A multiparametric approach to improve the prediction of response to immunotherapy in patients with metastatic NSCLC.

BACKGROUND: It is still unclear how to combine biomarkers to identify patients who will truly benefit from anti-PD-1 agents in NSCLC. This study investigates exosomal mRNA expression of PD-L1 and IFN-γ, PD-L1 polymorphisms, tumor mutational load (TML) in circulating cell-free DNA (cfDNA) and radiomic features as possible predictive markers of response to nivolumab and pembrolizumab in metastatic NSCLC patients. METHODS: Patients were enrolled and blood (12 ml) was collected at baseline before receiving anti-PD-1 therapy. Exosome-derived mRNA and cfDNA were extracted to analyse PD-L1 and IFN-γ expression and tumor mutational load (TML) by digital droplet PCR (ddPCR) and next-generation sequencing (NGS), respectively. The PD-L1 single nucleotide polymorphisms (SNPs) c.-14-368 T > C and c.*395G > C, were analysed on genomic DNA by Real-Time PCR. A radiomic analysis was performed on the QUIBIM Precision® V3.0 platform. RESULTS: Thirty-eight patients were enrolled. High baseline IFN-γ was independently associated with shorter median PFS (5.6 months vs. not reached p = 0.0057), and levels of PD-L1 showed an increase at 3 months vs. baseline in patients who progressed (p = 0.01). PD-L1 baseline levels showed significant direct and inverse relationships with radiomic features. Radiomic features also inversely correlated with PD-L1 expression in tumor tissue. In subjects receiving nivolumab, median PFS was shorter in carriers of c.*395GG vs. c.*395GC/CC genotype (2.3 months vs. not reached, p = 0.041). Lastly, responders had higher non-synonymous mutations and more links between co-occurring genetic somatic mutations and ARID1A alterations as well. CONCLUSIONS: A combined multiparametric approach may provide a better understanding of the molecular determinants of response to immunotherapy.

Carbon Monoxide Poisoning: From Occupational Health to Emergency Medicine.

Carbon monoxide poisoning remains a leading cause of accidental poisoning worldwide (both at home and at work), and it is also a cause of suicidal poisoning. Such poisoning can arise following prolonged exposure to low levels of CO or following brief exposure to high concentrations of the gas. In fact, despite exposure limits, high safety standards, and the availability of CO alarms, nearly 50,000 people in the United States visit the emergency department each year due to poisoning. Additionally, CO poisoning in the United States causes up to 500 deaths each year. Despite the widespread nature of this form of poisoning, known about for centuries and whose damage mechanisms have been recognized (or rather hypothesized about) since the 1800s, early recognition, especially of late complications, and treatment remain a medical challenge. A well-designed therapeutic diagnostic process is necessary so that indication for hyperbaric or normobaric therapy is correctly made and so that patients are followed up even after acute exposure to diagnose late complications early. Furthermore, it is necessary to consider that in the setting of emergency medicine, CO poisoning can be part of a differential diagnosis along with other more frequent conditions, making its recognition difficult. The last thirty years have been marked by a significant increase in knowledge regarding the toxicity of CO, as well as its functioning and its importance at physiological concentrations in mammalian systems. This review, taking into account the significant progress made in recent years, aims to reconsider the pathogenicity of CO, which is not trivially just poisonous to tissues. A revision of the paradigm, especially as regards treatment and sequelae, appears necessary, and new studies should focus on this new point of view.

Acute Oncologic Complications: Clinical-Therapeutic Management in Critical Care and Emergency Departments.

Introduction. It is now known that cancer is a major public health problem; on the other hand, it is less known, or rather, often underestimated, that a significant percentage of cancer patients will experience a cancer-related emergency. These conditions, depending on the severity, may require treatment in intensive care or in the emergency departments. In addition, it is not uncommon for a tumor pathology to manifest itself directly, in the first instance, with a related emergency. The emergency unit proves to be a fundamental and central unit in the management of cancer patients. Many cancer cases are diagnosed in the first instance as a result of symptoms that lead the patient's admittance into the emergency room. Materials and Methods. This narrative review aims to analyze the impact of acute oncological cases in the emergency setting and the role of the emergency physician in their management. A search was conducted over the period January 1981-April 2023 using the main scientific platforms, including PubMed, Scopus, Medline, Embase and Google scholar, and 156 papers were analyzed. Results. To probe into the main oncological emergencies and their management in increasingly overcrowded emergency departments, we analyzed the following acute pathologies: neurological emergencies, metabolic and endocrinological emergencies, vascular emergencies, malignant effusions, neutropenic fever and anemia. Discussion/Conclusions. Our analysis found that a redefinition of the emergency department connected with the treatment of oncology patients is necessary, considering not only the treatment of the oncological disease in the strict sense, but also the comorbidities, the oncological emergencies and the palliative care setting. The need to redesign an emergency department that is able to manage acute oncological cases and end of life appears clear, especially when this turns out to be related to severe effects that cannot be managed at home with integrated home care. In conclusion, a redefinition of the paradigm appears mandatory, such as the integration between the various specialists belonging to oncological medicine and the emergency department. Therefore, our work aims to provide what can be a handbook to detect, diagnose and treat oncological emergencies, hoping for patient management in a multidisciplinary perspective, which could also lead to the regular presence of an oncologist in the emergency room.

Hypothermia: Beyond the Narrative Review-The Point of View of Emergency Physicians and Medico-Legal Considerations.

Hypothermia is a widespread condition all over the world, with a high risk of mortality in pre-hospital and in-hospital settings when it is not promptly and adequately treated. In this review, we aim to describe the main specificities of the diagnosis and treatment of hypothermia through consideration of the physiological changes that occur in hypothermic patients. Hypothermia can occur due to unfavorable environmental conditions as well as internal causes, such as pathological states that result in reduced heat production, increased heat loss or ineffectiveness of the thermal regulation system. The consequences of hypothermia affect several systems in the body-the cardiovascular system, the central and peripheral nervous systems, the respiratory system, the endocrine system and the gastrointestinal system-but also kidney function, electrolyte balance and coagulation. Once hypothermia is recognized, prompt treatment, focused on restoring body temperature and supporting vital functions, is fundamental in order to avert preventable death. It is important to also denote the fact that CPR has specificities related to the unique profile of hypothermic patients.

Emergency Department Overcrowding: Understanding the Factors to Find Corresponding Solutions.

It is certain and established that overcrowding represents one of the main problems that has been affecting global health and the functioning of the healthcare system in the last decades, and this is especially true for the emergency department (ED). Since 1980, overcrowding has been identified as one of the main factors limiting correct, timely, and efficient hospital care. The more recent COVID-19 pandemic contributed to the accentuation of this phenomenon, which was already well known and of international interest. Considering what would appear to be a trivial definition of overcrowding, it may seem simple for the reader to hypothesize solutions for what seems to be one of the most avoidable problems affecting the hospital system. However, proposing solutions to overcrowding, as well as their implementation, cannot be separated from a correct and precise definition of the issue, which must consider the main causes and aggravating factors. In light of the need of finding solutions that can put an end to hospital overcrowding, this review aims, through a review of the literature, to summarize the triggering factors, as well as the possible solutions that can be proposed.

Pathophysiology and Therapy of High-Altitude Sickness: Practical Approach in Emergency and Critical Care.

