A single bout of vigorous intensity exercise enhances the efficacy of rituximab against human chronic lymphocytic leukaemia B-cells ex vivo.

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal proliferation and accumulation of mature B-cells and is often treated with rituximab, an anti-CD20 monoclonal antibody immunotherapy. Rituximab often fails to induce stringent disease eradication, due in part to failure of antibody-dependent cellular cytotoxicity (ADCC) which relies on natural killer (NK)-cells binding to rituximab-bound CD20 on B-cells. CLL cells are diffusely spread across lymphoid and other bodily tissues, and ADCC resistance in survival niches may be due to several factors including low NK-cell frequency and a suppressive stromal environment that promotes CLL cell survival. It is well established that exercise bouts induce a transient relocation of NK-cells and B-cells into peripheral blood, which could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab in blood. In this pilot study, n = 20 patients with treatment-naïve CLL completed a bout of cycling 15 % above anaerobic threshold for âˆ¼ 30-minutes, with blood samples collected pre-, immediately post-, and 1-hour post-exercise. Flow cytometry revealed that exercise evoked a 254 % increase in effector (CD3-CD56+CD16+) NK-cells in blood, and a 67 % increase in CD5+CD19+CD20+ CLL cells in blood (all p < 0.005). NK-cells were isolated from blood samples pre-, and immediately post-exercise and incubated with primary isolated CLL cells with or without the presence of rituximab to determine specific lysis using a calcein-release assay. Rituximab-mediated cell lysis increased by 129 % following exercise (p < 0.001). Direct NK-cell lysis of CLL cells - independent of rituximab - was unchanged following exercise (p = 0.25). We conclude that exercise improved the efficacy of rituximab-mediated ADCC against autologous CLL cells ex vivo and propose that exercise should be explored as a means of enhancing clinical responses in patients receiving anti-CD20 immunotherapy.

Coronary artery calcification is prevalent in systemic sclerosis and is associated with adverse prognosis.

Objective: Coronary artery calcification assessed on thoracic computed tomography represents the calcific component of established coronary artery disease, is a biomarker of total atheromatous plaque burden and predicts mortality. Systemic sclerosis is a pro-inflammatory condition, and inflammation is also a driver of coronary artery disease. We assessed coronary artery calcification prevalence, mortality risk and potential clinical impact on primary prevention in a cohort of patients with systemic sclerosis, differentiated by clinical phenotype including the presence of interstitial lung disease and pulmonary arterial hypertension. Methods: Retrospective analysis of 258 computed tomographies in systemic sclerosis patients from three prospectively maintained clinical and research databases at a single tertiary rheumatology/pulmonary hypertension (PH) service between March 2007 and September 2020 (mean age = 65 ± 12, 14% male). Co-morbidities, statin prescription and all-cause mortality were recorded. Patients were subtyped according to underlying systemic sclerosis complications. Computed tomographies were re-reviewed for coronary artery calcification; severity was graded using a 4-point scale per vessel and summed for total coronary artery calcification score. The impact of reporting coronary artery calcification was assessed against pre-existing statin prescriptions. Results: Coronary artery calcification was present in 58% (149/258). Coronary artery calcification was more prevalent in systemic sclerosis-pulmonary arterial hypertension than in systemic sclerosis subgroups with interstitial lung disease or without pulmonary arterial hypertension, controlling for age, sex, co-morbidities and smoking status (71%; χ 2(13) = 81.4; p < 0.001). The presence and severity of coronary artery calcification were associated with increased risk of mortality independently of age and co-morbidities (hazard ratio = 2.8; 95% confidence interval = 1.2-6.6; p = 0.018). The 'number needed to report' coronary artery calcification presence to potentially impact management was 3. Conclusions: Coronary artery calcification is common in systemic sclerosis. Coronary artery calcification predicts mortality independently of age and confounding co-morbidities which suggests this finding has clinical relevance and is a potential target for screening and therapeutic intervention.

Characterising how a single bout of exercise in people with myeloma affects clonal plasma cell and immune effector cell frequency in blood, and daratumumab efficacy in vitro.

