stayed &gt; 48 hours in critical care, the delivery of a preventive, complex psychological intervention, led by nurses, did not reduce the development of PTSD symptom severity at 6 months, when compared with usual care. Future work Prior to development and evaluation of subsequent psychological interventions, there is much to learn from post hoc analyses of the cluster RCT rich quantitative and qualitative data. Trial registration This trial is registered as ISRCTN61088114 and ISRCTN53448131. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research ; Vol. 23, No. 30. See the NIHR Journals Library website for further project information.

The Psychological Outcomes following a nurse-led Preventative Psychological Intervention for critically ill patients trial is a cluster-randomised controlled trial of the clinical and cost-effectiveness of a complex nurse-led preventative psychological intervention compared with usual care in reducing patient-reported post-traumatic stress disorder symptom severity, and other reported psychological morbidities, at six months among Level 3 (intensive care) patients in adult general critical care units in England, Wales and Northern Ireland. This paper describes the proposed statistical and health economic analyses for the Psychological Outcomes following a nurse-led Preventative Psychological Intervention for critically ill patients trial. It is important to complete and publish this plan before inspecting and locking the trial data to ensure that post hoc and data-derived decisions are avoided. Trial registration: ISRCTN53448131

e15560 Background: Detection of residual circulating tumour DNA (ctDNA) in patient plasma following curative intervention for localized non-small cell lung cancer (NSCLC) could identify patients who are at higher risk of relapse. These patients may benefit from adjuvant treatment, even if they have no macroscopic disease identified by radiographic imaging, which is the current standard of care. Here we evaluate the performance of the Inivata personalized sequencing assays to detect ctDNA in a cohort of 90 patients with early-stage NSCLC undergoing treatment with curative intent. Methods: The Inivata assay uses a highly sensitive next-generation sequencing platform, to identify tumor-specific variants from exome sequencing of tumor tissue and to track up to 48 patient-specific mutations in plasma specimens by multiplex PCR and ultra-high-depth next-generation sequencing. Samples from 90 patients with Stage I-III NSCLC who underwent radical treatment with curative intent, either surgery or radiotherapy ± chemotherapy, were collected as part of the LUng cancer - CIrculating tumor DNA (LUCID) study. Results: 350 plasma samples from 90 patients were analyzed using the Inivata assay, including samples collected before and after treatment and at subsequent follow-up visits. ctDNA was detected in pre-treatment samples in 38% of 32 patients (12/32) with Stage I NSCLC and in 90% of 21 patients (19/21) with Stage II/III disease, at allele fractions ranging from 6 parts per million (ppm, equivalent to 0.0006%) to over 20,000 ppm (equivalent to 2%). In plasma samples collected post-treatment, ctDNA was detected in close to 50% of cases. Conclusions: These findings highlight the Inivata assay is a sensitive method for detection of residual ctDNA and recurrence in early stage NSCLC. Initial detection rates ranged from 38% in Stage I disease to 90% for patients with Stage II/III disease prior to treatment, including detection of ctDNA to levels as low as a few parts per million. ctDNA was detected in at least one post-treatment timepoint in close to 50% patients. Together with additional data to be presented from the full 90 patient cohort, this suggests a possible route to improving treatment and designs of adjuvant trials for early stage NSCLC by detection of residual disease post-treatment and monitoring for early detection of relapse.

