Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma.

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.

Pathomic Features Reveal Immune and Molecular Evolution From Lung Preneoplasia to Invasive Adenocarcinoma.

Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials from ADC precursors. Here, we employed state-of-the-art deep learning and artificial intelligence techniques to robustly segment and recognize cells on routinely used hematoxylin and eosin histopathology images and extracted 9 biology-relevant pathomic features to decode lung preneoplasia evolution. We analyzed 3 distinct cohorts (Japan, China, and United States) covering 98 patients, 162 slides, and 669 regions of interest, including 143 normal, 129 atypical adenomatous hyperplasia, 94 AIS, 98 MIA, and 205 ADC. Extracted pathomic features revealed progressive increase of atypical epithelial cells and progressive decrease of lymphocytic cells from normal to AAH, AIS, MIA, and ADC, consistent with the results from tissue-consuming and expensive molecular/immune profiling. Furthermore, pathomics analysis manifested progressively increasing cellular intratumor heterogeneity along with the evolution from normal lung to invasive ADC. These findings demonstrated the feasibility and substantial potential of pathomics in studying lung cancer carcinogenesis directly from the low-cost routine hematoxylin and eosin staining.

Role of small airway dysfunction in unexplained exertional dyspnoea.

Background: Isolated small airway abnormalities may be demonstrable at rest in patients with normal spirometry; however, the relationship of these abnormalities to exertional symptoms remains uncertain. This study uses an augmented cardiopulmonary exercise test (CPET) to include evaluation of small airway function during and following exercise to unmask abnormalities not evident with standard testing in individuals with dyspnoea and normal spirometry. Methods: Three groups of subjects were studied: 1) World Trade Center (WTC) dust exposure (n=20); 2) Clinical Referral (n=15); and Control (n=13). Baseline evaluation included respiratory oscillometry. Airway function during an incremental workload CPET was assessed by: 1) tidal flow versus volume curves during exercise to assess for dynamic hyperinflation and expiratory flow limitation; and 2) post-exercise spirometry and oscillometry to evaluate for airway hyperreactivity. Results: All subjects demonstrated normal baseline forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). Dyspnoea was reproduced during CPET in WTC and Clinical Referral groups versus Control without abnormality in respiratory pattern and minute ventilation. Tidal flow-volume curves uncovered expiratory flow limitation and/or dynamic hyperinflation with increased prevalence in WTC and Clinical Referral versus Control (55%, 87% versus 15%; p<0.001). Post-exercise oscillometry uncovered small airway hyperreactivity with increased prevalence in WTC and Clinical Referral versus Control (40%, 47% versus 0%, p<0.05). Conclusions: We uncovered mechanisms for exertional dyspnoea in subject with normal spirometry that was attributable to either small airway dysfunction during exercise and/or small airway hyperreactivity following exercise. The similarity of findings in WTC environmentally exposed and clinically referred cohorts suggests broad relevance for these evaluations.

Pleural fluid microbiota as a biomarker for malignancy and prognosis.

Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk.

BACKGROUND: Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven. OBJECTIVES: The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure. METHODS: A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit. RESULTS: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), P = 0.005] without increasing the risk of infection. CONCLUSION AND RELEVANCE: Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.

Microbial signatures in the lower airways of mechanically ventilated COVID-19 patients associated with poor clinical outcome.

Respiratory failure is associated with increased mortality in COVID-19 patients. There are no validated lower airway biomarkers to predict clinical outcome. We investigated whether bacterial respiratory infections were associated with poor clinical outcome of COVID-19 in a prospective, observational cohort of 589 critically ill adults, all of whom required mechanical ventilation. For a subset of 142 patients who underwent bronchoscopy, we quantified SARS-CoV-2 viral load, analysed the lower respiratory tract microbiome using metagenomics and metatranscriptomics and profiled the host immune response. Acquisition of a hospital-acquired respiratory pathogen was not associated with fatal outcome. Poor clinical outcome was associated with lower airway enrichment with an oral commensal (Mycoplasma salivarium). Increased SARS-CoV-2 abundance, low anti-SARS-CoV-2 antibody response and a distinct host transcriptome profile of the lower airways were most predictive of mortality. Our data provide evidence that secondary respiratory infections do not drive mortality in COVID-19 and clinical management strategies should prioritize reducing viral replication and maximizing host responses to SARS-CoV-2.

Lung Cancer Characteristics in the World Trade Center Environmental Health Center.

