Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study.

BACKGROUND: The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. METHODS: The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. DISCUSSION: The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. ETHICS COMMITTEE APPROVAL NUMBER: 5420 - 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS - Università Cattolica del Sacro Cuore Ethics Committee. TRIAL REGISTRATION: clinicaltrial.gov - NCT05802771.

Peritoneal dialysis in heart failure: focus on kidney and ventricular dysfunction.

Heart failure is a significant health problem worldwide. Despite all the new therapies available nowadays, many patients will reach advanced stages of the disease. Diuretic resistance, kidney dysfunction, and refractory congestion, all highly prevalent in advanced heart failure, frequently complicate the situation, making it more challenging to manage. Ultrafiltration through hemodialysis or peritoneal dialysis can be alternative options to treat fluid overload. Peritoneal dialysis has gained increased interest in the last decades due to several benefits such as functional class improvement, reduction in hospital admissions, improvement in quality of life, and even a reduction in mortality shown by numerous cohort studies. However, the majority of the studies were observational and with a limited number of patients. In addition, the optimal timing for the initiation of this type of therapy and the subgroup of patients who would benefit the most from it is unknown. Hence, randomized controlled trials in this subject are urgently needed. We aim to review the contemporary evidence of peritoneal dialysis in patients with heart failure and diuretic resistance across the spectrum of ventricular dysfunction and degree of renal dysfunction.

Obstructive Sleep Apnea Syndrome as a Trigger of Cardiac Arrhythmias.

PURPOSE OF REVIEW: Obstructive sleep apnea syndrome (OSAS) has a high prevalence in western countries. Many papers have been published with the purpose of demonstrating that OSAS acts as an arrhythmia trigger and is responsible for an increase in cardiovascular morbidity and mortality. The aim of this study was to review our knowledge on this topic. RECENT FINDINGS: There is a lot of evidence demonstrating the relationship between OSAS and arrhythmias, but there remains a lack of an interventional randomized trial to demonstrate that by treating OSAS we can reduce arrhythmia burden. OSAS is a highly prevalent illness in western countries and is clearly related to an increase in cardiovascular mortality and morbidity. Cardiac arrhythmias are triggered by a repetitive hypoxemia, hypercapnia, acidosis, intrathoracic pressure fluctuations, reoxygenation, and arousals during apnea and hypopnea episodes. Early diagnosis and treatment of these patients can reduce further cardiovascular morbidity and mortality.

Realizing the actual magnitudes of aortic diameter and cardiac output: a multisensory learning approach.

The conventional physiology courses consist of theoretical lectures, clinical application seminars, numerical exercises, simulations, and laboratory practices. However, in subjects that involve relevant physical quantities, even students who successfully pass exams may be unable to realize the actual quantities involved. For example, students may know what the values of the aortic diameter and cardiac output are, and they may be skilled at calculating changes in variables without being able to realize the actual physical magnitudes of the variables, resulting in limited understanding. To address this problem, here we describe and discuss simple practical exercises specifically designed to allow students to multisensory experience (touch, see, hear) the actual physical magnitudes of aortic diameter and cardiac output in adult humans at rest and exercise. The results obtained and the feedback from a student survey both clearly show that the described approach is a simple and interesting tool for motivating students and providing them with more realistic learning.

Aging Impairs Reverse Remodeling and Recovery of Ventricular Function after Isoproterenol-Induced Cardiomyopathy.

Information about heart failure with reduced ejection fraction (HFrEF) in women and the potential effects of aging in the female heart is scarce. We investigated the vulnerability to develop HFrEF in female elderly mice compared to young animals, as well as potential differences in reverse remodeling. First, HF was induced by isoproterenol infusion (30 mg/kg/day, 28 days) in young (10-week-old) and elderly (22-month-old) female mice. In a second set of animals, mice underwent isoproterenol infusion followed by no treatment during 28 additional days. Cardiac remodeling was assessed by echocardiography, histology and gene expression of collagen-I and collagen-III. Following isoproterenol infusion, elderly mice developed similar HFrEF features compared to young animals, except for greater cell hypertrophy and tissue fibrosis. After beta-adrenergic withdrawal, young female mice experienced complete reversal of the HFrEF phenotype. Conversely, reversed remodeling was impaired in elderly animals, with no significant recovery of LV ejection fraction, cardiomyocyte hypertrophy and collagen deposition. In conclusion, chronic isoproterenol infusion is a valid HF model for elderly and young female mice and induces a similar HF phenotype in both. Elderly animals, unlike young, show impaired reverse remodeling, with persistent tissue fibrosis and cardiac dysfunction even after beta-adrenergic withdrawal.

Radiation therapy for bone-only metastases in breast cancer patients: A GOCO survey of current clinical practice.

INTRODUCTION: The role of radiation therapy (RT) for patients with bone-only metastatic (BOM) breast cancer has not been investigated sufficiently. The aim of this survey was to evaluate current clinical practice in treating breast cancer patients with BOM in Radiation Therapy Departments in Catalonia and Occitania within the scope of the GOCO group. MATERIALS AND METHODS: An electronic questionnaire was completed by experienced radiation oncologists from fourteen RT centers. The items surveyed the professional experience, therapeutic approach, technique, dose stereotactic body RT (SBRT) availability. RESULTS: All Radiation Oncology Departments (ROD) in Catalonia (12) and Occitania (2) responded to the survey. Eleven (78.5%) of the RODs advise RT for BOM as initial treatment in the oligometastatic setting. RT to asymptomatic bone oligometastases is more often restricted for "risky lesions". The most inconsistent approaches were the treatment for asymptomatic lesions, when to treat bone metastases with respect to systemic treatment (ST) and the indication for RT after a complete response to ST. CONCLUSION: While BOM breast cancer patients have a relatively good prognosis, there is a lack of consistency in their approach with RT. This can be explained by the absence of evidence-based guidelines and an incomplete availability of SBRT.

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice.

Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans.

Importance of iron deficiency in patients with chronic heart failure as a predictor of mortality and hospitalizations: insights from an observational cohort study.

BACKGROUND: Iron deficiency (ID) in patients with chronic heart failure (CHF) is considered an adverse prognostic factor. We aimed to evaluate if ID in patients with CHF is associated with increased mortality and hospitalizations. METHODS: We evaluated ID in patients with CHF at 3 university hospitals. ID was defined as absolute (ferritin < 100 µg/L) or functional (transferrin Saturation index < 20% and ferritin between 100 and 299 µg/L). We excluded patients who received treatment with intravenous Iron or Erythropoietin during follow-up. We evaluated if ID was a predictor of death or hospitalization due to heart failure or any cause using univariate and multivariate cox regression analysis. RESULTS: We included 1684 patients, 65% males, 38% diabetics, median age of 72 years, 37% in functional class III-IV and 30% of patients with a left ventricular ejection fraction > 45%. Patients were well treated, with 87% and 88% of patients receiving renin-angiotensin inhibitors and beta-blockers, respectively. Median transferrin saturation index was 20%, median ferritin 155 ng/mL and median haemoglobin 13 g/dL. ID was present in 53% of patients; in 35% it was absolute and in 18% functional. Median follow-up was 20 months. ID was a predictor of death, hospitalization due to heart failure or to any cause in univariate analysis but not after multivariate analysis. No differences were found between absolute or functional ID regarding prognosis. CONCLUSION: In a real life population of patients with CHF and a high prevalence of heart failure with preserved ejection fraction, ID did not predict mortality or hospitalizations after adjustment for comorbidities, functional class and neurohormonal treatment.

Prognostic significance of extracapsular spread in isolated neck recurrences in head and neck squamous cell carcinoma patients.

Few studies have analyzed the appearance of extracapsular spread (ECS) in salvage neck dissections carried out after regional recurrence of the disease. The aim of our study was to evaluate the frequency of ECS in patients with an isolated regional recurrence treated with a salvage neck dissection, and to assess the influence of ECS on prognosis. We conducted a retrospective study of 123 patients treated with a salvage neck dissection. Eighty-two patients (66.7 %) had nodes with ECS. Five-year salvage-specific survival for patients without ECS was 77.2 %, whereas for patients with ECS it was 32.0 % (P = 0.0001). According to the results of a multivariate analysis, the presence of ECS in the salvage neck dissection was the only variable significantly related to the salvage-specific survival. Sixty-six percent of the patients with nodes with ECS had adjuvant treatment with radiotherapy or chemoradiotherapy. Five-year salvage-specific survival for patients with ECS who had not received adjuvant treatment (n = 26) was 15.2 %, whereas for patients treated with adjuvant radiotherapy (n = 39) or chemotherapy (n = 17), 5-year salvage-specific survival was 36.4 and 47.1 %, respectively. Patients with ECS could benefit from adjuvant treatment with radiotherapy or chemoradiotherapy.

Low-cost, open-source device for simultaneously subjecting rodents to different circadian cycles of light, food, and temperature.

Exposure of experimental rodents to controlled cycles of light, food, and temperature is important when investigating alterations in circadian cycles that profoundly influence health and disease. However, applying such stimuli simultaneously is difficult in practice. We aimed to design, build, test, and open-source describe a simple device that subjects a conventional mouse cage to independent cycles of physiologically relevant environmental variables. The device is based on a box enclosing the rodent cage to modify the light, feeding, and temperature environments. The device provides temperature-controlled air conditioning (heating or cooling) by a Peltier module and includes programmable feeding and illumination. All functions are set by a user-friendly front panel for independent cycle programming. Bench testing with a model simulating the CO2 production of mice in the cage showed: a) suitable air renewal (by measuring actual ambient CO2), b) controlled realistic illumination at the mouse enclosure (measured by a photometer), c) stable temperature control, and d) correct cycling of light, feeding, and temperature. The cost of all the supplies (retail purchased by e-commerce) was <300 US$. Detailed technical information is open-source provided, allowing for any user to reliably reproduce or modify the device. This approach can considerably facilitate circadian research since using one of the described low-cost devices for any mouse group with a given light-food-temperature paradigm allows for all the experiments to be performed simultaneously, thereby requiring no changes in the light/temperature of a general-use laboratory.

Factors associated with disease progression in patients with atrial fibrillation and heart failure anticoagulated with rivaroxaban.

BACKGROUND: Patients with atrial fibrillation (AF) and heart failure (HF) have a high risk of thromboembolism and other outcomes and anticoagulation is recommended. HYPOTHESIS: This study was aimed to explore the risk factors associated with HF worsening in patients with AF and HF taking rivaroxaban in Spain. METHODS: Multicenter, prospective, observational study that included adults with AF and chronic HF, receiving rivaroxaban ≥4 months before entering. HF worsening was defined as first hospitalization or emergency visit because of HF exacerbation. RESULTS: A total of 672 patients from 71 Spanish centers were recruited, of whom 658 (97.9%) were included in the safety analysis and 552 (82.1%) in the per protocol analysis. At baseline, mean age was 73.7 ± 10.9 years, 64.9% were male, CHA2 DS2 -VASc was 4.1 ± 1.5, HAS-BLED was 1.6 ± 0.9% and 51.3% had HF with preserved ejection fraction. After 24 months of follow-up, 24.9% of patients developed HF worsening, 11.6% died, 2.9% had a thromboembolic event, 3.1% a major bleeding, 0.5% an intracranial bleeding and no patient had a fatal hemorrhage. Older age, the history of chronic obstructive pulmonary disease, the previous use of vitamin K antagonists, and restrictive or infiltrative cardiomyopathies, were independently associated with HF worsening. Only 6.9% of patients permanently discontinued rivaroxaban treatment. CONCLUSIONS: Approximately one out of four patients with HF and AF treated with rivaroxaban developed a HF worsening episode after 2 years of follow-up. The identification of those factors that increase the risk of HF worsening could be helpful in the comprehensive management of this population.

Results of radiotherapy in oropharyngeal carcinomas.

OBJECTIVE: To present the results of radiotherapy treatment in patients with oropharyngeal carcinomas. MATERIAL AND METHODS: Retrospective study of a cohort of 359 patients treated with radiotherapy, including chemo- and bio-radiotherapy, during the period 2000-2019. Information on human papillomavirus (HPV) status was available for 202 patients, of whom 26.2% were HPV-positive. RESULTS: Five-year local recurrence-free survival was 73.5% (95% CI: 68.8%-78.2%). The variables that were related to local disease control in a multivariate study were the local tumor extension category and the HPV status. Five-year local recurrence-free survival for patients with cT1 tumors was 90.0%, for cT2 88.0%, for cT3 70.6%, and for cT4 42.3%. Five-year local recurrence-free survival for HPV-negative tumors was 67.2% and for HPV-positive tumors 93.3%. Five-year specific-disease survival was 64.4% (95% CI: 59.1%-69.7%). Variables that were related to specific survival in a multivariate study were the patient's general condition, local and regional extent of the tumor, and HPV status. CONCLUSIONS: Five-year local recurrence-free survival of patients with oropharyngeal carcinomas treated with radiotherapy was 73.5%. Variables that were related to local control were local tumor extension and HPV status.

The natural history of QTc interval and its clinical impact in coronavirus disease 2019 survivors after 1 year.

Background and objective: Prolonged QTc interval on admission and a higher risk of death in SARS-CoV-2 patients have been reported. The long-term clinical impact of prolonged QTc interval is unknown. This study examined the relationship in COVID-19 survivors of a prolonged QTc on admission with long-term adverse events, changes in QTc duration and its impact on 1-year prognosis, and factors associated with a prolonged QTc at follow-up. Methods: We conducted a single-center prospective cohort study of 523 SARS-CoV-2-positive patients who were alive on discharge. An electrocardiogram was taken on these patients within the first 48 h after diagnosis and before the administration of any medication with a known effect on QT interval and repeated in 421 patients 7 months after discharge. Mortality, hospital readmission, and new arrhythmia rates 1 year after discharge were reviewed. Results: Thirty-one (6.3%) survivors had a baseline prolonged QTc. They were older, had more cardiovascular risk factors, cardiac disease, and comorbidities, and higher levels of terminal pro-brain natriuretic peptide. There was no relationship between prolonged QTc on admission and the 1-year endpoint (9.8% vs. 5.5%, p = 0.212). In 84% of survivors with prolonged baseline QTc, it normalized at 7.9 ± 2.2 months. Of the survivors, 2.4% had prolonged QTc at follow-up, and this was independently associated with obesity, ischemic cardiomyopathy, chronic obstructive pulmonary disease, and cancer. Prolonged baseline QTc was not independently associated with the composite adverse event at 1 year. Conclusions: Prolonged QTc in the acute phase normalized in most COVID-19 survivors and had no clinical long-term impact. Prolonged QTc at follow-up was related to the presence of obesity and previously acquired chronic diseases and was not related to 1-year prognosis.

Characteristics of Patients with Heart Failure and Advanced Chronic Kidney Disease (Stages 4-5) Not Undergoing Renal Replacement Therapy (ERCA-IC Study).

