Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Randomised controlled trial of analgesia for the management of acute severe pain from traumatic injury: study protocol for the paramedic analgesia comparing ketamine and morphine in trauma (PACKMaN).

BACKGROUND: Prehospital analgesia is often required after traumatic injury, currently morphine is the strongest parenteral analgesia routinely available for use by paramedics in the United Kingdom (UK) when treating patients with severe pain. This protocol describes a multi-centre, randomised, double blinded trial comparing the clinical and cost-effectiveness of ketamine and morphine for severe pain following acute traumatic injury. METHODS: A two arm pragmatic, phase III trial working with two large NHS ambulance services, with an internal pilot. Participants will be randomised in equal numbers to either (1) morphine or (2) ketamine by IV/IO injection. We aim to recruit 446 participants over the age of 16 years old, with a self-reported pain score of 7 or above out of 10. Randomised participants will receive a maximum of 20 mg of morphine, or a maximum of 30 mg of ketamine, to manage their pain. The primary outcome will be the sum of pain intensity difference. Secondary outcomes measure the effectiveness of pain relief and overall patient experience from randomisation to arrival at hospital as well as monitoring the adverse events, resource use and cost-effectiveness outcomes. DISCUSSION: The PACKMAN study is the first UK clinical trial addressing the clinical and cost-effectiveness of ketamine and morphine in treating acute severe pain from traumatic injury treated by NHS paramedics. The findings will inform future clinical practice and provide insights into the effectiveness of ketamine as a prehospital analgesia. TRIAL REGISTRATION: ISRCTN, ISRCTN14124474. Registered 22 October 2020, https://www.isrctn.com/ISRCTN14124474.

The nationwide impact of COVID-19 on life support courses. A retrospective evaluation by Resuscitation Council UK.

Aim: To determine the impact of the COVID-19 pandemic on Resuscitation Council UK Advanced Life Support (ALS) and Immediate Life Support (ILS) course numbers and outcomes. Methods: We conducted a before-after study using course data from the Resuscitation Council UK Learning Management System between January 2018 and December 2021, using 23 March 2020 as the cut-off between pre- and post-pandemic periods. Demographics and outcomes were analysed using chi-squared tests and regression models. Results: There were 90,265 ALS participants (51,464 pre-; 38,801 post-) and 368,140 ILS participants (225,628 pre-; 142,512 post-). There was a sharp decline in participants on ALS/ILS courses due to COVID-19. ALS participant numbers rebounded to exceed pre-pandemic levels, whereas ILS numbers recovered to a lesser degree with increased uptake of e-learning versions. Mean ALS course participants reduced from 20.0 to 14.8 post-pandemic (P < 0.001).Post-pandemic there were small but statistically significant decreases in ALS Cardiac Arrest Simulation Test pass rates (from 82.1 % to 80.1 % (OR = 0.90, 95 % CI = 0.86-0.94, P < 0.001)), ALS MCQ score (from 86.6 % to 86.0 % (mean difference = -0.35, 95 % CI -0.44 to -0.26, P < 0.001)), and overall ALS course results (from 95.2 %to 94.7 %, OR = 0.92, CI = 0.85-0.99, P = 0.023). ILS course outcomes were similar post-pandemic (from 99.4 % to 99.4 %, P = 0.037). Conclusion: COVID-19 caused a sharp decline in the number of participants on ALS/ILS courses and an accelerated uptake of e-learning versions, with the average ALS course size reducing significantly. The small reduction in performance on ALS courses requires further research to clarify the contributing factors.

Expert consensus on the systemic treatment of atopic dermatitis in special populations.

