Incorporating neoadjuvant chemotherapy into locally advanced colon cancer treatment pathways: Real-life experience of implementing FOxTROT.

AIM: The international FOxTROT trial, recently published in the Journal of Clinical Oncology is the first randomized controlled trial testing neoadjuvant chemotherapy (NAC) with oxaliplatin and 5-fluorouracil in locally advanced, but operable, colon cancer. The trial met its primary endpoint with fewer patients experiencing recurrent or residual disease at 2 years with NAC compared with the control (16.8% vs. 21.2%, risk ratio = 0.74, p  = 0.042). Translating the findings of the FOxTROT trial into improved patient outcomes is dependent on implementation of new neoadjuvant chemotherapy (NAC) pathways in colorectal cancer. METHOD: We describe our experience implementing a novel neoadjuvant treatment pathway in colorectal cancer at a large UK teaching hospital. RESULTS: To date 64 patients have been commenced on the novel pathway following presentation and adoption of the FOxTROT trial results. We present key lessons and strategies developed across the multidisciplinary team to minimize impact on person hours, service capacity and budget, whilst building patient safety and confidence. CONCLUSION: Use of NAC for locally advanced colon cancer has been shown to improve surgical outcomes and longer term cancer outcomes. Provision of NAC requires some modifications to current treatment pathways but can be delivered with team working and without the requirement for additional resources.

Comparison of published core outcome sets with outcomes recommended in regulatory guidance from the US Food and Drug Administration and European Medicines Agency: cross sectional analysis.

Objective: To compare the outcomes in published core outcome sets with the outcomes recommended in corresponding guidance documents from the European Medicines Agency (EMA) and US Food and Drug Administration (FDA), matched by health condition. Design: Cross sectional analysis. Setting: US and Europe. Population: Sample of core outcome sets related to drugs, devices, and gene therapy that involved patients in the consensus process, published between 1 January 2015 and 31 December 2019; and corresponding EMA and FDA guidance documents. Main outcome measures: The extent of matches between outcomes included within core outcome sets and those recommended in corresponding EMA and FDA guidance documents were assessed. Matches were considered to be general (ie, non-specific) or specific (ie, exact). General matches were assessed to determine whether the core outcome set or guidance document outcome was narrower. Results: Relevant guidance documents were found for for 38 (39%) of 98 eligible published core outcome sets. Among outcomes in core outcome sets, medians of 70% (interquartile range 48-86%) and 52% (33-77%) were matches with outcomes recommended in EMA and FDA documents, respectively. Medians of 46% (27-68%) and 26% (18-46%) were specific matches with outcomes in EMA and FDA documents, respectively. When outcomes were generally matched, the outcomes from core outcome sets were more frequently narrower than the regulatory outcomes (83% and 75% for EMA and FDA, respectively). Conclusion: Greater adoption of, and reference to, core outcome sets in regulatory guidance documents can encourage clinical trialists, especially those in industry, to measure and report consistent and agreed outcomes and improve the quality of guidance. Given the overlap between outcomes in core outcome sets and regulatory guidance, and given that most core outcome sets now involve patients in the consensus process, these sets could serve as a useful resource for regulators when recommending outcomes for studies evaluating regulated products. Developers are encouraged to appraise recommended outcomes in salient regulatory documents when planning a core outcome set.

Representation of published core outcome sets for research in regulatory guidance: protocol.

Background: The COMET Initiative promotes the development and use of 'core outcome sets' (COS), agreed standardised sets of outcomes that should be measured and reported in all studies in a particular clinical condition. COS are determined by consensus amongst key stakeholders, including health professionals, policymakers and patients, ensuring that the priorities and expertise of these representatives inform the choice of the most important outcomes to measure for a given condition. There is increased recognition of the need to integrate COS across the healthcare system and with existing regulatory apparatus, to ensure that outcomes being recorded are those of key relevance to important stakeholders. The aim of this study is to assess the degree of concordance between outcomes recommended in COS for research and in guidance provided by two key regulators: US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Methods: COS for research published during 2015-2019 with patient involvement and covering drug or device interventions will be compared against relevant regulatory guidelines, matched by condition. Guidance documents which match in scope (relating to intervention and population) to a COS for research will be scrutinised to identify all suggested outcomes for comparison against the core outcomes in the corresponding COS. Discussion: This study will identify variation between outcomes suggested in EMA and FDA regulatory guidance relative to outcomes included in published COS for research, thus demonstrating the degree of representation of COS in regulatory guidance and vice versa. If the findings of this study reveal a lack of concordance between COS and regulatory guidance overall or for particular disease areas, we will invite feedback from FDA and EMA and will seek to highlight where findings support the recommendations towards using well-developed COS or will make recommendations to COS developers on outcomes of importance to these key regulators.

