Sentinel lymph node biopsy versus elective neck dissection in management of the clinically negative (cN0) neck in patients with oral squamous cell carcinoma: A systematic review and meta-analysis.

Oral squamous cell carcinoma (OSCC) is the most prevalent type of head and neck cancer, and lymph node metastasis is a crucial prognostic factor that has a direct correlation with the survival rate. The standard procedure for managing clinically negative (cN0) neck in OSCC patients is elective neck dissection (END), but it can lead to various complications that affect the patient's quality of life. Therefore, medical professionals are exploring the use of the sentinel lymph node biopsy (SLNB) to manage cN0 neck in OSCC patients. The aim of this systematic review and meta-analysis was to compare the overall survival (OS) and disease-free survival (DFS) of patients undergoing SLNB and END in the surgical management of early cN0 neck in OSCC patients. To conduct this study, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used to report the systematic reviews. The study included all comparative clinical studies, including randomized clinical trials (RCTs), clinical perspective studies, and retrospective studies that compared END to SLNB for early cN0 neck in OSCC patients. The hazard ratio (HR) and risk ratio (RR) with 95% confidence interval (CI) were calculated using comprehensive meta-analysis. The primary outcome variables were OS, DFS, and disease-specific survival (DSS). The secondary outcome variable was the nodal recurrence rate without local or distant metastasis. The GRADE system was used to assess the evidence's certainty. The meta-analysis included 12 clinical studies, comprising three RCTs and seven non-RCTs. The results showed no statistically significant difference between END and SLNB concerning OS (HR = 0.993, CI: 0.814 to 1.211, P = 0.947, low-quality evidence), DFS (HR = 0.705, CI: 0.408 to 1.29, P = 0.21, low-quality evidence), and nodal recurrence (RR = 1.028, CI: 0.969 to 1.090, P = 0.907, low-quality evidence). Additionally, SLNB was non-inferior to END regarding DSS (RR = 1.028, CI: 0.969 to 1.090, P = 0.907, low-quality evidence). In conclusion, this research affirms the safety and precision of SLNB as a means to stage cN0 OSCC patients, with outcomes that are comparable to END in terms of survival and nodal recurrence. Nevertheless, it's crucial to acknowledge that the quality of evidence in this study was relatively low. Therefore, additional RCTs comparing END to SLNB are warranted to validate these results and offer more robust guidance for managing cN0 OSCC patients.

A CircRNA-miRNA-mRNA Network for Exploring Doxorubicin- and Myocet-Induced Cardiotoxicity in a Translational Porcine Model.

Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA-miRNA-mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA-miRNA-mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA-miRNA-mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity.

Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis.

We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet®, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF.

Effect of allogeneic adipose tissue-derived mesenchymal stromal cell treatment in chronic ischaemic heart failure with reduced ejection fraction - the SCIENCE trial.

AIMS: The aim of the SCIENCE trial was to investigate whether a single treatment with direct intramyocardial injections of adipose tissue-derived mesenchymal stromal cells (CSCC_ASCs) was safe and improved cardiac function in patients with chronic ischaemic heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The study was a European multicentre, double-blind, placebo-controlled phase II trial using allogeneic CSCC_ASCs from healthy donors or placebo (2:1 randomization). Main inclusion criteria were New York Heart Association (NYHA) class II-III, left ventricular ejection fraction (LVEF) <45%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels >300 pg/ml. CSCC_ASCs or placebo (isotonic saline) were injected directly into viable myocardium. The primary endpoint was change in left ventricular end-systolic volume (LVESV) at 6-month follow-up measured by echocardiography. A total of 133 symptomatic HFrEF patients were included. The treatment was safe without any drug-related severe adverse events or difference in cardiac-related adverse events during a 3-year follow-up period. There were no significant differences between groups during follow-up in LVESV (0.3 ± 5.0 ml, p = 0.945), nor in secondary endpoints of left ventricular end-diastolic volume (-2.0 ± 6.0 ml, p = 0.736) and LVEF (-1.6 ± 1.0%, p = 0.119). The NYHA class improved slightly within the first year in both groups without any difference between groups. There were no changes in 6-min walk test, NT-proBNP, C-reactive protein or quality of life the first year in any groups. CONCLUSION: The SCIENCE trial demonstrated safety of intramyocardial allogeneic CSCC_ASC therapy in patients with chronic HFrEF. However, it was not possible to improve the pre-defined endpoints and induce restoration of cardiac function or clinical symptoms.

Culprit site extracellular DNA and microvascular obstruction in ST-elevation myocardial infarction.

AIMS: Extracellular chromatin and deoxyribonuclease (DNase) have been identified as important players of thrombosis, inflammation, and homeostasis in a murine model. We previously demonstrated that activated neutrophils release neutrophil extracellular traps (NETs) at the culprit site in ST-elevation myocardial infarction (STEMI), which significantly contribute to extracellular chromatin burden, and are associated with larger infarcts. To understand the correlation between neutrophil activation, extracellular chromatin, and infarct size (IS), we investigated these parameters in a porcine myocardial infarction model, and at different time points and sites in a prospective STEMI trial with cardiac magnetic resonance (CMR) endpoints. METHODS AND RESULTS: In a prospective STEMI trial (NCT01777750), 101 STEMI patients were included and blood samples were obtained from first medical contact until 6 months after primary percutaneous coronary intervention (pPCI) including direct sampling from the culprit site. CMR was performed 4 ± 2 days and 6 months after pPCI. Neutrophil counts, markers of extracellular chromatin, and inflammation were measured. Double-stranded deoxyribonucleic acid (dsDNA), citrullinated histone 3, nucleosomes, myeloperoxidase, neutrophil elastase, and interleukin (IL)-6 were significantly increased, while DNase activity was significantly decreased at the culprit site in STEMI patients. High neutrophil counts and dsDNA levels at the culprit site correlated with high microvascular obstruction (MVO) and low ejection fraction (EF). High DNase activity at the culprit site correlated with low MVO and high EF. In correspondence, dsDNA correlated with IS in the porcine myocardial infarction model. In porcine infarcts, neutrophils and extracellular chromatin were detected in congested small arteries corresponding with MVO. Markers of neutrophil activation, extracellular chromatin, DNase activity and CMR measurements correlated with markers of systemic inflammation C-reactive protein and IL-6 in patients. CONCLUSIONS: NETs and extracellular chromatin are important determinants of MVO in STEMI. Rapid degradation of extracellular chromatin by DNases appears to be crucial for microvascular patency and outcome.

Multimarker Approach to Identify Patients with Coronary Artery Disease at High Risk for Subsequent Cardiac Adverse Events: The Multi-Biomarker Study.

In our prospective non-randomized, single-center cohort study (n = 161), we have evaluated a multimarker approach including S100 calcium binding protein A12 (S100A1), interleukin 1 like-receptor-4 (IL1R4), adrenomedullin, copeptin, neutrophil gelatinase-associated lipocalin (NGAL), soluble urokinase plasminogen activator receptor (suPAR), and ischemia modified albumin (IMA) in prediction of subsequent cardiac adverse events (AE) during 1-year follow-up in patients with coronary artery disease. The primary endpoint was to assess the combined discriminatory predictive value of the selected 7 biomarkers in prediction of AE (myocardial infarction, coronary revascularization, death, stroke, and hospitalization) by canonical discriminant function analysis. The main secondary endpoints were the levels of the 7 biomarkers in the groups with/without AE; comparison of the calculated discriminant score of the biomarkers with traditional logistic regression and C-statistics. The canonical correlation coefficient was 0.642, with a Wilk's lambda value of 0.78 and p < 0.001. By using the calculated discriminant equation with the weighted mean discriminant score (centroid), the sensitivity and specificity of our model were 79.4% and 74.3% in prediction of AE. These values were higher than that of the calculated C-statistics if traditional risk factors with/without biomarkers were used for AE prediction. In conclusion, canonical discriminant analysis of the multimarker approach is able to define the risk threshold at the individual patient level for personalized medicine.