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JAMA Oncology Nov 2023Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed...
IMPORTANCE
Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers.
OBJECTIVE
To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers.
DESIGN, SETTING, AND PARTICIPANTS
This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts.
INTERVENTIONS
High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control).
MAIN OUTCOMES AND MEASURES
The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation.
RESULTS
Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001).
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population.
TRIAL REGISTRATION
ANZCTR Identifier: ACTRN12618000811202.
Topics: Adult; Humans; Male; Aged; Anticoagulants; Enoxaparin; Venous Thromboembolism; Hemorrhage; Thrombosis; Gastrointestinal Neoplasms; Lung; Biomarkers
PubMed: 37733336
DOI: 10.1001/jamaoncol.2023.3634 -
Science Immunology Dec 2023Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even...
Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.
Topics: Humans; Immunity, Innate; Cell Differentiation; Lung; Killer Cells, Natural; Epithelial Cells
PubMed: 38100545
DOI: 10.1126/sciimmunol.adf9988 -
Immunity Sep 2023Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its...
Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4 T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4 T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4 T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4 T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.
Topics: Animals; Humans; Mice; Arginase; CD4-Positive T-Lymphocytes; Glutamine; Influenza, Human; Kinetics; Lung; Mammals
PubMed: 37572656
DOI: 10.1016/j.immuni.2023.07.014 -
Aging Cell Oct 2023Aging is a natural process associated with declined organ function and higher susceptibility to developing chronic diseases. A systemic single-cell type-based study...
Aging is a natural process associated with declined organ function and higher susceptibility to developing chronic diseases. A systemic single-cell type-based study provides a unique opportunity to understand the mechanisms behind age-related pathologies. Here, we use single-cell gene expression analysis comparing healthy young and aged human lungs from nonsmoker donors to investigate age-related transcriptional changes. Our data suggest that aging has a heterogenous effect on lung cells, as some populations are more transcriptionally dynamic while others remain stable in aged individuals. We found that monocytes and alveolar macrophages were the most transcriptionally affected populations. These changes were related to inflammation and regulation of the immune response. Additionally, we calculated the LungAge score, which reveals the diversity of lung cell types during aging. Changes in DNA damage repair, fatty acid metabolism, and inflammation are essential for age prediction. Finally, we quantified the senescence score in aged lungs and found that the more biased cells toward senescence are immune and progenitor cells. Our study provides a comprehensive and systemic analysis of the molecular signatures of lung aging. Our LungAge signature can be used to predict molecular signatures of physiological aging and to detect common signatures of age-related lung diseases.
Topics: Humans; Aged; Aging; Lung; Inflammation; DNA Repair; Monocytes; Cellular Senescence
PubMed: 37706427
DOI: 10.1111/acel.13969 -
Signal Transduction and Targeted Therapy Aug 2023Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis...
Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis of breast cancer. Infection with pathogens such as viruses and bacteria can alter the immune status of the lung. However, the effect of chronic inflammation caused by bacteria on the formation of a premetastatic niche within the lung is unclear, and the contribution of specific immune mediators to tumor metastasis also remains largely undetermined. Here, we used a mouse model revealing that chronic pulmonary bacterial infection augmented breast cancer lung metastasis by recruiting a distinct subtype of tumor-infiltrating MHCII neutrophils into the lung, which exhibit cancer-promoting properties. Functionally, MHCII neutrophils enhanced the lung metastasis of breast cancer in a cell-intrinsic manner. Furthermore, we identified CCL2 from lung tissues as an important environmental signal to recruit and maintain MHCII neutrophils. Our findings clearly link bacterial-immune crosstalk to breast cancer lung metastasis and define MHCII neutrophils as the principal mediator between chronic infection and tumor metastasis.
Topics: Mice; Animals; Neutrophils; Persistent Infection; Lung; Lung Neoplasms; Pneumonia; Bacteria; Bacterial Infections; Tumor Microenvironment
PubMed: 37563136
DOI: 10.1038/s41392-023-01542-0 -
Nature Communications Sep 2023The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar...
The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar ultraviolet (UV) radiation is not fully understood. Here, we show a possible negative correlation between solar UVB radiation and asthmatic inflammation in humans and mice. UVB exposure to the eyes induces hypothalamus-pituitary activation and α-melanocyte-stimulating hormone (α-MSH) accumulation in the serum to suppress allergic airway inflammation by targeting group 2 innate lymphoid cells (ILC2) through the MC5R receptor in mice. The α-MSH/MC5R interaction limits ILC2 function through attenuation of JAK/STAT and NF-κB signaling. Consistently, we observe that the plasma α-MSH concentration is negatively correlated with the number and function of ILC2s in the peripheral blood mononuclear cells (PBMC) of patients with asthma. We provide insights into how solar UVB radiation-driven neuroendocrine α-MSH restricts ILC2-mediated lung inflammation and offer a possible strategy for controlling allergic diseases.
Topics: Humans; Animals; Mice; alpha-MSH; Immunity, Innate; Leukocytes, Mononuclear; Lymphocytes; Asthma; Inflammation; Lung
PubMed: 37699899
DOI: 10.1038/s41467-023-41319-1 -
American Journal of Respiratory and... Dec 2023Despite the importance of inflammation in chronic obstructive pulmonary disease (COPD), the immune cell landscape in the lung tissue of patients with mild-moderate...