Abstract Introduction Identification of minimal residual disease (MRD) following curative intervention of localized non-small cell lung cancer (NSCLC) holds promise for identifying patients who are at higher risk of relapse and who would benefit from adjuvant treatment. Current routine clinical practice involves serial radiographic imaging following surgery to detect macroscopic disease. Liquid biopsy can identify patients who have MRD without macroscopic disease. Currently available assays have only identified circulating tumor DNA (ctDNA) in a limited number of cases with early stage NSCLC. More sensitive methods are needed to accurately identify the majority of patients who will relapse. Here we evaluate the performance of InVision®MRD, a personalized sequencing assay for plasma cell-free DNA, for detection of ctDNA in patients with early-stage NSCLC undergoing treatment with curative intent. Methods InVision®MRD is a highly sensitive in vitro diagnostic assay, currently available for research use only (RUO), that can detect the presence of tumor DNA traces in cell-free DNA from plasma samples of cancer patients. InVision®MRD identifies tumor-specific variants from exome sequencing of tumor tissue and tracks them in plasma specimens by multiplex PCR and high-depth next-generation sequencing. We evaluated the detection of ctDNA in plasma samples collected from the LUng cancer - CIrculating tumor DNA (LUCID) study, which collected plasma samples from 100 patients with NSCLC stages I-III who underwent radical treatment with curative intent, either surgery or radiotherapy ± chemotherapy. Of patients in the LUCID study, 60% had stage I NSCLC and 40% patients had stage II/III disease, according to TNM 7th edition. Results To evaluate the InVision®MRD assay, a subset of samples from the LUCID study were analyzed. Samples were collected before and after surgery and chemo-radiotherapy from patients with early-stage NSCLC. Using multiplexed analysis of 48 patient-specific variants and high-depth sequencing, ctDNA was detected in 50% of pre-treatment samples analyzed from the first set of 18 patients, at ctDNA fractions ranging from 20 ppm (equivalent to 0.002%) to 19576 ppm (equivalent to 1.958%). Conclusions These findings highlight an opportunity to improve ctDNA detection for early stage NSCLC using a patient-specific plasma sequencing assay. Initial detection rates have reached 50% for patients with early-stage disease prior to treatment, including detection of ctDNA to levels as low as a few parts per million. Together with further data to be presented, this suggests a possible route to improving treatment for early stage NSCLC by detection of residual disease post treatment and for monitoring for early detection of relapse. Citation Format: Katrin Heider, Davina Gale, Andrea Ruiz-Valdepenas, Giovanni Marsico, Garima Sharma, Malcolm Perry, Robert Osborne, Karen Howarth, Tadd Lazarus, Viona Rundell, Jelena Belic, Jerome Wulff, Susan Harden, Doris M. Rassl, Robert C. Rintoul, Nitzan Rosenfeld. Sensitive detection of ctDNA in early stage non-small cell lung cancer patients with a personalized sequencing assay [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 735.

BRAF+MEK inhibitors extend life expectancy of BRAF V600 mutant advanced melanoma patients; acquired resistance limits duration of benefit. Preclinical and case studies suggested that intermittent dosing could enable patients to remain on treatment longer, delay onset of disease progression and offer improved quality of life (QoL). INTERIM was a UK randomised multicentre phase II trial testing an intermittent dosing regimen. Patients with BRAFV600 mutant advanced melanoma with ECOG PS 0-1 due to start dabrafenib+trametinib were randomised to receive dabrafenib (150mg bid) and trametinib (2mg od) either continuously (CONT) or intermittently (INT; dabrafenib d1-22+trametinib d1–15) on a 28 day cycle. Prior immunotherapy and brain involvement was allowed. Patient recruitment, treatment compliance, QoL and progression-free survival (PFS) were evaluated for the primary endpoint. Secondary endpoints included response rate (ORR), overall survival (OS) and toxicity. The prognostic and predictive value of mutant BRAFV600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of >1% as the detection threshold. 79 patients (39 INT, 40 CONT) were recruited from Dec ‘17–Feb ’20; median age 67 years, 52% PS 1, 65% AJCC (7th ed) M1c, 29% had brain metastases and 46% had LDH > ULN. With median follow-up of 19 months, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95% CI 0.79–2.45, p = 0.255); median OS 18.1 mo vs not reached (HR 1.69, 95% CI 0.87–3.28, p = 0.121), ORR 57% vs 77%. INT patients experienced fewer treatment related AEs (76% vs 88%), but a higher proportion of grade >3 AEs (53% vs 42%). QoL at 6 months favoured CONT. 66 patients had baseline plasma collected for ctDNA analysis and 27 (41%) of these had detectable BRAFV600E ctDNA. Detection prior to treatment correlated with worse OS (HR 2.55, 95%CI 1.25-5.21, p=0.01) and higher disease burden (LDH>ULN; p<0.001). A change to undetected during treatment did not significantly predict better OS. The UK INTERIM study is consistent with other national studies suggesting that intermittent dosing does not improve efficacy of BRAF+MEKi.