Defining standards in colorectal optimisation: a Delphi study protocol to achieve international consensus on key standards for colorectal surgery prehabilitation.

INTRODUCTION: Prehabilitation in colorectal surgery is evolving and may minimise postoperative morbidity and mortality. With many different healthcare professionals contributing to the prehabilitation literature, there is significant variation in reported primary endpoints that restricts comparison. In addition, there has been limited work on patient-related outcome measures suggesting that patients with colorectal cancer needs and issues are being overlooked. The Defining Standards in Colorectal Optimisation Study aims to achieve international consensus from all stakeholders on key standards to provide a framework for reporting future prehabilitation research. METHODS AND ANALYSIS: A systematic review will identify key standards reported in trials of prehabilitation in colorectal surgery. Standards that are important to patients will be identified by a patient and public involvement (PPI) event. The longlist of standards generated from the systematic review and PPI event will be used to develop a three-round online Delphi process. This will engage all stakeholders (healthcare professionals and patients) both nationally and internationally. The results of the Delphi will be followed by a face-to-face interactive consensus meeting that will define the final standards for prehabilitation for elective colorectal surgery. ETHICS AND DISSEMINATION: The University of Glasgow College of Medical, Veterinary and Life Sciences Ethics Committee has approved this protocol, which is registered as a study (200190120) with the Core Outcome Measures in Effectiveness Trials Initiative. Publication of the standards developed by all stakeholders will increase the potential for comparative research that advances understanding of the clinical application of prehabilitation. PROSPERO REGISTRATION NUMBER: CRD42019120381.

'Let's talk about sex': a patient-led survey on sexual function after colorectal and pelvic floor surgery.

AIM: Discussions regarding sex after colorectal and pelvic floor surgery are often overlooked by clinicians. This is the first patient designed and delivered study to explore sexual function and practices after colorectal surgery. The aim was to explore the questions about sex that matter to patients and their partners following colorectal or pelvic floor surgery through a patient and public involvement survey. The results of this work will underpin the creation of a sex patient reported outcome measure. METHODS: An anonymous online survey tool (Survey Monkey™) was disseminated via social media (Twitter, Facebook). Thematic analysis was applied to 130 free text comments posted by participants to identify key themes. RESULTS: Some 632 individuals completed the survey. Most respondents were women (80% n = 507), 49.5% (n = 312) were married and 14% (n = 87) identified as LGBT+ (lesbian, gay, bisexual and transgender +). Indications for surgery varied: 34% were treated for ulcerative colitis (n = 214); 31% Crohn's (n = 196); 17% (n = 109) cancer; and 17% (n = 110) for perianal fistula. For patients who had a stoma formed (85%, n = 540), over half (51%, n = 324) lived with their stoma for 1-5 years. Respondents reported substantial alterations to their preferences for sexual positions, sexual activity and body confidence following surgery. Most respondents indicated that they were not offered advice about sex by a healthcare professional. CONCLUSIONS: The survey showed a substantial impact on the mechanics of sex following colorectal surgery. Few patients were offered preoperative information regarding sex, which has implications for informed consent. This study demonstrates a clear unmet need, voiced by patients, that open dialogue is necessary preoperatively to discuss sexual (dys)function.

Early antenatal counseling in the outpatient setting for high-risk pregnancies: a randomized control trial.