The destruction of the World Trade Center (WTC) towers on 11 September 2001 resulted in acute and chronic dust and fume exposures to community members, including local workers and residents, with well-described aerodigestive adverse health effects. This study aimed to characterize lung cancer in the WTC Environmental Health Center (WTC EHC) focusing on gender and smoking history. WTC EHC patients undergo an initial evaluation that includes WTC exposure information, demographics, and tobacco use. Detailed cancer characteristics are recorded from pathology reports. As of 31 December 2019, 248 WTC EHC patients had a diagnosis of lung cancer. More patients with lung cancer were women (57%) compared to men (43%). Many cases (47% women, 51% men) reported acute dust cloud exposure. Thirty-seven percent of lung cancer cases with available smoking history were never-smokers (≤1 pack-years) and 42% had a ≤5 pack-year history. The median age of cancer diagnosis in never-smoking women was 61 years compared to 66 years in men. Adenocarcinoma was more common in never-smokers compared to ever-smokers (72% vs. 65%) and in women compared to men (70% vs. 65%). We provide an initial description of lung cancers in local community members with documented exposure to the WTC dust and fumes.

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome.

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.

Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial.

OBJECTIVES: 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: 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: A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). 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.

Lower Airway Dysbiosis Affects Lung Cancer Progression.

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 the stage IIIB-IV tumor-node-metastasis lung cancer group 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 stage IIIB-IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, 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, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers. SIGNIFICANCE: Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.See related commentary by Zitvogel and Kroemer, p. 224.This article is highlighted in the In This Issue feature, p. 211.

A Propensity-Matched Cohort Study of Tocilizumab in Patients With Coronavirus Disease 2019.

To determine the impact of tocilizumab, a monoclonal antibody against the interleukin 6 receptor, on survival in patients with coronavirus disease 2019. DESIGN: Observational cohort study of patients hospitalized with coronavirus disease 2019 between March 1, 2020, and April 24, 2020. A propensity-matched (1:1) analysis was used to compare patients who received tocilizumab to controls who did not. Competing risk survival analysis was used to determine the primary outcome of time to mortality, and adjusted log-linear and logistic regression for secondary outcomes. SETTING: Three hospitals within the NYU Langone Health system in New York. PATIENTS: Consecutive adult patients hospitalized with coronavirus disease 2019. INTERVENTION: Tocilizumab 400-mg IV once in addition to standard of care or standard of care alone. MEASUREMENTS AND MAIN RESULTS: Data from 3,580 severe acute respiratory syndrome coronavirus 2 positive qualifying hospitalized patients were included, of whom 497 (13.9%) were treated with tocilizumab. In the analysis of tocilizumab-treated patients and matched controls, fewer tocilizumab-treated patients died (145/497, 29.2%) than did controls (211/497, 42.4%). In the adjusted competing risk regression model, tocilizumab therapy was associated with improved survival relative to controls (hazard ratio = 0.24, 95% CI = 0.18-0.33, p < 0.001). Tocilizumab-treated patients and controls had similar adjusted time to discharge from hospital (hazard ratio = 0.96, 95% CI = 0.78-1.17, p = 0.67). However, they had longer adjusted ICU length of stay (rate ratio = 3.1, 95% CI = 2.5-3.7, p < 0.001) and a higher adjusted infection rate (odds ratio = 4.18, 95% CI = 2.72-6.52, p < 0.001) than controls. CONCLUSIONS: Tocilizumab therapy was associated with significantly improved survival in coronavirus disease 2019 patients. This survival benefit was associated with increased ICU length of stay and increased infection rate, even as more patients in the tocilizumab group were rescued from rapid death. A prospective, randomized, placebo-controlled trial is needed to confirm these findings.

Value of metalloproteinases in predicting COPD in heavy urban smokers.

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: Three hundred sixteen study subjects were enrolled. Of the 222 patients who met the inclusion criteria, 46% had emphysema. Smokers with emphysema had increased pack-years of smoking compared to smokers without emphysema (51 ± 24 pack-years (mean ± sd) versus 37 ± 20; p < 0.0001). Smokers with emphysema also had lower FEV1/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: Emphysema was detected by CT in almost half of heavy urban smokers. Serum MMP levels provided minimal additional information to improve the detection of mild emphysema among smokers given their clinical characteristics (age, pack-years, and FEV1/FVC ratio).

Clinical Outcomes in Critically Ill Coronavirus Disease 2019 Patients: A Unique New York City Public Hospital Experience.