Multiple myeloma is a haematological cancer characterised by the accumulation of clonal plasma cells in the bone marrow and is commonly treated with daratumumab, an anti-CD38 monoclonal antibody immunotherapy. Daratumumab often fails to induce stringent complete responses, due in part to resistance to antibody-dependent cellular cytotoxicity (ADCC) exerted by natural killer (NK)-cells and monocytes. Exercise bouts undertaken by healthy people induce lymphocytosis in blood, including to NK-cells and B-cells, but the effects of exercise are unknown in myeloma patients. In addition, whether exercise mobilises plasma cells has not been adequately investigated, and as such the potential impact of exercise on daratumumab treatment is unclear. In this exploratory pilot study, n = 16 smouldering multiple myeloma participants enrolled and n = 9 completed the study which comprised a bout of cycling 15% above anaerobic threshold for ∼30-min, with blood samples collected pre-, immediately post-, and 30-min post-exercise. Peripheral blood mononuclear cells were isolated from blood samples and incubated with the RPMI-8226 plasmacytoma cell line, with or without the presence of daratumumab to determine specific lysis using a calcein-release assay. Daratumumab-mediated cell lysis increased from 18.8% to 23.2% pre- to post-exercise, respectively (p < 0.001), owing to an increased frequency of CD3-CD56+CD16+ NK-cells (+348%), HLA-DR+CD14dimCD16+ monocytes (+125%), and HLA-DR+CD14+CD32+ monocytes (+41%) in blood (p < 0.01). However, overall, total plasma cells (CD38+CD138+) nor clonal plasma cells (CD38brightCD138+CD45-/dimCD19- with light-chain restriction) increased in blood (p > 0.05). Notably, we observed a 305% increase in NK-cells expressing CD38, the daratumumab target antigen, which might render NK-cells more susceptible to daratumumab-mediated fratricide - whereby NK-cells initiate ADCC against daratumumab-bound NK-cells. In conclusion, exercise modestly improved the efficacy of daratumumab-mediated ADCC in vitro. However, plasma cells were largely unchanged, and NK-cells expressing CD38 - the daratumumab target antigen - increased in blood. Future research should consider the optimal timings of exercise during daratumumab treatment in myeloma to avert exacerbation of daratumumab-mediated NK-cell lysis.

'Super Rehab': can we achieve coronary artery disease regression? A feasibility study protocol.

INTRODUCTION: Patients diagnosed with coronary artery disease (CAD) are currently treated with medications and lifestyle advice to reduce the likelihood of disease progression and risk of future major adverse cardiovascular events (MACE). Where obstructive disease is diagnosed, revascularisation may be considered to treat refractory symptoms. However, many patients with coexistent cardiovascular risk factors, particularly those with metabolic syndrome (MetS), remain at heightened risk of future MACE despite current management.Cardiac rehabilitation is offered to patients post-revascularisation, however, there is no definitive evidence demonstrating its benefit in a primary prevention setting. We propose that an intensive lifestyle intervention (Super Rehab, SR) incorporating high-intensity exercise, diet and behavioural change techniques may improve symptoms, outcomes, and enable CAD regression.This study aims to examine the feasibility of delivering a multicentre randomised controlled trial (RCT) testing SR for patients with CAD, in a primary prevention setting. METHODS AND ANALYSIS: This is a multicentre randomised controlled feasibility study of SR versus usual care in patients with CAD. The study aims to recruit 50 participants aged 18-75 across two centres. Feasibility will be assessed against rates of recruitment, retention and, in the intervention arm, attendance and adherence to SR. Qualitative interviews will explore trial experiences of study participants and practitioners. Variance of change in CAD across both arms of the study (assessed with serial CT coronary angiography) will inform the design and power of a future, multi-centre RCT. ETHICS AND DISSEMINATION: Ethics approval was granted by South West-Frenchay Research Ethics Committee (reference: 21/SW/0153, 18 January 2022). Study findings will be disseminated via presentations to relevant stakeholders, national and international conferences and open-access peer-reviewed research publications. TRIAL REGISTRATION NUMBER: ISRCTN14603929.

Assessing the role of an artificial intelligence assessment tool for thoracic aorta diameter on routine chest CT.

