Standardized Classification of Lung Adenocarcinoma Subtypes and Improvement of Grading Assessment Through Deep Learning.

The histopathologic distinction of lung adenocarcinoma (LADC) subtypes is subject to high interobserver variability, which can compromise the optimal assessment of patient prognosis. Therefore, this study developed convolutional neural networks capable of distinguishing LADC subtypes and predicting disease-specific survival, according to the recently established LADC tumor grades. Consensus LADC histopathologic images were obtained from 17 expert pulmonary pathologists and one pathologist in training. Two deep learning models (AI-1 and AI-2) were trained to predict eight different LADC classes. Furthermore, the trained models were tested on an independent cohort of 133 patients. The models achieved high precision, recall, and F1 scores exceeding 0.90 for most of the LADC classes. Clear stratification of the three LADC grades was reached in predicting the disease-specific survival by the two models, with both Kaplan-Meier curves showing significance (P = 0.0017 and 0.0003). Moreover, both trained models showed high stability in the segmentation of each pair of predicted grades with low variation in the hazard ratio across 200 bootstrapped samples. These findings indicate that the trained convolutional neural networks improve the diagnostic accuracy of the pathologist and refine LADC grade assessment. Thus, the trained models are promising tools that may assist in the routine evaluation of LADC subtypes and grades in clinical practice.

Participant selection for lung cancer screening by risk modelling (the Pan-Canadian Early Detection of Lung Cancer [PanCan] study): a single-arm, prospective study.

BACKGROUND: Results from retrospective studies indicate that selecting individuals for low-dose CT lung cancer screening on the basis of a highly predictive risk model is superior to using criteria similar to those used in the National Lung Screening Trial (NLST; age, pack-year, and smoking quit-time). We designed the Pan-Canadian Early Detection of Lung Cancer (PanCan) study to assess the efficacy of a risk prediction model to select candidates for lung cancer screening, with the aim of determining whether this approach could better detect patients with early, potentially curable, lung cancer. METHODS: We did this single-arm, prospective study in eight centres across Canada. We recruited participants aged 50-75 years, who had smoked at some point in their life (ever-smokers), and who did not have a self-reported history of lung cancer. Participants had at least a 2% 6-year risk of lung cancer as estimated by the PanCan model, a precursor to the validated PLCOm2012 model. Risk variables in the model were age, smoking duration, pack-years, family history of lung cancer, education level, body-mass index, chest x-ray in the past 3 years, and history of chronic obstructive pulmonary disease. Individuals were screened with low-dose CT at baseline (T0), and at 1 (T1) and 4 (T4) years post-baseline. The primary outcome of the study was incidence of lung cancer. This study is registered with ClinicalTrials.gov, number NCT00751660. FINDINGS: 7059 queries came into the study coordinating centre and were screened for PanCan risk. 15 were duplicates, so 7044 participants were considered for enrolment. Between Sept 24, 2008, and Dec 17, 2010, we recruited and enrolled 2537 eligible ever-smokers. After a median follow-up of 5·5 years (IQR 3·2-6·1), 172 lung cancers were diagnosed in 164 individuals (cumulative incidence 0·065 [95% CI 0·055-0·075], incidence rate 138·1 per 10 000 person-years [117·8-160·9]). There were ten interval lung cancers (6% of lung cancers and 6% of individuals with cancer): one diagnosed between T0 and T1, and nine between T1 and T4. Cumulative incidence was significantly higher than that observed in NLST (4·0%; p<0·0001). Compared with 593 (57%) of 1040 lung cancers observed in NLST, 133 (77%) of 172 lung cancers in the PanCan Study were early stage (I or II; p<0·0001). INTERPRETATION: The PanCan model was effective in identifying individuals who were subsequently diagnosed with early, potentially curable, lung cancer. The incidence of cancers detected and the proportion of early stage cancers in the screened population was higher than observed in previous studies. This approach should be considered for adoption in lung cancer screening programmes. FUNDING: Terry Fox Research Institute and Canadian Partnership Against Cancer.

Developmental transcription factor NFIB is a putative target of oncofetal miRNAs and is associated with tumour aggressiveness in lung adenocarcinoma.

Genes involved in fetal lung development are thought to play crucial roles in the malignant transformation of adult lung cells. Consequently, the study of lung tumour biology in the context of lung development has the potential to reveal key developmentally relevant genes that play critical roles in lung cancer initiation/progression. Here, we describe for the first time a comprehensive characterization of miRNA expression in human fetal lung tissue, with subsequent identification of 37 miRNAs in non-small cell lung cancer (NSCLC) that recapitulate their fetal expression patterns. Nuclear factor I/B (NFIB), a transcription factor essential for lung development, was identified as a potential frequent target for these 'oncofetal' miRNAs. Concordantly, analysis of NFIB expression in multiple NSCLC independent cohorts revealed its recurrent underexpression (in ∼40-70% of tumours). Interrogation of NFIB copy number, methylation, and mutation status revealed that DNA level disruption of this gene is rare, and further supports the notion that oncofetal miRNAs are likely the primary mechanism responsible for NFIB underexpression in NSCLC. Reflecting its functional role in regulating lung differentiation, low expression of NFIB was significantly associated with biologically more aggressive subtypes and, ultimately, poorer survival in lung adenocarcinoma patients. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis.

Lung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking and exposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammation is the activation, expansion and infiltration of diverse immune cell types, including CD4+ T cells. Within this T cell subset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a fine balance to regulate appropriate adaptive immune responses.In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor foci development. Additionally, Th17 cells have been shown to be an integral component of the inflammatory milieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes. Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment, and that these two CD4+ T cell subsets play active roles in promoting lung cancer progression and metastasis.We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression, metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balance among Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognostic function and relationship to metastasis in lung cancer.

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema.

Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes. Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed. The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted. We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation.

Smoking status impacts microRNA mediated prognosis and lung adenocarcinoma biology.

BACKGROUND: Cigarette smoke is associated with the majority of lung cancers: however, 25% of lung cancer patients are non-smokers, and half of all newly diagnosed lung cancer patients are former smokers. Lung tumors exhibit distinct epidemiological, clinical, pathological, and molecular features depending on smoking status, suggesting divergent mechanisms underlie tumorigenesis in smokers and non-smokers. MicroRNAs (miRNAs) are integral contributors to tumorigenesis and mediate biological responses to smoking. Based on the hypothesis that smoking-specific miRNA differences in lung adenocarcinomas reflect distinct tumorigenic processes selected by different smoking and non-smoking environments, we investigated the contribution of miRNA disruption to lung tumor biology and patient outcome in the context of smoking status. METHODS: We applied a whole transcriptome sequencing based approach to interrogate miRNA levels in 94 patient-matched lung adenocarcinoma and non-malignant lung parenchymal tissue pairs from current, former and never smokers. RESULTS: We discovered novel and distinct smoking status-specific patterns of miRNA and miRNA-mediated gene networks, and identified miRNAs that were prognostically significant in a smoking dependent manner. CONCLUSIONS: We conclude that miRNAs disrupted in a smoking status-dependent manner affect distinct cellular pathways and differentially influence lung cancer patient prognosis in current, former and never smokers. Our findings may represent promising biologically relevant markers for lung cancer prognosis or therapeutic intervention.

Expression of matrix metalloproteinase-1 in alveolar macrophages, type II pneumocytes, and airways in smokers: relationship to lung function and emphysema.

BACKGROUND: An imbalance between proteolytic enzymes and their inhibitors is thought to be involved in the pathogenesis of chronic obstructive pulmonary disease. Matrix metalloproteinase-1, also known as interstitial collagenase, has been implicated as a potentially important proteinase in the genesis of chronic obstructive pulmonary disease and, more specifically, emphysema. METHODS: We performed quantitative immunohistochemical assessment of matrix metalloproteinase-1 expression in the resected lung of 20 smokers/ex-smokers who had varying severity of airflow obstruction and emphysema and compared this with the lungs of 5 nonsmokers. Emphysema was measured using a morphometric measure of the lungs' surface area/volume ratio and with qualitative and quantitative computed tomography (CT) measures of emphysema. RESULTS: There were significantly more matrix metalloproteinase-1-expressing alveolar macrophages and type II pneumocytes as well as a greater percentage of small airways that stained positively for matrix metalloproteinase-1 in the lungs of smokers than in those of nonsmokers (p < 0.0001, p < 0.0001, and p = 0.0003, respectively). The extent of staining of type II pneumocytes and airways for matrix metalloproteinase-1 was significantly related to the extent of smoking (p = 0.012 and p = 0.013, respectively). In addition, the extent of matrix metalloproteinase-1 staining of alveolar macrophages was related to the lung surface area/volume ratio and to qualitative estimates of emphysema on CT. CONCLUSION: These findings suggest that cigarette smoking increases expression of matrix metalloproteinase-1 in alveolar macrophages as well as in alveolar and small airway epithelial cells. Smokers who develop emphysema have increased alveolar macrophage expression of matrix metalloproteinase-1.

Overcoming the Interobserver Variability in Lung Adenocarcinoma Subtyping: A Clustering Approach to Establish a Ground Truth for Downstream Applications.

CONTEXT.­: The accurate identification of different lung adenocarcinoma histologic subtypes is important for determining prognosis but can be challenging because of overlaps in the diagnostic features, leading to considerable interobserver variability. OBJECTIVE.­: To provide an overview of the diagnostic agreement for lung adenocarcinoma subtypes among pathologists and to create a ground truth using the clustering approach for downstream computational applications. DESIGN.­: Three sets of lung adenocarcinoma histologic images with different evaluation levels (small patches, areas with relatively uniform histology, and whole slide images) were reviewed by 17 international expert lung pathologists and 1 pathologist in training. Each image was classified into one or several lung adenocarcinoma subtypes. RESULTS.­: Among the 4702 patches of the first set, 1742 (37%) had an overall consensus among all pathologists. The overall Fleiss κ score for the agreement of all subtypes was 0.58. Using cluster analysis, pathologists were hierarchically grouped into 2 clusters, with κ scores of 0.588 and 0.563 in clusters 1 and 2, respectively. Similar results were obtained for the second and third sets, with fair-to-moderate agreements. Patches from the first 2 sets that obtained the consensus of the 18 pathologists were retrieved to form consensus patches and were regarded as the ground truth of lung adenocarcinoma subtypes. CONCLUSIONS.­: Our observations highlight discrepancies among experts when assessing lung adenocarcinoma subtypes. However, a subsequent number of consensus patches could be retrieved from each cluster, which can be used as ground truth for the downstream computational pathology applications, with minimal influence from interobserver variability.

Lung Transplantation for COVID-19 Acute Respiratory Distress Syndrome: The British Columbian Experience With New Disease Pathology.

Lung transplantation is a life-saving treatment for patients with end-stage lung disease. COVID-19 has been associated with a severe and rapid decline in pulmonary function, in which case lung transplantation has been described to be effective. We herein describe 9 patients who underwent lung transplantation for COVID-19 acute respiratory distress syndrome, of whom 6 were bridged with extracorporeal membrane oxygenation (ECMO). The median time of pre-operative observation periods was 54 days to ensure no lung function recovery and the time to wean off extracorporeal membrane oxygenation was 3 days. Patients had comparable short-term survival outcomes to non-COVID-19 lung transplant recipients at our institution during the same time period. Lung transplantation for COVID-19-associated lung disease is feasible with comparable short-term outcomes and may liberate patients from extracorporeal supports.

The Clinically Actionable Molecular Profile of Early versus Late-Stage Non-Small Cell Lung Cancer, an Individual Age and Sex Propensity-Matched Pair Analysis.

Background: Despite meticulous surgery for non-small cell lung cancer (NSCLC), relapse is as high as 70% at 5 years. Many institutions do not conduct reflexive molecular testing on early stage specimens, although targeted gene therapy may extend life by years in the event of recurrence. This ultimately delays definitive treatment with additional biopsy risking suboptimal tissue acquisition and quality for molecular testing. Objective: To compare molecular profiles of genetic alterations in early and late NSCLC to provide evidence that reflexive molecular testing provides clinically valuable information. Methods: A single-center propensity matched retrospective analysis was conducted using prospectively collected data. Adults with early and late-stage NSCLC had tissue subject to targeted panel-based NGS. Frequencies of putative drivers were compared, with 1:3 matching on the propensity score; p < 0.05 deemed statistically significant. Results: In total, 635 NSCLC patients underwent NGS (59 early, 576 late); 276 (43.5%) females; age 70.9 (±10.2) years; never smokers 140 (22.0%); 527 (83.0%) adenocarcinomas. Unadjusted frequencies of EGFR mutations were higher in the early cohort (30% vs. 18%). Following adjustment for sex and smoking status, similar frequencies for both early and late NSCLC were observed for variants in EGFR, KRAS, ALK, MET, and ROS1. Conclusion: The frequency of clinically actionable variants in early and late-stage NSCLC was found to be similar, providing evidence that molecular profiling should be performed on surgical specimens. This pre-determined profile is essential to avoid treatment delay for patients who will derive clinical benefit from targeted systemic therapy, in the high likelihood of subsequent relapse.

Chronic Lung Allograft Dysfunction: Review of CT and Pathologic Findings.

Chronic lung allograft dysfunction (CLAD) is the most common cause of mortality in lung transplant recipients after the 1st year of transplantation. CLAD has traditionally been classified into two distinct obstructive and restrictive forms: bronchiolitis obliterans syndrome and restrictive allograft syndrome. However, CLAD may manifest with a spectrum of imaging and pathologic findings and a combination of obstructive and restrictive physiologic abnormalities. Although the initial CT manifestations of CLAD may be nonspecific, the progression of findings at follow-up should signal the possibility of CLAD and may be present on imaging studies prior to the development of functional abnormalities of the lung allograft. This review encompasses the evolution of CT findings in CLAD, with emphasis on the underlying pathogenesis and pathologic condition, to enhance understanding of imaging findings. The purpose of this article is to familiarize the radiologist with the initial and follow-up CT findings of the obstructive, restrictive, and mixed forms of CLAD, for which early diagnosis and treatment may result in improved survival. Supplemental material is available for this article. © RSNA, 2021.

Cystic Primary Lung Cancer: Evolution of Computed Tomography Imaging Morphology Over Time.

PURPOSE: Primary lung cancers associated with cystic airspaces are increasingly being recognized; however, there is a paucity of data on their natural history. We aimed to evaluate the prevalence, pathologic, and imaging characteristics of cystic lung cancer in a regional thoracic surgery center with a focus on the evolution of computed tomography morphology over time. MATERIALS AND METHODS: Consecutive patients referred for potential surgical management of primary lung cancer between January 2016 and December 2018 were included. Clinical, imaging, and pathologic data were collected at the time of diagnosis and at the time of the oldest computed tomography showing the target lesion. Descriptive analysis was carried out. RESULTS: A total of 441 cancers in 431 patients (185 males, 246 females), median age 69.6 years (interquartile range: 62.6 to 75.3 y), were assessed. Overall, 41/441 (9.3%) primary lung cancers were cystic at the time of diagnosis. The remaining showed solid (67%), part-solid (22%), and ground-glass (2%) morphologies. Histopathology of the cystic lung cancers at diagnosis included 31/41 (76%) adenocarcinomas, 8/41 (20%) squamous cell carcinomas, 1/41 (2%) adenosquamous carcinoma, and 1/41 (2%) unspecified non-small cell lung carcinoma. Overall, 8/34 (24%) cystic cancers at the time of diagnosis developed from different morphologic subtype precursor lesions, while 8/34 (24%) cystic precursor lesions also transitioned into part-solid or solid cancers at the time of diagnosis. CONCLUSIONS: This study demonstrates that cystic airspaces within lung cancers are not uncommon, and may be seen transiently as cancers evolve. Increased awareness of the spectrum of cystic lung cancer morphology is important to improve diagnostic accuracy and lung cancer management.

Integrative genomic analyses identify BRF2 as a novel lineage-specific oncogene in lung squamous cell carcinoma.

BACKGROUND: Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes--adenocarcinoma (AC) and squamous cell carcinoma (SqCC)--respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome. METHODS AND FINDINGS: We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage. CONCLUSIONS: This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy. Please see later in the article for the Editors' Summary.

Quantification of lung surface area using computed tomography.

OBJECTIVE: To refine the CT prediction of emphysema by comparing histology and CT for specific regions of lung. To incorporate both regional lung density measured by CT and cluster analysis of low attenuation areas for comparison with histological measurement of surface area per unit lung volume. METHODS: The histological surface area per unit lung volume was estimated for 140 samples taken from resected lung specimens of fourteen subjects. The region of the lung sampled for histology was located on the pre-operative CT scan; the regional CT median lung density and emphysematous lesion size were calculated using the X-ray attenuation values and a low attenuation cluster analysis. Linear mixed models were used to examine the relationships between histological surface area per unit lung volume and CT measures. RESULTS: The median CT lung density, low attenuation cluster analysis, and the combination of both were important predictors of surface area per unit lung volume measured by histology (p < 0.0001). Akaike's information criterion showed the model incorporating both parameters provided the most accurate prediction of emphysema. CONCLUSION: Combining CT measures of lung density and emphysematous lesion size provides a more accurate estimate of lung surface area per unit lung volume than either measure alone.

Minute pulmonary meningothelial-like nodules: a case of incidentally detected diffuse cystic micronodules on thin-section computed tomography.

Minute pulmonary meningothelial-like nodules are common incidental pathologic findings but are sparsely described in the radiology literature. They are of uncertain origin and significance, but they can occasionally manifest as mild restrictive lung disease or as incidental micronodules on computed tomography. We present a case of multiple incidentally detected, randomly distributed, cavitating micronodules with pathologic correlation. Awareness of the rare presentation of this entity is important because it may simulate neoplastic or other nonneoplastic diseases.

Radiological-pathological correlation of subsolid pulmonary nodules: A single centre retrospective evaluation of the 2011 IASLC adenocarcinoma classification system.

INTRODUCTION: The 2011 IASLC classification system proposes guidelines for radiologists and pathologists to classify adenocarcinomas spectrum lesions as preinvasive, minimally invasive adenocarcinoma (MIA), or invasive adenocarcinoma (IA). IA portends the worst clinical prognosis, and the imaging distinction between MIA and IA is controversial. MATERIALS AND METHODS: Subsolid pulmonary nodules resected by microcoil localization over a three-year period were retrospectively reviewed by three chest radiologists and a pulmonary pathologist. Nodules were classified radiologically based on preoperative computed tomography (CT), with the solid nodule component measured on mediastinal windows applied to high-frequency lung kernel reconstructions, and pathologically according to 2011 IASLC criteria. Radiology interobserver and radiological-pathological variability of nodule classification, and potential reasons for nodule classification discordance were assessed. RESULTS: Seventy-one subsolid nodules in 67 patients were included. The average size of invasive disease focus at histopathology was 5 mm (standard deviation 5 mm). Radiology interobserver agreement of nodule classification was good (Cohen's Kappa = 0.604, 95 % CI: 0.447 to 0.761). Agreement between consensus radiological interpretation and pathological category was fair (Cohen's Kappa = 0.236, 95 % CI: 0.054-0.421). Radiological and pathological nodule classification were concordant in 52 % (37 of 71) of nodules. The IASLC proposed CT solid component cut-off of 5 mm to distinguish MIA and IA yielded a sensitivity of 59 % and specificity of 80 %. Common reasons for nodule classification discordance included multiple solid components within a nodule on CT, scar and stromal collapse at pathology, and measurement variability. CONCLUSION: Solid component(s) within persistent part-solid pulmonary nodules raise suspicion for invasive adenocarcinoma. Preoperative imaging classification is frequently discordant from final pathology, reflecting interpretive and technical challenges in radiological and pathological analysis.

Metastatic Renal Cell Carcinoma to the Testis: A Clinicopathologic Analysis of Five Cases.

The testicular spread of renal cell carcinoma is extremely rare. Five cases of renal cell carcinoma metastatic to the testis are described. The patients ranged from 45 to 81 years of age. Four of the five patients had known renal cell carcinoma. The time intervals between the partial and radical nephrectomies for the primary kidney tumors and the occurrence of testicular metastases ranged from 29 to 34 months. In one patient, the testicular mass was the initial presentation leading to a diagnosis of renal cell carcinoma. There were three ipsilateral metastases, one contralateral metastasis, and one bilateral metastasis. The metastatic deposits ranged in size from 2.0 to 5.7 cm. One case had multiple metastatic tumor nodules. All of the metastatic tumors had clear cell histological features, microscopically concordant with the primary renal cell carcinoma subtype. Three patients died of the disease 17 to 42 months after orchiectomy. One patient is alive with additional metastatic lesions 13 months after orchiectomy. One patient had been free of disease at 87 months after orchiectomy but is now on targeted therapy for an additional metastasis at 93 months after orchiectomy. To date, this report is one of the largest single series of patients with renal cell carcinoma metastatic to the testis, and it has the longest follow-up and survival among all the reported cases.

The Association of Inflammatory Cytokines in the Pulmonary Pathophysiology of Respiratory Failure in Critically Ill Patients With Coronavirus Disease 2019.

OBJECTIVES: The majority of coronavirus disease 2019 mortality and morbidity is attributable to respiratory failure from severe acute respiratory syndrome coronavirus 2 infection. The pathogenesis underpinning coronavirus disease 2019-induced respiratory failure may be attributable to a dysregulated host immune response. Our objective was to investigate the pathophysiological relationship between proinflammatory cytokines and respiratory failure in severe coronavirus disease 2019. DESIGN: Multicenter prospective observational study. SETTING: ICU. PATIENTS: Critically ill patients with coronavirus disease 2019 and noncoronavirus disease 2019 critically ill patients with respiratory failure (ICU control group). INTERVENTIONS: Daily measurement of serum inflammatory cytokines. MEASUREMENTS AND MAIN RESULTS: Demographics, comorbidities, clinical, physiologic, and laboratory data were collected daily. Daily serum samples were drawn for measurements of interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor-α. Pulmonary outcomes were the ratio of Pao2/Fio2 and static lung compliance. Twenty-six patients with coronavirus disease 2019 and 22 ICU controls were enrolled. Of the patients with coronavirus disease 2019, 58% developed acute respiratory distress syndrome, 62% required mechanical ventilation, 12% underwent extracorporeal membrane oxygenation, and 23% died. A negative correlation between interleukin-6 and Pao2/Fio2 (rho, -0.531; p = 0.0052) and static lung compliance (rho, -0.579; p = 0.033) was found selectively in the coronavirus disease 2019 group. Diagnosis of acute respiratory distress syndrome was associated with significantly elevated serum interleukin-6 and interleukin-1ß on the day of diagnosis. CONCLUSIONS: The inverse relationship between serum interleukin-6 and Pao2/Fio2 and static lung compliance is specific to severe acute respiratory syndrome coronavirus 2 infection in critically ill patients with respiratory failure. Similar observations were not found with interleukin-ß or tumor necrosis factor-α.

Lung nodules: CT-guided placement of microcoils to direct video-assisted thoracoscopic surgical resection.

PURPOSE: To prospectively assess the safety and effectiveness of computed tomography (CT)-guided placement of fiber-coated microcoils used to guide video-assisted thoracoscopic surgical (VATS) excision of small peripheral lung nodules, with successful excision as the primary outcome and successful CT-guided microcoil placement and procedural complications as secondary outcomes. MATERIALS AND METHODS: The institutional review board approved the study protocol. Informed consent was obtained from all 69 enrolled patients (30 men, 39 women; mean age, 60.7 years +/- 10.1 [standard deviation]) with 75 nodules. At CT, one end of an 80-mm long, 0.018-inch-diameter fiber-coated microcoil was placed deep to the small peripheral lung nodule, and the other end was coiled in the pleural space. VATS excision of lung tissue, nodules, and the microcoil was performed with fluoroscopic guidance. RESULTS: Seventy-three (97%) 4-24-mm nodules were successfully removed at fluoroscopically guided VATS excision; two nodules could not be removed. CT-guided microcoil placement was successful in all cases; however, two (3%) of 75 coils were displaced at VATS excision. Pneumothorax requiring chest tube placement occurred in two (3%) patients, and asymptomatic hemothorax occurred in one (1%) patient. The microcoil did not impede intraoperative frozen-section histopathologic analysis, which facilitated accurate clinical management in all patients. For 19 (28%) patients, the preoperative treatment plan based on bronchoscopy, needle biopsy, and positron emission tomography findings changed after VATS excision. CONCLUSION: Microcoil localization of small peripheral lung nodules enabled fluoroscopically guided VATS resection of 97% of the nodules, with a low rate of intervention (3%) for procedural complications.

Lessons from lung transplantation: Cause for redefining the pathophysiology of pulmonary hypertension in gaucher disease.

BACKGROUND: Gaucher disease type 1 (GD1) is a lysosomal storage disease rarely resulting in end stage pulmonary hypertension (PH) and interstitial lung disease. There have only been two previous case reports of patients with GD1 receiving lung transplants. CASE PRESENTATION: We report a case of successful bilateral sequential lung transplantation in a patient with end-stage GD1-related PH. Prior to transplant, the patient was on enzyme replacement therapy with imiglucerase and pulmonary vasodilator therapy with bosentan, sildenafil and epoprostenol. The patient had pre-transplant comorbidities of prior splenectomy and osteopenia. She underwent bilateral sequential lung transplantation with basiliximab, methylprednisolone and mycophenolate mofetil induction. Her explanted lungs demonstrated severe pulmonary arterial hypertensive changes, but no Gaucher cells. She was maintained on MMF, tacrolimus, prednisone, imiglucerase and warfarin post-transplant. Her post-transplant course was complicated by hemorrhagic shock, prolonged support with extracorporeal membrane oxygenation, and acute renal failure requiring dialysis. Despite these complications, the patient was discharged and is doing well nine months post-transplantation. CONCLUSIONS: This is one of only three reported cases of lung transplantation in patients with GD1. Each case has involved previously splenectomised, female patients with GD1. This is the first to report transplantation in a patient with severe PH and no pulmonary parenchymal disease. As evidenced in our patient, long term treatment with imiglucerase may eliminate the Gaucher cells in the lungs. The PH in these patients is most consistent with pulmonary arterial hypertension, raising the question of whether this should be reclassified as WHO Group 1 PH.