Lung adenocarcinoma promotion by air pollutants

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden

Falling in serum β human chorionic gonadotropin levels between days 1 and 7 as a new protocol to predict successful single-dose of methotrexate therapy for ectopic pregnancy

Objective: To study the patterns of serum βhCG levels on days 1–4 and days 1–7 after single-dose methotrexate injection (MTX) for ectopic pregnancy (EP) and to determine the sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the best cut-off points for the “percentage of fall” in serum βhCG levels for predicting a successful outcome. Patients and methods: This is a retrospective cohort study including forty-nine consecutive patients treated with single-dose MTX (50 mg/m2). We analyzed patterns of falling in βhCG levels on D1, D4 and D7 of follow up. Our main outcome measures included the overall success rate, the “percentage of fall” variable of serum βhCG levels on D4 and D7 and the best cut-off point for the “percentage of fall” that predicts a successful outcome. Results: The success rate of single-dose MTX treatment in EP was 77.5%. A cut-off “percentage of fall” in βhCG serum levels on D1–D7 of ⩾33% has the best sensitivity (96%) and PPV (85%) for predicting a successful outcome. This is out performing any cut-off on days 1–4 and comparable to the standard D4–D7 protocol. Conclusions: After single-dose MTX injection for EP, the use of D1 to D7 follow up protocol outperforms that of D1 to D4; with possible elimination of D4 routine βhCG blood draw. A cut-off “percentage of fall” in βhCG serum levels on D1–D7 of ⩾33% has the best sensitivity and PPV

After implementation of a lung protective ventilation strategy, what are the outcome improvement predictors in acute respiratory distress syndrome?

Aim of the study: To identify outcome improvement factors in ARDS patients managed with lung protective ventilation and defined according to the Berlin diagnostic criteria. Patients and methods: A retrospective observational study was conducted in a total of 41 ARDS patients who were diagnosed according to the Berlin ARDS criteria. Demographic, clinical, laboratory, and radiological criteria were assessed for all patients, and sputum, blood, and urine samples were obtained on the first day of hospitalization and on the day of ventilator-associated pneumonia diagnosis. In addition, fluid balance was assessed by the end of the first week of ventilation. Significant factors associated with survival improvement and predictors of mortality were identified using the bivariate analysis. ROC curves were created to evaluate the accuracy of some of the factors affecting survival. Results: In this study 25 variables were significantly correlated with mortality. The non-surviving patients had tachypnea and tachycardia; lower diastolic blood pressure, PaO2/FiO2, PO2, O2sat, and HCO3 values; and higher FiO2 and PCO2 values. Additionally, they had lower serum Na and higher K, pH, and creatinine levels. The level of CRP and GCS score were significantly lower in the non-surviving patients. However, the average fluid balance in the non-surviving patients was positive. Additionally, 4 non-surviving patients (33.3%) developed hospital-acquired pneumonia. A good general condition, indicated by a GCS score was the most accurate improvement prediction factor, then proper oxygenation. In contrast, a delay in ICU admission, increase in serum creatinine level, and a positive fluid balance were accurate predictive factors of mortality. Conclusions: Early diagnosis and ICU admission, a PaO2/FiO2 ratio maintained above 90, a GCS score above 9, a negative fluid balance, a serum creatinine level less than 1.5 mg/dl, and the prevention of HAP were factors associated with an improved outcome in ARDS

Diagnostic accuracy of nasopharyngeal swab cultures in children less than five years with chronic wet cough

Background: It is necessary to find a non-invasive and accurate procedure to predict persistent bacterial bronchitis (PBB) causative organisms and guide antibiotic therapy. The study objective was to compare the diagnostic accuracy of nasopharyngeal swab cultures with bronchoalveolar lavage (BAL) cultures in children with PBB. Methods: Nasopharyngeal swab and BAL fluid specimens were collected and cultured for bacterial pathogens prospectively from less than five-year-old children undergoing flexible bronchoscopy for chronic wet cough. Results: Of the 59 children included in the study, 26 (44.1%) patients had a positive BAL bacterial culture with neutrophilic inflammation. Prevalence of positive cultures for any of the four common respiratory pathogens implicated in PBB (Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae) was significantly higher (p = 0.001) in NP swabs compared to BAL fluids (86.4% and 44.1% of PBB cases, respectively). NP swab cultures for any of the four main bacterial pathogens had 85% (95% CI: 65–96%) and 48% (95% CI: 31–66%) sensitivity and specificity of detecting PBB, respectively. Positive and negative predictive values were 56% (95% CI: 47–65%) and 80% (95% CI: 60–91%), respectively. In conclusion, in children less than 5 years of age with chronic wet cough (PBB-clinical), a negative NP swab result reduces the likelihood of lower airway infection; however, a positive NP swab does not accurately predict the presence of lower airway pathogens. Flexible bronchoscopy should be considered in those with recurrent PBB-clinical or with clinical pointers of central airway anomalies. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Prediction of acute myeloid leukaemia risk in healthy individuals

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure 1 . The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion 2,3 . However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH) 4-8 . Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention. © 2018 Macmillan Publishers Ltd., part of Springer Nature

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes