The role of neutrophils in cancer.

Introduction: It has been known for some time that neutrophils are present in the tumour microenvironment, but only recently have their roles been explored. Sources of data: Comprehensive literature search of neutrophils and cancer (PubMed, Google Scholar and CrossRef) for key articles (systematic reviews, meta-analyses, primary research). References from these articles cross-checked for additional relevant studies. Areas of agreement: Neutrophils are a heterogeneous population with both pro- and antitumour roles, and display plasticity. Several neutrophil subpopulations have been identified, defined by a combination of features (density, maturity, surface markers, morphology and anatomical site). Areas of controversy: Limitations in translating murine tumour models to human pathology and paucity of human data. Consensus in defining human neutrophil subpopulations. Growing points: Neutrophils as therapeutic targets and as possible playmakers in the biological response to newer targeted cancer drugs. Areas timely for developing research: Understanding the metabolic programming of neutrophils in the tumour microenvironment.

Early prehabilitation reduces admissions and time in hospital in patients with newly diagnosed lung cancer.

OBJECTIVES: Lung cancer is the leading cause of cancer death in the UK. Prehabilitation aims to maximise patient fitness and minimise the negative impact of anticancer treatment. What constitutes prehabilitation before non-surgical anticancer treatment is not well established. We present data from a pilot project of Early prehabilitation In lung Cancer. METHODS: All new patients with likely advanced lung cancer were offered prehabilitation at respiratory clinic, if fit for further investigation. Prehabilitation included assessment and appropriate intervention from a consultant in palliative medicine, registered dietitian and rehabilitation physiotherapist. Four objective endpoints were identified, namely admissions to hospital, time spent in the hospital, treatment rates and overall survival. Outcomes were to be compared with 178 prehab eligible historical controls diagnosed from 2019 to 2021. RESULTS: From July 2021 to June 2023, 65 patients underwent prehabilitation and 72% of patients underwent all 3 interventions. 54 patients had a stage 3 or 4 lung cancer. In the prehab group, fewer patients attended Accident and Emergency (31.5 vs 37.4 attendances per 100 patients) and fewer were admitted (51.9 vs 67.9) when compared with historical controls. Those receiving prehab spent a lot less time in the hospital (129.7 vs 543.5 days per 100 patients) with shorter admissions (2.5 vs 8 days). Systemic anticancer treatment rates increased in the short term but were broadly similar overall. Median survival was higher in the prehabilitation group (0.73 vs 0.41 years, p=0.046). CONCLUSIONS: Early prehabilitation appears to reduce time spent in the hospital. It may improve survival. Further work is required to understand its full effect on treatment rates.

Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism.

Limiting dysfunctional neutrophilic inflammation while preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks, and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labeled amino acids into metabolic enzymes, proinflammatory mediators, and granule proteins, we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycemia, characteristic of inflamed tissues, promoted this extracellular protein scavenging with activation of the lysosomal compartment, further driving exploitation of the protein-rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways that enable neutrophils to sustain synthetic and effector functions in the tissues.

-------A type I IFN, prothrombotic hyperinflammatory neutrophil signature is distinct for COVID-19 ARDS--.

Background: Acute respiratory distress syndrome (ARDS) is a severe critical condition with a high mortality that is currently in focus given that it is associated with mortality caused by coronavirus disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS and there is also accumulating evidence of neutrophil mediated lung injury in patients who succumb to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We undertook a functional proteomic and metabolomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS and non-COVID-19 ARDS to understand the molecular basis of neutrophil dysregulation. Results: Expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in ARDS, irrespective of cause. Release of neutrophil granule proteins, neutrophil activation of the clotting cascade and upregulation of the Mac-1 platelet binding complex with formation of neutrophil platelet aggregates is exaggerated in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I interferon responses is seen in ARDS following infection with SARS-CoV-2, with associated rewiring of neutrophil metabolism, and the upregulation of antigen processing and presentation. Whilst dexamethasone treatment constricts the immature low density neutrophil population, it does not impact upon prothrombotic hyperinflammatory neutrophil signatures. Conclusions: Given the crucial role of neutrophils in ARDS and the evidence of a disordered myeloid response observed in COVID-19 patients, this work maps the molecular basis for neutrophil reprogramming in the distinct clinical entities of COVID-19 and non-COVID-19 ARDS.

Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis.

Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.

Pneumomediastinum: a rare manifestation of hypersensitivity pneumonitis in a patient presenting with unexplained breathlessness at the Borders General Hospital.

A 48-year-old woman from the Scottish Borders presented to her general practitioner with exertional dyspnoea. There was a delay in diagnosis of the underlying respiratory condition, due to initial investigations being suggestive of cardiac disease. Subsequently, the patient developed clinical symptoms and signs of pneumomediastinum, which was discovered on radiological imaging. Detailed history-taking and further clinical testing confirmed the cause of this to be hypersensitivity pneumonitis due to sensitisation to pet birds. The patient was treated with high dose steroids and went on to make a good recovery. The birds were rehomed.

Acute hepatic failure following intravenous amiodarone.

A 73-year-old gentleman presented to the hospital after an episode of loss of consciousness. He had a defibrillator in situ, which on interrogation was found to have fired for an episode of ventricular fibrillation. As an inpatient he developed frequent episodes of self-terminating ventricular tachycardia, treated initially with oral amiodarone. A 24 h amiodarone infusion was started on day 3 of admission, following which the patient developed hyperventilation. Investigations revealed that this was secondary to acute hepatic and renal failure, requiring haemofiltration on the intensive care unit. Cessation of amiodarone was associated with normalisation of liver function over 48 h. The patient had normal blood and jugular venous pressures throughout days 1-4 of admission. We discuss the role of amiodarone as the predominant factor in the deterioration of this patient's liver function, versus the differential diagnosis of ischaemia-induced hepatotoxicity, citing recent research regarding this subject.