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Alveolar macrophages (AM) play critical roles in lung tissue homeostasis, host defense, and modulating lung injury. The rate of AM turnover (donor AM replacement by circulating monocytes) after transplantation has been incompletely characterized. Furthermore, the anatomic pattern of recipient-derived lung macrophages repopulation has not been reported, nor has their ability to accumulate and present donor major histocompatibility complex (a process we refer to as MHC cross-decoration). We longitudinally characterized the myeloid content of bronchoalveolar lavage (BAL) and biopsy specimens of lung transplant recipients and found a biphasic rate in AM turnover in the allograft, with a rapid turnover perioperatively, accelerated by both the type of induction immunosuppression and the presence of primary graft dysfunction. We found that recipient myeloid cells with cell surface AM phenotype repopulated the lung in a disorganized pattern, comprised mainly of large clusters of cells. Finally, we show that recipient AM take up and present donor peptide-MHC complexes yet are not able to independently induce an in vitro alloreactive response by circulating recipient T cells.
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Transplante de Pulmão , Macrófagos Alveolares , Líquido da Lavagem Broncoalveolar , Humanos , Pulmão , Transplante de Pulmão/efeitos adversos , Macrófagos Alveolares/metabolismo , Complexo Principal de Histocompatibilidade , TransplantadosRESUMO
BACKGROUND: Whole lung tissue transcriptomic profiling studies in chronic obstructive pulmonary disease (COPD) have led to the identification of several genes associated with the severity of airflow limitation and/or the presence of emphysema, however, the cell types driving these gene expression signatures remain unidentified. METHODS: To determine cell specific transcriptomic changes in severe COPD, we conducted single-cell RNA sequencing (scRNA seq) on n = 29,961 cells from the peripheral lung parenchymal tissue of nonsmoking subjects without underlying lung disease (n = 3) and patients with severe COPD (n = 3). The cell type composition and cell specific gene expression signature was assessed. Gene set enrichment analysis (GSEA) was used to identify the specific cell types contributing to the previously reported transcriptomic signatures. RESULTS: T-distributed stochastic neighbor embedding and clustering of scRNA seq data revealed a total of 17 distinct populations. Among them, the populations with more differentially expressed genes in cases vs. controls (log fold change >|0.4| and FDR = 0.05) were: monocytes (n = 1499); macrophages (n = 868) and ciliated epithelial cells (n = 590), respectively. Using GSEA, we found that only ciliated and cytotoxic T cells manifested a trend towards enrichment of the previously reported 127 regional emphysema gene signatures (normalized enrichment score [NES] = 1.28 and = 1.33, FDR = 0.085 and = 0.092 respectively). Among the significantly altered genes present in ciliated epithelial cells of the COPD lungs, QKI and IGFBP5 protein levels were also found to be altered in the COPD lungs. CONCLUSIONS: scRNA seq is useful for identifying transcriptional changes and possibly individual protein levels that may contribute to the development of emphysema in a cell-type specific manner.
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Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/genética , Proteínas de Ligação a RNA/genética , RNA/genética , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Adulto , Idoso , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/biossíntese , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , RNA/metabolismo , Proteínas de Ligação a RNA/biossíntese , Índice de Gravidade de Doença , Adulto JovemRESUMO
Castleman disease (CD) is a rare lymphoproliferative disorder that may present with various autoimmune, inflammatory, or neurologic syndromes. This is a case of a 21-year-old woman who presented with signs and symptoms of pseudotumour cerebri (PTC) who subsequently developed myasthenia gravis (MG), and was incidentally found to have a large mass in the posterior mediastinum. Upon resection, the mass was classified as unicentric CD involved with follicular dendritic cell sarcoma. Following treatment with IVIG in the setting of progressive weakness and dyspnea, she has had complete symptom resolution while maintained on a low dose of pyridostigmine for the last two years. There are 13 cases of MG and five cases of optic disc edema described as PTC associated with CD in the literature, but to our knowledge, this is the sole case reported of the intersection of all three conditions in one patient. Increased serum levels of interleukin-6 and vascular endothelial growth factor may provide clues as to the association of CD with these neurologic syndromes.
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AIMS: The 2013 College of American Pathologists, the Association for Molecular Pathology and the International Association for the Study of Lung Cancer guideline for EGFR and ALK testing in lung carcinoma indicates that either the primary tumour or the metastasis is suitable for testing. The heterogeneity of gene mutations has been studied extensively, while similar reports on gene rearrangements are limited. The aim of this study was to determine if ALK status between primary tumour and matched metastasis differs. METHODS AND RESULTS: Fifteen ALK fluorescence in-situ hybridization (FISH) rearranged and 19 non-ALK FISH rearranged adenocarcinomas were collected retrospectively based on availability of tissue from a matched metastatic site. Sixty-eight samples were tested by ALK FISH (Vysis ALK break-apart FISH kit) and ALK immunohistochemistry (IHC) (Ventana ALK D5F3 CDx assay). Overall agreement of FISH and IHC was 88%, with IHC showing 100% specificity and 71% sensitivity. Concordance between primary site and metastasis by ALK FISH was seen in 30 cases (88%), and in 32 cases (94%) by ALK IHC. Five discordant cases were found (15%). Three ALK FISH discordant cases had low percentage of ALK FISH-positive tumour cells (average 23%, range: 18-31%) and all were negative by ALK IHC. One IHC discordant case had a high percentage of ALK FISH-positive tumour cells (67%), and was ALK IHC-negative. One FISH discordant case showed ALK FISH- and ALK IHC-positive primary tumour, but ALK FISH- and ALK IHC-negative metastasis. CONCLUSIONS: ALK FISH results show more frequent discordances between primary tumour and matched metastases than ALK IHC, due probably to technical challenges and sample quality. This observation indicates that the quality of sample and technical expertise of the laboratory should guide the decision about ALK testing in clinical practice.
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Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Técnicas de Diagnóstico Molecular/métodos , Metástase Neoplásica/genética , Receptores Proteína Tirosina Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico , Feminino , Rearranjo Gênico , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Receptores Proteína Tirosina Quinases/análise , Reprodutibilidade dos TestesRESUMO
Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases, from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP).
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Calcinose/diagnóstico por imagem , Doenças Genéticas Inatas/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Idoso , Biópsia , Calcinose/patologia , Calcinose/terapia , Diagnóstico Diferencial , Progressão da Doença , Feminino , Doenças Genéticas Inatas/patologia , Doenças Genéticas Inatas/terapia , Humanos , Pneumopatias/patologia , Pneumopatias/terapia , Transplante de Pulmão , Oxigenoterapia , Testes de Função RespiratóriaRESUMO
Histological subtyping of surgically resected lung adenocarcinoma has been shown to be of prognostic significance, and limited surgical resection has been proposed as a treatment of choice for early-stage lung adenocarcinoma. The accuracy of histological subtyping has been recently assessed in the surgical resection and small biopsy specimens; however, the accuracy of intraoperative subtyping on frozen sections remains relatively unknown. The aim of this study was to determine diagnostic accuracy and interobserver variability in histological subtyping of lung adenocarcinoma on intraoperative frozen sections. Overall, 112 consecutive cases of surgically resected stage I lung adenocarcinoma were reviewed independently by three pathologists. Histological patterns (acinar, lepidic, papillary, micropapillary, and solid) and mucinous variant were recorded in 5% increments for each intraoperative frozen and permanent sections. Primary and secondary histological patterns were assigned in each case. Kappa scores were calculated to evaluate agreement between pathologists in the assessment of histological subtype on intraoperative frozen sections versus permanent sections. Overall agreement between intraoperative frozen and permanent sections was moderate for primary pattern (69.7% of cases), with kappa scores ranging from 0.43 to 0.58, with more consistent agreement for stage IA tumors. Kappa scores for the secondary pattern ranged from 0.16 to 0.32. Acinar and solid patterns were most likely to be correctly identified as primary growth patterns. Micropapillary pattern was recognized in only 11-55% of cases. The main reasons for discrepancies between intraoperative frozen and permanent sections were inadequate sampling and poor quality of frozen sections. Our study suggests that it is difficult to predict the primary adenocarcinoma pattern on a single representative frozen section. This observation suggests a potential impact on the extent of frozen section sampling by pathologists at the time of intraoperative consultation, if surgical management of stage I lung adenocarcinoma will be guided by its histological subtype.
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Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Secções Congeladas , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Estadiamento de Neoplasias/métodos , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Cuidados Intraoperatórios , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
Acute cellular rejection is common after lung transplantation and is associated with an increased risk of early chronic rejection. We present combined single-cell RNA and TCR sequencing on recipient-derived T cells obtained from the bronchoalveolar lavage of three lung transplant recipients with rejection and compare them with T cells obtained from the same patients after treatment of rejection with high-dose systemic glucocorticoids. At the time of rejection, we found an oligoclonal expansion of cytotoxic CD8+ T cells that all persisted as tissue resident memory T cells after successful treatment. Persisting CD8+ allograft-resident T cells have reduced gene expression for cytotoxic mediators after therapy with glucocorticoids but accumulate around airways. This clonal expansion is discordant with circulating T cell clonal expansion at the time of rejection, suggesting in situ expansion. We thus highlight the accumulation of cytotoxic, recipient-derived tissue resident memory T cells within the lung allograft that persist despite the administration of high-dose systemic glucocorticoids. The long-term clinical consequences of this persistence have yet to be characterized.
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Glucocorticoides , Transplante de Pulmão , Linfócitos T CD8-Positivos/metabolismo , Glucocorticoides/metabolismo , Rejeição de Enxerto/genética , Rejeição de Enxerto/metabolismo , Humanos , Células T de MemóriaRESUMO
Expansion of α-smooth muscle actin (α-SMA)-expressing airway smooth muscle of the large airways in asthma is well-studied. However, the contribution of α-SMA-expressing cells in the more distal alveolated parenchyma, including pericytes and myofibroblasts within the alveolar septum, to asthma pathophysiology remains relatively unexplored. The objective of this study was to evaluate α-SMA expression in the alveolated parenchyma of individuals with severe asthma (SA), compared with healthy controls or individuals with chronic obstructive pulmonary disease. Using quantitative digital image analysis and video-assisted thoracoscopic surgery lung biopsies, we show that alveolated parenchyma α-SMA expression is markedly reduced in SA in comparison to healthy controls (mean %positive pixels: 12% vs. 23%, P=0.005). Chronic obstructive pulmonary disease cases showed a similar, but trending, decrease in α-SMA positivity compared with controls (mean %positivity: 17% vs. 23%, P=0.107), which may suggest loss of α-SMA expression is a commonality of obstructive lung diseases. The SA group had similar staining for ETS-related gene protein, a specific endothelial marker, comparatively to controls (mean %positive nuclei: 34% vs. 42%, P=0.218), which suggests intact capillary endothelium and likely intact capillary-associated, α-SMA-positive pericytes. These findings suggest that the loss of α-SMA expression in SA may be because of changes in myofibroblast α-SMA expression or cell number. Further study is necessary to fully evaluate possible mechanisms and consequences of this phenomenon.