OBJECTIVE: To assess the diagnostic accuracy and clinical impact of automated artificial intelligence (AI) measurement of thoracic aorta diameter on routine chest CT. METHODS: A single-centre retrospective study involving three cohorts. 210 consecutive ECG-gated CT aorta scans (mean age 75 ± 13) underwent automated analysis (AI-Rad Companion Chest CT, Siemens) and were compared to a reference standard of specialist cardiothoracic radiologists for accuracy measuring aortic diameter. A repeated measures analysis tested reporting consistency in a second cohort (29 patients, mean age 61 ± 17) of immediate sequential pre-contrast and contrast CT aorta acquisitions. Potential clinical impact was assessed in a third cohort of 197 routine CT chests (mean age 66 ± 15) to document potential clinical impact. RESULTS: AI analysis produced a full report in 387/436 (89%) and a partial report in 421/436 (97%). Manual vs AI agreement was good to excellent (ICC 0.76-0.92). Repeated measures analysis of expert and AI reports for the ascending aorta were moderate to good (ICC 0.57-0.88). AI diagnostic performance crossed the threshold for maximally accepted limits of agreement (>5 mm) at the aortic root on ECG-gated CTs. AI newly identified aortic dilatation in 27% of patients on routine thoracic imaging with a specificity of 99% and sensitivity of 77%. CONCLUSION: AI has good agreement with expert readers at the mid-ascending aorta and has high specificity, but low sensitivity, at detecting dilated aortas on non-dedicated chest CTs. ADVANCES IN KNOWLEDGE: An AI tool may improve the detection of previously unknown thoracic aorta dilatation on chest CTs vs current routine reporting.

Deep-Learning for Epicardial Adipose Tissue Assessment With Computed Tomography: Implications for Cardiovascular Risk Prediction.

BACKGROUND: Epicardial adipose tissue (EAT) volume is a marker of visceral obesity that can be measured in coronary computed tomography angiograms (CCTA). The clinical value of integrating this measurement in routine CCTA interpretation has not been documented. OBJECTIVES: This study sought to develop a deep-learning network for automated quantification of EAT volume from CCTA, test it in patients who are technically challenging, and validate its prognostic value in routine clinical care. METHODS: The deep-learning network was trained and validated to autosegment EAT volume in 3,720 CCTA scans from the ORFAN (Oxford Risk Factors and Noninvasive Imaging Study) cohort. The model was tested in patients with challenging anatomy and scan artifacts and applied to a longitudinal cohort of 253 patients post-cardiac surgery and 1,558 patients from the SCOT-HEART (Scottish Computed Tomography of the Heart) Trial, to investigate its prognostic value. RESULTS: External validation of the deep-learning network yielded a concordance correlation coefficient of 0.970 for machine vs human. EAT volume was associated with coronary artery disease (odds ratio [OR] per SD increase in EAT volume: 1.13 [95% CI: 1.04-1.30]; P = 0.01), and atrial fibrillation (OR: 1.25 [95% CI: 1.08-1.40]; P = 0.03), after correction for risk factors (including body mass index). EAT volume predicted all-cause mortality (HR per SD: 1.28 [95% CI: 1.10-1.37]; P = 0.02), myocardial infarction (HR: 1.26 [95% CI:1.09-1.38]; P = 0.001), and stroke (HR: 1.20 [95% CI: 1.09-1.38]; P = 0.02) independently of risk factors in SCOT-HEART (5-year follow-up). It also predicted in-hospital (HR: 2.67 [95% CI: 1.26-3.73]; P ≤ 0.01) and long-term post-cardiac surgery atrial fibrillation (7-year follow-up; HR: 2.14 [95% CI: 1.19-2.97]; P ≤ 0.01). CONCLUSIONS: Automated assessment of EAT volume is possible in CCTA, including in patients who are technically challenging; it forms a powerful marker of metabolically unhealthy visceral obesity, which could be used for cardiovascular risk stratification.

Assessing splenic switch-off in Adenosine stress CMR for patients with atrial fibrillation: a propensity-matched study.

OBJECTIVES: Splenic switch-off (SSO) is a validated indicator of adequate vasodilator stress unique to adenosine stress cardiac MR (CMR). Patients in atrial fibrillation (AF) may have a reduced adenosine response due to lower hyperaemic coronary flow reserve and may achieve SSO less frequently versus sinus rhythm (SR). METHODS: 1100 stress CMR studies were identified from a clinical CMR database (2016-2021). 70 patients in AF were propensity score matched to a SR group for age, sex, and body mass index. The adenosine dose administered, symptoms, heart-rate change and scan result were recorded. SSO was evaluated subjectively and semi-quantitatively via changes in splenic and myocardial signal intensity (SI) from rest to stress. RESULTS: SSO occurred significantly less frequently in AF than SR (34/70 [49%] vs 53/70 [76%], p = 0.003). Semi-quantitative assessment supported this, with a smaller splenic SI difference between stress and rest in AF vs SR (median splenic stress:rest peak SI ratio 0.92 [IQR:0.61-1.11] vs 0.56 [IQR:0.45-0.75], p < 0.001). A heart-rate increase >10 bpm predicted visual SSO in SR but not AF. Fewer patients in AF than SR had inducible ischaemia (9/70 [13%] vs 17/69 [25%], p = 0.058). This difference was not driven by inducible ischaemia rates in patients who did not achieve SSO (6/36 [17%] AF vs 4/17 [24%] SR, p = 0.403). CONCLUSIONS: SSO occurs significantly less frequently with AF. This may risk the under diagnosis of inducible ischaemia and requires further assessment. ADVANCES IN KNOWLEDGE: SSO, a validated marker of adequate stress in CMR, occurs significantly less frequently in the presence of AF, risking a suboptimal functional assessment of coronary disease.

CT coronary angiography first prior to rapid access chest pain clinic review: a retrospective feasibility study.

OBJECTIVES: Since rapid access chest pain clinics (RACPC) were established to streamline stable chest pain assessment, CT coronary angiography (CTCA) has become the recommended investigation for patients without known coronary artery disease (CAD), with well-defined indications. This single-centre retrospective study assessed the feasibility of General Practice (GP)-led CTCA prior to RACPC. METHODS: RACPC pathway patients without pre-existing CAD electronic records were reviewed (September-October 2019). Feasibility assessments included appropriateness for RACPC, referral clinical data vs RACPC assessment for CTCA indication and safety, and a comparison of actual vs hypothetical pathways, timelines and hospital encounters. RESULTS: 106/172 patients screened met inclusion criteria (mean age 61 ± 14, 51% female). 102 (96%) referrals were 'appropriate'. No safety concerns were identified to preclude a GP-led CTCA strategy. The hypothetical pathway increased CTCA requests vs RACPC (84 vs 71), whilst improving adherence to guidelines and off-loading other services. 22% (23/106) had no CAD, representing cases where one hospital encounter may be sufficient. The hypothetical pathway would have reduced referral-to-diagnosis by at least a median of 27 days (interquartile range 14-33). CONCLUSION: A hypothetical GP-led CTCA pathway would have been feasible and safe in a real-world RACPC patient cohort without pre-existing CAD. This novel strategy would have increased referrals for CTCA, whilst streamlining patient pathways and improved NICE guidance adherence. ADVANCES IN KNOWLEDGE: GP-led CTCA is a feasible and safe pathway for patients without pre-existing CAD referred to RACPC, reducing hospital encounters required and may accelerate time to diagnosis. This approach may have implications and opportunities for other healthcare pathways.

Acute coronary syndrome leading to a new diagnosis of phaeochromocytoma following a profound intraprocedural hypertensive surge.

Phaeochromocytomas are rare neuroendocrine tumours, which can significantly increase the risk of cardiovascular morbidity and mortality. They are also recognised as 'the great mimic' and can present in many ways. A 42-year-old male patient presented with a non-ST elevation acute coronary syndrome and was medically treated pending an invasive coronary angiogram. During this procedure, he suffered a profound, symptomatic hypertensive surge documented with invasive pressure monitoring. This raised concern for potential secondary causes of hypertension, particularly given his age. He was subsequently diagnosed with a phaeochromocytoma, and after surgical resection of the tumour, his blood pressure control improved and he remains on single therapy only. As clinicians, it is important to remain alert for previously undiagnosed comorbidities contributing to common pathology, including rare, but life-threatening conditions as we present in this case.

Takotsubo stress cardiomyopathy following explantation of sEEG electrodes.

