European Society of Cardiology quality indicators for the prevention and management of cancer therapy-related cardiovascular toxicity in cancer treatment.

AIMS: To develop quality indicators (QIs) for the evaluation of the prevention and management of cancer therapy-related cardiovascular toxicity. METHODS AND RESULTS: We followed the European Society of Cardiology (ESC) methodology for QI development which comprises (i) identifying the key domains of care for the prevention and management of cancer therapy-related cardiovascular toxicity in patients on cancer treatment, (ii) performing a systematic review of the literature to develop candidate QIs, and (iii) selecting of the final set of QIs using a modified Delphi process. Work was undertaken in parallel with the writing of the 2022 ESC Guidelines on Cardio-Oncology and in collaboration with the European Haematology Association, the European Society for Therapeutic Radiology and Oncology and the International Cardio-Oncology Society. In total, 5 main and 9 secondary QIs were selected across five domains of care: (i) Structural framework, (ii) Baseline cardiovascular risk assessment, (iii) Cancer therapy related cardiovascular toxicity, (iv) Predictors of outcomes, and (v) Monitoring of cardiovascular complications during cancer therapy. CONCLUSION: We present the ESC Cardio-Oncology QIs with their development process and provide an overview of the scientific rationale for their selection. These indicators are aimed at quantifying and improving the adherence to guideline-recommended clinical practice and improving patient outcomes.

Mathematically aggregating experts' predictions of possible futures.

Structured protocols offer a transparent and systematic way to elicit and combine/aggregate, probabilistic predictions from multiple experts. These judgements can be aggregated behaviourally or mathematically to derive a final group prediction. Mathematical rules (e.g., weighted linear combinations of judgments) provide an objective approach to aggregation. The quality of this aggregation can be defined in terms of accuracy, calibration and informativeness. These measures can be used to compare different aggregation approaches and help decide on which aggregation produces the "best" final prediction. When experts' performance can be scored on similar questions ahead of time, these scores can be translated into performance-based weights, and a performance-based weighted aggregation can then be used. When this is not possible though, several other aggregation methods, informed by measurable proxies for good performance, can be formulated and compared. Here, we develop a suite of aggregation methods, informed by previous experience and the available literature. We differentially weight our experts' estimates by measures of reasoning, engagement, openness to changing their mind, informativeness, prior knowledge, and extremity, asymmetry or granularity of estimates. Next, we investigate the relative performance of these aggregation methods using three datasets. The main goal of this research is to explore how measures of knowledge and behaviour of individuals can be leveraged to produce a better performing combined group judgment. Although the accuracy, calibration, and informativeness of the majority of methods are very similar, a couple of the aggregation methods consistently distinguish themselves as among the best or worst. Moreover, the majority of methods outperform the usual benchmarks provided by the simple average or the median of estimates.

Fungal and bacterial coinfections increase mortality of severely ill COVID-19 patients.

BACKGROUND: SARS-CoV-2 predisposes patients to secondary infections; however, a better understanding of the impact of coinfections on the outcome of hospitalized COVID-19 patients is still necessary. AIM: To analyse death risk due to coinfections in COVID-19 patients. METHODS: The odds of death of 212 severely ill COVID-19 patients were evaluated, with detailed focus on the risks for each pathogen, site of infection, comorbidities and length of hospitalization. FINDINGS: The mortality rate was 50.47%. Fungal and/or bacterial isolation occurred in 89 patients, of whom 83.14% died. Coinfected patients stayed hospitalized longer and had an increased odds of dying (odds ratio (OR): 13.45; R2 = 0.31). The risk of death was increased by bacterial (OR: 11.28) and fungal (OR: 5.97) coinfections, with increased levels of creatinine, leucocytes, urea and C-reactive protein. Coinfections increased the risk of death if patients suffered from cardiovascular disease (OR: 11.53), diabetes (OR: 6.00) or obesity (OR: 5.60) in comparison with patients with these comorbidities but without pathogen isolation. The increased risk of death was detected for coagulase-negative Staphylococcus (OR: 25.39), Candida non-albicans (OR: 11.12), S. aureus (OR: 10.72), Acinetobacter spp. (OR: 6.88), Pseudomonas spp. (OR: 4.77), and C. albicans (OR: 3.97). The high-risk sites of infection were blood, tracheal aspirate, and urine. Patients with coinfection undergoing invasive mechanical ventilation were 3.8 times more likely to die than those without positive cultures. CONCLUSION: Severe COVID-19 patients with secondary coinfections required longer hospitalization and had higher risk of death. The early diagnosis of coinfections is essential to identify high-risk patients and to determine the right interventions to reduce mortality.

What Does a Cardio-oncology Service Offer to the Oncologist and the Haematologist?

Cardio-oncology is an emerging subspecialty arising from the need for multidisciplinary collaboration to address the increasing prominence of cardiovascular disease (CVD) among cancer patients. This overview outlines the case for establishing cardio-oncology services and defines the ways in which these services benefit cancer patients. The primary objective of cardio-oncology is to manage CVDs in order to allow cancer patients to complete the best cancer treatments safely and with minimal interruption. In the decades since the first discovery of heart failure induced by anthracycline chemotherapy, both cardiovascular and oncological science have advanced considerably. Cardio-oncology services aim to bring together expertise from these two fast moving fields in order to provide optimal evidence-based care for cancer patients with CVDs. Here we discuss the basis of cardio-oncology services by presenting their rationale and key components, as well as their essential roles in education, training and research. At each stage of the cancer care pathway, a cardio-oncology service can add value by ensuring cancer patients have timely access to specialist care backed up by cutting edge diagnostic tools and treatment options, as well as holistic supports. We highlight areas of recent and upcoming developments in the field that are likely to change established clinical practice. Improved cardiac imaging modalities can detect chemotherapy-related cardiac dysfunction earlier and are also essential for the prompt diagnosis of an expanding range of cardiovascular effects complicating newer cancer therapeutics, such as immune checkpoint inhibitors and other targeted therapies. Modern cancer therapy has dramatically improved cancer survival and as such CVD is becoming one of the principal determinants of overall outcome for cancer patients. A dedicated cardio-oncology service can facilitate the optimisation of cardiovascular treatment and enable the completion of cancer therapy. A multidisciplinary collaborative approach is key to achieving these objectives.

The prevalence of iron deficiency and anemia and their impact on survival in patients at a cardio-oncology clinic.

BACKGROUND: Iron deficiency (ID) and anemia are common in both heart failure (HF) and cancer patients and are associated with poor quality of life and survival. The aims of this study were (1) to evaluate the prevalence, types, and confounding factors of ID and anemia in patients referred to cardio-oncology clinic, and (2) identify the association between iron metabolism parameters and survival of cardio-oncology patients. METHODS: We assessed iron, ferritin, hemoglobin concentrations, transferrin saturation (TSAT), cancer type, brain natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), kidney function, cardiovascular risk factors and survival in 599 patients who were referred to cardio-oncology clinic from 2011 to 2017. ID was defined by a TSAT < 20%, absolute iron deficiency (AID) with a serum ferritin level < 100 µg/L while serum ferritin level of ≥ 100 µg/L was considered as functional iron deficiency (FID) and TSAT ≥ 20% was considered as no ID. RESULTS: The prevalence of ID, AID, and FID was 46, 31, and 15% of study patients, respectively. Anemia was present in approximately half (54%) of the patients with any ID. Multivariate Cox analyses showed that male gender (HR 1.704 [1.207-2.404] p = 0.002); previous cancer history (HR 1.879 [1.079-3.272] p = 0.026); elevated BNP (HR 2.126 [1.258-3.590] p = 0.005); TSAT< 20% (HR 1.721 [1.214-2.439] p = 0.002); ferritin ≥ 100 µg/L (HR 2.008 [1.088-3.706] p = 0.026); serum iron concentration < 12 µmol/L (HR 2.292 [1.614-3.255] p < 0.001); FID (HR 2.538 [1.1618-3.981] p < 0.001) and anemia (HR 2.462 [1.734-3.495] p < 0.001) were significantly associated with increased risk of all-cause death. CONCLUSIONS: About half of cardio-oncology patients had anemia and iron deficiency, with the absolute type being twice as prevalent as the functional one. Patients with breast, gastrointestinal, and genitourinary cancer were affected more often. Both anemia and iron deficiency independently predicted all-cause mortality. Future studies are required to confirm ID as a risk factor and evaluate the clinical benefits of iron replacement therapy.

Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

Expert Consensus on the Management of Adverse Events During Treatment with Lenvatinib for Thyroid Cancer.

AIMS: Lenvatinib is an oral multi-kinase inhibitor approved for the treatment of adults with progressive, locally advanced or metastatic, differentiated thyroid carcinoma refractory to radioactive iodine. MATERIALS AND METHODS: A literature review was undertaken to inform the development of consensus-based guidance for the routine management of adverse events associated with lenvatinib. PubMed was searched on 24 October 2017; the search terms were 'lenvatinib' and 'thyroid cancer'. RESULTS: Hypertension, diarrhoea, weight loss, skin toxicities and cardiovascular adverse events were considered. For grade 1/2 diarrhoea, initial treatment should be loperamide with a 1-week treatment interruption if diarrhoea persists and dose reduction if diarrhoea recurs on reinitiation of lenvatinib. Blood pressure should be monitored daily in patients with pre-existing hypertension, otherwise from 1 week after the initiation of lenvatinib and weekly for the first 2 months. For patients with systolic blood pressure ≥135 mmHg to <160 mmHg or diastolic blood pressure ≥85 mmHg to <100 mmHg, lenvatinib should be continued but antihypertensive therapy initiated/intensified. For patients who remain hypertensive, a treatment break can be considered with lenvatinib reinitiated at a reduced dose once the patient's blood pressure has stabilised for at least 48 h. Weight loss of 10% of baseline body weight or the onset of anorexia should be managed with a 1-week treatment break; patients should maintain a healthy, active lifestyle. For patients with grade 2 proteinuria, lenvatinib may be continued, but an angiotensin II receptor blocker or angiotensin converting enzyme inhibitor should be commenced. For grade >3 proteinuria, lenvatinib should be interrupted until proteinuria returns to 1+. For chronic proteinuria, lenvatinib should be stopped. Skin toxicities should be managed with moisturisers or emollients and soap substitutes. CONCLUSIONS: Prophylaxis, regular monitoring and symptomatic management with appropriate short treatment breaks and, for persistent adverse events, dose reductions, are recommended to enable patients to remain on the optimal dose regimen.

Improving the clinical understanding of hypertrophic cardiomyopathy by combining patient data, machine learning and computer simulations: A case study.

Most patients with hypertrophic cardiomyopathy (HCM), the most common genetic cardiac disease, remain asymptomatic, but others may suffer from sudden cardiac death. A better identification of those patients at risk, together with a better understanding of the mechanisms leading to arrhythmia, are crucial to target high-risk patients and provide them with appropriate treatment. However, this currently remains a challenge. In this paper, we present a successful example of implementing computational techniques for clinically-relevant applications. By combining electrocardiogram and imaging data, machine learning and high performance computing simulations, we identified four phenotypes in HCM, with differences in arrhythmic risk, and provided two distinct possible mechanisms that may explain the heterogeneity of HCM manifestation. This led to a better HCM patient stratification and understanding of the underlying disease mechanisms, providing a step further towards tailored HCM patient management and treatment.

Cardiotoxicity Following Cancer Treatment.

More than half of those born after 1960 will develop cancer during their lifetime. Fortunately, owing to improved diagnosis and treatment, cure rates have risen steadily over the last three decades. With an increased survivorship, more will experience adverse effects of cancer therapeutics on the heart. As the oncologist's focus begins to encompass the issues of cancer survivorship, awareness of the management of cardiac toxicity would be prudent for all physicians looking after patients with cancer.

Increasing medical students' engagement in public health: case studies illustrating the potential role of online learning.

BACKGROUND: The value of e-learning in medical education is widely recognized but there is little evidence of its value in teaching medical students about public health. Such evidence is needed because medical students' engagement with public health has been low. We present three recent case studies from UK medical schools to illustrate diverse ways in which online approaches can increase medical students' engagement with learning public health. METHODS: A comparative case study approach was used applying quantitative and qualitative data to examine engagement in terms of uptake/use amongst eligible students, acceptability and perceived effectiveness using an analytic framework based on Seven Principles of Effective Teaching. RESULTS: Across the three case studies, most (67-85%) eligible students accessed online materials, and rated them more favourably than live lectures. Students particularly valued opportunities to use e-learning flexibly in terms of time and place. Online technologies offered new ways to consolidate learning of key public health concepts. Although students found contributing to online discussions challenging, it provided opportunities for students to explore concepts in depth and enabled students that were uncomfortable speaking in face-to-face discussions to participate. CONCLUSIONS: E-learning can be applied in diverse ways that increase medical student engagement with public health teaching.