With the increasing number of options for the treatment of moderate-to-severe atopic dermatitis, clinicians need guidance on a practical approach to selecting a systemic agent for specific patient populations. We convened an expert panel consisting of 12 members to conduct a literature review and summarize relevant data related to six scenarios of clinical interest: comorbid asthma, ocular surface disease, history of cancer, past and ongoing infections of interest (including herpes simplex virus, herpes zoster, hepatitis B, and tuberculosis), pregnancy and lactation, and the elderly. We performed a literature search and examined each clinical scenario with respect to three major categories of available systemic agents: traditional systemics (azathioprine, cyclosporine A, methotrexate, and mycophenolate mofetil), Janus kinase inhibitors (abrocitinib, baricitinib, and upadacitinib), and biologics (dupilumab, lebrikizumab, and tralokinumab). The expert panel and steering committee met virtually to review the data and discuss the drafted consensus statements. A modified Delphi process was used to arrive at a set of final consensus statements related to the systemic treatment of AD in these specific patient populations. To provide practical guidance on the choice of systemic therapy for atopic dermatitis in these six topics of clinical interest, 25 expert consensus statements and a summary of the supporting data are presented herein.

mGluR1α expression in the hippocampus, subiculum, entorhinal cortex and superior temporal gyrus in Alzheimer's disease.

Glutamate is the main excitatory neurotransmitter in the central nervous system, responsible for a plethora of cellular processes including memory formation and higher cerebral function and has been implicated in various neurological disease states. Alzheimer's disease (AD) is the leading neurodegenerative disorder worldwide and is characterized by significant cell loss and glutamatergic dysfunction. While there has been a focus on ionotropic glutamatergic receptors few studies have attempted to elucidate the pathological changes of metabotropic glutamate receptors (mGluRs) in AD. mGluRs are G-protein coupled receptors which have a wide-ranging functionality, including the regulation of neuronal injury and survival. In particular, the group I mGluRs (mGluR1 and mGluR5) are associated with ionotropic receptor activation and upregulation with resultant glutamate release in normal neuronal functioning. The mGluR subtype 1 splice variant a (mGluR1α) is the longest variant of the mGluR1 receptor, is localized to dendritic processes and is mainly plasma membrane-bound. Activation of mGluR1a has been shown to result in increased constitutive activity of ionotropic receptors, although its role in neurodegenerative and other neurological diseases is controversial, with some animal studies demonstrating potential neuroprotective properties in excito- and neurotoxic environments. In this study, the expression of mGluR1a within normal and AD human hippocampal tissue was quantified using immunohistochemistry. We found a significantly reduced expression of mGluR1α within the stratum pyramidale and radiatum of the CA1subregion, subiculum, and entorhinal cortex. This downregulation could result in potential dysregulation of the glutamatergic system with consequences on AD progression by promoting excitotoxicity, but alternatively may also be a neuroprotective mechanism to prevent mGluR1α associated excitotoxic effects. In summary, more research is required to understand the role and possible consequences of mGluR1α downregulation in the human AD hippocampus, subiculum and entorhinal cortex and its potential as a therapeutic target.

Initial experience of TAS-102 chemotherapy in Australian patients with Chemo-refractory metastatic colorectal cancer.

For patients with refractory metastatic colorectal cancer (mCRC) treatment with Trifluridine/Tipiracil, also known as TAS-102, improves overall survival. This study aims to investigate the efficacy and safety of TAS-102 in a real-world population from Victoria, Australia. A retrospective analysis of prospectively collected data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was undertaken. The characteristics and outcomes of patients receiving TAS-102 were assessed and compared to those enrolled in the registration study (RECOURSE). Across 13 sites, 107 patients were treated with TAS-102. The median age was 60 years (range: 31-83), compared to 63 for RECOURSE. Comparing registry TAS-102-treated and RECOURSE patients, 75% vs 100% were ECOG performance status 0-1, 74% vs 79% had initiated treatment more than 18 months from diagnosis of metastatic disease and 36% vs 49% were RAS wild-type. Median time on treatment was 10.4 weeks (range: 1.7-32). Median progression-free survival (PFS) was 3.3 months compared to 2 months in RECOURSE, while median overall survival was the same at 7.1 months. Two patients (2.3%) had febrile neutropenia and there were no treatment-related deaths, where TAS-102 dose at treatment initiation was at clinician discretion.TRACC registry patients treated with TAS-102 were younger than those from the RECOURSE trial, with similar overall survival observed. Less strict application of RECIST criteria and less frequent imaging may have contributed to an apparently longer PFS.

In-circuit high-frequency jet ventilation to reduce organ motion in a child undergoing sarcoma ablation.

Patients with primary or metastatic solid tumours can be treated with minimally invasive image-guided procedures as an alternative to surgical resection. Reducing organ motion during these procedures is crucial so that tumours can be accurately targeted and treatment delivered within a small margin, limiting potential damage to adjacent structures. As ventilation is the main cause of motion, there has been a shift from conventional ventilation towards the use of in-circuit high-frequency jet ventilation techniques for these procedures. We present the case of a 7-year-old who required computed tomography-guided microwave ablation of a right lung metastatic nodule under general anaesthesia. The patient's lungs were ventilated with in-circuit high-frequency jet ventilation in order to provide optimum conditions for ablation. The treatment was successfully completed and she was discharged home the following day. High-frequency jet ventilation is regularly used in our institution for adult computed tomography-guided treatments and to our knowledge, this application has not been described yet in a child this young. Our experience suggests that this technique can be safely used in paediatric patients, though further investigation of the optimum parameters for in-circuit high-frequency jet ventilation in this population is warranted.

Clinical manifestations and treatment outcomes in degos disease: a systematic review.

Degos disease (atrophic papulosis) is a rare vasculopathy with cutaneous and systemic manifestations. Although potentially fatal, the characteristics of and treatments for Degos disease variants are not adequately described. We conducted a systematic review to summarize cutaneous and systemic presentations, treatments and outcomes of malignant (MAP) and benign (BAP) variants of Degos disease. A comprehensive search was conducted on Embase, MEDLINE, CINAHL and CENTRAL on 27 October 2020, which yielded 254 original studies reporting cases of Degos disease. A total of 357 patients were included in the analysis. Mean age of onset was 33.9 years. MAP was most commonly reported (63.8%, n = 228/357), with 56.6% (n = 129/228) mortality. Cutaneous lesions were usually asymptomatic (26.3%, n = 81/308) and localized to the trunk (57.7%, n = 206/357) and extremities (56.8%, n = 203/357). Systemic involvement developed within 2 years on average, ranging from 0 to 28 years. Anti-platelet monotherapy had a complete resolution rate of 42.3% (n = 11/26) in BAP and 20.0% (n = 7/35) in MAP. Based on the findings of the study, most cases of Degos disease are malignant with high mortality, and even benign cutaneous cases may develop systemic disease in as late as 28 years. Anti-platelet monotherapies may prove effective against both variants. Further studies are needed to confirm these findings.

Contrast enhanced ultrasound of carotid plaque in acute ischemic stroke (CUSCAS study).