OBJECTIVES: Determine if antenatal counseling delivered in the outpatient setting improves parental knowledge and satisfaction without contributing to anxiety. STUDY DESIGN: Randomized control trial at a large academic institution. Mothers at risk for preterm delivery were enrolled following routine maternal-fetal medicine (MFM) visits and randomized to early antenatal counseling of prematurity or standard counseling by MFM providers. The primary outcome was parental knowledge of prematurity. Secondary outcomes included parental satisfaction, anxiety scores, and compliance with recommended follow-up. RESULTS: Seventy-six women were enrolled, 38 in each group. Early counseling group had higher knowledge scores (86.3 vs 64.3, p = <0.001) and parental satisfaction (p = 0.003). Anxiety scores were similar between the two groups (38.2 vs 40.4, p = 0.53). No difference was noted in compliance with follow-up. CONCLUSIONS: Antenatal counseling in the high-risk outpatient setting improved parental knowledge and satisfaction without leading to increased anxiety.

"Vicarious thinking" was a key driver of score change in Delphi surveys for COS development and is facilitated by feedback of results.

OBJECTIVE: The objectives of this nested study were to (1) assess whether changes in scores between rounds altered the final degree of consensus achieved in three Delphi surveys conducted as part of COS development projects (anal, gastric, and prostate cancer), and (2) explore participants' reasons for changing scores between rounds. STUDY DESIGN AND SETTING: All Delphi surveys were conducted online using DelphiManager software and included healthcare professionals and participating patients. Participants were invited to give a free-text reason whenever they changed their score across an important threshold on a 1-9 Likert scale (1-3 not important, 4-5 important, 7-9 critically important). Reasons for score change were coded by four researchers independently using an inductive-iterative approach. RESULTS: In all three Delphi surveys, the number of outcomes reaching criteria for consensus was greater in R2 than R1. Twelve themes and 23 subthemes emerged from 2298 discrete reasons given for score change. The most common reasons for the change were "time to reflect" (482 responses, 23%) and vicarious thinking (424, 21%), with 68% (291) of vicarious thinking attributed to seeing other participant's scores. CONCLUSION: Our findings support conducting a Delphi survey over the use of a single questionnaire where building consensus is the objective. Time to reflect and vicarious thinking, facilitated by seeing other participant's scores, were important drivers of score change. How results are presented to participants between rounds and the duration of and time between rounds in a Delphi survey may, therefore, influence the results and should be clearly reported.

Antenatal counseling in the gray zone of viability.

OBJECTIVE: The objective of this study is to determine the resuscitation choices at 22-24 weeks gestation, related to whether mothers received antenatal counseling and the timing relative to delivery. STUDY DESIGN: A retrospective chart review was performed of infants inborn at 22-24 weeks, over a 5-year period. Infants were excluded if they had major birth defects, were still hospitalized, or the consult occurred before 22 weeks. RESULT: Of 121 infants born at 220-246 weeks, 91 were born to mothers who received a neonatology consult. For 80 infants resuscitated after consult, the median time between consult and delivery was 51.7 h (range: 0.1-366.3 h). For 11 infants who received comfort care after consult, the median time between consult and delivery was 20.0 h (range: 0.8-64.4 h). CONCLUSIONS: After receiving counseling on the morbidity and mortality of delivery at 22-24 weeks, most parents chose resuscitation. Overall, 12-24 h between consult and delivery, parents were more likely to choose comfort care.

Developing a Workplace-Based Learning Culture in the NHS: Aspirations and Challenges.

BACKGROUND: The delivery of patient care in the United Kingdom is under increasing financial pressure. The need to continuously improve service delivery while making financial savings is challenging. Alongside this, National Health Service (NHS) Trusts must provide a suitable educational environment that meets the needs of all learners while meeting performance standards and targets set by external regulating authorities. This research addresses the gap in literature concerning educational culture in the NHS. METHODS: This case study examines the delivery of postgraduate medical education in the workplace. Semi-structured interviews were conducted with 6 lead educators in the Medical Division of a North West NHS Trust to glean their insights into what works and what needs to change. RESULTS: A thematic analysis of the transcripts revealed a number of factors that facilitated and hindered educational opportunities for doctors in training, including the role of leadership, the demands of external regulatory authorities, and the pressures on frontline staff to deliver safe, personal, and effective care. CONCLUSION: Opportunities for developing a collaborative approach between educational and clinical leaders and the individuals delivering education in the workplace to enhance the educational environment are discussed. Finally, an evaluatory toolkit based on the themes emerging from the data is proposed, as a resource for other health care organisations to help improve the delivery of workplace-based medical education.

