Citations

Abstract The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Objective To develop a core outcome set (COS) for randomised controlled trials (RCTs) evaluating the effectiveness of interventions for the treatment of pregnant women with pregestational diabetes mellitus (PGDM). Design A consensus developmental study. Setting International. Population Two hundred and five stakeholders completed the first round. Methods The study consisted of three components. (1) A systematic review of the literature to produce a list of outcomes reported in RCTs assessing the effectiveness of interventions for the treatment of pregnant women with PGDM. (2) A three‐round, online eDelphi survey to prioritise these outcomes by international stakeholders (including healthcare professionals, researchers and women with PGDM). (3) A consensus meeting where stakeholders from each group decided on the final COS. Main outcome measures All outcomes were extracted from the literature. Results We extracted 131 unique outcomes from 67 records meeting the full inclusion criteria. Of the 205 stakeholders who completed the first round, 174/205 (85%) and 165/174 (95%) completed rounds 2 and 3, respectively. Participants at the subsequent consensus meeting chose 19 outcomes for inclusion into the COS: trimester‐specific haemoglobin A1c, maternal weight gain during pregnancy, severe maternal hypoglycaemia, diabetic ketoacidosis, miscarriage, pregnancy‐induced hypertension, pre‐eclampsia, maternal death, birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, mode of birth, shoulder dystocia, neonatal hypoglycaemia, congenital malformations, stillbirth and neonatal death. Conclusions This COS will enable better comparison between RCTs to produce robust evidence synthesis, improve trial reporting and optimise research efficiency in studies assessing treatment of pregnant women with PGDM. Tweetable abstract 165 key stakeholders have developed #Treatment #CoreOutcomes in pregnant women with #diabetes existing before pregnancy.

Background & Purpose: Seizures are a recognized complication of stroke. However, available data are conflicting in terms of incidence, risk factors for occurrence, and impact on functional outcome and mortality. The aim of this study was to assess the incidence and characteristics of seizures following ischemic stroke in a well-defined population, and their effect on long-term patient outcome. Methodology: Utilizing the Rochester Epidemiology Project medical record linkage system, we identified all incident cases of ischemic stroke (IS) that occurred between January 1, 1990, and December 31, 1994. We identified all patients who developed seizures following first IS. Detailed data regarding stroke (including TOAST subtype, anatomic location, functional outcome), seizures (date, type, functional outcome, recurrence, presence of status epilepticus, complications, treatment, EEG findings), and patient status at the last follow-up were recorded and analyzed. Results: We identified 490 patients with first IS. Mean follow-up was 6.5 years (range 0.0 - 23.8). Of these, 35 (7.1%) developed seizures. Early seizures (occurring within 14 days of stroke) were present in 13 (37.1%), of which 9 (69.2%) had their seizure within the first 24 hours. Partial seizures were the most common type (23 patients, 65.7%). Status epilepticus occurred in two cases (5.7%). Tongue biting was the most common complication of poststroke seizures (4 patients, 11.4%). Treatment with antiepileptic drugs (AEDs) was initiated in 32 cases (91.4%). Only one drug was necessary for seizure control in all treated patients. The mean modified Rankin Scale score was 2.9 (SD 1.48) after the first IS, and worsened to 3.3 (SD 1.43) after the first seizure. Mortality at the last follow-up was higher in the seizure group compared to the non-seizure group, even after adjusting for TOAST subtype (HR 1.52; 95% CI 1.07 - 2.16; P = 0.02). Conclusion: Seizures are mostly a late complication of IS. They do not bear a high risk of life-threatening complications and are readily controllable by a single AED. However, patients who developed poststroke seizures tended to have a worse functional outcome and an increased mortality.

Introduction: An increasing number of healthy adults consume energy drinks to enhance their physical and mental performance. Energy drinks contain caffeine and multiple other “natural” stimulants and their combined effects on cardiac hemodynamics in healthy individuals are unclear. Hypothesis: We hypothesized that drinking a commercially available energy drink, Rockstar , compared to a placebo drink, increases resting blood pressure and heart rate in healthy adults, and these increases would be further accentuated by stress conditions. Methods: We enrolled 25 healthy, normotensive subjects (14 males), aged 29±1 years, with body mass index 24.5±1 kg/m 2 , in a randomized, double-blind, placebo-controlled, crossover study. Each subject consumed a placebo drink and a commercially available Rockstar energy drink (473 ml), in random order on two separate study days. Blood pressure and heart rate responses were recorded and compared before and 30 minutes after drink consumption, both at rest and then in response to physical, mental and cold stressors. Results: The Rockstar energy drink induced a 6±1% increase in resting systolic blood pressure, compared to 3±1% with the placebo drink (P=0.0078). Diastolic blood pressure increased by 7±1% vs 0±1% with the placebo drink (P=0.0007; Figure 1). Heart rate increased similarly in both groups, by 5±2% in the energy drink group vs. 7±2% in the placebo group. Blood pressure and heart rate increases during the stress stimuli (sustained handgrip, mental stress and cold stress) did not differ between energy drink and placebo. Conclusions: Drinking a commercially available Rockstar energy drink significantly increases resting blood pressure in young healthy adults. Blood pressure increases are not further accentuated by exercise, mental or cold pressor stress stimuli. These hemodynamic changes induced by energy drink consumption could predispose to cardiovascular events.