BACKGROUND: Despite the frequent coexistence of heart failure (HF) in patients with advanced chronic kidney disease (CKD), it has been understudied, and little is known about its prevalence and prognostic relevance. METHODS: A retrospective study of 217 patients with advanced CKD (stages 4 and 5) who did not undergo renal replacement therapy (RRT). The patients were followed up for two years. The primary outcome was all-cause death or the need for RRT. RESULTS: Forty percent of patients had a history of HF. The mean age was 78.2 ± 8.8 years and the mean eGFR was 18.4 ± 5.5 mL/min/1.73 m2. The presence of previous HF identified a subgroup of high-risk patients with a high prevalence of cardiovascular comorbidities and was significantly associated with the composite endpoint of all-cause hospitalization or need for RRT (66.7% vs. 53.1%, HR 95% CI 1.62 (1.04-2.52), p = 0.034). No differences were found in the need for RRT (27.6% vs. 32.2%, p = 0.46). Nineteen patients without HF at baseline developed HF during the follow-up and all-cause death was numerically higher (36.8 vs. 19.8%, p = 0.1). CONCLUSIONS: Patients with advanced CKD have a high prevalence of HF. The presence of previous HF identified a high-risk population with a worse prognosis that required close follow-up.

Subclinical congestion assessed by lung ultrasound in ST segment elevation myocardial infarction.

OBJECTIVE: We evaluated the prognostic value of subclinical congestion assessed by lung ultrasound (LUS) in patients admitted for ST segment elevation myocardial infarction (STEMI). METHODS: This was a multicentre study that prospectively enrolled 312 patients admitted for STEMI without signs of heart failure (HF) at admission. LUS was performed during the first 24 hours after revascularisation and classified patients as having either wet lung (three or more B-lines in at least one lung field) or dry lung. The primary endpoint was a composite of acute HF, cardiogenic shock or death during hospitalisation. The secondary endpoint was a composite of readmission for HF or new acute coronary syndrome or death during 30-day follow-up. Zwolle score was calculated in all patients to assess predictive improvement by adding the result of the LUS to this score. RESULTS: 14 patients (31.1%) in the wet lung group presented the primary endpoint vs 7 (2.6%) in the dry lung group (adjusted RR 6.0, 95% CI 2.3 to 16.2, p=0.007). The secondary endpoint occurred in five patients (11.6%) in the wet lung group and in three (1.2%) in the dry lung group (adjusted HR 5.4, 95% CI 1.0 to 28.7, p=0.049). Addition of LUS improved the ability of the Zwolle score to predict the follow-up composite endpoint (net reclassification improvement 0.99). LUS showed a very high negative predictive value in predicting in-hospital and follow-up endpoints (97.4% and 98.9%, respectively). CONCLUSION: Early subclinical pulmonary congestion identified by LUS in patients with Killip I STEMI at hospital admission is associated with adverse outcomes during hospitalisation and 30-day follow-up.

Prognostic Utility of a New Risk Stratification Protocol for Secondary Prevention in Patients Attending Cardiac Rehabilitation.

Several risk scores have been used to predict risk after an acute coronary syndrome (ACS), but none of these risk scores include functional class. The aim was to assess the predictive value of risk stratification (RS), including functional class, and how cardiac rehabilitation (CR) changed RS. Two hundred and thirty-eight patients with ACS from an ambispective observational registry were stratified as low (L) and no-low (NL) risk and classified according to exercise compliance; low risk and exercise (L-E), low risk and control (no exercise) (L-C), no-low risk and exercise (NL-E), and no-low risk and control (NL-C). The primary endpoint was cardiac rehospitalization. Multivariable analysis was performed to identify variables independently associated with the primary endpoint. The L group included 56.7% of patients. The primary endpoint was higher in the NL group (18.4% vs. 4.4%, p < 0.001). After adjustment for age, sex, diabetes, and exercise in multivariable analysis, HR (95% CI) was 3.83 (1.51−9.68) for cardiac rehospitalization. For RS and exercise, the prognosis varied: the L-E group had a cardiac rehospitalization rate of 2.5% compared to 26.1% in the NL-C group (p < 0.001). Completing exercise training was associated with reclassification to low-risk, associated with a better outcome. This easy-to-calculate risk score offers robust prognostic information. No-exercise groups were independently associated with the worst outcomes. Exercise-based CR program changed RS, improving classification and prognosis.