Abstract Introduction There is little research on identifying modifiable risk factors that predict future interference of pain with daily activity in people with joint pain, and the estimation of the corresponding population attributable risk (PAR). The present study therefore investigated modifiable predictors of pain interference and estimated maximum potential gain from intervention in adults with joint pain. Methods A population‐based cohort aged ≥50 years was recruited from eight general practices in North Staffordshire, UK. Participants ( n = 1878) had joint pain at baseline lasting ≥3 months and indicated no pain interference. Adjusted associations of self‐reported, potentially modifiable prognostic factors (body mass index, anxiety/depressive symptoms, widespread pain, inadequate joint pain control, physical inactivity, sleep problems, smoking and alcohol intake) with onset of pain interference 3 years later were estimated via Poisson regression, and corresponding PAR estimates were obtained. Results Inadequate joint‐specific pain control, insomnia and infrequent walking were found to be independently significantly associated with the onset of pain interference after 3 years, with associated PARs of 6.3% (95% confidence interval −0.3, 12.4), 7.6% (−0.4, 15.0) and 8.0% (0.1, 15.2), respectively, with only the PAR for infrequent walking deemed statistically significant. The PAR associated with insomnia, infrequent walking and inadequate control of joint pain simultaneously was 20.3% (8.6, 30.4). Conclusions There is potential to reduce moderately the onset of pain interference from joint pain in the over‐50s if clinical and public health interventions targeted pain management and insomnia, and promoted an active lifestyle. However, most of the onset of significant pain interference in the over‐50s, would not be prevented, even assuming that these factors could be eliminated.

Active surveillance (AS) is a preferred management option for men with prostate cancer with favourable prognosis. However, nearly half of men on AS switch to treatment within 5 years, so therapeutic strategies to prevent or delay disease progression could be considered. The androgen receptor is the pre-eminent oncogenic driver in prostate cancer.To explore image-based tumour responses and the patient impact of short-duration androgen-targeted therapy (ATT) to abrogate disease progression during AS.Men on AS with Cambridge Prognostic Group 1 & 2 (low and favourable intermediate risk) prostate cancer and lesions visible on magnetic resonance imaging (MRI) were recruited to an open-label, single-centre, phase 2 feasibility study of short-term ATT (the TAPS01 study).Apalutamide 240 mg was administered for 90 days.MRI-measured tumour volume (TV), gland volume (GV), and the TV/GV ratio were calculated at baseline, at day 90 (end of treatment), and at 6- and 18-month follow-up. Quality of life metrics were measured at day 0, day 90, and 6 weeks after ATT.Eleven patients (40% of eligible men approached) agreed to participate, of whom nine completed treatment. At day 90, the median percentage reduction was -38.2% (range -51.8% to -23.5%) for GV, -54.2% (range -74.1% to -13.8%) for TV, and -27.2% (range -61.5% to -7.5%) for TV/GV (all p < 0.0001). At 6 mo, while GV had returned to baseline (p = 0.95) both TV (-31.9%; p = 0.0007) and TV/GV (-28.7%; p = 0.0009) remained significantly reduced. This reduction was sustained at 18 months (TV -18%, TV/GV -23.8%; p = 0.01). European Organization for Research and Treatment of Cancer QoL core 30-item questionnaire scores for global, physical, role, and social functioning decreased during treatment, but all were recovering by 6 weeks. EQ-VAS scores were unchanged compared to baseline.TAPS01 has demonstrated feasibility and patient tolerability for short-term ATT in men on AS. Our data suggest a selective and durable antitumour effect in the short term and support a larger-scale randomised trial.We investigated the feasibility of short-term treatment with an androgen inhibitor to prevent or delay disease progression for men on active surveillance for prostate cancer. Results for a small group of patients show that 90-day treatment led to a sustained decrease in tumour volume over 18 months. The findings warrant a larger clinical trial for this approach, which could allow patients to delay or even avoid longer-term active treatments.

Abstract Blood-based assays have shown increasing ability to detect circulating tumour DNA (ctDNA) in patients with early-stage cancer. However, detection of ctDNA in patients with non-small cell lung cancer (NSCLC) has continued to prove challenging. We performed retrospective analysis to quantify ctDNA levels in a cohort of 100 patients with early-stage NSCLC prior to treatment with curative intent enrolled in the LUCID study ( NCT04153526 ). Where tumour tissue was available for whole exome sequencing, mutations identified were used to define patient-specific sequencing assays. For those 90 patients, plasma cell-free DNA was sequenced to high depth across capture panels targeting a median of 328 mutations specific to each patient. Data was analysed using Integration of Variant Reads (INVAR), detecting ctDNA in 66.7% of patients, including 52.7% (29 of 55) patients with stage I disease and &gt;88% detection for patients with stage II and III disease (16/18 and 15/17). ctDNA was detected in plasma at fractional concentrations as low as 9.1×10 −6 , and in patients with tumour volumes as low as 0.23 cm 3 . A 36-gene sequencing panel (InVisionFirst-Lung™) was used to analyse plasma DNA in 27 samples including the 10 cases without tumour exome data, and detected ctDNA in 59% of samples tested (16 of 27). Across the entire cohort, detection rates were higher in squamous cell carcinoma patients compared to adenocarcinoma patients (81% vs. 59%). Detection of ctDNA prior to treatment was associated with significantly shorter time free from relapse, across all patients and in patient subgroups, with Hazard Ratios &gt;11 for selected patient subsets. Our analysis indicates that for patients with stage I NSCLC, the median ctDNA fraction in plasma is approx. 12 parts per million (0.0012%). This indicates the limits of detection that would be required for ctDNA-based liquid biopsies to detect ctDNA in the majority of patients with early-stage NSCLC.

Abstract Background A major focus on preventing resistant organisms and hospital-acquired infections over the past 10 years has seen well-documented reductions in MRSA and C. difficileat hospital and national level. Less is known about national changes in epidemiology of bloodstream infections, and such data is important to frame future national priorities and targets. Methods Data from the Intensive Care National Audit and Research Centre Program on MRSA, C. difficile and VRE colonization and ICU-acquired bloodstream infections (UABSIs) from 1,195,103 consecutive patients admitted to 276 UK ICUs (excluding Scotland) from 2007 to 2015 was analyzed. Results MRSA and C. difficile colonizations per 1000 patients decreased significantly (MRSA admissions 38.8 to 12.03 (P = 0.00003); MRSA acquisitions 25.4 to 3.1(P = 0.0008); C. difficile admissions 10.6 to 4.1(P = 0.0001); C. difficile acquisitions 11.1 to 3.3 (p = 0.0005). Reductions predominantly occurred between 2007 and 2011 with MRSA but not C. difficile. In contrast VRE admissions and ICU-acquisitions increased from 1.9 to 5.8 (P = 0.002) and 1.5 to 5.6 (P = 0.005), respectively. There were 13,147 UABSI episodes in 11,075 (1.8%) of 621,859 patients staying &amp;gt;48 hours. The UABSI rate fell from 6.6 (95% CI 6.33–6.97) to 1.7 (95% CI 1.5–1.7)/1000 bed days (P &amp;lt; 0.0001), with the reduction taking place between 2007 and 2011 and no significant reduction since. A fixed effect model identified lower age, male sex, severity of illness, larger ICU-size, immunosuppressive therapy (but not immunosuppressive illness) as significant risk factors for UABSI. MSSA, E. coli, Enterococci, Yeast, Klebsiella sp and P. aeruginosa accounted for 73% of all recorded first UABSIs. Greatest reduction was seen for MRSA (97%), Pseudomonas aeruginosa(80%), S. aureus (77%) and Yeast (71%), with lower reductions for E. coli (54%) and Klebsiella(42%). Conclusion Large decreases in ICU-acquired bloodstream infections occurred across UK ICUs at the same time as reductions in MRSA and C. difficile, but rates have been static since 2011. Reductions were seen for all organisms. The observation that no material reductions in UABSIs were observed during the last 5 years of the study, despite continued focus on improving infection control practice throughout, implies that benefits from the current intervention framework have been achieved. Disclosures All authors: No reported disclosures.

Abstract Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. Germline BRCA (gBRCA) breast cancer and TNBC share some phenotypic and molecular similarities, with 10%-20% of TNBC patients having gBRCA mutations. Homologous recombination deficient tumours are particularly sensitive to PARP inhibitors such as olaparib (Lynparza). It has been shown that adjuvant olaparib for patients with high-risk, HER2-negative early breast cancer and gBRCA pathogenic or likely pathogenic variants after adjuvant or neoadjuvant chemotherapy significantly improves 3-year invasive and distant disease-free survival compared to placebo (OlympiA). Aim: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR) rate). Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) aiming to establish if the addition of new agents (ATR inhibitor and PDL1 inhibitor) can improve response in those patients with evidence of residual disease before surgery. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; clinical stage T1-4 N0-2; performance status 0-1; treatment commenced within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and the TNBC non-gBRCA cohort) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy. It is planned to recruit a minimum of 188 gBRCA patients. A maximum of 15 patients will be allocated into each PARTNERING cohort. Present accrual: Recruitment commenced 27 May 2016 and 678 patients from 30 sites have been accrued to date. The IDSMC reviewed the trial after Stages 1 and 2 and recommended to continue the trial without change. Data analysis for Stage 2 revealed no safety concerns and research arm 2 (olaparib on day 3 to day 14) was selected. Stage 3 Phase I recruitment is in progress (recruiting TNBC non-gBRCA and gBRCA patients) and we anticipate moving to Phase II (recruiting gBRCA patients only) by early 2022. Four patients have been accrued to the PARTNERING optional pathway to date. The trial is open and enrolling patients to UK and international sites. Contact information: partner@addenbrookes.nhs.uk Citation Format: Lynsey M Drewett, Karen A Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Jessica Martin, Camila Maida de Pontes, Nicola Johnson, Caron Harvey, Erdem Demir, Kimberley St John Green, James Jones, Gemma Young, Anne-Laure Vallier, Wendi Qian, Andrea Machin, Karen McAdam, Rebecca Roylance, Ellen R Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-01.