Evaluation of an online training tool for scoring programmed cell death ligand-1 (PD-L1) diagnostic tests for lung cancer.

BACKGROUND: Numerous studies indicate that higher tumour programmed cell death ligand-1 (PD-L1) expression is associated with greater response to anti-programmed cell death-1 (PD-1)/PD-L1 immunotherapy in non-small cell lung cancer (NSCLC). In the era of precision medicine, there is a need to provide reliable, standardised training for pathologists to improve their accuracy of interpretation and scoring, as the results are used directly to inform clinical decisions. Here we present findings regarding reader reproducibility of PD-L1 tumour cell (TC) staining scoring for NSCLC using a PD-L1 e-trainer tool as part of a PD-L1 immunohistochemistry reader training course. METHODS: The PD-L1 training course was developed based on the use of VENTANA PD-L1 (SP263) and Dako PD-L1 IHC PharmDx 22C3 stained NSCLC samples in combination with a PD-L1 e-trainer tool. Five-hundred formalin-fixed, paraffin-embedded archival samples were obtained from commercial sources and stained for PD-L1. Slides were scored by two expert pathologists, then scanned to produce digital images and re-scored. Thirty-three cases were selected and sorted into three sets: a training set and two self-assessment tests (pre-test and 'competence' test). Participants (all selected board-certified pathologists) received face-to-face training including use of an e-trainer tool. Statistical analyses were performed using the competence test set. Overall percentage agreement (OPA) was assessed between the participant pathologists' registered scores and the reference scores assigned by expert pathologists at clinically relevant PD-L1 cut-offs (≥1%, ≥25% and ≥ 50%). RESULTS: Seven sessions were held and 69 participant pathologists completed the training. Inter-reader concordance indicated high OPA (85-95%) for PD-L1 TC scoring at clinically relevant cut-offs, with Fleiss' Kappa > 0.5. CONCLUSIONS: Use of this web-based training tool incorporated into classroom-style training was associated with an overall moderately good level of inter-reader reproducibility at key cut-offs for TC PD-L1 expression testing in NSCLC. Overall, the online training tool offers a means of standardised training for practising pathologists in a clinical setting.

Experiences of shame and intellectual disabilities: Two case studies.

Shame is a trans-diagnostic phenomenon that underlies a variety of mental health difficulties. People with intellectual disabilities (IDs) are reported to be one of the most stigmatized and excluded groups in society and are more likely to experience mental health problems than the general population. Consequently, this group may be at a significant risk of shame-related distress. However, there is a lack of research that investigates the experience of shame in people with ID, and there is currently a lack of interventions targeting shame in people with ID. Two case studies were undertaken to document the experiences of stigma, discrimination, and shame in people with ID and to explore how shame may present in this population. Shame was found to be a significant barrier to social inclusion and to contribute towards poor psychological health in people with ID. The development of interventions that specifically target shame in this population is recommended.

"Moving on" through the locked ward system for women with intellectual disabilities.

BACKGROUND: The move to community support for all people with intellectual disabilities is an aspiration with international significance. In this article, we draw on rich accounts from women with intellectual disabilities detained under the Mental Health Act (E&W) 1983 and staff at an National Health Service secure setting in England to explore how "moving on" is defined and perceived. METHODS: The study reports on an ethnographic study using the field-notes and the 26 semi-structured interviews with detained women and staff on three wards. RESULTS: We first explore staff conceptions of moving on, which include behavioural change and utilizing coping strategies. Then, we discuss the areas of analysis that women discussed: taking back responsibility, success in arranged relationships, acceptance of regime and resistance to progression. CONCLUSION: The concepts of moving on were not determined by the women but by the service. We recommend further research which explores women's own rehabilitation requirements.

Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865).

The design, optimization, and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABAA ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries that had the greatest odds of delivering the target profile. These efforts ultimately led to the identification of two precandidates from this subseries, which were advanced to preclinical safety studies and subsequently to the identification of the clinical candidate PF-06372865.

A core outcome set for clinical trials of chemoradiotherapy interventions for anal cancer (CORMAC): a patient and health-care professional consensus.

