Characterization of pneumonia and other factors leading to poorer survival across all age groups in patients with non-small cell lung cancer (NSCLC).

BACKGROUND: Lung cancer death rates and incidence in both men and women have decreased over the past two decades. However, certain subsets of non-small cell lung cancer (NSCLC) have arisen with poor outcomes. Identifying factors which contribute to poorer outcomes as well as those that inform early detection strategies remain unmet needs. We present data from a contemporaneous group of NSCLC patients that received care at a single University teaching hospital to understand clinical and pathological factors influencing outcomes in the past decade. METHODS: A cohort of 2,289 patients with NSCLC who established care at the Rogel Cancer Center, University of Michigan between January 2011 and April 2019 were identified. Patient characteristics and clinical outcomes were recorded using electronic health records. The Kaplan-Meier method and the Cox proportional model were used to assess relationship between clinic-pathological factors and survival. RESULTS: Of the 2,289 patients, 92% were >50 years of age while 8% were <50 years of age. The majority (70%) of older patients were former smokers. The majority (61%) of younger patients were diagnosed as having Stage IV NSCLC. Among younger patients, 87% had histologically confirmed non-squamous histology. Univariate analysis revealed that overall survival was significantly lower in patients diagnosed with pneumonia prior to the diagnosis of NSCLC than in those who were not diagnosed with pneumonia (1.9 vs. 21.8 months; P<0.001). Multivariate analysis revealed that older patients had poorer survival than younger patients (HR 1.57, 95% CI: 1.10-2.06, P=0.01) and that patients diagnosed with pneumonia prior to their lung cancer diagnosis had poorer survival across all age groups, particularly in those with advanced-stage disease. CONCLUSIONS: Findings from this study merit prospective studies to understand cost-benefit ratio of follow- up cross sectional imaging of all patients diagnosed with unprovoked pneumonia, including in younger non/current smokers.

Cyclin-dependent kinase inhibitors for the treatment of lung cancer.

INTRODUCTION: Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression in both normal and malignant cells, functioning through complex molecular interactions. Deregulation of CDK-dependent pathways is commonly found in both non-small cell and small cell lung cancer, and these derangements suggest vulnerabilities that can be exploited for clinical benefit. AREAS COVERED: In this review, the authors present an overview of the biology of CDKs in normal and malignant cells, with a focus on lung cancer, followed by an assessment of preclinical work that has demonstrated the vital role of CDKs in lung cancer development and progression, and the activity of CDK inhibitors in a variety of lung cancer models. Finally, the experience with clinical trials of CDK inhibitors in lung cancer is discussed along with the current status of these agents in cancer therapy. EXPERT OPINION: Despite strong biological rationale and promising preclinical studies, the results of clinical trials of CDK inhibitors in lung cancer have thus far been disappointing. Further clinical development of CDK inhibitors in lung cancer will depend on the identification of predictive biomarkers and the design of combination regimens that take advantage of the unique molecular alterations that drive lung cancer growth and survival.

Hyperoxia-induced premature senescence requires p53 and pRb, but not mitochondrial matrix ROS.

Senescence is a potential tumor-suppressing mechanism and a commonly used model of cellular aging. One current hypothesis to explain senescence, based in part on the correlation of oxygen with senescence, postulates that it is caused by oxidative damage from reactive oxygen species (ROS). Here, we further test this theory by determining the mechanisms of hyperoxia-induced senescence. Exposure to 70% O(2) led to stress-induced, telomere-independent senescence. Although hyperoxia elevated mitochondrial ROS production, overexpression of antioxidant proteins was not sufficient to prevent hyperoxia-induced senescence. Hyperoxia activated AMPK; however, overexpression of a kinase-dead mutant of LKB1, which prevented AMPK activation, did not prevent hyperoxia-induced senescence. Knocking down p21 via shRNA, or suppression of the p16/pRb pathway by either BMI1 or HPV16-E7 overexpression, was also insufficient to prevent hyperoxia-induced senescence. However, suppressing p53 function resulted in partial rescue from senescence, suggesting that hyperoxia-induced senescence involves p53. Suppressing both the p53 and pRb pathways resulted in almost complete protection, indicating that both pathways cooperate in hyperoxia-induced senescence. Collectively, these results indicate a ROS-independent but p53/pRb-dependent senescence mechanism during hyperoxia.

Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors.

Mutations of the human type Ialpha regulatory subunit (RIalpha) of cyclic AMP-dependent protein kinase (PKA; PRKAR1A) lead to altered kinase activity, primary pigmented nodular adrenocortical disease, and tumors of the thyroid and other tissues. To bypass the early embryonic lethality of Prkar1a(-/-) mice, we established transgenic mice carrying an antisense transgene for Prkar1a exon 2 (X2AS) under the control of a tetracycline-responsive promoter. Down-regulation of Prkar1a by up to 70% was achieved in transgenic mouse tissues and embryonic fibroblasts, with concomitant changes in kinase activity and increased cell proliferation, respectively. Mice developed thyroid follicular hyperplasia and adenomas, adrenocortical hyperplasia, and other features reminiscent of primary pigmented nodular adrenocortical disease, histiocytic and epithelial hyperplasias, lymphomas, and other mesenchymal tumors. These were associated with allelic losses of the mouse chromosome 11 Prkar1a locus, an increase in total type II PKA activity, and higher RIIbeta protein levels. This mouse provides a novel, useful tool for the investigation of cyclic AMP, RIalpha, and PKA functions and confirms the critical role of Prkar1a in tumorigenesis in endocrine and other tissues.