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Actinas/biossíntese , Asma , Regulação da Expressão Gênica , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Alvéolos Pulmonares , Adulto , Idoso , Asma/metabolismo , Asma/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Lung carcinoma arising in association with scar tissue is a well-reported but much debated phenomenon. Scar tissue complicates imaging and pathologic tumor measurement for cancer staging. To the best of our knowledge, the cytological findings in lung scar carcinoma (LSC) have not been described in the literature. Therefore, the aim of this study was to characterize the findings in fine-needle aspirations (FNA) from histologically confirmed LSCs. METHODS: LSCs were identified on retrospective search. Cases with preoperative FNA material were reviewed, including non-scar cases that were used for comparison. The clinical and histopathology findings were recorded. RESULTS: Twenty-seven cases associated with scar tissue had material for review and 35 cases not associated with scar tissue were used for comparison. The proportion of fibrosis in resection specimens ranged from 10% to 80%. Five (19%) FNA cases were hypocellular. There was no statistically significant difference between the scar and non-scar groups in terms of overall cellularity and diagnostic categories (P = .113 and P = .17, respectively). There was correlation between cytology and dominant pattern on histology in 19 (79%) adenocarcinoma cases. Spindle cells and fibrous or fibroelastotic fragments were present in 22 (81%) cases. CONCLUSION: This is the first study describing the cytology associated with LSCs. The presence of fibrosis did not adversely impact cellularity, which is likely due to multiple excursions and selective microdissection of tumor cells by the FNA needle. The cytomorphological and histological patterns correlated in most cases. FNA is able to provide a preoperative diagnosis of carcinoma despite the presence of fibrosis.
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Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cicatriz/complicações , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina , Carcinoma Pulmonar de Células não Pequenas/complicações , Feminino , Humanos , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1hi and FABP4hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.
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Fibrose Pulmonar Idiopática/imunologia , Interferons/imunologia , Doenças Pulmonares Intersticiais/imunologia , Pulmão/imunologia , Escleroderma Sistêmico/imunologia , Transdução de Sinais/imunologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologiaRESUMO
Asthma is a common disease with profoundly variable natural history and patient morbidity. Heterogeneity has long been appreciated, and much work has focused on identifying subgroups of patients with similar pathobiological underpinnings. Previous studies of the Severe Asthma Research Program (SARP) cohort linked gene expression changes to specific clinical and physiologic characteristics. While invaluable for hypothesis generation, these data include extensive candidate gene lists that complicate target identification and validation. In this analysis, we performed unsupervised clustering of the SARP cohort using bronchial epithelial cell gene expression data, identifying a transcriptional signature for participants suffering exacerbation-prone asthma with impaired lung function. Clinically, participants in this asthma cluster exhibited a mixed inflammatory process and bore transcriptional hallmarks of NF-κB and activator protein 1 (AP-1) activation, despite high corticosteroid exposure. Using supervised machine learning, we found a set of 31 genes that classified patients with high accuracy and could reconstitute clinical and transcriptional hallmarks of our patient clustering in an external cohort. Of these genes, IL18R1 (IL-18 Receptor 1) negatively associated with lung function and was highly expressed in the most severe patient cluster. We validated IL18R1 protein expression in lung tissue and identified downstream NF-κB and AP-1 activity, supporting IL-18 signaling in severe asthma pathogenesis and highlighting this approach for gene and pathway discovery.
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Asma/genética , Interleucina-18/metabolismo , Aprendizado de Máquina/normas , Adulto , Asma/patologia , Estudos de Casos e Controles , Feminino , Humanos , MasculinoRESUMO
There is growing interest in tissue procurement for cancer research through autopsy. Establishing an autopsy/tissue donation programme for breast cancer research within an academic medical centre in the United States requires consideration, planning, multi-departmental collaboration and labour-intensive maintenance. It is the purpose of this paper to outline the necessary considerations in implementing and maintaining a tissue donation and autopsy programme within a breast cancer centre at a comprehensive cancer centre. Considerations of programme planning include: patient engagement, the recruitment of patients and families into the programme, the role and scope of work of the clinical coordinator, regulatory issues and the coordination with both pathology and the research team at time of death and autopsy/tissue donation. All aspects of the tissue donation/rapid autopsy programme development and implementation are discussed and illustrated through case study. An Autopsy/ Tissue Donation for breast cancer research can be successfully developed and implemented.
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Neoplasias da Mama , Obtenção de Tecidos e Órgãos , Autopsia , Feminino , Humanos , Pesquisa , Doadores de TecidosRESUMO
We describe the case of a 79-year-old woman with a history of Erdheim-Chester disease who presented with bradyarrhythmia and infiltration of the superior vena cava and right atrium. This case highlights an important consideration in type of pacemaker placement given the frequency of right atrial involvement in Erdheim-Chester disease. (Level of Difficulty: Advanced.).
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OBJECTIVES: Staging of non-small cell lung carcinoma associated with scar is not discussed in detail in the current American Joint Committee on Cancer staging manual. The recommendation is to include the scar area in the tumor size measurement unless the tumor represents a small focus at the edge of the scar. The aim of this study is to investigate if subtraction of the size of the central scar from the total gross size of surgically resected peripheral clinical stage I non-small cell lung carcinoma improves patient stratification into more accurate prognostic groups. MATERIALS AND METHODS: Hematoxylin and eosin sections of 148 non-small cell lung carcinomas (98 adenocarcinomas and 50 squamous cell carcinomas) were reviewed, including 44 adenocarcinomas and 9 squamous cell carcinomas with scar and 54 adenocarcinomas and 41 squamous cell carcinomas without scar. The microscopic size of the invasive tumor component was determined after the average percentage of scar tissue was subtracted from the grossly measured tumor diameter. Manual results were compared to digital image analysis. RESULTS: Adenocarcinoma with scar were associated with better overall (80.5 % vs. 63.2 %, p = 0.026) and cancer specific survival (95.2 % vs. 73.3 %, p = 0.0053) when compared to adenocarcinoma without scar. Better cancer specific survival was observed in acinar and papillary predominant adenocarcinoma (95.8 % with scar vs. 67.8 % without scar, p = 0.01); while similar trend although not statistically significant was observed in adenocarcinomas with solid or micropapillary component. Using microscopic size, pathologic T stage was down-staged in 21 adenocarcinomas. Squamous cell carcinoma with or without scar did not show a difference in survival. Manual and quantitative image analysis showed strong correlation (r = 0.9769, p < 0.0001). CONCLUSION: Our study suggests that microscopic size of the invasive component in acinar and papillary predominant adenocarcinoma with scar might be a better predictor of survival than the total gross size.
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Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Cicatriz/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Pediatric laryngotracheal stenosis is a complex congenital or acquired airway injury that may manifest into a potentially life-threatening airway emergency condition. Depending on the severity of obstruction, treatment often requires a combination of endoscopic techniques, open surgical repair, intraluminal stenting, or tracheostomy. A balloon expandable biodegradable airway stent maintaining patency while safely degrading over time may address the complications and morbidity issues of existing treatments providing a less invasive and more effective management technique. Previous studies have focused on implementation of degradable polymeric scaffolds associated with potentially life-threatening pitfalls. The feasibility of an ultra-high ductility magnesium-alloy based biodegradable airway stents was demonstrated for the first time. The stents were highly corrosion resistant under in vitro flow environments, while safely degrading in vivo without affecting growth of the rabbit airway. The metallic matrix and degradation products were well tolerated by the airway tissue without exhibiting any noticeable local or systemic toxicity.
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Ligas , Materiais Biocompatíveis , Lítio , Magnésio , Stents , Zinco , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/terapia , Animais , Biópsia , Criança , Modelos Animais de Doenças , Humanos , Imageamento Tridimensional , Imuno-Histoquímica , Nanotecnologia , Coelhos , Radiografia , Estenose Traqueal/diagnóstico , Estenose Traqueal/terapia , Resultado do Tratamento , Microtomografia por Raio-XRESUMO
BACKGROUND: Vocal cord dysfunction (VCD) is defined as inappropriate movement of the vocal cords resulting in functional airway obstruction and symptoms including cough, wheezing, and dyspnea. VCD is often misdiagnosed with asthma but can also co-exist with asthma. The association of VCD with other serious pulmonary conditions has not been described to date. CASE REPORTS: We describe the first case series of two adult patients evaluated at a university asthma clinic who in addition to having VCD also had significant pulmonary pathology other than asthma. Patient 1 had VCD and pulmonary veno-occulsive disease which necessitated a lung transplant. Patient 2 had VCD and a patent ductus arteriosis who necessitated surgical closure. CONCLUSION: It is important to recognize that VCD can exist with pulmonary conditions other than asthma. Lack of improvement in respiratory symptoms after appropriate treatment for VCD should alert the clinician to evaluate for additional conditions.
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Calcifying fibrous tumor of the pleura (CFTP) is a rare mesenchymal tumor of unknown pathogenesis. The diagnosis often requires exclusion of other common entities. Our aim was to determine if genomic changes were associated with CFTP that could contribute to mechanisms underlying tumorigenesis. Three cases of CFTP with their corresponding uninvolved control lung tissue were identified. Two patients were male, and 1 was female (age range, 21-32 years). Tumors were multifocal in 2 cases and solitary in 1. Immunohistochemistry for STAT6, BCL-2, CD34, cytokeratin AE1/AE3, calretinin, desmin, S100, ALK, and ß-catenin was used. All immunohistochemistries were negative in CFTPs. DNA was isolated from all 3 pairs of CFTPs and matching normal lungs for whole-exome sequencing. Damaging, tumor-specific, coding variants were identified in 3 genes including multiple heterozygotic, de novo mutations in the Zinc Finger Protein 717 (ZNF717), fascioscapulohumeral muscular dystrophy-1 (FRG1) and cell division cycle 27 (CDC27) genes. Whole-exome sequencing revealed statistically significant, focal, tumor-specific copy number losses among all CFTPs including a large (302 kb) loss at 6p22.2 comprising 32 genes of the histone cluster 1 family and the hemochromatosis (HFE) gene. This is the first study to evaluate the molecular pathogenesis of CFTP and to identify novel deleterious mutations in ZN717, FRG1, and CDC27 genes as well as significant copy number losses on 8 chromosomes with a large loss common to all samples on chromosome 6. These mutations deleteriously altered coding domains in a manner predicted to be damaging to protein function and may contribute to CFTP tumorigenesis.
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Variações do Número de Cópias de DNA/genética , Mutação/genética , Neoplasias de Tecido Fibroso/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Feminino , Humanos , Masculino , Neoplasias de Tecido Fibroso/diagnóstico , Análise de Sequência de DNA/métodos , Sequenciamento do Exoma/métodosRESUMO
Usual interstitial pneumonia (UIP) is characterized by progressive scarring of the lungs and is associated with high morbidity and mortality despite therapeutic interventions. Sex steroid receptors have been demonstrated to play an important role in chronic lung conditions; however, their significance is unknown in patients with UIP. We retrospectively reviewed 40 idiopathic UIP cases for the expression of hormonal receptors. Forty cases including 10 normal lung, 10 cryptogenic organizing pneumonia, 10 idiopathic organizing diffuse alveolar damage, 7 hypersensitivity pneumonitis, and 3 nonspecific interstitial pneumonitis served as controls. Immunohistochemistry for estrogen receptor α, progesterone receptor (PR), and androgen receptor was performed in all groups. Expression of these receptors was assessed in 4 anatomic/pathologic compartments: alveolar and bronchiolar epithelium, arteries/veins, fibroblastic foci/airspace organization, and old scar. All UIPs (100%) stained positive for PR in myofibroblasts in the scarred areas, whereas among the control cases, only 1 nonspecific interstitial pneumonitis case stained focally positive and the rest were negative. PR was positive in myocytes of the large-sized arteries within the fibrotic areas in 31 cases (77.5%). PR was negative within the alveolar and bronchial epithelium, airspace organization, and center of fibroblastic foci; however, weak PR positivity was noted in the peripheral fibroblasts of the fibroblastic foci where they merged with dense fibrous connective tissue scar. All UIP and control cases were negative for androgen receptor and estrogen receptor α. This is the first study to show the expression of PR within the established fibrotic areas of UIP, indicating that progesterone may have profibrotic effects in UIP patients. Hormonal therapy by targeting PR could be of potential benefit in patients with UIP/IPF.
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Fibrose Pulmonar Idiopática/metabolismo , Pulmão/química , Receptores de Progesterona/análise , Biomarcadores/análise , Biópsia , Células Epiteliais/química , Células Epiteliais/patologia , Receptor alfa de Estrogênio/análise , Feminino , Humanos , Fibrose Pulmonar Idiopática/patologia , Imuno-Histoquímica , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/química , Miofibroblastos/patologia , Artéria Pulmonar/química , Artéria Pulmonar/patologia , Veias Pulmonares/química , Veias Pulmonares/patologia , Receptores Androgênicos/análise , Estudos RetrospectivosRESUMO
Information for patients regarding their clinical conditions and treatment options is widely available online. The American Medical Association and National Institutes of Health recommend that online patient-oriented materials be written at no higher than a seventh-grade reading level to ensure full comprehension by the average American. This study sought to determine whether online patient-oriented materials explaining common pathology procedures are written at appropriate reading levels. Ten pathology procedures that patients would likely research were queried into Google search, and plain text from the first 10 Web sites containing patient education materials for each procedure was analyzed using 10 validated readability scales. We determined mean reading levels of materials grouped by readability scale, procedure, and Web site domain, the overall average reading level of all resources, and popular Web site domains. One hundred Web sites were accessed; one was omitted for short length (<100 words). The average reading grade level of the 99 materials, none of which met national health literacy guidelines (range, 7.3-17.4), was 10.9. Twenty-nine articles (29%) required a high school education for full comprehension, and 4 (4%) required an undergraduate college education. Most frequently accessed Web site domains included medlineplus.gov, webmd.com (both accessed 7 times), and labtestsonline.org (accessed 6 times). Average reading levels of the 11 most commonly accessed Web sites ranged from 8.25 (patient.info) to 12.25 (mayoclinic.org). Readability levels of most online pathology-related patient education materials exceeded those recommended by national health literacy guidelines. These patient education materials should be revised to help patients fully understand them.
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Compreensão , Informação de Saúde ao Consumidor , Conhecimentos, Atitudes e Prática em Saúde , Letramento em Saúde , Internet , Patologia/educação , Educação de Pacientes como Assunto/métodos , Leitura , Acesso à Informação , Informação de Saúde ao Consumidor/normas , Fidelidade a Diretrizes , Guias como Assunto , Letramento em Saúde/normas , Humanos , Internet/normas , Informática Médica , Patologia/normas , Educação de Pacientes como Assunto/normas , Terminologia como AssuntoRESUMO
The histologic changes occurring in severe/therapy-resistant asthma (SA) as defined by the European Respiratory Society/American Thoracic Society guidelines, particularly at the level of the distal airways are unknown. This study describes the clinical, radiologic, and histologic characteristics of 29 SA patients who underwent video-assisted thoracoscopic surgery lung biopsy. Pathologic observations were correlated with clinical features, especially the presence of autoimmune disease (AID) (15/29, 51.7%). Ten biopsies (10/29, 34.5%) showed only small airway manifestations of asthma, whereas in 19 (65.5%) asthmatic granulomatosis, manifested by asthmatic bronchiolitis supplemented by an alveolar septal mononuclear infiltrates with non-necrotizing granulomas, was present. SA patients without asthmatic granulomatosis showed more striking small airway injury, subbasement membrane thickening, and neutrophilic infiltrates. Cases with concurrent AID had a tendency to more parenchymal eosinophilic inflammation, more bronchiolocentric granulomas, and a suggestion of increased responsivity to nonsteroidal immunosuppressive therapy. Histologic examination of video-assisted thoracoscopic surgery lung biopsies in SA demonstrates diverse pathologies including cases associated with granulomatous inflammation in addition to eosinophilic infiltrates. This spectrum of histologies may link to a high incidence of AID.