Non-neoplastic Lung Disease Research Articles

The role of vascularity and the fibrovascular interface in interstitial lung diseases.

Interstitial lung disease (ILD) is a clinical term that refers to a diverse group of non-neoplastic lung diseases. This group includes idiopathic and secondary pulmonary entities that are often associated with progressive pulmonary fibrosis. Currently, therapeutic approaches based on specific structural targeting of pulmonary fibrosis are limited to nintedanib and pirfenidone, which can only slow down disease progression leading to a lower mortality rate. Lung transplantation is currently the only available curative treatment, but it is associated with high perioperative mortality. The pulmonary vasculature plays a central role in physiological lung function, and vascular remodelling is considered a hallmark of the initiation and progression of pulmonary fibrosis. Different patterns of pulmonary fibrosis commonly exhibit detectable pathological features such as morphomolecular changes, including intussusceptive and sprouting angiogenesis, vascular morphometry, broncho-systemic anastomoses, and aberrant angiogenesis-related gene expression patterns. Dynamic cellular interactions within the fibrovascular interface, such as endothelial activation and endothelial-mesenchymal transition, are also observed. This review aims to summarise the current clinical, radiological and pathological diagnostic algorithm for different ILDs, including usual interstitial pneumonia/idiopathic pulmonary fibrosis, non-specific interstitial pneumonia, alveolar fibroelastosis/pleuroparenchymal fibroelastosis, hypersensitivity pneumonitis, systemic sclerosis-related ILD and coronavirus disease 2019 injury. It emphasises an interdisciplinary clinicopathological perspective. Additionally, the review covers current therapeutic strategies and knowledge about associated vascular abnormalities.

Krebs von den Lungen-6 (KL-6) as a diagnostic and prognostic biomarker for non-neoplastic lung diseases.

Important advancements have been made in understanding the pathogenetic mechanisms underlying acute and chronic lung disorders. But although a wide variety of innovative biomarkers have and are being investigated, they are not largely employed to evaluate non-neoplastic lung diseases. The current work aims to examine the use of Krebs von den Lungen-6 (KL-6), a mucin-like glycoprotein predominantly expressed on the surface of type II alveolar epithelial cells (AEC2s), to evaluate the stage, response to treatment, and prognosis in patients with non-neoplastic lung disorders. Data analysis suggests that KL-6 can be utilized as an effective diagnostic and prognostic biomarker in individuals with interstitial lung disease and as a predictor of clinical outcomes in subjects with SARS-CoV-2-related pneumonia. Moreover, KL-6 can be reliably used in routine clinical settings to diagnose and predict the outcome of patients with chronic obstructive pulmonary disease (COPD) exacerbation. The optimal cut-off points within the European population should be defined to improve KL-6's diagnostic efficacy.

Detection of High-Risk Human Papillomavirus (HPV), p16 and EGFR in Lung Cancer: Insights from the Mediterranean Region of Turkey.

Human papillomavirus (HPV) is an oncogenic DNA virus that plays a role in different cancer types. The aim of this study was to detect the prevalence and types of HPV and its relation with p16, EGFR and clinical findings in lung cancer. HPV and EGFR detection and genotyping of HPV were performed by polymerase chain reaction (PCR) and p16 by immunohistochemistry. Fifty lung cancer patients and seven patients with non-neoplastic lung disease were enrolled in this study. HPV was positive in 78% (39/50) of lung cancer cases. HPV 51 was the most frequent type, followed by HPV 16. Moreover, p16 was positive in 24% (12/50) of the cancer patients, and all of these patients were HPV-positive, while 27 HPV-positive patients showed no p16 expression. There was no relationship between HPV infection and p16 (p = 0.05), gender (p = 0.42), age (p = 0.38), or smoking history (p = 0.68). Although not statistically significant, the HPV prevalence was found to be higher in cancer patients compared to non-neoplastic patients. The prevalence of HPV in lung cancer varies across different studies, which may be due to differences in the detection methods, number of patients, geographic regions, and vaccination status. Further studies are necessary to understand the role of HPV in lung cancer pathogenesis.

Large retrospective validation study of metabolomic biomarkers for resectable lung cancer detection and risk assessment.

3071 Background: Cancer can be regarded as a metabolic disease and many studies published aimed at identifying robust metabolites for lung cancer diagnosis using plasma samples. Regardless of the lung cancer staging, most of these studies were performed on relatively small sample sizes. The purpose of this study is to validate whether a panel of metabolomic biomarkers would improve risk assessment for lung cancer detection in 800 plasma samples from patients that underwent lung cancer resection, and to understand the potential role and intersection between lung cancer and other lung diseases. Methods: A blinded case-control study was performed using plasma samples from 586 patients with biopsy-confirmed lung cancer compared to 214 controls from the same institutional biorepository to evaluate the performance of a 5+ metabolites biomarker panel for lung cancer detection. The control group consists of 90 healthy individuals and 124 with other non-neoplastic lung diseases including asthma, COPD, bronchiectasis and COVID. The lung cancer subgroups include early-stage (Stage I &II) adenocarcinoma and squamous cells carcinoma, advanced stages (Stage III & IV) NSCLC and neuroendocrine tumors. In this study, plasma metabolic profiles were performed using different liquid chromatography methods coupled with a targeted and quantitative mass spectrometry approach. Metabolite concentrations, clinical data, and smoking history were used to develop logistic regression models to identify lung cancer at different stages using significant biomarkers. The area under the receiver operator characteristic curves (AUC), sensitivities and specificities at selected cut off points were calculated for each cancer stage. Results: Univariate and multivariate statistical analyses confirmed the performance of our 5+ metabolites panel (β-HBA, PC aa C38:0, PC ae C40:6, citric acid, tryptophan, and etc.) as being significantly different between controls and lung cancer cases. Linear regression model using metabolites alone yielded an AUC of 0.89 for lung cancer at all stages. When adding smoking status, the models achieved an AUC of 0.91 with sensitivity of 91% and specificity over 78% using a risk prediction threshold of 0.657. Conclusions: The blood-based metabolites panel validated on our current retrospective study exhibited robust performance for resectable lung cancer detection and risk assessment. This metabolomic panel assay demonstrates potential diagnostic applications and clinical utility for patient selection that require further follow-up and confirmation using LDCT or other lung imaging modalities. The inclusion of other lung diseases in the control group is more representative of a real clinical setting suggesting that this blood-based assay could be offered to the medical community. Further studies may also confirm its utility in the context of a lung cancer screening program.

Utility of Bronchoalveolar Lavage, Bronchial Brushing, and Transbronchial Needle Aspiration in Nonneoplastic Lung Diseases – A Single-Center Experience

Context: Accurate diagnosis may be challenging in nonneoplastic lung diseases. Newer techniques such as bronchoalveolar lavage (BAL), bronchial brushing (BB), and transbronchial needle aspiration (TBNA) have been studied mainly in lung cancers. Aim: This study assesses the efficacy of BAL, BB, and TBNA in non-neoplastic lung diseases, against a gold standard of transbronchial lung biopsy (TBLB). Settings and Design: Three-year prospective study in a tertiary care center in North India. Methodology: Adult patients (n = 137) with nonimproving respiratory complaints and clinical and radiological suspicion of having a pulmonary pathology were recruited. Patients of malignancy were excluded. Patients for whom all four samples of BAL, BB, TBNA, and TBLB were unavailable were excluded. Statistical Analysis Used: Sensitivity (SN), specificity (SP), positive predictive value, and negative predictive value for all tests were computed and represented with 95% confidence intervals. TBLB was taken to be the gold standard. Two or more tests taken in combination were also analyzed. Results: We studied the patients of tuberculosis, interstitial pneumonia, acute and chronic nonspecific inflammation, sarcoidosis, fungal infection, interstitial lung disease, eosinophilic pneumonitis, and pulmonary alveolar proteinosis in this study. TBNA had higher SN and SP (59.8% and 96.7%) than BB (57.0% and 93.3%) or BAL (54.2% and 86.7%). When combined, SN increased to 68.2% and SP decreased to 76.7%. Diagnostic yield for interstitial pneumonia and chronic inflammation was relatively high but poor for tuberculosis and sarcoidosis. Conclusions: TBNA had the highest SN and SP in diagnosing the various nonneoplastic lesions. However, BAL and BB are useful and complementary tools in the definitive diagnosis of localized and diffuse pulmonary infections.

Feasibility of the Utility of Bronchoalveolar Lavage, Bronchial Brushings, and Transbronchial Needle Aspiration in Nonneoplastic Lung Diseases

Feasibility of the Utility of Bronchoalveolar Lavage, Bronchial Brushings, and Transbronchial Needle Aspiration in Nonneoplastic Lung Diseases

B CELL LYMPHOMA PRESENTING AS A CYSTIC LUNG DISEASE

TOPIC: Lung Cancer TYPE: Fellow Case Reports INTRODUCTION: Cystic lung airspaces can be seen in a multitude of diseases including lymphangioleiomyomatosis, Langerhan cell histiocytosis, Birt-Hogg-Dube syndrome, cystic metastases, or even postinfectious pneumatoceles. Lymphoma, however, is not often included in the differential diagnosis. We describe a rare presentation of B cell lymphoma presenting as a cystic lung disease. CASE PRESENTATION: Forty five year old female with a past medical history of diabetes mellitus and hypertension was originally referred to us for a lung biopsy. Patient had worsening shortness of breath for 1 year. She had a computed tomography of the chest at another facility which showed extensive cystic spaces in the lungs, suspicious for lymphangiomyomatosis. Patient was evaluated by a pulmonologist as an outpatient and had a bronchoscopy with biopsy. After receiving inconclusive results, she was given a course of antibiotics and had relief of her symptoms for some time. Months later the patient had an episode of severe coughing which prompted a visit to a hospital within our system where she had another computed tomography of the chest with contrast revealing the same diffuse cystic disease that was worse at the bases. She was subsequently referred to us and underwent video-assisted thoracic surgery with right upper, middle, and lower lobe biopsies. Pathology of the right middle lobe was revealed diffuse large B-cell lymphoma. Cystic change was seen in all of the biopsies. DISCUSSION: Lymphoma is one of the great masqueraders in medicine. Because of this, it should be included in the differential diagnosis for patients such as this with multiple cystic airspaces. Primary pulmonary extranodal lymphomas are rare, accounting for 0.4% of all lymphomas, and only 15-20% of these are high grade. These lymphomas are usually either mucosa-associated (MALT) or bronchus-associated lymphoid tissue (BALT) lymphomas. Presentations vary but are most often found as solitary nodules or masses and may be found incidentally. With more diffuse disease, other symptoms like shortness of breath, cough, chest pain, or even hemoptysis may arise. There is an association between immunosuppression and pulmonary lymphomas, as well with human immunodeficiency virus (HIV) infection and inflammatory conditions like rheumatoid arthritis and Sjogren disease. Diagnosis requires surgical biopsy because a bronchoalveolar lavage or fine needle biopsy may show lymphoma cell infiltration but cannot exclude other differential diagnoses such as reactive lymphoid proliferation, or lymphoid interstitial pneumonia. CONCLUSIONS: Lymphoma is one of the great masqueraders in medicine and can present in many different ways. Because of this, it should be included in the differential diagnosis in patients such as this with multiple cystic airspaces of the lungs. Diagnosis requires a surgical biopsy which should be included in these cases. REFERENCE #1: Girard, N., & Cadranel, J. (n.d.). Rare Primary Lung Tumors. In Murray and Nadel's Textbook of Respiratory Medicine (6th ed., pp. 965-980). Elsevier. REFERENCE #2: Hagga, John. "Nonneoplastic Parenchymal Lung Disease." CT and MRI of the whole body, 6th ed., Elsevier, 2017, pp. 928–983. REFERENCE #3: Myers, J. L. (2018). Lung. In Rosai and Ackerman's Surgical Pathology (11th ed., pp. 372-443). Elsevier. DISCLOSURES: no disclosure on file for Bishoy Hanna; No relevant relationships by Diego Marin, source=Web Response no disclosure on file for Christina Migliore Patel; no disclosure on file for Xinlai Sun

Concordance of Bronchoalveolar Lavage Cytology with Transbronchial Lung Biopsies in Non-neoplastic Pulmonary Diseases

Introduction: In many pulmonary diseases, despite radiological & clinical investigations, laboratory tests and function studies, the diagnosis becomes difficult. Bronchoalveolar Lavage (BAL) is a minimally invasive method in which cells are collected from bronchial and alveolar spaces for cytology. This is facilitated by using a flexible bronchoscope with which a biopsy is taken following BAL. Bronchoscopy with BAL when used appropriately can offer correct diagnosis which in turn aids in proper management of the patient. Aim: To find the concordance of BAL findings with the histopathological features of Transbronchial Lung Biopsy (TBLB) in non-neoplastic lung diseases. Materials and Methods: It was a retrospective study conducted in Kempegowda Institute of Medical Sciences, Bengaluru, Karnataka. A total of 40 patients presenting with clinico-radiological findings, suggesting a non-neoplastic lung disease in the year 2019, undergoing bronchoscopy with BAL and concurrent TBLB were chosen. The BAL fluid was processed and differential count of cells was done to classify according to the American Thoracic Society Guidelines. Concordance was checked between the diagnoses made on TBLB and BAL analysis. Results: In the present study, a total of 40 cases were included of which 13 (32.5%) cases showed neutrophilic, 16 (40%) cases showed lymphocytic, 5 (12.5%) cases showed eosinophilic and 6 (15%) cases showed normal cellular distribution on BAL cytology. Diagnoses on studying TBLB included nine cases of Nonspecific Interstitial Pneumonia, seven cases of Usual Interstitial Pneumonia, six cases of Bronchiolitis Obliterans Organising Pneumonia, three cases of Bronchiolitis, two cases each of pulmonary tuberculosis and granulomatous inflammation. There was one case each of actinomycosis, sarcoidosis, lung abscess and mucor mycosis. Normal histology was noted in seven cases. The sensitivity of BAL fluid analysis was found to be 84.84% and the concordance was 80%. The Kappa value obtained was 0.71 indicating good agreement/concordance between BAL cytology and TBLB. Conclusion: The data from the current study suggest that differential cell counts in BAL provide diagnostic information of fundamental importance in frequently occurring non-neoplastic lung diseases in the community.

Corpora amylacea in sputum smears: Incidence and clinical significance.

To examine conventional sputum smears for the presence of corpora amylacea (CA), determining their incidence and clinical significance. A retrospective 4-year cohort study was undertaken of sputum samples from 1176 consecutive patients for the presence of CA. Variables such as age, sex, smoking status, and the presence or absence of haemoptysis were extracted from the medical record. A random group of 50 patients was selected as a control group, and a random group of 50 patients whose ages were below 49years was also included as an age-based control. A total of 1075 of the initial cohort of consecutive patients were included in the study. from these, there were 6898 sputum smears, of which 1.91% (132 smears) contained CA, corresponding to 9.86% of the cohort of patients (106 patients). There was a strong, positive, statistically significant correlation between age and CA presence (τb =.402, P<.001), which supports that CA are associated with older patients. The results of a binary logistic regression indicated that there was a significant association between age, diagnosis of chronic obstructive pulmonary disease and CA presence (χ2 =49.051, df=2, P<.001). The presence of CA in sputum smears is related to age, being much more frequent in older people. Moreover, CA are related to non-neoplastic lung diseases.

Feasibility study of cryobiopsy for practical pathological diagnosis of primary lung cancer including immunohistochemical assessment.

Precision medicine in non-small cell lung cancer requires attainment of a sufficient amount of high-quality tumor tissue. Transbronchial cryobiopsy has emerged as a new diagnostic method for non-neoplastic lung disease with a better potential to assess morphology compared with conventional methods. However, the influence of cryobiopsy on specimen quality, particularly detection of protein expression, is unknown. We performed a comparative immunohistochemical study in specimens obtained by cryobiopsy versus conventional sampling to evaluate the feasibility of cryobiopsy for lung cancer diagnosis. Pairs of artificial biopsy specimens, collected using a cryoprobe or conventional scalpel, were obtained from 43 surgically resected primary lung tumors. Formalin-fixed, paraffin-embedded blocks were prepared in an ISO15189-certified laboratory. Immunohistochemical staining of thyroid transcription factor-1, p40, Ki67 and programmed death-ligand 1 (22C3) was performed. The H-scores for thyroid transcription factor-1 and p40, labeling index for Ki67 and tumor proportion score for programmed death-ligand 1 were assessed. Pearson's correlation coefficients between two sampling types were calculated. The thyroid transcription factor-1 and p40 H-scores showed perfect correlations between the cryobiopsy and conventional scalpel-obtained specimens (R2=0.977 and 0.996, respectively). Ki67 labeling index and PD-L1 tumor proportion score also showed strong correlations between the two sample types (R2=0.896 and 0.851, respectively). Five cases (11.6%) exhibited differences in tumor proportion score category between sample types, potentially because of intratumoral heterogeneity. Immunohistochemical expression of certain tumor markers showed a high concordance between cryobiopsy and conventional scalpel sampling. Cryobiopsy is feasible for pathological diagnostics including PD-L1 evaluation.

Correlation between transbronchial lung biopsy and lung cytology

Respiratory diseases are an important cause of morbidity and mortality worldwide. Although conventional histopathology is the gold standard for their diagnosis, cytology is a useful adjunctive diagnostic test.In the present study we evaluated the efficacy of cytology in providing a rapid diagnosis. We included lesions which were both visible and not visible on bronchoscopy. We evaluated the role of bronchoalveolar lavage (BAL), brush cytology and imprint smears both separately and in combination, and compared them with the histopathological findings of transbronchial lung biopsy (TBLB). Among 100 cases the highest concordance was seen between imprint cytology (77.78%) and biopsy for malignancy, followed by bronchoalveolar lavage (40.91%) and brush cytology (40.00%). The concordance and level of agreement between cytology and biopsy was very poor in general for non-neoplastic lesions. However, it increased when BAL and imprint smears (42.50%) were performed together, compared to other combinations.We recommend a combination of cytological techniques in suspected cases of malignancy, as more useful than a single test, and to include imprint smears in all cases. However, biopsy remains the gold standard for diagnosis in non-neoplastic lung disease.

Blood Chromogranin A Is Not Effective as a Biomarker for Diagnosis or Management of Bronchopulmonary Neuroendocrine Tumors/Neoplasms

Background: Identification of circulating tumor markers for clinical management in bronchopulmonary (BP) neuroendocrine tumors/neoplasms (NET/NEN) is of considerable clinical interest. Chromogranin A (CgA), a “universal” NET biomarker, is considered controversial as a circulating biomarker of BPNEN. Aim: Assess utility of CgA in the diagnosis and management of BPNEN in a multicentric study. Material and Methods: CgA diagnostic metrics were assessed in lung NET/NENs (n = 200) and controls (n = 140), randomly assigned to a Training and Test set (100 BPC and 70 controls in each). Assay specificity was evaluated in neoplastic lung disease (n = 137) and nonneoplastic lung disease (n = 77). CgA efficacy in predicting clinical status was evaluated in the combined set of 200 NET/NENs. CgA levels in bronchopulmonary neuroendocrine tumor (BPNET) subtypes (atypical [AC] vs. typical [TC]) and grade was examined. The clinical utility of an alteration of CgA levels (±25%) was evaluated in a subset of 49 BPNET over 12 months. CgA measurement was by NEOLISA^TM kit (EuroDiagnostica). Results: Sensitivity and specificity in the training set were 41/98%, respectively. Test set data were 42/87%. Training set area under receiver operator characteristic analysis differentiated BPC from control area under the curve (AUC) 0.61 ± 0.05 p = 0.015. Test set the data were AUC 0.58 ± 0.05, p = 0.076. In the combined set (n = 200), 67% BPNET/NEN (n = 134) had normal CgA levels. CgA levels did not distinguish histological subtypes (TC vs. AC, AUC 0.56 ± 0.04, p = 0.21), grade (p = 0.45–0.72), or progressive from stable disease (AUC 0.53 ± 0.05 p = 0.47). There was no correlation of CgA with Ki-67 index (Pearson r = 0.143, p = 0.14). For nonneoplastic diseases (chronic obstructive pulmonary disorder and idiopathic pulmonary fibrosis), CgA was elevated in 26–37%. For neoplastic disease (NSCLC, squamous cell carcinoma), CgA was elevated in 11–16%. The neuroendocrine SCLC also exhibited elevated CgA (50%). Elevated CgA was not useful for differentiating BPNET/NEN from these other pathologies. Monitoring BPNET/NEN over a 12-month period identified neither CgA levels per se nor changes in CgA were reflective of somatostatin analog treatment outcome/efficacy or the natural history of the disease (progression). Conclusions: Blood CgA levels are not clinically useful as a biomarker for lung BPNET/NEN. The low specificity and elevations in both nonneoplastic as well as other common neoplastic lung diseases identified limited clinical utility for this biomarker.

Incidental nonneoplastic parenchymal findings in patients undergoing lung resection for mass lesions

The prevalence of incidental nonneoplastic lung disease in patients undergoing resection for mass lesions is unknown. We determined the prevalence and characteristics of parenchymal findings in patients with lung nodules, aiming to increase awareness of findings that could potentially impact patient management. A total of 397 patients with benign or malignant mass lesions with available presurgical chest computed tomography scans resected between January 2001 and July 2015 were included. Retrospective histologic assessment of parenchymal abnormalities in at least 1 section of grossly normal lung was performed for each case by 2 pulmonary pathologists and correlated with original pathology reports, clinical history, and radiologic findings. A total of 233 women and 164 men underwent resections for carcinomas (78%) or benign nodules (22%). One hundred one (25%) patients showed parenchymal abnormalities, including 14 patients with multiple findings. The most common abnormal findings were fibrotic interstitial changes (10%), including usual interstitial pneumonia (1%), followed by granulomatous processes (8%). Other findings included aspiration (4%), intravascular thrombi (2%), Langerhans cell histiocytosis (1.5%), constrictive bronchiolitis (1%), atypical lymphoid infiltrates (1%), and amyloidosis (0.5%). Abnormalities were more likely to have been documented in the original pathology report by pulmonary pathologists (68%) than by general pathologists (15%) (P < .0001). Cases with histologic parenchymal abnormalities were more likely to show radiologic interstitial lung abnormalities than those without (16% versus 5%; P = .001). Evaluation of background lung parenchyma may yield valuable and unanticipated information in patients undergoing surgical resections for lung masses that may correlate with radiographic interstitial lung abnormalities and influence clinical management.

Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease.

Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women's Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.

Utility of Core Needle Biopsies and Transbronchial Biopsies for Diagnosing Nonneoplastic Lung Diseases.

- Small lung biopsies (core needle biopsies and transbronchial biopsies) are the most common-and often the first-lung sample obtained when a radiologic abnormality is detected and tissue diagnosis is required. When a neoplastic diagnosis cannot be made but pathologic abnormalities are present, it is useful for pathologists to have a list ("menu") of specific nonneoplastic diagnoses that can be made in these samples. - To provide surgical pathologists and pathology trainees with menus of nonneoplastic entities that can be diagnosed in small lung biopsies, and to briefly describe and illustrate some of these entities as they appear in small lung biopsies. - Published literature and the authors' experience with small lung biopsies for diagnosis of nonneoplastic lung diseases. - Although sampling error imposes some limitations, core needle biopsies and transbronchial lung biopsies can contribute to the diagnosis of a variety of nonneoplastic lung diseases and reduce the need for invasive surgical intervention.

Exciting Advances in the Pathogenesis of Neoplastic and Nonneoplastic Lung Diseases, Their Diagnosis, Prognosis, and Treatment

Exciting Advances in the Pathogenesis of Neoplastic and Nonneoplastic Lung Diseases, Their Diagnosis, Prognosis, and Treatment

Injury, intense dust exposure, and chronic disease among survivors of the World Trade Center terrorist attacks of September 11, 2001

BackgroundThe World Trade Center attack of September 11, 2001 in New York City (9/11) exposed thousands of people to intense concentrations of hazardous materials that have resulted in reports of increased levels of asthma, heart disease, diabetes, and other chronic diseases along with psychological illnesses such as post-traumatic stress disorder (PTSD). Few studies have discriminated between health consequences of immediate (short-term or acute) intense exposures versus chronic residential or workplace exposures.MethodsWe used proportional hazards methods to determine adjusted hazard ratios (AHRs) for associations between several components of acute exposures (e.g., injury, immersion in the dust cloud) and four chronic disease outcomes: asthma, other non-neoplastic lung diseases, cardiovascular disease, and diabetes, in 8701 persons free of those conditions prior to exposure and who were physically present during or immediately after the World Trade Center attacks. Participants were followed prospectively up to 11 years post-9/11.ResultsHeart disease exhibited a dose-response association with sustaining injury (1 injury type: AHR =2.0, 95% CI (Confidence Interval) 1.1–3.6; 2 injury types: AHR = 3.1, 95% CI 1.2–7.9; 3 or more injury types: AHR = 6.8, 95% CI 2.0–22.6), while asthma and other lung diseases were both significantly associated with dust cloud exposure (AHR = 1.3, 95% CI 1.0–1.6). Diabetes was not associated with any of the predictors assessed in this study.ConclusionIn this study we demonstrated that the acute exposures of injury and dust cloud that were sustained on 9/11/2001 had significant associations with later heart and respiratory diseases. Continued monitoring of 9/11 exposed persons’ health by medical providers is warranted for the foreseeable future.

Histological Diagnoses of Military Personnel Undergoing Lung Biopsy After Deployment to Southwest Asia.

The current understanding of associations between lung disease and military deployment to Southwest Asia, including Iraq and Afghanistan, is both controversial and limited. We sought to clarify the relation between military deployment and biopsy-proven lung disease. Retrospective data were analyzed for military personnel with non-neoplastic lung biopsies evaluated at the Armed Forces Institute of Pathology or Joint Pathology Center (January 2005 to December 2012). Of 391 subjects, 137 (35.0%) had deployed to Southwest Asia prior to biopsy. Compared to non-deployed subjects, those deployed were younger (median age 37 vs. 51years) with higher representation of African Americans (30.0 vs. 16.9%). Deployed patients were more likely diagnosed with non-necrotizing granulomas (OR 2.4). Non-deployed subjects had higher frequency of idiopathic interstitial pneumonias, particularly organizing pneumonia. Prevalence of small airways diseases including constrictive bronchiolitis was low. This study provides a broader understanding of diversity of biopsy-proven non-neoplastic lung disease as it relates to military deployment to Southwest Asia and importantly did not show an increased prevalence of small airway disease to include constrictive bronchiolitis.

Blood and lung microRNAs as biomarkers of pulmonary tumorigenesis in cigarette smoke-exposed mice

Cigarette smoke (CS) is known to dysregulate microRNA expression profiles in the lungs of mice, rats, and humans, thereby modulating several pathways involved in lung carcinogenesis and other CS-related diseases. We designed a study aimed at evaluating (a) the expression of 1135 microRNAs in the lung of Swiss H mice exposed to mainstream CS during the first 4 months of life and thereafter kept in filtered air for an additional 3.5 months, (b) the relationship between lung microRNA profiles and histopathological alterations in the lung, (c) intergender differences in microRNA expression, and (d) the comparison with microRNA profiles in blood serum. CS caused multiple histopathological alterations in the lung, which were almost absent in sham-exposed mice. An extensive microRNA dysregulation was detected in the lung of CS-exposed mice. Modulation of microRNA profiles was specifically related to the histopathological picture, no effect being detected in lung fragments with non-neoplastic lung diseases (emphysema or alveolar epithelial hyperplasia), whereas a close association occurred with the presence and multiplicity of preneoplastic lesions (microadenomas) and benign lung tumors (adenomas). Three microRNAs regulating estrogen and HER2-dependent mechanisms were modulated in the lung of adenoma-bearing female mice. Blood microRNAs were also modulated in mice affected by early neoplastic lesions. However, there was a poor association between lung microRNAs and circulating microRNAs, which can be ascribed to an impaired release of mature microRNAs from the damaged lung. Studies in progress are evaluating the feasibility of analyzing blood microRNAs as a molecular tool for lung cancer secondary prevention.

BRCA1-associated protein 1 deficiency in lung adenocarcinoma predicts poor outcome and increased tumor invasion.

BackgroundThe major pathological type of non-small cell lung cancer is lung adenocarcinoma (LAC), which has a poor prognosis. BRCA1-associated protein-1 (BAP1) is a newly identified tumor suppressor that regulates a number of cellular functions in somatic malignancies. However, the impact of BAP1 expression in LAC has not been investigated.MethodsA total of 112 cases of LAC and 101 cases of non-neoplastic lung diseases were included in this study. The study focused on BAP1 expression in lung tissues and its relationship to patients’ clinical and pathological features. BAP1 expression was detected by immunohistochemistry. A human LAC cell line NCI-H1299 was transfected with lipofectamine p3xFLAG-BAP1. BAP1 gene expression was silenced in another LAC cell line NCI-H1650, in order to test the inhibitory effect of BAP1 on cell migration and invasion, as well as cell cycle regulation.ResultsBAP1 expression showed a negative correlation with tumorigenesis of LAC (p <0.001) and lymph node metastasis (p = 0.010). High expression of BAP1 predicted longer disease free survival (p = 0.040) and overall survival (p = 0.021) of LAC patients. In functional assays, BAP1 was found to inhibit the migration and invasion of LAC cells, and promoted their apoptosis and necrosis.ConclusionsWe identify BAP1 as a LAC precursor as well as a robust prognostic indicator in LAC patients. This study provides in vitro rationale for the further investigation of BAP1 in preclinical studies.