To explore demographics, comorbidities, transfers, and mortality in critically ill patients with confirmed severe acute respiratory syndrome coronavirus 2. DESIGN: Retrospective cohort study. SETTING: Data were collected from a large tertiary care public hospital ICU that is part of the largest public healthcare network in the United States. PATIENTS: One-hundred thirty-seven adult (≥ 18 yr old) ICU patients admitted between March 10, 2020, and April 7, 2020, with follow-up collected through May 18, 2020. INTERVENTIONS: None. MEASUREMENTS: Demographic, clinical, laboratory, treatment, and outcome data extracted from electronic medical records. MAIN RESULTS: The majority of patients were male (99/137; 72.3%) and older than 50 years old (108/137; 78.9%). The most reported ethnicity and race were Hispanic (61/137; 44.5%) and Black (23/137; 16.7%). One-hundred six of 137 patients had at least one comorbidity (77.4%). One-hundred twenty-one of 137 (78.1%) required mechanical ventilation of whom 30 (24.8%) moved to tracheostomy and 46 of 137 (33.6%) required new onset renal replacement therapy. Eighty-two of 137 patients (59.9%) died after a median of 8 days (interquartile range 5-15 d) in the ICU. Male sex had a trend toward a higher hazard of death (hazard ratio, 2.1 [1.1-4.0]) in the multivariable Cox model. CONCLUSIONS: We report a mortality rate of 59.9% in a predominantly Hispanic and Black patient population. A significant association between comorbidities and mortality was not found in multivariable regression, and further research is needed to study factors that impact mortality in critical coronavirus disease 2019 patients. We also describe how a public hospital developed innovative approaches to safely manage a large volume of interhospital transfers and admitted patients.

Management of Indwelling Tunneled Pleural Catheters: A Modified Delphi Consensus Statement.

BACKGROUND: The management of recurrent pleural effusions remains a challenging issue for clinicians. Advances in management have led to increased use of indwelling tunneled pleural catheters (IPC) because of their effectiveness and ease of outpatient placement. However, with the increase in IPC placement there have also been increasing reports of complications, including infections. Currently there is minimal guidance in IPC-related management issues after placement. RESEARCH QUESTION: Our objective was to formulate clinical consensus statements related to perioperative and long-term IPC catheter management based on a modified Delphi process from experts in pleural disease management. STUDY DESIGN AND METHODS: Expert panel members used a modified Delphi process to reach consensus on common perioperative and long-term management options related to IPC use. Members were identified from multiple countries, specialties, and practice settings. A series of meetings and anonymous online surveys were completed. Responses were used to formulate consensus statements among panel experts, using a modified Delphi process. Consensus was defined a priori as greater than 80% agreement among panel constituents. RESULTS: A total of 25 physicians participated in this project. The following topics were addressed during the process: definition of an IPC infection, management of IPC-related infectious complications, interventions to prevent IPC infections, IPC-related obstruction/malfunction management, assessment of IPC removal, and instructions regarding IPC management by patients and caregivers. Strong consensus was obtained on 36 statements. No consensus was obtained on 29 statements. INTERPRETATION: The management of recurrent pleural disease with IPC remains complex and challenging. This statement offers statements for care in numerous areas related to IPC management based on expert consensus and identifies areas that lack consensus. Further studies related to long-term management of IPC are warranted.

Emerging Treatments for Malignant Pleural Mesothelioma: Where Are We Heading?

Malignant pleural mesothelioma (MPM) is an uncommon but aggressive and treatment resistant neoplasm with low survival rates. In the last years we assisted to an exponential growth in the appreciation of mesothelioma pathobiology, leading several new treatments to be investigated both in the early stage of the disease and in the advanced setting. In particular, expectations are now high that immunotherapy will have a leading role in the next years. However, caution is required as results from phase II studies in MPM were often not replicated in larger, randomized, phase III trials. In this review, we describe the most promising emerging therapies for the treatment of MPM, discussing the biological rationale underlying their development as well as the issues surrounding clinical trial design and proper selection of patients for every treatment.

Malignant Mesothelioma: Has Anything Changed?

Malignant pleural mesothelioma is a rare cancer associated with asbestos exposure and portends a dismal prognosis. Its worldwide incidence has been increasing, and treatment options are currently suboptimal and noncurative. However, since the turn of the century, several encouraging steps have been made toward improving outcomes for mesothelioma patients. An increased understanding of disease pathophysiology has led to more accurate diagnosis and staging, and the establishment of the standard of care first-line pemetrexed/platin doublet chemotherapy regimen in 2003 initially revolutionized treatment. While significant debate remains regarding the preferred approach to surgical and radiation therapy in the context of multimodal therapy, recent breakthroughs in immunotherapy offer hope for another paradigm shift in the near future. This review will summarize the current clinical approach to diagnosis, staging, and treatment of malignant pleural mesothelioma.

Tumor-draining lymph nodes demonstrate a suppressive immunophenotype in patients with non-small cell lung cancer assessed by endobronchial ultrasound-guided transbronchial needle aspiration: A pilot study.