Abstract Background: While pre-existing cardiovascular disease (CVD) appears to be associated with poor outcomes in patients with Coronavirus Disease 2019 (COVID-19), data on patients with CVD and concomitant cancer is limited. Evaluate the effect of underlying CVD and CVD risk factors with cancer history on in-hospital mortality in those with COVID-19.Methods: Data from symptomatic adults hospitalized with COVID-19 at 86 hospitals in the US enrolled in the American Heart Association’s COVID-19 CVD Registry was analyzed. The primary exposure was cancer history. The primary outcome was in-hospital death. Multivariable logistic regression models were adjusted for demographics, CVD risk factors, and CVD. Interaction between history of cancer with concomitant CVD and CVD risk factors were tested.Results: Among 8222 patients, 892 (10.8%) had a history of cancer and 1501 (18.3%) died. Cancer history had significant interaction with CVD risk factors of age, body mass index (BMI), and smoking history, but not underlying CVD itself. History of cancer was significantly associated with increased in-hospital death (among average age and BMI patients, adjusted odds ratio [aOR]=3.60, 95% confidence interval [CI]: 2.07-6.24; p<0.0001 in those with a smoking history and aOR=1.33, 95%CI: 1.01 - 1.76; p=0.04 in non-smokers). Among the cancer subgroup, prior use of chemotherapy within 2 weeks of admission was associated with in-hospital death (aOR=1.72, 95%CI: 1.05-2.80; p=0.03). Underlying CVD demonstrated a numerical but statistically nonsignificant trend toward increased mortality (aOR=1.18, 95% CI: 0.99 - 1.41; p=0.07).Conclusion: Among hospitalized COVID-19 patients, cancer history was a predictor of in-hospital mortality. Notably, among cancer patients, recent use of chemotherapy, but not underlying CVD itself, was associated with worse survival. These findings have important implications in cancer therapy considerations and vaccine distribution in cancer patients with and without underlying CVD and CVD risk factors.

AbstractBackgroundCoronavirus disease 2019 (COVID‐19) ranges from asymptomatic disease to respiratory failure and requires invasive mechanical ventilation (IMV). Data about the sequelae after infection are scarce. The study aims to describe the prevalence of symptoms, pulmonary function tests (PFTs), and radiological changes after four months of follow‐up.MethodsA prospective, cross‐sectional, multicentre study was performed. Patients with different illness severities were consecutively included (mild; moderate: hospitalized without IMV; severe: hospitalized with IMV). Clinical variables, health‐related quality of life (HRQoL), PFT (spirometry, diffusing capacity of the lungs for carbon monoxide (DLCO)), and (CT) scans of the chest were obtained. The association between the risk of sequelae (DLCO <80%) and altered CT was analysed using logistic regression adjusted for confounding variables.Results60 patients (18 mild, 17 moderate, and 25 severe) were included. Fatigue was found in 11% of the mild, 47% of the moderate and 36% of the severe group. Altered DLCO (mild: 5.5%, moderate: 41%, severe: 28%, p < .05) and change in HRQoL (mild: 50%, moderate: 94%, severe: 60%), while the severe group showed a higher prevalence of altered CT (88% vs. 64%). Awake prone position (APP) and high‐flow nasal cannula (HFNC) was independently associated with altered DLCO, Odds ratio (OR) 7.28 (CI, 1.10‐47.81; p < .05), and altered CT, OR 9.50 (CI, 1.26‐71.5; p < .05). Besides, prolonged time in IMV was associated with altered CT, OR 1.24 (CI, 1.05‐1.46; p < .05).DiscussionIt is common to find sequelae in symptoms, radiology, and PFT. In our series, the use of APP+HFNC and days on IMV were associated with an increased risk of sequelae.

Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin’s oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 µM of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin’s oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors.