The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation.

Pediatric Acute Myeloid Leukemia (AML) is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations. Despite the improvement of survival in the last years, about 50% of patients still experience a relapse. It is not possible to improve prognosis only with further intensification of chemotherapy, as come with a severe cost to the health of patients, often resulting in treatment-related death or long-term sequels. To design more effective and less toxic therapies we need a better understanding of pediatric AML biology. The NUP98-KDM5A chimeric protein is exclusively found in a particular subgroup of young pediatric AML patients with complex karyotypes and poor prognosis. In this study, we investigated the impact of NUP98-KDM5A expression on cellular processes in human Pluripotent Stem Cell models and a patient-derived cell line. We found that NUP98-KDM5A generates genomic instability through two complementary mechanisms that involve accumulation of DNA damage and direct interference of RAE1 activity during mitosis. Overall, our data support that NUP98-KDM5A promotes genomic instability and likely contributes to malignant transformation.

Comparison of the Use of Desflurane vs. Propofol in Aortic Valve Replacement Surgery: Differences in Nephroprotection: An Explorative and Hypothesis-Generating Study.

Introduction: The cardioprotective effect of halogenated drugs in cardiac surgery has been the subject of several studies. However, there is scarcity of data on their potential nephroprotective effects. Aortic valve replacement and coronary revascularization are the most frequent cardiac surgery procedures. The objective of this explorative study was to examine the effect of desflurane vs. propofol on renal function, when administered in aortic valve replacement surgery, including the extracorporeal circulation period. Method: A quasi-experimental prospective study was performed in 60 patients, who were allocated to receive either desflurane or propofol intraoperatively during aortic valve replacement surgery. As a hypnotic, group 1 received propofol, whereas group 2 received desflurane. Markers of renal function and level of cardiac preservation were determined based on biochemical parameters (troponin I, NTProBNP). Results: In the propofol group, there were significant variations between postoperative values of urinary NGAL and creatinine and baseline values. In contrast, no variations were found in the desflurane group in terms of hemodynamic parameters and myocardial damage. Conclusions: The use of propofol vs. desflurane during aortic valve replacement surgery is associated with a decrease in renal function.

Mallampati Class Zero airway: a narrative review.

INTRODUCTION: Mallampati Class Zero airway describes a visible epiglottis on pharyngoscopic view. It was first noted by Tobold A in 1869 and was proposed as a new class in modified Mallampati Classification by Ezri T. et al. We aim to summarize the current knowledge about Mallampati Class Zero airway and its implication on airway management. EVIDENCE ACQUISITION: We reviewed the reported studies about visible epiglottis on pharyngoscopy and 34 publications were selected. EVIDENCE SYNTHESIS: The diagnosis of Mallampati Class Zero airway is usually achieved as a casual finding during airway assessment of Mallampati Test, during a regular checkup at the dentist, or even after a medical consultation due to a suspected visualization of a foreign body at the back of the throat. Mallampati Class Zero airway has a low prevalence in the general population (prevalence of 0.7-1.7% of adults and 0.3-6% of children) and it is more frequent in children and female. The cause for this phenomenon is not well understood but in clinical practice it is associated with an easy airway. Interestingly, in the pediatric population with Mallampati class zero airway, the difficult airway has not been reported to date. CONCLUSIONS: Mallampati Class Zero is associated with an easy airway and it should be included as a different class in the modified Mallamapti classification, which would also contribute to its spread between professionals involved in the airway management and will favour increasing investigation and knowledge about it.

Liquid biopsy approach to pancreatic cancer.

Pancreatic cancer (PC) continues to pose a major clinical challenge. There has been little improvement in patient survival over the past few decades, and it is projected to become the second leading cause of cancer mortality by 2030. The dismal 5-year survival rate of less than 10% after the diagnosis is attributable to the lack of early symptoms, the absence of specific biomarkers for an early diagnosis, and the inadequacy of available chemotherapies. Most patients are diagnosed when the disease has already metastasized and cannot be treated. Cancer interception is vital, actively intervening in the malignization process before the development of a full-blown advanced tumor. An early diagnosis of PC has a dramatic impact on the survival of patients, and improved techniques are urgently needed to detect and evaluate this disease at an early stage. It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position; however, liquid biopsies are readily available and can provide useful information for the diagnosis, prognosis, stratification, and follow-up of patients with PC and for the design of individually tailored treatments. The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates, proteins, cell-free nucleic acids, circulating tumor cells, metabolome compounds, exosomes, and platelets in blood as potential biomarkers for PC, focusing on their clinical relevance and potential for improving patient outcomes.

Breast Cancer and Anaesthesia: Genetic Influence.

Breast cancer is the leading cause of mortality in women. It is a heterogeneous disease with a high degree of inter-subject variability even in patients with the same type of tumor, with individualized medicine having acquired significant relevance in this field. The clinical and morphological heterogeneity of the different types of breast tumors has led to a diversity of staging and classification systems. Thus, these tumors show wide variability in genetic expression and prognostic biomarkers. Surgical treatment is essential in the management of these patients. However, the perioperative period has been found to significantly influence survival and cancer recurrence. There is growing interest in the pro-tumoral effect of different anaesthetic and analgesic agents used intraoperatively and their relationship with metastatic progression. There is cumulative evidence of the influence of anaesthetic techniques on the physiopathological mechanisms of survival and growth of the residual neoplastic cells released during surgery. Prospective randomized clinical trials are needed to obtain quality evidence on the relationship between cancer and anaesthesia. This document summarizes the evidence currently available about the effects of the anaesthetic agents and techniques used in primary cancer surgery and long-term oncologic outcomes, and the biomolecular mechanisms involved in their interaction.

NGS of microRNAs Involved in Cardioprotection Induced by Sevoflurane Compared to Propofol in Myocardial Revascularization Surgery: The ACDHUVV-16 Clinical Trial.

BACKGROUND: Numerous studies have demonstrated that halogenated agents elicit myocardial conditioning effects when administered perioperatively in cardiac surgery. Recent evidence has been published on the benefits of maintaining exposure to halogenated agents during the early postoperative period. The enzymatic mechanisms by which this beneficial effect is exerted were explained recently. OBJECTIVES: Our study was performed to investigate whether this phenomenon is mediated by either the activation or suppression of miRNAs targeted by halogenated anesthetics. METHODS: A double-blind, two-stage trial was conducted. The results of the first stage of the trial are presented in this paper. The sample was composed of patients undergoing off-pump myocardial revascularization surgery. Patients were randomized to receive either sevoflurane [S] or propofol [P] during the intraoperative and early postoperative period (during the first six hours after the intervention). Hemodynamics (heart rate, blood pressure, central venous pressure, cardiac index, systolic volume index, LVEF) and myocardial enzymes (troponin I) were monitored at six hour intervals during the first 48 hours. In the first stage of the trial, blood was drawn for gene sequencing from eight patients (four per group) at baseline and at 24 h. In the second stage of the study, a qPCR analysis was performed of the miRNAs identified as significant by gene sequencing. Levels of cardioprotective enzymes (serine/threonine protein kinase (Akt), tumor necrosis factor alpha (TNFα), extracellular regulated protein kinase (ERK 1/2), and caspase 3) were measured to assess their role in myocardial conditioning pathways. The purpose was to identify the miRNAs that play a major role in myocardial conditioning induced by halogenated agents. Concentrations of cardioprotective enzymes were higher in patients who received sevoflurane than the patients who were administered propofol. RESULTS: NGS differences were observed between baseline and 24-h values in the two study groups. In group P, miRNA 197-3p was overexpressed, whereas miRNAs 4443 and 1294, 708-3p were underexpressed. In group S, miRNAs 615-3p, 4466, 29, 937-3p, 636, 197-3P, 184, 4685, 296-3p, 147b, 3199, 6815, 1294 and 3176 were underexpressed; whereas 708-3p was overexpressed. qPCR showed significant variations in miRNAs 197-3p, 4443, 708-3p and 1294 in the P group, and in miRNAs 937-3p, 636, 197- 3p, 296-3p and 708-3p in the S group. CONCLUSION: In the P Group, changes in the expression of some miRNAs were associated with lower concentrations of the enzymes involved in myocardial pre- and postconditioning. In contrast, in Group S, variations in miRNAs were associated with the activation of mediators of anesthetic-induced pre- and post-conditioning, a reduction in cell apoptosis, and a decrease in caspase and TnBF alpha concentrations. Changes in these miRNAs were associated with better prognosis in patients with ischemic heart disease. The main limitation of this study will be overcome in the second stage of the trial, where the specific role of each miRNA will be determined.

Case Report: COVID-19 with cytokine storm in a 16-year-old patient: if heart failures comes think about levosimendan.

Introduction: Our case is unique because the differential diagnosis was a challenge. At first, the patient presented with septic shock and multi-organ failure in the context of a suspected lymphoproliferative syndrome. Once the lymphoproliferative process had been ruled out, hemophagocytic syndrome due to COVID-19 infection was suspected, so he is probably one of the few patients with such an exhaustive study that could contribute to our understanding of COVID-19. We followed therapeutic guidelines that differ from the usual, using adrenalin and levosimendan. Corticosteroids helped to modulate the cytokine storm. Case report: A 16-year-old adolescent was admitted to the intensive care unit with fever, diarrhea, multiorgan failure and septic shock. He was IgG positive for COVID-19 and IgM negative. Thoraco-abdominal computed tomography demonstrated multiple para-aortic and peri-pancreatic lymphadenopathy and acute respiratory distress syndrome. The first suspected diagnosis was a lymphoproliferative syndrome and bacterial infection. The second possibility was a hemophagocytic syndrome in a patient recovering from COVID-19. He was treated with broad spectrum antibiotics because the differential diagnosis was difficult, and we removed them when the microbiological screening was negative. During the course of the disease he presented with severe biventricular dysfunction, probably due to the cytokine storm, so we used inotropic drugs (adrenaline, levosimendan). Infection with Salmonella species group B was diagnosed later, when the patient was in the Internal Medicine ward, although he was asymptomatic. Conclusion: The severity of COVID-19 infection ranges from mild to severe, causing serious disease in some people. Although the pathophysiology is not well known, it seems that in some cases an immune storm is triggered, and it is related to more serious and prolonged disease. In our case, heart failure was important, because it could have worsened the prognosis. Fortunately, the response to levosimendan and corticosteroids was adequate and he recovered favorably until discharge.

Anaesthesia and cancer: can anaesthetic drugs modify gene expression?

Cancer remains a primary cause of morbidity and mortality worldwide, and its incidence continues to increase. The most common cause of death in cancer patients is tumour recurrence. Surgery is the gold standard in the treatment of most tumours. However, cancer surgery can lead to the release of tumour cells into the systemic circulation. Surgical stress and several perioperative factors have been suggested to boost tumour growth, thereby increasing the risk of metastatic recurrence. Preclinical and clinical studies suggest that anaesthetics and adjuvants administered during the perioperative period may impact cancer recurrence and survival. This document summarises the current evidence regarding the effects of anaesthetic drugs and analgesic techniques on the immune system, systemic inflammatory response and tumour cells, as well as their impact on cancer recurrence.

Renal and Neurologic Benefit of Levosimendan vs Dobutamine in Patients With Low Cardiac Output Syndrome After Cardiac Surgery: Clinical Trial FIM-BGC-2014-01.

BACKGROUND: Low-cardiac output syndrome (LCOS) after cardiac surgery secondary to systemic hypoperfusion is associated with a higher incidence of renal and neurological damage. A range of effective therapies are available for LCOS. The beneficial systemic effects of levosimendan persist even after cardiac output is restored, which suggests an independent cardioprotective effect. METHODS: A double-blind clinical trial was conducted in patients with a confirmed diagnosis of LCOS randomized into two treatment groups (levosimendan vs. dobutamine). Monitoring of hemodynamic (cardiac index, systolic volume index, heart rate, mean arterial pressure, central venous pressure, central venous saturation); biochemical (e.g. creatinine, S100B protein, NT-proBNP, troponin I); and renal parameters was performed using acute kidney injury scale (AKI scale) and renal and brain ultrasound measurements [vascular resistance index (VRI)] at diagnosis and during the first 48 h. RESULTS: Significant differences were observed between groups in terms of cardiac index, systolic volume index, NT-proBNP, and kidney injury stage at diagnosis. In the levosimendan group, there were significant variations in AKI stage after 24 and 48 h. No significant differences were observed in the other parameters studied. CONCLUSION: Levosimendan showed a beneficial effect on renal function in LCOS patients after cardiac surgery that was independent from cardiac output and vascular tone. This effect is probably achieved by pharmacological postconditioning. CLINICAL TRIAL REGISTRATION: EUDRA CT, identifier 2014-001461-27. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001461-27.

Anesthesia in Combination with Propofol Increases Disease-Free Survival in Bladder Cancer Patients Who Undergo Radical Tumor Cystectomy as Compared to Inhalational Anesthetics and Opiate-Based Analgesia.

BACKGROUND: The effect of anesthetic techniques on cancer recurrence has been the subject of intensive research in the past years, as it affects a large proportion of the population. The use of opioids and halogenated agents in cancer patients during the perioperative period may be related to higher rates of cancer recurrence and reduced disease-free survival. METHODS: This was a prospective study. The sample was composed of 100 patients who underwent a radical cystectomy for infiltrating bladder cancer in a reference center. We compared disease-free survival associated with combined anesthesia versus opiate-based analgesia. The relationship between the administered hypnotic and disease-free survival was also investigated. RESULTS: The median disease-free survival of the patients who received combined anesthesia was 585 (240-1,005) days versus 210 (90-645) days in the other group. A significant difference was observed between the two groups (p = 0.01). Combined analysis of all groups revealed significant differences in disease-free survival between patients who received combined anesthesia with propofol (510 [315-1,545] disease-free days) and those who received sevoflurane and opioids (150 [90-450] disease-free days) (p = 0.02). CONCLUSIONS: Anesthesia may play a crucial role in tumor relapse, as it is administered at the moment of the greatest risk of dissemination: surgical handling of the tumor. Opioids and volatile agents have been related to an increased risk for cancer recurrence. We compared the use of propofol + local anesthesia versus sevoflurane + opioids and also found that disease-free survival was longer among patients who received propofol + local anesthesia. Disease-free survival increases with the use of propofol in combination with epidural anesthesia in patients who undergo surgery for infiltrating bladder cancer.

Anesthetic-induced Myocardial Conditioning: Molecular Fundamentals and Scope.