Transitioning to intravitreal aflibercept following a previous treat-and-extend dosing regimen in neovascular age-related macular degeneration: 24-month results.

PURPOSE: To evaluate frequency of injections, visual and anatomical outcomes of neovascular age-related macular degeneration (nAMD) patients transitioned to intravitreal aflibercept after failure to extend treatment interval beyond 8 weeks with prior intravitreal bevacizumab or ranibizumab. METHODS: Retrospective review of patients with nAMD switched to aflibercept following ≥ 6 prior intravitreal ranibizumab or bevacizumab injections at 4-8-week intervals. Three monthly aflibercept injections were given followed by a treat-and-extend dosing regimen. RESULTS: Twenty-one eyes of 18 patients who had received a mean of 23.8 ± 18.8 (mean ± SD; range 6-62) prior ranibizumab or bevacizumab injections were included. Over a mean follow-up of 24 months after the transition, 9.2 ± 2.9 (range 4-21) aflibercept injections were required. Interval between aflibercept injections increased to 57.3 days (range 35-133 days), as compared with 37 ± 6.1 days (range 29-54 days) with the prior agents (P = 0.01). Mean best-corrected visual acuity was preserved (0.42 ± 0.31 vs 0.42 ± 0.23 logMAR; P = 0.2). Mean OCT central subfoveal thickness (292.1 ± 83.2 µm to 283.6 ± 78.6 µm; P = 0.4) and mean macular volume (7.9 ± 0.95 mm(3) to 7.67 ± 0.94 mm(3); P = 0.16) remained stable. CONCLUSION: Patients requiring treatment more frequently than every 8 weeks with ranibizumab and bevacizumab were transitioned to > 8-week treatment interval with aflibercept while maintaining the anatomic and visual gains.

Myocardial MiR-30 downregulation triggered by doxorubicin drives alterations in ß-adrenergic signaling and enhances apoptosis.

The use of anthracyclines such as doxorubicin (DOX) has improved outcome in cancer patients, yet associated risks of cardiomyopathy have limited their clinical application. DOX-associated cardiotoxicity is frequently irreversible and typically progresses to heart failure (HF) but our understanding of molecular mechanisms underlying this and essential for development of cardioprotective strategies remains largely obscure. As microRNAs (miRNAs) have been shown to play potent regulatory roles in both cardiovascular disease and cancer, we investigated miRNA changes in DOX-induced HF and the alteration of cellular processes downstream. Myocardial miRNA profiling was performed after DOX-induced injury, either via acute application to isolated cardiomyocytes or via chronic exposure in vivo, and compared with miRNA profiles from remodeled hearts following myocardial infarction. The miR-30 family was downregulated in all three models. We describe here that miR-30 act regulating the ß-adrenergic pathway, where preferential ß1- and ß2-adrenoceptor (ß1AR and ß2AR) direct inhibition is combined with Giα-2 targeting for fine-tuning. Importantly, we show that miR-30 also target the pro-apoptotic gene BNIP3L/NIX. In aggregate, we demonstrate that high miR-30 levels are protective against DOX toxicity and correlate this in turn with lower reactive oxygen species generation. In addition, we identify GATA-6 as a mediator of DOX-associated reductions in miR-30 expression. In conclusion, we describe that DOX causes acute and sustained miR-30 downregulation in cardiomyocytes via GATA-6. miR-30 overexpression protects cardiac cells from DOX-induced apoptosis, and its maintenance represents a potential cardioprotective and anti-tumorigenic strategy for anthracyclines.

Gastroesophageal reflux in laparoscopic sleeve gastrectomy: hiatal findings and their management influence outcome.