Abstract Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and Germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination deficient tumours, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Aim: To establish if the addition of Olaparib to neoadjuvant Platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant Paclitaxel and Carboplatin +/- Olaparib, followed by clinicians' choice of Anthracycline regimen. Stages 1 and 2: Randomisation (1:1:1) to control (3-weekly carboplatin AUC5/weekly with paclitaxel 80mg/m2 for 4 cycles), or to one of two research arms. These use an identical chemotherapy regimen and also include different treatment schedules of Olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either the control or research arm chosen following stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and Olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) for patients with evidence of residual disease after six chemotherapy cycles. This aims to establish if the addition of new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and TNBC non-gBRCA cohort) and 20% (gBRCA patients) by combining Olaparib with Platinum based chemotherapy. A minimum of 478 TNBC non-gBRCA and 188 gBRCA patients will be recruited. Each PARTNERING cohort will consist of 15 patients. Current Enrollment: Since May 2016, 756 patients from 30 sites have been enrolled. Stages 1 and 2 are completed. An IDSMC review identified no safety concerns and Research Arm 2 was selected. This arm involves Olaparib administration on days 3-14. Stage 3 Phase I (recruitment of non-gBRCA and gBRCA patients) completed in December 2021. Stage 3 Phase II (recruitment of gBRCA patients only) remains open to patients to UK and internationally. 5 patients have been enrolled in PARTNERING. ClinicalTrials.gov Identifier: NCT03150576 Citation Format: Lynsey Drewett, Karen A. Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Rebecca Lucey, Anne-Laure Vallier, Wendi Qian, Andrea Machin, PARTNER Research Team, Karen McAdam, Rebecca Roylance, Ellen R. Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E. Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of Olaparib to Platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT562.

Aims & Objectives: Optimal targets for systemic oxygenation in paediatric critical illness are unknown. A U-shaped relationship exists between PaO2 and PICU mortality. Oxidative stress or iatrogenic injury from unnecessarily intensive treatments are potential mechanisms of harm from hyperoxia. We estimated biomarkers of oxidative stress in subjects in a randomized clinical trial (Oxy-PICU) of oxygen saturation targets to inform on the relative contributions of these mechanisms. Methods Whole blood and urine samples were collected at two time points; within 24 hours and up to 72 hours of randomisation in recruits to the Oxy-PICU multiple centre randomised study (March-July 2017). This involved comparison of SpO2 targets of 88–92% (Conservative) with >94% (liberal). Plasma component of samples were analysed for markers of oxidative/ischaemic stress, namely ischaemia modified albumin (IMA) and malondialdehyde (MDA; lipid peroxidation marker), which were measured using spectrophotometric and fluorescent assays respectively. Urine was analysed spectrophotometrically for nitrite and nitrate levels as markers of reactive nitrogen species. Results MDA levels ranged from 1.6μM to 18.4μM (n= 102, median= 4.7μM). IMA levels expressed a corrected ratio to baseline albumin ranged from 0.00451 to 0.021 (n=102, median= 0.0096). Total Nitrate/nitrite content was 43.2μM to 1106.6μM (n=47, median= 275.3μM). There was no significant difference between conservative and liberal SpO2 groups. Conclusions These preliminary data do not demonstrate differences in oxidative stress with permissive and conservative SpO2 targets. It is feasible to measure biomarkers of oxidative stress in a PICU population. These data will assist with power calculations for the planned larger definitive trial.