Despite the importance of inflammation in chronic obstructive pulmonary disease (COPD), the immune cell landscape in the lung tissue of patients with mild-moderate disease has not been well characterized at the single-cell and molecular level. To define the immune cell landscape in lung tissue from patients with mild-moderate COPD at single-cell resolution. We performed single-cell transcriptomic, proteomic, and T-cell receptor repertoire analyses on lung tissue from patients with mild-moderate COPD ( = 5, Global Initiative for Chronic Obstructive Lung Disease I or II), emphysema without airflow obstruction ( = 5), end-stage COPD ( = 2), control ( = 6), or donors ( = 4). We validated in an independent patient cohort ( = 929) and integrated with the murine model of COPD. Mild-moderate COPD lungs have increased abundance of two CD8 T cell subpopulations: cytotoxic KLRG1TIGITCX3CR1 TEMRA (T effector memory CD45RA) cells, and DNAM-1CCR5 T resident memory (T) cells. These CD8 T cells interact with myeloid and alveolar type II cells via and have hyperexpanded T-cell receptor clonotypes. In an independent cohort, the CD8KLRG1 TEMRA cells are increased in mild-moderate COPD lung compared with control or end-stage COPD lung. Human CD8KLRG1 TEMRA cells are similar to CD8 T cells driving inflammation in an aging-related murine model of COPD. CD8 TEMRA cells are increased in mild-moderate COPD lung and may contribute to inflammation that precedes severe disease. Further study of these CD8 T cells may have therapeutic implications for preventing severe COPD.
Topics: Humans; Animals; Mice; CD8-Positive T-Lymphocytes; Disease Models, Animal; Proteomics; Lung; Pulmonary Disease, Chronic Obstructive; Inflammation; Receptors, Antigen, T-Cell
PubMed: 37756440
DOI: 10.1164/rccm.202305-0924OC -
Ugeskrift For Laeger Aug 2023In this case report, we present a 70-year-old male who was brought to our hospital with signs of upper gastrointestinal bleeding. The patient was diagnosed with aortitis...
In this case report, we present a 70-year-old male who was brought to our hospital with signs of upper gastrointestinal bleeding. The patient was diagnosed with aortitis two and a half months prior. We suspected upper gastrointestinal bleeding, and the patient was taken to the operating room for an acute endoscopy, which showed blood in the oesophagus, ventricle, and duodenum, but no bleeding source. CT angiography showed erosion of aortic aneurism, at the site of known aortitis, with bleeding into the lung and pleura. The patient was transported to the nearest university hospital for thoracic endovascular repair and survived.
Topics: Male; Humans; Aged; Hematemesis; Hemoptysis; Aortitis; Gastrointestinal Hemorrhage; Aortic Aneurysm; Hospitals, University
PubMed: 37767877
DOI: No ID Found -
Nature Communications Dec 2023Pulmonary fibrosis (PF), a condition characterized by inflammation and collagen deposition in the alveolar interstitium, causes dyspnea and fatal outcomes. Although the...
Pulmonary fibrosis (PF), a condition characterized by inflammation and collagen deposition in the alveolar interstitium, causes dyspnea and fatal outcomes. Although the bleomycin-induced PF mouse model has improved our understanding of exogenous factor-induced fibrosis, the mechanism governing endogenous factor-induced fibrosis remains unknown. Here, we find that Ifngr1Rag2 mice, which lack the critical suppression factor for group 2 innate lymphoid cells (ILC2), develop PF spontaneously. The onset phase of fibrosis includes ILC2 subpopulations with a high Il1rl1 (IL-33 receptor) expression, and fibrosis does not develop in ILC-deficient or IL-33-deficient mice. Although ILC2s are normally localized near bronchioles and blood vessels, ILC2s are increased in fibrotic areas along with IL-33 positive fibroblasts during fibrosis. Co-culture analysis shows that activated-ILC2s directly induce collagen production from fibroblasts. Furthermore, increased IL1RL1 and decreased IFNGR1 expressions are confirmed in ILC2s from individuals with idiopathic PF, highlighting the applicability of Ifngr1Rag2 mice as a mouse model for fibrosis research.
Topics: Animals; Mice; Pulmonary Fibrosis; Immunity, Innate; Interleukin-33; Lymphocytes; Fibrosis; Collagen; Lung; Mice, Inbred C57BL; Interleukin-1 Receptor-Like 1 Protein
PubMed: 38097562
DOI: 10.1038/s41467-023-43336-6 -
American Journal of Respiratory and... May 2024Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange... (Randomized Controlled Trial)
Randomized Controlled Trial
Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH ( = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).
Topics: Humans; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Male; Female; Middle Aged; Hemorrhage; Aged; Plasma Exchange; Glucocorticoids; Respiration, Artificial; Lung Diseases; Pulmonary Alveoli; Adult; Treatment Outcome
PubMed: 38346237
DOI: 10.1164/rccm.202308-1426OC