BACKGROUND: Sleeve gastrectomy (SG) has become a definitive treatment for morbid obesity. There is conflicting evidence on the effects of SG on gastroesophageal reflux disease (GERD). OBJECTIVE: The objective of this study was to assess whether taking an aggressive approach to managing hiatal weakness in patients undergoing SG results in an alteration in GERD symptoms. SETTING: Tertiary public hospital and private hospital, Sydney, Australia. METHODS: Patients undergoing laparoscopic extended (beginning within 2 cm from pylorus) SG were included. If evidence of weakness was present, an anterior hiatal dissection and tight suture repair was performed. If a hiatus hernia was present, formal repair was undertaken. Patients were questioned and scored on preoperative and postoperative reflux symptom frequency and severity, proton pump inhibitor (PPI) usage, current weight, and satisfaction. RESULTS: A continuous cohort of 262 patients experienced a significant reduction in heartburn frequency (P = .035) and severity (P = .017). Moderate/severe preoperative reflux (Visick score 3 and 4) often improved whether there was a defect requiring repair or not (no repair P = .02, hiatal suture P = .001, hiatus hernia repair P<.001). The severity of symptoms also improved (no repair P = 0.005, hiatal suture P<.001, hiatus hernia repair P< .001). CONCLUSION: Moderate or severe preexisting gastroesophageal reflux improved for most of our obese patients undergoing an extended SG when hiatal defects were routinely repaired. Moderate to severe preoperative reflux also improved in the average obese patient when there was no hiatal defect to repair.

Validation of an obstetric comorbidity index in an external population.

OBJECTIVES: An obstetric comorbidity index has been developed recently with superior performance characteristics relative to general comorbidity measures in an obstetric population. This study aimed to externally validate this index and to examine the impact of including hospitalisation/delivery records only when estimating comorbidity prevalence and discriminative performance of the obstetric comorbidity index. DESIGN: Validation study. SETTING: Alberta, Canada. POPULATION: Pregnant women who delivered a live or stillborn infant in hospital (n = 5995). METHODS: Administrative databases were linked to create a population-based cohort. Comorbid conditions were identified from diagnoses for the delivery hospitalisation, all hospitalisations and all healthcare contacts (i.e. hospitalisations, emergency room visits and physician visits) that occurred during pregnancy and 3 months pre-conception. Logistic regression was used to test the discriminative performance of the comorbidity index. MAIN OUTCOME MEASURES: Maternal end-organ damage and extended length of stay for delivery. RESULTS: Although prevalence estimates for comorbid conditions were consistently lower in delivery records and hospitalisation data than in data for all healthcare contacts, the discriminative performance of the comorbidity index was constant for maternal end-organ damage [all healthcare contacts area under the receiver operating characteristic curve (AUC) = 0.70; hospitalisation data AUC = 0.67; delivery data AUC = 0.65] and extended length of stay for delivery (all healthcare contacts AUC = 0.60; hospitalisation data AUC = 0.58; delivery data AUC = 0.58). CONCLUSIONS: The obstetric comorbidity index shows similar performance characteristics in an external population and is a valid measure of comorbidity in an obstetric population. Furthermore, the discriminative performance of the comorbidity index was similar for comorbidities ascertained at the time of delivery, in hospitalisation data or through all healthcare contacts.

Physiological, pharmacological and toxicological considerations of drug-induced structural cardiac injury.

The incidence of drug-induced structural cardiotoxicity, which may lead to heart failure, has been recognized in association with the use of anthracycline anti-cancer drugs for many years, but has also been shown to occur following treatment with the new generation of targeted anti-cancer agents that inhibit one or more receptor or non-receptor tyrosine kinases, serine/threonine kinases as well as several classes of non-oncology agents. A workshop organized by the Medical Research Council Centre for Drug Safety Science (University of Liverpool) on 5 September 2013 and attended by industry, academia and regulatory representatives, was designed to gain a better understanding of the gaps in the field of structural cardiotoxicity that can be addressed through collaborative efforts. Specific recommendations from the workshop for future collaborative activities included: greater efforts to identify predictive (i) preclinical; and (ii) clinical biomarkers of early cardiovascular injury; (iii) improved understanding of comparative physiology/pathophysiology and the clinical predictivity of current preclinical in vivo models; (iv) the identification and use of a set of cardiotoxic reference compounds for comparative profiling in improved animal and human cellular models; (v) more sharing of data (through publication/consortia arrangements) on target-related toxicities; (vi) strategies to develop cardio-protective agents; and (vii) closer interactions between preclinical scientists and clinicians to help ensure best translational efforts.