Abstract Background Methicillin-Resistant Staphylococcus aureus (MRSA) and C. difficile infection have reduced across the UK National Health Service in the last decade following implementation of an infection control campaign. The national impact on hospital-acquired infections in the ICU however has not been comprehensively documented. Methods Data on MRSA, C. difficile, vancomycin-resistant Enterococcus (VRE) and ICU-acquired bloodstream infection (UABSIs) were analyzed from 1,189,142 consecutive patients from 2007 to 2016 recorded prospectively and standardized by highly trained assessors. Initial coverage was 139 ICUs increasing to 275 ICUs representing 100% of general, adult UK ICUs. Results ICU MRSA and C. difficile admissions and acquisitions per 1000 patients decreased between 2007 and 2012 (MRSA admissions 38.8 to 13.1; acquisitions 25.4 to 4.1; C. difficile admissions 10.6 to 4.2; acquisitions 11.1 to 3.5), whereas VRE admissions and acquisitions increased from 1.9 to 5.3 and 1.5 to 5.9, respectively. There were 13,114 UABSIs in 1.8% patients staying &gt;48 hours. UABSIs fell from 7.3 (95% CI 6.9–7.6) to 1.6 (95% CI 1.5–1.7)/1,000 bed-days between 2007 and 2012. Adjusting for patient admission and ICU factors the IRR was 0.21 (95% CI 0.19–0.23, P &lt; 0.001) from 2007 to 2016. Reductions in UABSIs were seen for all main organisms excluding VRE with greatest reductions for MRSA (97%), Pseudomonas aeruginosa (80%), S. aureus (77%) and Candida spp. (71%) but lower reductions for E. coli (54%) and Klebsiella (42%). Conclusion Large decreases in ICU-acquired infections occurred across the UK ICU network between 2007 and 2012 linked with the first few years of the national infection control campaign, but rates have been static since. Further reductions in ICU will likely require a new intervention framework. Disclosures All authors: No reported disclosures.

Abstract Introduction Overall survival of non-small-cell lung cancer (NSCLC) patients remains poor as patients are frequently diagnosed at late stage. The evaluation of circulating tumor DNA (ctDNA) has been shown to offer a non-invasive method for cancer detection. However, detection rates of ctDNA in patients with early stage cancers have been low. The distribution of ctDNA levels in this population is unknown, and the analytical requirements for a test to detect the majority of cancers cannot be defined. Methods The LUCID study (LUng cancer - CIrculating tumour DNA study) recruited 100 patients with stage I-IIIB NSCLC according to the TNM 7th edition and collected plasma samples before and after radical treatment by surgery or radiotherapy +/- chemotherapy with curative intent. To measure levels of ctDNA in patients with early stage disease and very low tumor burden we developed a method for INtegration of VAriant Reads (INVAR), which uses sequencing data across hundreds to thousands of tumor-mutated loci to detect ctDNA in plasma samples at high sensitivity. We applied INVAR to 90 of the patients from the LUCID study, where tumor sequencing data was available. To measure ctDNA in the remaining LUCID patients, we applied the InVision® amplicon-based plasma sequencing assay. Results Across the 100 patients, ctDNA signals were observed in 67% of samples obtained prior to treatment. ctDNA was detected in 66% of cases, with ctDNA levels as low as 9.1x10-6 (9 parts per million), at a detection threshold with 95% specificity. ctDNA was detected in 52% of 60 patients with stage I NSCLC and in 88% of 40 patients with stage II/III disease. Analyzing different histological subtypes, ctDNA was detected in 79% of squamous cell carcinomas and 60% of adenocarcinomas. We found a good agreement when comparing the ctDNA results obtained from INVAR and the InVision® assay. Conclusions Our findings suggest that an assay with sensitivity to below 10 parts per million may be able to detect ctDNA in as many as 2/3 of patients with early stage NSCLC prior to treatment, including the majority of adenocarcinoma cases. Additionally, patient-specific analysis of ctDNA has the potential to aid in longitudinal cancer monitoring and in detection of low tumor burden and minimal residual disease. We aim to apply this approach to serial samples obtained through the LUCID study to investigate its application in treatment management. Citation Format: Katrin Heider, Jonathan C. Wan, Davina Gale, Andrea Ruiz-Valdepenas, Florent Mouliere, James Morris, Nagmi R. Qureshi, Wendi Qian, Jerome Wulff, Nikolaos Demiris, Karen Howarth, Emma Green, Viona Rundell, Tim Eisen, Wendy Cooper, Christopher G. Smith, Charles Massie, Susan Harden, Doris M. Rassl, Robert C. Rintoul, Nitzan Rosenfeld. ctDNA detection in early stage non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 736.