INTRODUCTION: Carotid atherosclerosis represents 8 to 15% of ischemic strokes in relation to the concept of "vulnerable" plaque. Contrast enhanced ultrasound (CEUS) can detect moving microbubbles within the plaque corresponding to neovessels that constitute "precursors" of vulnerable plaque and intraplaque hemorrhage. CEUS was not studied specifically in acute ischemic strokes. The aim of this study is to analyse the prevalence of CEUS carotid plaque ipsilateral at the ischemic stroke as well as the main characteristics of contrast-plaques. METHOD: A single-centre prospective pilot study involving 33 consecutive patients with a stroke ≤10 days, diagnosed by an MRI with positive diffusion sequence and having a carotid plaque thickness ≥2.5mm with low or heterogeneous echogenicity, located in the ipsilateral carotid territory at the stroke. Plaque echogenicity was done by visual analysis and by measurement of the gray scale median (GSM). A transcranial Doppler monitoring was carried out in search of HITS. The contrast ultrasound was performed after 2.5 cc IV injection of SonoVue®. A video clip was recorded after injection which was used for interpretation by visual analysis in 3 grades, provided by two independent expert readers. RESULTS: The population consisted of 10 women and 23 men aged 73 on average. The topography of strokes in the carotid territory was located on the right in 11 (33%) cases and on the left in 22 (67%) cases. Seventeen patients had carotid stenosis between 0 and 49% according to the Nascet method and 16 patients had stenosis of 50 to 99%. The visual characterisation of the plaques had echolucent dominance (Type 1-2) in 18 cases and echogenic dominance (Type 3-4a) in 15 cases. Cardiovascular risk factors were common with no difference by sex. The inter-observer agreement of plaque enhancement was moderate in first reading (k=0.48) and excellent at consensus (k=0.91). Only one disagreement was found. Contrast agent enhancement of carotid plaque was observed in 11/32 patients, representing a prevalence of 34.4% - CI95% [17.9-50.9]. Variables associated with contrast plaque included the absence of antiplatelet drug (63.6% vs. 23.8%, P=0.05) and the presence of a regular edge on the plaque (91% vs. 48%, P=0.04). There was no difference in contrast enhancement for stenosis>or<50% in diameter and neither for the type of plaque. CONCLUSION: In a consecutive cohort of 33 patients, the prevalence of CEUS from an ipsilateral carotid plaque to a recent acute ischemic stroke was 34.4%. There was a statistically significant association between the contrast enhancement of the plaque and the absence of antiplatelet drug (P=0.05) and also the presence of a regular edge on the plaque (P=0.04). There was no correlation between plaque contrast and clinical and biological characteristics of patients or the presence of HITS.

Spaced learning versus massed learning in resuscitation - A systematic review.

AIM: Skill decay is a recognised problem in resuscitation training. Spaced learning has been proposed as an intervention to optimise resuscitation skill performance compared to traditional massed learning. A systematic review was performed to answer 'In learners taking resuscitation courses, does spaced learning compared to massed learning improve educational outcomes and clinical outcomes?' METHODS: This systematic review followed the PRISMA guidelines. We searched bibliographic databases (Embase, MEDLINE and the Cochrane Library (CENTRAL)) from inception to 2 December 2019. Randomised controlled trials and non-randomised studies were eligible for inclusion. Two reviewers independently scrutinized studies for relevance, extracted data and assessed quality of studies. Risk of bias of studies and quality of evidence were assessed using RoB, ROBINS-I tool and GRADEpro respectively. Educational outcomes studied were skill retention and performance 1 year after completion of training; skill performance between completion of training and 1 year; and knowledge at course conclusion. Clinical outcomes were skill performance at actual resuscitation, patient survival to discharge with favourable neurological outcome. This systematic review was registered in PROSPERO (CRD42019150358). RESULTS: From 2,042 references, we included data from 17 studies (13 randomised studies, 4 cohort studies) in courses with manikins and simulation in the narrative synthesis. Eight studies reported results from basic life support training (with or without automatic external defibrillator); three studies reported from paediatric life support training; five were in neonatal resuscitation and one study reported results from a bespoke emergency medicine course which included resuscitation teaching. Fifteen out of seventeen studies reported improved performance with the use of spaced learning. The overall certainty of evidence was rated as very low for all outcomes primarily due to a very serious risk of bias. Heterogeneity across studies precluded any meta-analyses. There was a lack of data on the effectiveness of spaced learning on skill acquisition compared to maintaining skill performance and/or preventing skill decay. There was also insufficient data to examine the effectiveness of spaced learning on laypeople compared to healthcare providers. CONCLUSIONS: Despite the very low certainty of evidence this systematic review suggests that spaced learning can improve skill performance at 1 year post course conclusion and skill performance between course conclusion and 1 year. There is a lack of data from this educational intervention on skill performance in clinical resuscitation and patient survival at discharge with favourable neurological outcomes.