BACKGROUND: The pre- and post-conditioning effects of halogenated anesthetics make them most suitable for cardiac surgery. Several studies have demonstrated that the mechanism of drug-induced myocardial conditioning is enzyme-mediated via messenger RNA and miRNA regulation. The objective of this study was to investigate the role that miRNAs play in the cardioprotective effect of halogenated anesthetics. For such purpose, we reviewed the literature to determine the expression profile of miRNAs in ischemic conditioning and in the complications prevented by these phenomena. METHODS: A review was conducted of more than 100 studies to identify miRNAs involved in anesthetic-induced myocardial conditioning. Our objective was to determine the miRNAs that play a relevant role in ischemic disease, heart failure and arrhythmogenesis, which expression is modulated by the perioperative administration of halogenated anesthetics. So far, no studies have been performed to assess the role of miRNAs in anesthetic-induced myocardial conditioning. The potential of miRNAs as biomarkers and miRNAs-based therapies involving the synthesis, inhibition or stimulation of miRNAs are a promising avenue for future research in the field of cardiology. RESULTS: Each of the cardioprotective effects of myocardial conditioning is related to the expression of several (not a single) miRNAs. The cumulative evidence on the role of miRNAs in heart disease and myocardial conditioning opens new therapeutic and diagnostic opportunities. CONCLUSION: Halogenated anesthetics regulate the expression of miRNAs involved in heart conditions. Further research is needed to determine the expression profile of miRNAs after the administration of halogenated drugs. The results of these studies would contribute to the development of new hypnotics for cardiac surgery patients.

Breast Cancer and Anesthesia.

Breast cancer is a complex heterogeneous disease that is categorized into several histological and genomic subtypes with relevant prognostic and therapeutical implications. Such diversity requires a multidisciplinary approach for a comprehensive treatment that will involve surgeons, radiotherapists and medical oncologists. Breast cancer is classified as either local (or locoregional), which stands for 90-95% of cases, or metastatic, representing 5% of cases. The management of breast cancer will be determined by the stage of the disease. The treatment of local breast cancer is based on surgery and/or radiotherapy. Systemic breast cancer requires chemotherapy and/or endocrine and/or biological therapy.

Opioid Free Anaesthesia and Cancer.

Opioid-free anesthesia is revolutionizing anesthetic practices for its potential benefits in selected patients. Opioid-free anesthesia represents a step forward in anesthetic practice as it has been suggested to provide potential clinical benefits for selected patients. Opioid-free anesthesia spares the use of opioids and involves the administration of multiple adjuvant anesthetics, which may have an impact on cancer progression. All this have added to the growing interest in the immune response to anesthetics, making opioid-free anesthesia a promising avenue for future research. Assessing the role of anesthetics in immunomodulation in the surgical setting is challenging, and results are often contradictory. Indeed, there is a scarcity of data of studies on humans, which hinder the interpretation of results. However, promising evidence has been published that cancer progression can be delayed by the administration of specific anesthetic agents.

Cardioprotection with halogenated gases: how does it occur?

Numerous studies have studied the effect of halogenated agents on the myocardium, highlighting the beneficial cardiac effect of the pharmacological mechanism (preconditioning and postconditioning) when employed before and after ischemia in patients with ischemic heart disease. Anesthetic preconditioning is related to the dose-dependent signal, while the degree of protection is related to the concentration of the administered drug and the duration of the administration itself. Triggers for postconditioning and preconditioning might have numerous pathways in common; mitochondrial protection and a decrease in inflammatory mediators could be the major biochemical elements. Several pathways have been identified, including attenuation of NFκB activation and reduced expression of TNFα, IL-1, intracellular adhesion molecules, eNOS, the hypercontraction reduction that follows reperfusion, and antiapoptotic activating kinases (Akt, ERK1/2). It appears that the preconditioning and postconditioning triggers have numerous similar paths. The key biochemical elements are protection of the mitochondria and reduction in inflammatory mediators, both of which are developed in various ways. We have studied this issue, and have published several articles on cardioprotection with halogenated gases. Our results confirm greater cardioprotection through myocardial preconditioning in patients anesthetized with sevoflurane compared with propofol, with decreasing levels of troponin and N-terminal brain natriuretic peptide prohormone. The difference between our studies and previous studies lies in the use of sedation with sevoflurane in the postoperative period. The results could be related to a prolonged effect, in addition to preconditioning and postconditioning, which could enhance the cardioprotective effect of sevoflurane in the postoperative period. With this review, we aim to clarify the importance of various mechanisms involved in preconditioning and postconditioning with halogenated gases, as supported by our studies.

Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase.

