CT Scan Screening for Lung Cancer: Risk Factors for Nodules and Malignancy in a High-Risk Urban Cohort

Low-dose computed tomography (CT) for lung cancer screening can reduce lung cancer mortality. The National Lung Screening Trial reported a 20% reduction in lung cancer mortality in high-risk smokers. However, CT scanning is extremely sensitive and detects non-calcified nodules (NCNs) in 24-50% of subjects, suggesting an unacceptably high false-positive rate. We hypothesized that by reviewing demographic, clinical and nodule characteristics, we could identify risk factors associated with the presence of nodules on screening CT, and with the probability that a NCN was malignant.We performed a longitudinal lung cancer biomarker discovery trial (NYU LCBC) that included low-dose CT-screening of high-risk individuals over 50 years of age, with more than 20 pack-year smoking histories, living in an urban setting, and with a potential for asbestos exposure. We used case-control studies to identify risk factors associated with the presence of nodules (n=625) versus no nodules (n=557), and lung cancer patients (n=30) versus benign nodules (n=128).The NYU LCBC followed 1182 study subjects prospectively over a 10-year period. We found 52% to have NCNs >4 mm on their baseline screen. Most of the nodules were stable, and 9.7% of solid and 26.2% of sub-solid nodules resolved. We diagnosed 30 lung cancers, 26 stage I. Three patients had synchronous primary lung cancers or multifocal disease. Thus, there were 33 lung cancers: 10 incident, and 23 prevalent. A sub-group of the prevalent group were stable for a prolonged period prior to diagnosis. These were all stage I at diagnosis and 12/13 were adenocarcinomas.NCNs are common among CT-screened high-risk subjects and can often be managed conservatively. Risk factors for malignancy included increasing age, size and number of nodules, reduced FEV1 and FVC, and increased pack-years smoking. A sub-group of screen-detected cancers are slow-growing and may contribute to over-diagnosis and lead-time biases

Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial

Background Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. Methods This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3–5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. Discussion In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. Trial registration ClinicalTrials.gov NCT04397718. Registered on May 21, 202

Molecular Characterization of the Peripheral Airway Field of Cancerization in Lung Adenocarcinoma

<div><p><i>Field of cancerization</i> in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR <0.1) up-regulated and 38 mRNAs and 12 miRNAs that were significantly down-regulated in the cancer patients when compared to smoker controls. Functional analysis identified differential transcriptomic expressions related to tumorigenesis. Integration of miRNA-mRNA data into interaction network analysis showed modulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the contralateral lung field of cancerization. In conclusion, patients with lung adenocarcinoma have tumor related molecules and pathways in histologically normal appearing peripheral airway epithelial cells, a substantial distance from the tumor itself. This finding can potentially provide new biomarkers for early detection of lung cancer and novel therapeutic targets.</p></div

ERK/MAPK Signaling Pathway.

<p>IPA was used to generate a network of molecules from mRNA and miRNA that were significantly different in peripheral airway field of cancerization in lung cancer patients compared to smoker controls. This composite network merge three top networks based on “network score,” which converges on the ERK/MAPk pathway: specifically merging on Extracellular signal-related kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases (JNKs), and p38 kinases subfamily. <b>Red</b> is up-regulated and <b>Green</b> is down-regulated.</p

Correlation between miR-374a and ASCL1.

<p>Quantitative RT-PCR for miR-374a and ASCL1 were performed in each individual’s peripheral airway epithelial cells (n = 17 cancer patient and n = 13 smoker controls) to confirm miRNA-mRNA negative correlation in the array. We confirm that ASCL1 expression was negatively correlated with miRNA-374a expression in peripheral airway epithelial cells (Pearson’s = -0.56, p = 0.013).</p

Top 30 Gene expressions in the peripheral airway epithelial cells.

<p><b>A)</b> Using Affymetrix Gene Chip HG U133 Plus 2.0, Top 30 differentiated mRNAs in peripheral airway field of cancerization of cancer patients <b>(black bar)</b> vs. peripheral airways of smoker controls <b>(gray bar)</b> are shown. 13 mRNAs were strongly up-regulated and 17 mRNAs were strongly down-regulated in peripheral airway field of cancerization. Gene expression fold change is shown as the mean expression relative to a reference value. Table below shows FDR value base on Benjamini-Hochberg multiple testing and log2 fold change value of cancer patient relative to smoker control. <b>B)</b> Individual dot plot of cancer patients (n = 17) compared to smoker controls (n = 13) with <b>up-regulated</b> mRNAs. <b>C)</b> Individual dot plot with <b>down-regulated</b> mRNAs.</p

MicroRNA expression in the peripheral airway epithelial cells.

<p><b>A)</b> Using TaqMan miRNA Array, 5 miRNAs were highly (FDR <0.1) up-regulated in peripheral airway field of cancerization of cancer patients <b>(black bar)</b> vs. peripheral airways of smoker controls <b>(gray bar).</b> 12 miRNAs (FDR<0.1) were strongly down-regulated. MiRNA fold change is shown as the mean expression relative to a reference value. Table below shows FDR value base on Benjamini-Hochberg multiple testing and log2 fold change value of cancer patient relative to smoker control. <b>B)</b> Individual dot plot of cancer patients (n = 17) compared to peripheral airways of smoker controls (n = 13) with <b>up-regulated</b> miRNAs. <b>C)</b> Individual dot plot with <b>down-regulated</b> miRNAs.</p

Demographic & clinical characteristics.

<p><i>Definition of abbreviations</i>: <i>Adeno Ca = adenocarcinoma</i></p><p>Mean and standard deviation (SD) were calculated.</p><p>^†p-values calculated using Student's t-test or Fisher exact test.</p><p>^‡Missing pack-years for 1 subject</p><p>Demographic & clinical characteristics.</p