High altitude can be a hostile environment and a paradigm of how environmental factors can determine illness when human biological adaptability is exceeded. This paper aims to provide a comprehensive review of high-altitude sickness, including its epidemiology, pathophysiology, and treatments. The first section of our work defines high altitude and considers the mechanisms of adaptation to it and the associated risk factors for low adaptability. The second section discusses the main high-altitude diseases, highlighting how environmental factors can lead to the loss of homeostasis, compromising important vital functions. Early recognition of clinical symptoms is important for the establishment of the correct therapy. The third section focuses on high-altitude pulmonary edema, which is one of the main high-altitude diseases. With a deeper understanding of the pathogenesis of high-altitude diseases, as well as a reasoned approach to environmental or physical factors, we examine the main high-altitude diseases. Such an approach is critical for the effective treatment of patients in a hostile environment, or treatment in the emergency room after exposure to extreme physical or environmental factors.

Use of a natural multicomponent mouthwash plus oral hygiene vs oral hygiene alone to prevent everolimus-induced stomatitis: the STOP multicenter, randomized trial.

BACKGROUND: Stomatitis is highly prevalent in patients with cancer treated with the mammalian target of rapamycin inhibitor everolimus; it usually has an early onset and may compromise treatment dose intensity and patients' quality of life. Within the randomized controlled Stomatitis Prevention trial (STOP, ISRCTN14568888), we investigated the possibility of using a commercial natural multicomponent mouthwash (Orasol Plus®) to prevent the development of stomatitis of any grade in patients with advanced renal cell carcinoma (RCC) treated with everolimus. METHODS: Overall, 62 patients were randomized to receive either Orasol Plus in addition to oral hygiene or oral hygiene alone (31 patients per treatment arm). RESULTS: In the whole study population, 28 episodes of stomatitis were observed (41.9%); in only 2 patients, stomatitis occurred more than once (2 episodes). As expected, the episodes of stomatitis occurred early in the course of treatment with everolimus. Treatment with Orasol Plus prevented the onset of everolimus-induced stomatitis: only 8 episodes of stomatitis were observed in the treated group with Orasol Plus in addition to oral hygiene vs 20 episodes in the group treated with oral hygiene only (p = 0021). Also, a reduction in the average duration of mucositis in patients treated with Orasol Plus compared to patients treated with oral hygiene only was observed (8 days vs 11.2 days, p = 0.0416). CONCLUSION: This study showed that the use of a natural multicomponent mouthwash coupled with regular oral hygiene was able to reduce the severity and duration of everolimus-induced stomatitis in patients with RCC. TRIAL REGISTRATION NUMBER: ISRCTN14568888.

The effect of a treatment delay on outcome in metastatic renal cell carcinoma.

OBJECTIVES: To investigate if a first-line treatment delay (TD) can negatively affect the outcomes of patients affected by metastatic renal cancer. PATIENTS AND METHODS: Patients with a diagnosis of metastatic renal cancer who were ineligible for active surveillance were included in the sample. A TD was defined as the time from the diagnosis of metastatic disease to the start of first-line therapy with tyrosine kinase inhibitors. RESULTS: A total of 835 patients were assessed and 635 were included in the final analysis. The median TD was 6.3 weeks. No significant differences were found in baseline characteristics between patients experiencing a TD below/equal to or above the median value, with the exceptions being the rate of bone metastases (25.3% vs. 35.9%) and advanced disease at diagnosis (34.7% vs. 54.9%). In patients who had received a previous nephrectomy for localized disease, the TD was 5.3 compared to 8.0 weeks for those with metastatic disease at diagnosis (P = 0.001). Among this latter group, 68.7% had received a cytoreductive nephrectomy. In patients with a TD below/equal to and above the median value, the median progression-free survival was 10.3 and 11.2 months, respectively (hazard ratio = 1.03; 95% confidence intervals, 0.86-1.22; P = 0.78); the median overall survival was 27.3 and 28.2 months, respectively (hazard ratio = 1.04; 95% confidence intervals, 0.86-1.27; P = 0.68). The lack of differences was confirmed when adjusted for prognostic factors and baseline characteristics. CONCLUSIONS: This study reports that patients with bone metastases and advanced disease at diagnosis have a significant probability of experiencing delayed first-line therapy of more than 6 weeks from the time of diagnosis. However, a TD does not significantly affect outcomes and survival.