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CONTEXT.: Mesothelioma is an uncommon tumor that can be difficult to diagnose. OBJECTIVE.: To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. DATA SOURCES.: Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS.: There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions.
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Mesotelioma , Humanos , Mesotelioma/epidemiologia , Mesotelioma/induzido quimicamente , AmiantoRESUMO
Asbestosis, defined as diffuse pulmonary fibrosis caused by inhalation of asbestos fibers, occurs after heavy exposures to asbestos dust over several decades. Because workplace exposures have been significantly curtailed since the banning of asbestos in insulation products, we were interested in examining the clinicopathological characteristics of cases diagnosed in the 21st century. The consultation files of one of the authors (VLR) were reviewed for cases of asbestosis diagnosed since 1/1/2001. 102 cases were identified, with a median age of 75 years (range: 45-89). There were 100 men and 2 women. The women were from Turkey and Brazil (none from the United States). Malignancies were present in 78 cases, including 38 lung cancers, 29 pleural mesotheliomas, and 8 peritoneal mesotheliomas. The grade of asbestosis was available in 88 cases (median severity of 2; scale: 1-4). Pleural plaque was present in 94% of cases. The most common exposure categories were insulators (39), shipyard workers (16), asbestos manufacturing (9), boiler workers (8) and pipefitter/welders (6). The median duration of exposure was 33 years (range: 2-49 years). Lung fiber burden analysis was performed in 34 cases, with amosite being the predominant fiber type. Results were compared with similar information for 475 cases diagnosed prior to 1/1/2001.
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Amianto , Asbestose , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Exposição Ocupacional , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Asbestose/patologia , Pulmão/patologia , Mesotelioma/complicações , Mesotelioma/patologia , Amianto Amosita , Neoplasias Pulmonares/patologiaRESUMO
BACKGROUND: The diagnosis of mesothelioma may be challenging. We investigated a large database of cases in order to determine the frequency with which a diagnosis of mesothelioma was made incorrectly and the most frequent causes of error. DESIGN: A database including more than 4000 consultation cases of histologically confirmed mesothelioma was examined to identify cases in which mesothelioma was diagnosed by at least one pathologist when the available information pointed towards a different diagnosis. RESULTS: There were 311 cases misdiagnosed as mesothelioma. The most common category was metastatic carcinoma to the pleura or peritoneum (129 cases: 73 lung carcinomas, 15 renal cell carcinomas). The next most common category was primary lung cancer (111 cases: 55 sarcomatoid carcinoma, 56 pseudomesotheliomatous carcinoma). The third most common category was primary malignancies arising from or near the serosal membranes (33 cases). The fourth most common category was fibrous pleurisy (38 cases). The most common errors were failure to consider important radiographic information regarding the gross distribution of tumor, lack of awareness or consideration of another malignancy, overreliance on certain immunohistochemical results, and failure to perform certain diagnostic histochemical, immunohistochemical, or ultrastructural studies. CONCLUSIONS: There are a number of diagnostic pitfalls that can lead to the over diagnosis of mesothelioma. Careful attention to clinical and radiographic information as well as performance of appropriate ancillary tests can help to prevent such misdiagnoses. Detailed examples will be presented to assist in the avoidance of these pitfalls with emphasis on the most commonly observed errors.
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Carcinoma , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Sobrediagnóstico , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/patologia , Biomarcadores Tumorais/análise , Mesotelioma/diagnóstico , Mesotelioma/patologia , Mesotelioma Maligno/diagnóstico , Carcinoma/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Diagnóstico DiferencialRESUMO
Despite efforts to ban asbestos mining and manufacturing, mesothelioma deaths in the United States have remained stable at approximately 2500 cases annually. This trend is not unique to the United States but is also a global phenomenon, associated with increased aging of populations worldwide. Although geoeconomic factors such as lack of regulations and continued asbestos manufacturing in resource-poor countries play a role, it is essential to consider biological factors such as immune senescence and increased genetic instability associated with aging. Recognizing that mesothelioma shares genetic instability and immune system effects with other age-related cancers is crucial because the impact of aging on mesothelioma is frequently assessed in the context of disease latency after asbestos exposure. Nevertheless, the long latency period, often cited as a reason for mesothelioma's elderly predominance, should not overshadow the shared mechanisms. This communication focuses on the role of immune surveillance in mesothelioma, particularly exploring the impact of immune escape resulting from altered TSG function during aging, contributing to the phylogenetic development of gene mutations and mesothelioma oncogenesis. The interplay between the immune system, TSGs, and aging not only shapes the immune landscape in mesothelioma but also contributes to the development of heterogeneous tumor microenvironments, significantly influencing responses to immunotherapy approaches and survival rates. By understanding the complex interplay between aging, TSG decline, and immune senescence, health care professionals can pave the way for more effective and personalized immunotherapies, ultimately offering hope for better outcomes in the fight against mesothelioma.
