Peak oxygen consumption and long-term all-cause mortality in nonsmall cell lung cancer

Identifying strong markers of prognosis is critical to optimize treatment and survival outcomes in patients with non-small cell lung cancer (NSCLC). We investigated the prognostic significance of preoperative cardiorespiratory fitness (VO2peak) among operable candidates with NSCLC

Outcomes Following Lung Transplant for COVID-19-Related Complications in the US

IMPORTANCE: The COVID-19 pandemic led to the use of lung transplant as a lifesaving therapy for patients with irreversible lung injury. Limited information is currently available regarding the outcomes associated with this treatment modality. OBJECTIVE: To describe the outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, lung transplant recipient and donor characteristics and outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis were extracted from the US United Network for Organ Sharing database from March 2020 to August 2022 with a median (IQR) follow-up period of 186 (64-359) days in the acute respiratory distress syndrome group and 181 (40-350) days in the pulmonary fibrosis group. Overall survival was calculated using the Kaplan-Meier method. Cox proportional regression models were used to examine the association of certain variables with overall survival. EXPOSURES: Lung transplant following COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. MAIN OUTCOMES AND MEASURES: Overall survival and graft failure rates. RESULTS: Among 385 included patients undergoing lung transplant, 195 had COVID-19-related acute respiratory distress syndrome (142 male [72.8%]; median [IQR] age, 46 [38-54] years; median [IQR] allocation score, 88.3 [80.5-91.1]) and 190 had COVID-19-related pulmonary fibrosis (150 male [78.9%]; median [IQR] age, 54 [45-62]; median [IQR] allocation score, 78.5 [47.7-88.3]). There were 16 instances of acute rejection (8.7%) in the acute respiratory distress syndrome group and 15 (8.6%) in the pulmonary fibrosis group. The 1-, 6-, and 12- month overall survival rates were 0.99 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.91-0.98), and 0.88 (95% CI, 0.80-0.94) for the acute respiratory distress syndrome cohort and 0.96 (95% CI, 0.92-0.98), 0.92 (95% CI, 0.86-0.96), and 0.84 (95% CI, 0.74-0.90) for the pulmonary fibrosis cohort. Freedom from graft failure rates were 0.98 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.90-0.97), and 0.88 (95% CI, 0.79-0.93) in the 1-, 6-, and 12-month follow-up periods in the acute respiratory distress cohort and 0.96 (95% CI, 0.92-0.98), 0.93 (95% CI, 0.87-0.96), and 0.85 (95% CI, 0.74-0.91) in the pulmonary fibrosis cohort, respectively. Receiving a graft from a donor with a heavy and prolonged history of smoking was associated with worse overall survival in the acute respiratory distress syndrome cohort, whereas the characteristics associated with worse overall survival in the pulmonary fibrosis cohort included female recipient, male donor, and high recipient body mass index. CONCLUSIONS AND RELEVANCE: In this study, outcomes following lung transplant were similar in patients with irreversible respiratory failure due to COVID-19 and those with other pretransplant etiologies

Alterations of LKB1 and KRAS and risk of brain metastasis: Comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma

Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC

Differential Pathogenesis of Lung Adenocarcinoma Subtypes Involving Sequence Mutations, Copy Number, Chromosomal Instability, and Methylation

Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors.The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes.The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response

Alterations of LKB1 and KRAS and Risk of Brain Metastasis: Comprehensive Characterization by Mutation Analysis, Copy Number, and Gene Expression in Non-Small-Cell Lung Carcinoma.

BACKGROUND: Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC. MATERIALS AND METHODS: Patients treated at University of North Carolina Hospital from 1990 to 2009 with NSCLC provided frozen, surgically extracted tumors for analysis. GE was measured using Agilent 44,000 custom-designed arrays, CN was assessed by Affymetrix GeneChip Human Mapping 250K Sty Array or the Genome-Wide Human SNP Array 6.0 and gene mutation was detected using ABI sequencing. Integrated analysis was conducted to assess the relationship between these genetic markers and brain metastasis. A model was proposed for brain metastasis prediction using these genetic measurements. RESULTS: 17 of the 174 patients developed brain metastasis. LKB1 wild type tumors had significantly higher LKB1 CN (p CONCLUSION: LKB1 CN in combination with KRAS mutation predicted brain metastasis in NSCLC

Coordination of DNA copy number and gene expression among subtypes.

<p>Each point represents one of the 26 subtype-associated copy number (CN) regions, which are colored by the subtype having the greatest absolute copy number (GACN). The vertical axis is the difference in median CN between the GACN subtype and other subtypes. For the genes in each region, the differences in median expression between the GACN subtype and other subtypes were calculated and the median of these differences is the value on the horizontal axis. The association of CN difference and gene expression difference across these regions was compared by a Spearman correlation test (two-sided <i>P</i>). Two example DNA regions are circled. Region 1q21–23 had GACN in Magnoid. Hepatoma-derived growth factor (<i>HDGF</i>) was one of the most Magnoid overexpressed genes in this region. CN and gene expression for <i>HDGF</i> is displayed in which each point is one tumor (B). Region 7p22-12 had GACN in Squamoid. Fascin (<i>FSCN1</i>) was the most Squamoid overexpressed gene in this region (C). For reference, black lines in (B, C) indicate median gene expression and DNA CN. LAD tumors with copy number and expression arrays from all cohorts were used (<i>n</i> = 362).</p

: Molecular subtypes compared by gene sequence mutations.

<p>Percentages are the proportion of tumors having a mutation within a subtype, e.g. 37% of Bronchioid tumors have an <i>EGFR</i> mutation in the discovery cohorts. Corresponding numbers of patients with gene mutations are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036530#pone.0036530.s008" target="_blank">Table S5</a>. The association of subtype and mutations in the discovery cohorts were compared by Fisher's exact tests on three subtypes (two-sided <i>P</i>′). For significantly associated genes (<i>P</i>′<0.10), the subtype with the greatest mutation frequency was identified and is listed. In the validation cohort, Fisher's exact tests evaluated the null hypothesis that each gene's subtype with greatest mutation frequency had not greater mutation frequency than the other subtypes (one-sided <i>P</i>″). Benjamini-Hochberg false discovery rates (q-values) are also displayed for the discovery and validation cohort.</p