OBJECTIVES: Tumor draining lymph nodes (TDLN) are key sites of early immunoediting in patients with non-small cell lung cancer (NSCLC) and play an important role in generating anti-tumor immunity. Immune suppression in the tumor microenvironment has prognostic implications and may predict therapeutic response. T cell composition of draining lymph nodes may reflect an immunophenotype with similar prognostic potential which could be measured during standard-of-care bronchoscopic assessment. In this study, we compared the immunophenotype from different sites within individuals to primary tumor characteristics in patients with NSCLC to see whether there were tumor-regional differences in immunophenotype which could be evaluated from transbronchial needle aspirates. MATERIALS AND METHODS: Twenty patients were enrolled in this study and had tissue (lymph node aspirates and/or peripheral blood) obtained during standard of care bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis or staging of known or suspected NSCLC. Aspirates and blood underwent flow-assisted cell sorting and a subset of sorted effector T cells underwent RNA quantitation to determine feasibility of this approach. Immunophenotypic patterns from twelve patients with paired data from tumor-draining and non-tumor draining lymph nodes (NDLN) were compared relative to one another and based on PD-L1 immunohistochemistry and primary tumor histology. RESULTS: TDLN had significantly fewer CD4+ T cells (12.68% vs 27%, p = 0.002) and significantly more regulatory T cells (Treg, 12.03% vs 9.52%, p = 0.03) relative to paired NDLN suggesting tumor-regional immunosuppression. There were significantly more Treg in NDLN relative to paired PBMC (9.52% vs 5.6%, p = 0.016). Patients with PD-L1 expression ≥50% had significantly greater tumor-regional CD4+ T cell depletion compared to patients with PD-L1 expression <50% (-35.98% vs -1.89%, p = 0.0357; negative values represent absolute difference between paired TDLN and NDLN). CONCLUSIONS: In patients with NSCLC, TDLN have a suppressive immunophenotype correlating with tumor PD-L1 status and can be assessed during routine EBUS-TBNA.

First-ever Abscopal Effect after Palliative Radiotherapy and Immuno-gene Therapy for Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly aggressive disease, with few, if any, curative interventions. While there is growing interest in using immunotherapy and immuno-gene therapy to treat MPM, very limited data currently exist for combining these modalities with radiotherapy. Preclinical data suggest that radiotherapy may be combined with immunotherapy to produce disease regression, with abscopal effects in mice with MPM. We report the first-ever case of abscopal effect in a patient with MPM, following radiotherapy and immuno-gene therapy. The patient was a 67-year-old male with prior asbestos exposure who presented with progressive dyspnea and thoracic pain. He underwent partial right pleurectomy, pleural biopsy, and talc pleurodesis, with pathology revealing epithelioid MPM. A subsequent chest computed tomography (CT) scan and fluoro-deoxyglucose positron-emission tomography (FDG-PET) CT scan showed extensive, right-sided, fluoro-deoxyglucose (FDG) avid mass-like pleural thickening encasing the right lung, with likely mediastinal extension, nodal metastases, and vascular compression. He enrolled in a clinical trial in which he received intrapleural interferon-alpha gene therapy but needed to discontinue therapy due to supraventricular tachycardia and superior vena cava syndrome induced from tumor burden. He was emergently treated with palliative radiotherapy to 30 Gy in 10 fractions. He was then started on pemetrexed and cisplatin chemotherapy. His subsequent chest CT scan two months after radiotherapy completion showed a dramatic treatment response within, as well as outside of, the irradiated field. After completion of radiotherapy, he did experience radiation esophagitis requiring nasogastric tube placement. Herein, we highlight the feasibility and efficacy of combining immuno-gene therapy with palliative radiotherapy to produce a substantial treatment response and an abscopal effect in a patient with unresectable MPM.

Intrapleural immunotherapy: An update on emerging treatment strategies for pleural malignancy.

OBJECTIVES: Malignant pleural mesothelioma and malignant pleural effusions are a major therapeutic challenge, and are associated with impairment in quality of life and increased mortality. Advances in systemic therapies of malignant pleural mesothelioma have demonstrated limited clinical benefit and there is ongoing interest in intrapleural immunotherapies which have been demonstrated to be well tolerated overall with variable clinical responses. We have reviewed the literature to provide a comprehensive summary of novel intrapleural immunotherapeutic paradigms, including oncolytic virus therapy, gene-mediated cytotoxic immunotherapy, direct cytokine-mediated immunotherapies, innate immunomodulators and adoptive transfer of intrapleural chimeric antigen receptor T-cell therapy. DATA SOURCES: A review of PubMed for original manuscripts and conference reports published between 1998 and 2018 pertaining to intrapleural immunotherapy, as well as examination of reference lists from reviewed manuscripts. STUDY SELECTION: Human clinical trials on intrapleural immunotherapies in subjects with malignant pleural mesothelioma or malignant pleural effusion were included in this review, including some relevant preclinical studies and anticipated ongoing trials reported on Clinicaltrials.gov. RESULTS: Twenty-six clinical trials were identified, in addition to three trials currently in progress. CONCLUSION: Intrapleural immunotherapies for pleural malignancy have demonstrated promise with regard to generating durable tumor-specific immune responses with possible clinical benefits which merit further investigation as part of multimodal chemotherapeutic and immunotherapeutic regimens.