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Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM.

Abstract Aims To develop quality indicators (QIs) that may be used to evaluate the quality of care and outcomes for adults with atrial fibrillation (AF). Methods and results We followed the ESC methodology for QI development. This methodology involved (i) the identification of the domains of AF care for the diagnosis and management of AF (by a group of experts including members of the ESC Clinical Practice Guidelines Task Force for AF); (ii) the construction of candidate QIs (including a systematic review of the literature); and (iii) the selection of the final set of QIs (using a modified Delphi method). Six domains of care for the diagnosis and management of AF were identified: (i) Patient assessment (baseline and follow-up), (ii) Anticoagulation therapy, (iii) Rate control strategy, (iv) Rhythm control strategy, (v) Risk factor management, and (vi) Outcomes measures, including patient-reported outcome measures (PROMs). In total, 17 main and 17 secondary QIs, which covered all six domains of care for the diagnosis and management of AF, were selected. The outcome domain included measures on the consequences and treatment of AF, as well as PROMs. Conclusion This document defines six domains of AF care (patient assessment, anticoagulation, rate control, rhythm control, risk factor management, and outcomes), and provides 17 main and 17 secondary QIs for the diagnosis and management of AF. It is anticipated that implementation of these QIs will improve the quality of AF care.

Glial fibrillary acidic protein (GFAP) is cleared by the Food and Drug Administration (FDA) to determine need for head computed tomography (CT) within 12 h after mild traumatic brain injury (TBI) (Glasgow Coma Score [GCS] 13–15); S100 calcium-binding protein B (S100B) serves this function in Europe. This phase 1 biomarker cohort analysis of the multi-center, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study compares GFAP's diagnostic performance, measured on a rapid point-of-care platform, against protein S100B to predict intracranial abnormalities on CT within 24 h post-injury across the spectrum of TBI (GCS 3–15). Head CT scan performed in TBI subjects and blood was collected for all consenting subjects presenting to 18 United States level 1 trauma centers. Plasma was analyzed on a point-of-care device prototype assay for GFAP and serum was analyzed for S100B. In 1359 patients with TBI (GCS 3–15), mean (standard deviation [SD]) age = 40.1 (17.0) years; 68% were male. Plasma GFAP levels were significantly higher in CT+ TBI subjects (median = 1358 pg/mL, interquartile range [IQR]: 472–3803) than in CT- TBI subjects (median = 116 pg/mL, IQR: 26–397) or orthopedic trauma controls ( n = 122; median = 13 pg/mL, IQR: 7–20), p < 0.001. Serum S100B levels were likewise higher in CT+ TBI subjects (median = 0.17 μg/L, IQR: 0.09–0.38) than in CT- TBI subjects (median = 0.10 μg/L, IQR: 0.06–0.18), p < 0.001. Receiver operating characteristic curves were generated for prediction of intracranial injury on admission CT scan; area under the curve (AUC) for GFAP was significantly higher than for S100B in the same cohort (GFAP AUC – 0.85, 95% confidence interval [CI] 0.83–0.87; S100B AUC – 0.67, 95% CI 0.64-0.70; p < 0.001). GFAP, measured on a point-of-care platform prototype assay, has high discriminative ability to predict intracranial abnormalities on CT scan in patients with TBI across the full injury spectrum of GCS 3–15 through 24 h post-injury. GFAP substantially outperforms S100B.

e20519 Background: Radiation Therapy Oncology Group 9402 compared PCV chemotherapy plus radiation therapy (PCV+RT) versus RT alone for anaplastic oligodendroglioma. Here we report 1) longitudinal changes in cognition and quality of life, 2) effects of patient factors and treatments on cognition, quality of life and survival, and 3) prognostic implications of cognition and quality of life. Methods: Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL) by repeat assessments. Scores were analyzed for survivors and within five years of death. Shared parameter models evaluated MMSE/B-QOL with survival. Results: For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those dying within 5 years, MMSE scores were stable initially, while B-QOL scores decreased; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (P=0.0413 for MMSE; P=0.0016 for B-QOL) and were superior with age < 50 years (P<0.001 for MMSE; P=0.0554 for B-QOL) and KPS 80–100 (P<0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV+RT (HR=0.66, 95% CI=0.49–0.9, P=0.0084; HR=0.74, 95% CI=0.54–1.01, P=0.0592) in models with MMSE and B-QOL. There were no differences in MMSE and B-QOL scores between arms (P=0.4752 and P=0.2767, respectively); higher scores predicted longer survival. Conclusions: MMSE and B-QOL scores held steady in both arms for survivors. For those who died, B-QOL scores declined slowly until the last year of life, then rapidly. Younger, fitter patients had better MMSE and B-QOL scores and longer survival. No significant financial relationships to disclose.

8072 Background: Figitumumab (CP-751,871) is a fully human, IgG2monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR). We reported in a randomized phase II study (ASCO 2008), preliminary evidence of high activity of the combination of paclitaxel (T), carboplatin (C) and figitumumab (F) in advanced treatment-naïve NSCLC of squamous cell histology (n=11 pts). A single arm trial extension cohort was conducted to confirm those findings. Methods: Fifty-six pts with non-adenocarcinoma NSCLC were enrolled. Pts received T (200 mg/m2), C (AUC of 6) and F (20 mg/kg) q3weeks for up to 6 cycles; pts with response (PR) or stable disease were eligible to continue F as single agent until disease progression. Statistical hypotheses were 30% (null) versus 50% (response of interest). Protein expression of the IGF-IR in core tumor biopsies was quantified using automated quantitative analysis (AQUA) technology. Results: Pts were 72% male, 28% >70 years old and 91% stage IV. Median number of treatment cycles was 4, with 46% of pts receiving single agent F beyond cycle 4. TCF was well tolerated. The most common all-causality grade 3, 4 CTCAE adverse events were neutropenia (21%), hyperglycemia (14%) and fatigue (14%). Hyperglycemia adverse events almost always occurred within the first treatment cycle and were manageable with standard measures. Responses in squamous pts are currently 25 out of 40 pts according to RECIST, with final response assessment still pending for 7 additional pts (≥53%, p<0.001). One complete response and 7 striking PRs (50–80% tumor size reduction at cycle 2) were observed. Tumor size reductions with F maintenance treatment were also seen in 2 pts. Median progression free survival has not been yet reached at 4 months follow up. A trend (p=0.1) for higher IGF-IR expression in patients responding to TCF was observed in a small data set (n=12). Median tumor IGF-IR expression in pts responding to TCF therapy and non-responders were respectively 6287 and 4131 AQUA scores. Analysis of IGF-IR and other members of the IGF-IR pathway continues. Conclusions: These data further support the activity of figitumumab combination therapy in pts with squamous NSCLC. [Table: see text]

Due to geographic‐specific patient and institutional‐related barriers to care, data extrapolation and expert opinion on global burden of disease in otolaryngology–head and neck surgery may under‐ or overestimate the presence and effect of common head and neck conditions. The group of conditions that fail to present to local physicians and/or missed in data extrapolation methods is the unseen burden of disease. This article presents opinions from otolaryngology–head and neck surgery physicians in high‐ and low/middle‐income countries to help explain the contributing factors and ultimately how to use this unseen burden of disease.

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.

Abstract Background: Older adults with acute myeloid leukemia (AML) represent a vulnerable population in whom disease-based and clinical risk factors, patient goals, prognosis, and practitioner- and patient-perceived treatment risks and benefits influence treatment recommendations. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about management of AML in older adults. Methods: ASH formed a multidisciplinary guideline panel that included specialists in myeloid leukemia, geriatric oncology, patient-reported outcomes and decision-making, frailty, epidemiology, and methodology, as well as patients. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline-development process, including performing systematic evidence reviews (up to 24 May 2019). The panel prioritized clinical questions and outcomes according to their importance to patients, as judged by the panel. The panel used the GRADE approach, including GRADE’s Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 6 critical questions in managing older adults with AML, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management, the intensity of therapy, the role and duration of postremission therapy, combination vs monotherapy for induction and beyond, duration of less-intensive therapy, and the role of transfusion support for patients no longer receiving antileukemic therapy. Conclusions: Treatment is recommended over best supportive management. More-intensive therapy is recommended over less-intensive therapy when deemed tolerable. However, these recommendations are guided by the principle that throughout a patient’s disease course, optimal care involves ongoing discussions between clinicians and patients, continuously addressing goals of care and the relative risk-benefit balance of treatment.