PURPOSE: To evaluate if the preoperative administration of levosimendan in patients with right ventricular (RV) dysfunction, pulmonary hypertension, and high perioperative risk would improve cardiac function and would also have a protective effect on renal and neurological functions, assessed using two biomarkers neutrophil gelatinase-associated lipocalin (N-GAL) and neuronal enolase. METHODS: This is an observational study. Twenty-seven high-risk cardiac patients with RV dysfunction and pulmonary hypertension, scheduled for cardiac valve surgery, were prospectively followed after preoperative administration of levosimendan. Levosimendan was administered preoperatively on the day before surgery. All patients were considered high risk of cardiac and perioperative renal complications. Cardiac function was assessed by echocardiography, renal function by urinary N-GAL levels, and the acute kidney injury scale. Neuronal damage was assessed by neuron-specific enolase levels. RESULTS: After surgery, no significant variations were found in mean and SE levels of N-GAL (14.31 [28.34] ng/mL vs 13.41 [38.24] ng/mL), neuron-specific enolase (5.40 [0.41] ng/mL vs 4.32 [0.61] ng/mL), or mean ± SD creatinine (1.06±0.24 mg/dL vs 1.25±0.37 mg/dL at 48 hours). RV dilatation decreased from 4.23±0.7 mm to 3.45±0.6 mm and pulmonary artery pressure from 58±18 mmHg to 42±19 mmHg at 48 hours. CONCLUSION: Preoperative administration of levosimendan has shown a protective role against cardiac, renal, and neurological damage in patients with a high risk of multiple organ dysfunctions undergoing cardiac surgery.

Sevoflurane in intraoperative and postoperative cardiac surgery patients. Our experience in intensive care unit with sevoflurane sedation.

Recently, many studies have shown a decrease in myocardial damage in patients undergoing coronary artery bypass surgery where the anesthetic agent used was sevoflurane compared with propofol. The basis for this protective effect of the myocardium occurs through the mechanisms of preconditioning and postconditioning of halogenated agents. Both relate to the benefit of prior or subsequent administration of the drug (halogenated anesthetic agent) to the harmful stimulus for myocardial cells. The two mechanisms have similar effector mechanisms. The intraoperative administration of sevoflurane is common in anesthetic practice, but the continuation of the administration in the first postoperative hours is made possible by the AnaConDa ® device (ACD; Sedana Medical AB, Uppsala, Sweden) designed for halogenated sedation of patients admitted to intensive care units (ICU). This device has proven useful to facilitate the treatment of pathological conditions. The object of our review is to determine if there are beneficial effects to extending exposure to halogenated agents in the immediate post-operative period . In the post-operative phase, the pathological myocardium is in a reperfusion process in the coronary microcirculation and expression of certain receptors and chemical mediators can reduce potential injury secondary to reperfusion of previously hibernating and/or stunned tissue.

The open mesh repair of Spigelian hernia.

BACKGROUND: Spigelian hernias are rare defects of the abdominal wall usually appearing between the abdominal muscles, lateral to the rectus abdominis and through a debilitated Spigelian aponeurosis. Recently, mesh repair has been introduced for the treatment of these types of hernias and different approaches have been proposed. METHODS: Nine patients with Spigelian hernia were prospectively treated by placing a mesh prosthesis between the external oblique and the internal oblique muscles, based on principles of mesh repair established by the Lichtenstein group. RESULTS: Five women and 4 men, mean age 75.7 years, were operated on. In 1 patient the Spigelian hernia was an incidental finding during an inguinal hernia repair. Two patients were operated on an emergency basis. Elective operations were undertaken in ambulatory facilities in 3. Two patients had postoperative ecchymosis with no associated morbidity. No recurrences have been observed during follow-up. CONCLUSIONS: Open mesh repair of Spigelian hernias placing the mesh between the external and internal oblique muscles is a simple and safe approach that can prevent morbidity related to other techniques.