Interstitial Lung Research Articles

AXL Expression on Homeostatic Resident Liver Macrophages Is Reduced in Cirrhosis Following GAS6 Production by Hepatic Stellate Cells

AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14+HLA-DR+AXL+) and acute-on-chronic liver failure (CD14+MERTK+). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced tumor necrosis factor-α/interleukin-6 production and T-cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment, but not interstitial lung- and tissue-resident synovial lining macrophages. We assessed AXL expression on tissue macrophages in patients with cirrhosis. Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n= 22), chronic liver disease (n= 8), non-cirrhotic portal hypertension (n= 4), and healthy controls (n= 4). Phenotype and function of isolated primary human liver macrophages were characterized by flow cytometry (cirrhosis, n= 11; control, n= 14) exvivo. Also, AXL expression was assessed on peritoneal (n= 29) and gut macrophages (n= 16) from cirrhotic patients. Regulation of AXL expression was analyzed invitro and exvivo using primary hepatic stellate cells (HSCs), LX-2 cells, and GAS6 in co-culture experiments. AXL was expressed on resident (CD68+) but not tissue-infiltrating (MAC387+) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68+AXL+ cells significantly decreased with cirrhosis progression: (healthy, 90.2%; Child-Pugh A, 76.1%; Child-Pugh B, 64.5%; and Child-Pugh C, 18.7%; all P < .05) and negatively correlated with Model for End-Stage Liver Disease and C-reactive protein (all P < .05). AXL-expressing hepatic macrophages were CD68highHLA-DRhighCD16highCD206high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL invitro. Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSCs-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.

The removal of ammonia from contaminated water by using various solid waste biosorbents

Water is an essential natural resource for sustaining life and it is not free everywhere. Ammonia (NH3) in drinking water may be beneficial or harmful depending on their concentration in water. NH3 is colorless, pungent gas composed of nitrogen and hydrogen. The acute exposures to high levels of ammonia have also been associated with diseases of the lower airways and interstitial lung. Ammonia occurs naturally and is produced by human activity. It is an important source of nitrogen which is needed by plants and animals. The removal of ammonia from contaminated water by treatment with biosorbents is one of the most effective methods. Biosorption is a simple, economical and environment-friendly method for removal of ammonia from water. Every biosorbent had different physical, chemical and biological properties for removal of ammonia by biosorption from the water. The order of percentage removal of ammonia from water by using three different biosorbents was as follows: Orange peels> Coconut wire waste> Tea waste. The optimum sorption was obtained at basic pH is 4, dosage is 3.9gm, contact time is 60min, temperature is 30°C and agitation speed is 60rpm. In the SEM and XRD characterization observed that the particle size and crystallite size of orange peels biosorbent was 2.54µm and 3.02nm respectively with the end-centered cubic structures. In the FTIR analysis of orange peels biosorbents observed that the O-H, C-H, alkynes with -C=C- stretch, carbonyls, amines and aromatics group peaks are presence. In the BET characterization observed that orange peels biosorbents has a higher surface area (45.42m2/g) and pore volume (0.512cm3/g) as compared to other biosorbents. In orange peels biosorbents observed that the presence of heterogeneous surface with non-uniform distribution of heat adsorption and the adsorption process is multilayer. In the regeneration process observed that the reusing of orange peels biosorbent continuously for three times the adsorption capacity of ammonia from water reduced by 100 to 93.32%. This procedure can be made economical by regenerating and reusing of the biosorbent after removing the ammonia from water.

Increased Interleukin-17 and Glucocorticoid Receptor-β Expression in Interstitial Lung Diseases and Corticosteroid Insensitivity.

BackgroundTreatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases.ObjectiveTo determine the associations among expression of IL-17, glucocorticoid receptor-β and responsiveness to corticosteroid treatment in interstitial lung diseases.MethodsImmunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line.ResultsCompared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-β and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-β/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-β and GR-β/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-β expression and dexamethasone’s suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17.ConclusionUp-regulation of GR-β/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.

A network analysis to identify lung cancer comorbid diseases

Cancer patients with comorbidities face various life problems, health costs, and quality of life. Therefore, determining comorbid diseases would significantly affect the treatment of cancer patients. Because cancer disease is very complex, we can represent the relationship between cancer and its comorbidities as a network. Furthermore, the network analysis can be employed to determine comorbidities as a community detection problem because the relationship between cancer and its comorbidities forms a community. This study investigates which community detection algorithms are more appropriate to determine the comorbid of cancer. Given different community findings, this study attempted to analyze the modularity generated by the algorithm to decide the significant comorbid diseases. We retrieved lung cancer comorbid data on the basis of text mining manuscripts in PubMed, searched through disease ontologies, and calculated disease similarity. We investigate 20 algorithms using five modularity metrics and 16 fitness function evaluations to determine the significant comorbid diseases. The results show the five best modularity algorithms, namely label propagation, spinglass, Chinese whispers, Louvain, RB Pots. These five algorithms found significant comorbidities: blood vessels, immune system, bone, pancreas, and metabolic disorders, atrial cardiac septal defect, atrial fibrillation respiratory system, interstitial lung, and diabetes mellitus. The fitness function justifies the results of the community algorithm, and the ones that have a significant effect are average internal degree, size, and edges inside. This study contributes to more comprehensive knowledge and management of diseases in the healthcare context.

Quantitative proteomic analysis of bronchoalveolar lavage fluid in West Highland white terriers with canine idiopathic pulmonary fibrosis

BackgroundCanine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial fibrosing lung disease, manifesting as cough, exercise intolerance and ultimately, dyspnea and respiratory failure. It mainly affects West Highland white terriers (WHWTs), lacks curable treatment and has a poor prognosis. Aspiration of gastroesophageal refluxate may play a role in the development of CIPF. In the first part of this study, we completed label-free quantitative proteomic analysis of bronchoalveolar lavage fluid (BALF) from CIPF and healthy WHWTs. In the second part, we evaluated potential protein markers of reflux aspiration from canine gastric juice and vomitus and whether these were present in BALF from the two groups.ResultsAcross all BALF samples, 417 proteins were identified, and of these, 265 proteins were identified by two or more unique tryptic peptides. Using the 265 high confidence assignments, the quantitative proteome profiles were very similar in the two cohorts, but they could be readily resolved by principal component analysis on the basis of differential protein expression. Of the proteins that were differentially abundant in the two groups, several (including inflammatory and fibrotic markers) were elevated in CIPF, and a smaller, more diverse group of proteins were diminished in CIPF. No protein markers indicative of reflux aspiration were identified.ConclusionsLabel-free proteomics allowed discrimination between CIPF and healthy WHWTs, consistent with fibrotic process but did not provide clear evidence for gastrointestinal aspiration. The measurement of proteins may provide a proteomics signature of CIPF that could be used to evaluate treatment options.

Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature

IntroductionAminoacyl transfer RNA (tRNA) synthetases are associated with diseases when mutations occur in their encoding genes. Pulmonary alveolar proteinosis can be caused by mutation in the methionyl-tRNA synthetase (MARS) gene while mutations in the leucine-tRNA synthetase (LARS) gene lead to infantile liver failure syndrome type 1.We report the case of a patient with LARS1 pathogenics variants and two patients with MARS1 pathogenics variants. The aim of this study was to analyze the phenotypes of our three patients in detail and classify cases in the literature using Human Phenotype Ontology (HPO) terms. ResultsThe first patient has two previously undescribed heterozygous variants in LARS1 (c.1818dup and c.463A>G). The other two patients' MARS1 variants (c.1177G>A and c.1700C>T) have already been described in the literature.All three patients had anemia, hepatomegaly, feeding difficulties, failure to thrive and hypoalbuminemia.Including ours, 65 patients are described in total, for whom 117 phenotypic abnormalities have been described at least once, 41.9% of which both in patients with LARS1 and MARS1 mutations. ConclusionPatients with LARS1 and MARS1 mutations seem to share a common phenotype but further deep phenotyping studies are required to clarify the details of these complex pathologies.

The Adding Role and Accuracy of Chest Ultrasound and Doppler in Peripheral Lung Lesions

Abstract Background: Chest ultrasound (US) and color Doppler sonography play important roles in the diagnosis and charac-terization of different pathologies of peripheral lung lesions, especially in the emergency setting. Aim of Study: The aim of this study is to assess the role of chest US and Doppler examination in the assessment of peripheral lung lesions in comparison with chest CT, which is the gold standard for chest diagnosis. Subjects and Methods: This cross-sectional study involved 120 patients who underwent chest CT examination, full chest US, and Doppler. Results were assessed blindly and compared with CT. Results: The main lung lesions assessed by US and Doppler were lung collapse, consolidation, interstitial lung changes, and peripheral pulmonary nodules, with the estimated sensi-tivity, specificity, positive predictive value, negative predictive value, and accuracy of detection ranging from 63.9%-76.9%, 94%-95%, 79.2%-95%, 85.9%-91.5%, and 85%-93.3% re-spectively. There was a significant correlation between US and Doppler in comparison with CT. Conclusion: Chest US proved its value as a complementary tool for the diagnosis of peripheral lung lesions, with high specificity and accuracy. This finding was enforced by Doppler, history, and clinical suspicion, although the use of CT to obtain the final diagnosis would be more applicable.

Systemic AL amyloidosis presenting with diffuse alveolar septal involvement and respiratory failure: a case report and review of the literature

BackgroundAmyloidosis is the extracellular deposition of amyloid fibril protein in any tissue or organ. The clinical manifestations of pulmonary amyloidosis are variable and without specific symptoms. We report a rare case of diffuse alveolar septal amyloidosis which is an extremely rare pattern of involvement, with a very poor prognosis, to improve our understanding of the disease.Case presentationA 27-year-old man complained of shortness of breath and cyanosis. High-resolution computed tomography revealed diffuse ground-glass opacifications with interlobular septal thickening in both lungs. The immune-histochemistry showed monoclonal lambda light chains. This case also showed nephrotic syndrome and cardiac arrhythmia, suggesting an involvement of the kidney and the heart. Diagnosis: The diagnosis was finally established by tru-cut transthoracic sonar guided lung biopsy (TSLB), and histological examination revealed Congo red-positive amorphous eosinophilic deposits in the alveolar sept. Interventions: The patient was admitted to a respiratory intensive care unit and put on non-invasive ventilation, then discharged on domiciliary oxygen therapy, and started treatment with chemotherapy melphalan 2 mg daily plus prednisone 60 mg daily immediately after the result of histopathology. Outcomes: Three months after treatment, dyspnea and hypoxemia improved, and he continued treatment. The patient was in a good clinical condition after 10 months of follow-up, but he died suddenly.ConclusionAs it is difficult to distinguish diffuse alveolar septal amyloidosis from other interstitial and granulomatous lung diseases because of their similar symptoms and imaging findings, thus, transthoracic sonar guided lung biopsy and histological examination is very important in the diagnosis of diffuse alveolar septal amyloidosis.

КЛИНИЧЕСКАЯ ХАРАКТЕРИСТИКА ГРУППЫ ПАЦИЕНТОВ С СИНДРОМОМ ГАПЛОНЕДОСТАТОЧНОСТИ CTLA4: ОПЫТ ОДНОГО ЦЕНТРА

CTLA4 deficiency is a primary immunodeficiency state (PIDS) caused by monoallelic mutations in the gene of the same name, and belongs to the group of immunodeficiencies with immune dysregulation. This work analyzes the results of 11 patients with CTLA4 mutations observed at the Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology from October 2012 to January 2021. In 10 of 11 patients had some manifestations of immune dysregulation, the most frequent were cytopenias (10/11), lymphoproliferation (9/11) and lung damage caused by the type of interstitial lymphocytic lungs disease (9/11). Almost all patients had such abnormal immune parameters as hypogammaglobulinemia or dysgammaglobulinemia, lymphopenia. Currently, there is no standardized treatment for these patients, however, targeted therapy with biologically modified CTLA4 is a promising approach to the treatment of autoimmune complications in patients with CTLA4 deficiency. The only curative treatment option for patients with PIDS is hematopoietic stem cell transplantation, but in order to make conclusions about the effectiveness and safety of this treatment, a long period of observation and large groups of patients are required.

Response to pembrolizumab in a patient with primary lung adenocarcinoma originated from indium lung

BackgroundIndium is a metal used as a compound called indium-tin oxide for liquid crystal display. Its inhalation causes lung toxicity, resulting in a new occupational lung disease called indium lung. Although the carcinogenicity of indium has been reported in an animal model, its carcinogenicity in humans is unknown.Case presentationThis is the first reported case of a primary lung cancer originating from indium lung. In this report, we describe a 46-year-old man with interstitial pneumonia-type indium lung diagnosed 16 years ago. The initial symptom was left chest pain, and computed tomography showed a mass adjacent to the aorta with left pleural effusion. Specimens collected using video-assisted thoracoscopy revealed an adenocarcinoma with a high expression of programmed cell death-ligand 1 (cT4N0M1a stage IVA). Although the lesions showed a remarkable aggressive nature, the patient benefited from pembrolizumab, a monoclonal antibody against programmed cell death 1, which was used as second-line therapy for 2 years.ConclusionsIt is important for clinicians to be aware of lung cancer development in indium-exposed workers or in patients with indium lung, as this could have an aggressive behavior. Treatment with immune checkpoint inhibitors is an option even in patients with interstitial pneumonia-type indium lung.

Differential Diagnosis of New-Onset Pulmonary Ground Glass Changes During the COVID-19 Pandemic: a Case Report

The paper describes a clinical case of hypersensitivity pneumonitis in a young patient during the COVID-19 pandemic when the patient having complaints of dyspnea and interstitial lung changes as ground glass opacity was initially unambiguously diagnosed with viral COVID-related bilateral pneumonia. The chief computed tomography manifestations in the lung were infiltrative inflammatory changes as numerous areas of predominantly interstitial infiltration by the type of ground glass, with consolidation areas and reticular changes, varying in extent, peripheral localization, mainly in the lower lobes and with the 25–50% involvement of the right and left lung parenchyma. The diagnosis of hypersensitivity pneumonitis was confirmed by cytological and histological examinations of the biopsy material obtained during bronchoscopy using a set of biopsies and endobronchial cryobiopsy.This clinical case demonstrates that the chest computed tomography detection of pulmonary ground glasstype changes is a reason for further patient examinations and requires morphological verification of the diagnosis, since the cost of a diagnostic error is the life of a patient.

间质性肺疾病与血清肿瘤标记物的关系

间质性肺疾病与血清肿瘤标记物的关系

Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3.

BackgroundAbemaciclib demonstrated efficacy in hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer. Here we provide a comprehensive summary of the most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression‐free survival (PFS), in the MONARCH 2 and 3 trials.Materials and MethodsIncidence of the most clinically relevant AEs, management, and outcomes were summarized. Time‐dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia.ResultsThe most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib‐treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities.ConclusionAbemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS.Implications for PracticeTreatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any‐grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.

EP05 COVID-19 and the biliary tree: atypical manifestations of disease during the pandemic

Case report - IntroductionCOVID-19, the infectious disease caused by the novel coronavirus SARS-CoV-2, and first described in Wuhan, China in December 2019, has affected more than 19 million patients worldwide and resulted in more than 700,000 deaths at the time of writing1. Patients with rheumatic diseases and those receiving immunosuppressive treatment are felt to be at greater risk of complications from this illness, though registry and trial data should help refine our understanding of these risks. We hereby describe a case of COVID-19 complicating an unusual rheumatic illness, resulting in severe multi-system disease and premature death.Case report - Case descriptionA 69 year-old male presented to rheumatology and haematology with symmetrical polyarthritis, thrombocytopenia (18 x 109/L), eosinophilia (25.4 x 109/L), raised C-reactive protein (CRP, 43 mg/L), positive rheumatoid factor (>200), antinuclear antibody (ANA) and anti-Ro. Bone marrow biopsy did not demonstrate evidence of haematological malignancy. Seropositive rheumatoid arthritis and connective tissue disease overlap were diagnosed, and treatment with Prednisolone 60mg daily was initiated. Despite rituximab and intravenous immunoglobulins, thrombocytopenia deteriorated on reducing corticosteroids, however the addition of mycophenolate mofetil (MMF) allowed gradual prednisolone tapering to 3mg daily. Hydroxychloroquine was briefly added but discontinued due to headaches. MMF was discontinued after he developed fungal pneumonia followed by jaundice. Liver biopsy was consistent with drug-induced cholestasis, attributed to co-amoxiclav, and his liver function tests (LFTs) improved on ursodeoxycholic acid. Following a further deterioration in thrombocytopenia, hyperferritinaemia and new onset erythema nodosum, he had a repeat bone marrow examination. This demonstrated large areas of fibrosis and granulomatous inflammation with a dense, pleomorphic T-cell infiltrate, but no haemophagocytosis. Haematologists felt this was reactive and prednisolone dose was increased to 10mg daily.Six months later he developed cholangitis. Magnetic resonance cholangiopancreatography (MRCP) demonstrated a tight 4cm stricture of the distal common bile duct (CBD) within the head of pancreas, which was diffusely swollen without any clear focal mass. Serum amylase was mildly elevated (316 units/L). Concurrent CT thorax, abdomen and pelvis demonstrated bilateral ground-glass changes within the lungs, and a SARS-CoV-2 nasopharyngeal PCR test was positive, though he had no respiratory symptoms or oxygen requirement at that stage.Sadly, four days after the CT scan and before a planned endoscopic retrograde cholangiopancreatography (ERCP) could be performed, he became markedly hypoxic with plain chest x-ray features suggestive of COVID-19 pneumonia. Despite medical management, including doubling of his prednisolone dose, he rapidly deteriorated and died.Case report - DiscussionThis case highlights an unusual presentation of COVID-19 in a patient with a complex background of inflammatory arthritis with immune-mediated thrombocytopenia. At the time of his final illness, these conditions were managed with steroid monotherapy. Based on the COVID-19 risk matrix recommended by the British Society for Rheumatology, he was not identified as a patient requiring shielding.Cholangitis was the major problem precipitating his final admission to hospital, and at the time of admission he had no respiratory symptoms. One week prior to this admission, his father-in-law had died of COVID-19 pneumonia, though they had not been in recent direct contact. Interstitial lung changes were incidentally noted on a CT performed to identify the cause of cholangitis, which prompted the nasopharyngeal PCR that detected SARS-CoV-2. This occurred prior to widespread routine testing of hospital inpatients for SARS-CoV-2 by PCR. Unfortunately he then rapidly developed COVID-19 pneumonia and died before the underlying cause of cholangitis could be definitively identified, though an MRCP demonstrated an obstructed CBD within a diffusely swollen pancreas, where a differential diagnosis of pancreatic malignancy or autoimmune pancreatitis was suggested by the reporting radiologist. There are emerging case reports of COVID-19 resulting in significant pancreatic injuryand a further recent laboratory analysis has suggested that ACE2 receptors, which are utilised by SARS-CoV-2 to gain entry to host cells, are highly expressed on cholangiocytes at a comparable level to type II alveolar cells. Whilst the ultimate cause of cholangitis will remain unknown in this patient, this case highlights the potential for atypical presentations and extra-pulmonary manifestations of COVID-19. Case report - Key learning points COVID-19 is a multi-system illness which can cause significant extra-pulmonary as well as pulmonary pathology, with emerging reports that the biliary tract and pancreas are frequently affected.Evidence to inform accurate prediction of which patients with rheumatic diseases are at highest risk of acquiring severe COVID-19 disease remains insufficient, with current shielding guidelines based on expert consensus.This case highlights the importance of widespread testing for COVID-19 in hospital patients, as not all patients carrying the SARS-CoV-2 virus will demonstrate classical respiratory features of the disease at the point of admission.

28 Association of serum sodium concentration, fluid balance and weight loss with bronchopulmonary dysplasia in very preterm infants

Abstract Background Bronchopulmonary dysplasia (BPD) affects 20% of very preterm infants born &amp;lt;33 weeks gestational age (GA). In this subgroup of neonates, postnatal fluid adaptation may be inefficient due to kidney immaturity, resulting in increased pulmonary interstitial fluid content, lung damage and impaired air-gas exchange. Early postnatal fluid status might contribute to the risk of developing BPD and requires further investigation. Objectives To investigate the association of three indicators of early postnatal fluid status (median serum sodium concentration, cumulative fluid balance and maximum percentage weight loss) measured over the first 10 days after delivery with death and/or BPD in infants born &amp;lt;33 weeks. Design/Methods This retrospective cohort study included infants born 23-32 weeks GA, admitted to the Montreal Children’s Hospital’s NICU from 2015-2018. Neonates moribund on admission, with any major congenital malformation and/or admitted to the NICU &amp;gt;1 day after birth were excluded. Data was collected from the Canadian Neonatal Network database and individual chart review. BPD was defined as oxygen therapy or respiratory support at 36 weeks’ corrected GA. Unadjusted comparisons were made using the Wilcoxon test. Associations between exposures (median serum sodium concentration, cumulative fluid balance and maximum percentage weight loss in the first 10 days after delivery) and outcomes (death and/or BPD) were assessed using multivariable logistic regression analyses adjusting for sex, steroid use, GA, small-for-gestational-age status, Apgar at 5 min&amp;lt;7, surfactant use and mode of delivery. Results Among 439 eligible infants, 125 died and/or developed BPD (29%). Median serum sodium concentration was 139 mmol/L (IQR 136-141) among BPD-free survivors and 136 mmol/L (IQR 134-139) among infants with death and/or BPD (p&amp;lt;0.001). Cumulative fluid balance was 4.09 dL/kg (IQR 2.98-4.78) among BPD-free survivors and 4.88 dL/kg (IQR 3.96-5.95) among infants with death and/or BPD (p&amp;lt;0.001). Maximum percentage weight loss was 8.5% (IQR 5.4-11.6) among BPD-free survivors and 9.2% (IQR 4.9-12.9) among infants with death and/or BPD (p=0.41). Adjusted odds ratios (95% confidence interval) are presented in Table 1. Conclusion Among very preterm infants, higher cumulative fluid balance in the first 10 days after delivery is associated with higher odds of death and/or BPD. Thus, targeting lower cumulative fluid balance may improve BPD-free survival.

Abstract CT139: Ceritinib (Cer) in combination with gemcitabine (Gem)-based chemotherapy in patients (pts) with advanced solid tumors, a phase I study

Abstract Introduction: Cer is an oral ALK/ROS1 inhibitor. Aberrancies in ALK and ROS1 have been observed in many cancer types and ALK inhibition has synergistic effects with chemotherapy in ALK or ROS1 rearranged tumors in preclinical models. We launched a Phase I study of Cer in combination with Gem-based chemotherapy in advanced solid tumors. Herein we present initial results of this study. Methods: Phase I, dose-escalation study of Cer in combination with A1: Gem 1000 mg IV D1/8/15 q28 days; A2: Gem 1000 mg IV + nanoparticle albumin-bound Paclitaxel 125 mg IV both D1/8/15 q28 days; A3: Gem 1000 mg IV + Cisplatin 60 mg IV D1/8 q21 days in pts with advanced, solid malignancies until disease progression, intolerable toxicity or withdrawal. A 3 + 3 dose-escalation design was used starting at Cer 450 mg once daily (DL1) in all arms; DL2 was 600 mg once daily. Primary objective was to determine the maximum tolerated dose (MTD) of Cer. Key inclusion criteria: diagnosis of advanced solid malignancy for which Gem-based treatment was appropriate, &amp;gt;18 years old, ECOG PS 0/1, adequate bone marrow/renal/liver function. Key exclusion criteria: interstitial lung fibrosis/disease, recent acute coronary event, CHF NYHA III/IV, corrected QTc &amp;gt; 450 ms. Pts in A3 could have up to 2 prior lines of therapy. Prior use of ALK inhibitors allowed. Plasma was collected for PK on C1D1, C2D1, and C1D15. Archival tumor tissue was tested for ALK/ROS1/JNK/MET by IHC. Results: Thirty-eight patients were enrolled with 21 evaluable for dose-limiting toxicity (DLT) in A1 and A3. A2 (n=4) closed to accrual for toxicity. Median age was 61 years. Seven pts (41%) had cholangiocarcinoma. A1 had one DLT (G3 ALT increase) in DL2; MTD was 600 mg. A3 had one DLT in DL1 (G3 acute renal failure) and two DLTs in DL2 (G3 thrombocytopenia and G3 dyspnea); MTD was 450 mg. G3-5 AEs in all pts: anemia (A1: 3/19, A3: 2/15), nausea (A1: 1/19, A3: 2/15), emesis (A1: 1/19, A3: 1/15), neutropenia (A1: 2/19, A3: 8/15), thrombocytopenia (A1: 1/19, A3: 4/15), hyperbilirubinemia (A3: 3/15), pneumonia (A1: 2/19), acute renal failure (A3: 1/15), fatigue (A3: 2/15). Fifteen patients were evaluable for response; the overall response rate was 20% with two PR (pt with head and neck carcinoma in A1 and pt with carcinoma of unknown primary in A3) - and one CR in a pt with cholangiocarcinoma (A3) lasting 10.3 months. Overall, disease control rate was 47%. Of 5 evaluable pts with cholangiocarcinoma 3 had clinical benefit. Median PFS 3.4 mo (A1)/4.8 mo (A3) and OS 13.7 mo (A1)/29.1 mo (A3). PK and IHC data will be presented at the conference. Conclusions: The MTD of Cer is 600 mg in combination with Gem and 450 mg in combination with Gem/Cisplatin. Further evaluation of Cer plus Gem-based chemotherapy is planned in ALK/ROS1 positive cholangiocarcinomas. Citation Format: Christos Fountzilas, Alex Adjei, Mateusz Opyrchal, Rachel Evans, Kristopher Attwood, Andrew Goey, John Wilton, Wen Wee Ma, Renuka Iyer. Ceritinib (Cer) in combination with gemcitabine (Gem)-based chemotherapy in patients (pts) with advanced solid tumors, a phase I study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT139.

Histomorphometrical and Stereological Study of the Lungs in Neonatal Rats Born to Paraquat-poisoned Pregnant Rats: Protective Effect of Coenzyme Q10

Background: Paraquat (PQ), an herbicide, is a very poisonous compound for both humans and animals. This study was conducted to examine the protective effect of the Coenzyme Q10 (CoQ10) in newborn rats from pregnant rats pre-treated with PQ. Methods: The experiments were conducted on 25 rats, divided in five groups randomly and equally: 1. Control Group received normal saline (0.1 ml/day); 2. PQ Group received PQ only (5 mg/kg/day); 3. PQ+CoQ10 Group received PQ (5 mg/kg) and CoQ10 (10 mg/kg) daily; 4. PQ+olive oil Group received PQ (5 mg/kg) and olive oil (10 mg/kg) daily; 5. Olive oil Group received olive oil (10 mg/kg/day). All of the injections were made intraperitoneally and started on the 16th day of pregnancy through to parturition. Sixteen days after parturition, the lungs were removed from the newborn rats, paraffin sections were made and stained with hematoxylin and eosin, and analyzed histomorphometrically and stereologically. Results: The results revealed that interstitial tissue and lung alveoli had normal structures in the control and olive oil groups. In PQ and PQ-olive oil groups alveolar hemorrhage, inflammation, extensive fibrosis, decreased alveolar numbers, increased mast cells, and changes in the epithelia were observed. In PQ-CoQ10 Group there was a significant recovery in all of the histological alterations. Conclusion: Generally, Coenzyme Q10 had a protective effect against lung damages caused by PQ, but a complete recovery of the damaged lung tissue would probably take longer than 16 days after birth.

Effect of the patient information brochure in communicating the risks associated with crizotinib treatment to patients with non-small cell lung cancer (NSCLC) in Europe.

Crizotinib (XALKORI®) is indicated for anaplastic lymphoma kinase‐positive and ROS1‐positive advanced non‐small cell lung cancer. This study evaluated the distribution of the crizotinib patient information brochure (PIB) in Europe and patient knowledge of the key messages in the PIB. A cross‐sectional survey was conducted in 10 European countries among patients who received crizotinib to ascertain whether each patient received and read the PIB, and his/her knowledge of its key messages on hepatotoxicity, interstitial lung disease/pneumonitis, QTc prolongation, bradycardia, and vision disorders. Of the 341 patients contacted, 40 responded (11.7%), and 39 patients were eligible. A total of 77% of respondents acknowledged receiving the PIB, of which, 93% reported reading it. Knowledge of the individual side effects ranged from 36% to 85%, and precautions for use ranged from 56% to 67%. Understanding the reasons for calling a physician ranged from 54% to 85%. Knowledge of each of the 6 key side effects was greater among readers of the PIB compared to non‐readers or respondents who did not recall receiving the PIB. Approximately three‐quarters of survey respondents recalled receiving the crizotinib PIB and respondents who read the PIB were more knowledgeable of the key side effects of crizotinib than those who did not read or receive. Caution should be taken in generalizing these results because of the potential for selection bias and small sample size. These survey results suggest that the crizotinib PIB may be an effective risk communication tool for crizotinib‐treated patients in Europe.

Effect of human placental mesenchymal stem cells transplantation on pulmonary vascular endothelial permeability and lung injury repair in mice with acute lung injury

To investigate the effects of human placental mesenchymal stem cells (hPMSCs) transplantation on pulmonary vascular endothelial permeability and lung injury repair in mice with lipopolysaccharide (LPS)-induced acute lung injury (ALI). The hPMSCs were isolated from the human placental tissue by enzyme digestion and passaged. The cell phenotype of the 3rd generation hPMSCs was detected by flow cytometry. Twenty-four 6-week-old healthy male C57BL/6 mice were randomly divided into 3 groups ( n=8). The mice were instilled with LPS in the airway to prepare an ALI model in the ALI model group and the hPMSCs treatment group, and with saline in the control group. At 12 hours after LPS infusion, the mice were injected with 3rd generation hPMSCs via the tail vein in hPMSCs treatment group and with saline in the ALI model group and the control group. At 24 hours after injection, the lung tissues of all mice were taken. The pathological changes were observed by HE staining. The wet/dry mass ratio (W/D) of lung tissue was measured. The Evans blue leak test was used to detect the pulmonary vascular endothelial permea bility in mice. The expression of lung tissue permeability-related protein (VE-cadherin) was detected by Western blot. Flow cytometry examination showed that the isolated cells had typical MSCs phenotypic characteristics. Mice in each group survived. The alveolar structure of the ALI model group significantly collapsed, a large number of inflammatory cells infiltrated, and local alveolar hemorrhage occurred; while the alveolar structure collapse of the hPMSCs treatment group significantly improved, inflammatory cells infiltration significantly reduced, and a few red blood cells were in the interstitial lung. W/D and exudation volume of Evans blue stain were significantly higher in the ALI model group than in the control group and the hPMSCs treatment group ( P<0.05), in the hPMSCs treatment group than in the control group ( P<0.05). The relative protein expression of VE-cadherin was significantly lower in the ALI model group than in the control group and the hPMSCs treatment group ( P<0.05), and in the hPMSCs treatment group than in the control group ( P<0.05). Intravenous injection of hPMSCs can effectively reduce the increased pulmonary vascular endothelial permeability mediated by LPS, relieve the degree of lung tissue damage, and play a therapeutic role in ALI mice.

ДИФФЕРЕНЦИАЛЬНАЯ ДИАГНОСТИКА НЕСПЕЦИФИЧЕСКОЙ ИНТЕРСТИЦИАЛЬНОЙ ПНЕВМОНИИ

A retrospective analysis of case histories of 82 patients with nonspecific interstitial pneumonia, 24 patients with idiopathic pulmonary fibrosis, 8 with exogenous allergic alveolitis, 12 with systemic scleroderma and 6 with drug pneumonia was carried out in hospital treatment in the pulmonology department of the Samarkand city medical hospital in 2010-2019 years. It has been established that in the differential diagnosis of nonspecific interstitial pneumonia and other lung diseases, particular attention should be paid to the anamnesis, clinical presentation and CT signs