Objective: Takotsubo stress cardiomyopathy is characterized by dysfunction of the left ventricle of the heart including apical ballooning and focal wall-motion abnormalities. Although reported in association with seizures and intracerebral hemorrhage, there are no studies reporting its occurrence in patients having stereoelectroencephalography (sEEG). Methods: A 38-year-old lady with no prior history of cardiac disease experienced sudden onset chest pain and acute left ventricular failure 4 hours following explantation of stereoelectroencephalogram electrodes. Results: A small parenchymal hematoma related to the right posterior temporal electrode had been noted postelectrode insertion but was asymptomatic. Focal-onset seizures from nondominant mesial temporal structures were recorded during sEEG. Following the presentation with LVF, new-onset anterolateral T-wave inversion with reciprocal changes in leads II, III, and aVF was noted on electrocardiogram (ECG) and the chest X-ray findings were consistent with pulmonary edema. Echocardiography demonstrated hypokinesis of the cardiac apex and septum consistent with Takotsubo stress cardiomyopathy. Significance: Awareness of the possible complication of Takotsubo stress cardiomyopathy is required in an epilepsy surgery program.

Predictors of abnormalities on magnetic resonance cholangiopancreatography: is there a role when the biliary tree is normal on previous imaging?

BACKGROUND: There is limited evidence supporting the use of magnetic resonance cholangiopancreatography (MRCP) if the biliary tree is within normal limits on ultrasound scan (US) or computed tomography (CT). The aim of this study was to assess the role of MRCP in the absence of a dilated biliary system on index imaging. METHODS: A retrospective observational study of consecutive MRCP investigations (n=427) was performed between October 2010 and June 2013 at a single district general hospital. Data collected included patient demographics, clinical presentation, liver function tests (LFTs) and radiological presence of stones. Binary logistic regression and chi-square test were performed using SPSS v23. RESULTS: We included 358 cases, 65% female (n=231) and 35% male (n=127), with a mean age of 60 years. Of these, 63% presented with abdominal pain (n=225), with 20% having concurrent deranged LFTs (n=44) and 8% jaundice (n=18). Index imaging demonstrated a dilated biliary system >6 mm in 68% (n=245). Alkaline phosphatase (ALP) elevation was an independent positive predictor for an abnormal MRCP (P=0.003). Abnormal index imaging, ALP and clinical jaundice were all significantly associated with a positive MRCP (P<0.001, P=0.028, P=0.018). CONCLUSIONS: It is efficacious to proceed to MRCP with abnormal findings on index imaging, clinical jaundice or elevated ALP. An MRCP scan should be strongly considered in the context of elevated ALP and normal US/CT biliary system.

A new method of applying randomised control study data to the individual patient: A novel quantitative patient-centred approach to interpreting composite end points.

BACKGROUND: Modern randomised controlled trials typically use composite endpoints. This is only valid if each endpoint is equally important to patients but few trials document patient preference and seek the relative importance of components of combined endpoints. If patients weigh endpoints differentially, our interpretation of trial data needs to be refined. METHODS AND RESULTS: We derive a quantitative, structured tool to determine the relative importance of each endpoint to patients. We then apply this tool to data comparing angioplasty with drug-eluting stents to bypass surgery. The survey was administered to patients undergoing cardiac catheterisation. A meta-analysis comparing coronary artery bypass grafting (CABG) to percutaneous coronary interventuin (PCI) was then performed using (a) standard MACE and (b) patient-centred MACE. Patients considered stroke worse than death (stroke 102.3 ± 19.6%, p < 0.01), and MI and repeat revascularisation less severe than death (61.9 ± 26.8% and 41.9 ± 25.4% respectively p < 0.01 for both). 7 RCTs (5251 patients) were eligible. Meta-analysis demonstrated that standard MACE occurs more frequently with PCI than surgery (OR 1.44; 95% CI 1.10 to 1.87; p = 0.007). Re-analysis using patient-centred MACE found no significant difference between PCI and CABG (OR 1.22, 95% CI 0.97 to 1.53; p = 0.10). CONCLUSIONS: Patients do not consider the constituent endpoints of MACE equal. We derive a novel patient-centred metric that recognises and quantifies the differences attributed to each endpoint. When patient preference data are applied to contemporary trial results, there is no significant difference between PCI and CABG. Responses from individual patients in clinic could be used to give individual patients a recommendation that is truly personalised.