Faculty Bibliography

Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.

OBJECTIVES/OBJECTIVE:Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy. MATERIALS AND METHODS/METHODS:Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy. RESULTS:). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p < 0.001), and a moderate correlation between tumor volume and serum fibulin-3 levels (r = 0.36, p = 0.014). Twenty-eight patients in the immunotherapy trial had longitudinal serologic and radiographic data. Fold-changes in SMRP and fibulin-3 did not show significant correlations with modified RECIST measurements. CONCLUSIONS:Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally.

Information on outcomes of COVID-19 in pulmonary arterial hypertension (PAH) patients is limited to a few case series and surveys. Here, we describe our experience at a large Pulmonary Hypertension Center in New York City at the height of the pandemic. We performed a retrospective chart review of eleven consecutive PAH patients who were diagnosed with SARS-CoV-2 infection. We analyzed demographics, PAH severity, risk factors for COVID-19, and COVID-19 severity and outcomes. We found in our sample that 63.6% of patients required intensive care, and there was a 45.45% overall mortality. Most patients had a known COVID-19 contact and mean duration of symptoms prior to presentation was 12 days. Only 4/11 (36%) patients presented to a center with pulmonary hypertension expertise, all of whom survived. Most patients had at least moderate pulmonary hypertension with an average REVEAL score of 7.81 despite double or triple PAH therapy. Our cases series underscores the gravity of SARS-CoV-2 infection in patients with PAH. It also suggests possible interventions to prevent unfavorable outcomes such as preserving social distancing, PAH management optimization, and early and preferential presentation to a center with specialized expertise in PAH.

In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in group IIIB-IV TNM stage lung cancer and is associated with poor prognosis, as shown by decreased survival among subjects with early stage disease (I-IIIA) and worse tumor progression as measured by RECIST scores among subjects with IIIB-IV stage disease. In addition, this lower airway microbiota signature was associated with upregulation of IL-17, PI3K, MAPK and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL-17 inflammatory phenotype and activation of checkpoint inhibitor markers.

INTRODUCTION/BACKGROUND:Recent evidence suggests that patients with malignant pleural mesothelioma (MPM) undergoing extended pleurectomy/decortication (eP/D) with metastasis to the posterior intercostal lymph nodes (PILN) have a worse prognosis. In this study, we determine if MPM PILN metastasis can be reliably detected on computed tomography (CT). MATERIALS AND METHODS/METHODS:Preoperative staging CT exams were reviewed for the presence of PILN in MPM patients undergoing eP/D between 2007-2013 with surgical sampling of their PILN. CT images were reviewed by two thoracic radiologists blinded to clinical records, including operative pathology reports. The number and short axis size of PILN were recorded and correlated with surgical pathology. Statistical analysis examined the value of preoperative CT to detect metastatic PILN. RESULTS:Of 36 patients that underwent eP/D with PILN sampling had preoperative CT images for review. At surgery, 22 of these patients had metastatic PILN and 14 had benign PILN. The positive and negative predictive values for one or more nodes seen on preoperative CT were 60 % and 38 % respectively. The number of PILN on preoperative CT did not predict metastasis (p = 0.40) with an average of 2 PILN seen, regardless of PILN pathology. The average nodal short axis size was 4.6 mm and 4.8 mm for benign and malignant PILN, respectively, and PILN short axis size did not predict metastasis (p = 0.39). There was little inter-observer variability between the size and number of nodes detected by each radiologist. CONCLUSIONS:CT does not reliably identify metastatic PILN on preoperative CT for patients with MPM undergoing extended pleurectomy/decortication.

To determine the impact of tocilizumab, a monoclonal antibody against the interleukin 6 receptor, on survival in patients with coronavirus disease 2019.

Treatment of mesothelioma is evolving, with recent randomised trial data supporting the addition of bevacizumab to pemetrexed and cisplatin therapy. Single-agent immune checkpoint inhibitors have failed to demonstrate survival benefits in randomised trials; however, using a combination of programmed death receptor/ligand 1 (PD-(L)1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonists may be more effective. Use of immunotherapy agents in the front-line setting may also yield better results. Other immunotherapeutic approaches, such as oncolytic viruses and chimeric antigen receptor (CAR) T-cells, are progressing closer to evaluation in full-scale clinical trials, as are targeted agents, particularly those focussed on mesothelin. Arginine deprivation may be effective in patients with poor prognosis, non-epithelioid tumours. It is likely that the next decade will yield substantial progress, and the future of mesothelioma treatment looks more hopeful than it has for decades.
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To explore demographics, comorbidities, transfers, and mortality in critically ill patients with confirmed severe acute respiratory syndrome coronavirus 2.

BACKGROUND:Emphysema in asymptomatic heavy smokers can be detected during CT-scan screening for lung cancer. Metalloproteinases (MMPs) have been found to play a role in the pathogenesis of chronic obstructive pulmonary disease and to possibly serve as biomarkers for emphysema. METHODS:The NYU Lung Cancer Biomarker Center enrolled study subjects over 50 years of age with lung cancer risk factors from January 1, 2010, to December 31, 2015. These subjects received chest multi-detector computed tomography, spirometry, and provided serum for immunoassays for metalloproteinases (MMP) -1, -2, -7, -9, -10 and tissue inhibitor of metalloproteinases (TIMP) -1 and -2. RESULTS:/FVC percent compared to smokers without emphysema (68 ± 11 (mean ± sd) versus 75 ± 8; p < 0.0001). Increased age and pack-years of smoking were associated with increased odds of emphysema. None of the metalloproteinases or tissue inhibitors of metalloproteinases were useful to predict the presence of emphysema in smokers. CONCLUSION/CONCLUSIONS:/FVC ratio).