Chemoradiotherapy is the primary treatment for patients with squamous cell carcinoma of the anus, but variations in the reported outcomes have restricted between-study comparisons. Treatment-related morbidity is considerable; however, no trial has comprehensively quantified long-term side-effects or quality of life. Therefore, we established the first international health-care professional and patient consensus to develop a core outcome set, using the Core Outcome Measures in Effectiveness Trials method. We used the results from our previous systematic review and combined them in this Review with patient interviews to derive a comprehensive list of outcomes, followed by a two-round Delphi survey completed by 149 participants (55 patients and 94 health-care professionals) from 11 countries. The Delphi results were discussed at a consensus meeting of health-care professionals and patients. Agreement was reached on 19 outcomes across four domains: disease activity, survival, toxicity, and life impact. Implementation of the Core Outcome Research Measures in Anal Cancer (CORMAC) set in future trials will serve as a framework to achieve standardisation, facilitate selection of health-area-specific evaluation tools, reduce redundancy of outcome lists, allow between-study comparisons, and ultimately enhance the relevance of trial findings to health-care professionals, trialists, and patients.

A taxonomy has been developed for outcomes in medical research to help improve knowledge discovery.

OBJECTIVES: There is increasing recognition that insufficient attention has been paid to the choice of outcomes measured in clinical trials. The lack of a standardized outcome classification system results in inconsistencies due to ambiguity and variation in how outcomes are described across different studies. Being able to classify by outcome would increase efficiency in searching sources such as clinical trial registries, patient registries, the Cochrane Database of Systematic Reviews, and the Core Outcome Measures in Effectiveness Trials (COMET) database of core outcome sets (COS), thus aiding knowledge discovery. STUDY DESIGN AND SETTING: A literature review was carried out to determine existing outcome classification systems, none of which were sufficiently comprehensive or granular for classification of all potential outcomes from clinical trials. A new taxonomy for outcome classification was developed, and as proof of principle, outcomes extracted from all published COS in the COMET database, selected Cochrane reviews, and clinical trial registry entries were classified using this new system. RESULTS: Application of this new taxonomy to COS in the COMET database revealed that 274/299 (92%) COS include at least one physiological outcome, whereas only 177 (59%) include at least one measure of impact (global quality of life or some measure of functioning) and only 105 (35%) made reference to adverse events. CONCLUSIONS: This outcome taxonomy will be used to annotate outcomes included in COS within the COMET database and is currently being piloted for use in Cochrane Reviews within the Cochrane Linked Data Project. Wider implementation of this standard taxonomy in trial and systematic review databases and registries will further promote efficient searching, reporting, and classification of trial outcomes.

Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865.

BACKGROUND AND PURPOSE: Benzodiazepines, non-selective positive allosteric modulators (PAMs) of GABAA receptors, have significant side effects that limit their clinical utility. As many of these side effects are mediated by the α1 subunit, there has been a concerted effort to develop α2/3 subtype-selective PAMs. EXPERIMENTAL APPROACH: In vitro screening assays were used to identify molecules with functional selectivity for receptors containing α2/3 subunits over those containing α1 subunits. In vivo receptor occupancy (RO) was conducted, prior to confirmation of in vivo α2/3 and α1 pharmacology through quantitative EEG (qEEG) beta frequency and zolpidem drug discrimination in rats respectively. PF-06372865 was then progressed to Phase 1 clinical trials. KEY RESULTS: PF-06372865 exhibited functional selectivity for those receptors containing α2/3/5 subunits, with significant positive allosteric modulation (90-140%) but negligible activity (≤20%) at GABAA receptors containing α1 subunits. PF-06372865 exhibited concentration-dependent occupancy of GABAA receptors in preclinical species. There was an occupancy-dependent increase in qEEG beta frequency and no generalization to a GABAA α1 cue in the drug-discrimination assay, clearly demonstrating the lack of modulation at the GABAA receptors containing an α1 subtype. In a Phase 1 single ascending dose study in healthy volunteers, evaluation of the pharmacodynamics of PF-06372865 demonstrated a robust increase in saccadic peak velocity (a marker of α2/3 pharmacology), increases in beta frequency qEEG and a slight saturating increase in body sway. CONCLUSIONS AND IMPLICATIONS: PF-06372865 has a unique clinical pharmacology profile and a highly predictive translational data package from preclinical species to the clinical setting.