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Amianto , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Humanos , Estados Unidos , Idoso , Filogenia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mesotelioma/genética , Mesotelioma/terapia , Mesotelioma Maligno/genética , Genes Supressores de Tumor , Microambiente TumoralRESUMO
AIMS: Mesothelioma is a rare malignancy of the serosal membranes that is commonly related to exposure to asbestos. Despite extensive research and clinical trials, prognosis to date remains poor. Consistent, comprehensive and reproducible pathology reporting form the basis of all future interventions for an individual patient, but also ensures that meaningful data are collected to identify predictive and prognostic markers. METHODS AND RESULTS: This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the international consensus mesothelioma reporting data set. It describes the 'core' and 'non-core' elements to be included in pathology reports for mesothelioma of all sites, inclusive of clinical, macroscopic, microscopic and ancillary testing considerations. An international expert panel consisting of pathologists and a medical oncologist produced a set of data items for biopsy and resection specimens based on a critical review and discussion of current evidence, and in light of the changes in the 2021 WHO Classification of Tumours. The commentary focuses particularly upon new entities such as mesothelioma in situ and provides background on relevant and essential ancillary testing as well as implementation of the new requirement for tumour grading. CONCLUSION: We recommend widespread and consistent implementation of this data set, which will facilitate accurate reporting and enhance the consistency of data collection, improve the comparison of epidemiological data, support retrospective research and ultimately help to improve clinical outcomes. To this end, all data sets are freely available worldwide on the ICCR website (www.iccr-cancer.org/data-sets).
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Mesotelioma Maligno , Mesotelioma , Patologia Clínica , Humanos , Peritônio , Pleura , Estudos Retrospectivos , Mesotelioma/diagnóstico , Pericárdio , Patologia Clínica/métodosRESUMO
Lymphomas are among the most common malignant tumors occurring in the anterior/prevascular mediastinum. Their diagnoses can be challenging in small biopsies, the current most common method of sampling of an anterior mediastinal mass. Because the initial clinical and/or imaging impression may not be that of lymphoma, these specimens may first be evaluated by cytopathologists, surgical pathologists, and thoracic pathologists rather than hematopathologists. Therefore, it is crucial for this group of pathologists to have a practical diagnostic approach to these neoplasms, know their common diagnostic pitfalls, and their main differential diagnoses. This is important because the diagnosis of lymphoma carries significant therapeutic implications (chemotherapy and/or radiotherapy and not surgical resection). Similarly, securing and properly triaging a sample at the time of tissue collection will translate into direct patient benefit since a subset of lymphomas (T-lymphoblastic lymphoma) may present exclusively as an anterior mediastinal mass and the tissue obtained from this site may be the only one available to evaluate prognostic markers and potential targetable molecular alterations. Once a proper initial diagnostic work-up has been performed, a case can be transferred to a hematopathologist for assistance with a refined diagnosis. In this review, we focus on the practical diagnostic approach to the most common prevascular/anterior mediastinal lymphomas with an emphasis on the findings in small biopsies and provide best practice tips for case triage.
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Pulmonary lymphomas are rare. With the current less invasive approaches used to obtain material for diagnosis, the diagnosis of pulmonary lymphoma is now frequently established in a small biopsy rather than in a resection. Therefore, the diagnosis has become more challenging and requires correlation with the clinico-radiologic presentation and with ancillary studies (immunohistochemistry, flow cytometry, cytogenetics, and/or molecular analysis). Due to the rarity of pulmonary lymphomas, clinical suspicion of a lymphomatous process is low at initial presentation, and material may be only submitted for histopathology. For this reason, herein, we provide recommendations to arrive at the correct diagnosis of the most common lung B-cell lymphomas (marginal zone lymphoma of mucosa-associated lymphoid tissue, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, lymphomatoid granulomatosis) in the setting of small biopsies, utilizing only immunohistochemistry. The differential diagnosis varies according to the lymphoma subtype and includes reactive conditions, solid tumors, and other hematolymphoid malignancies. Although morphology and immunohistochemistry may be sufficient to establish a diagnosis, in some cases, the best recommendation is to obtain additional tissue via a VATS biopsy/wedge resection with material submitted for flow cytometry, cytogenetics, and/or molecular studies to be able to properly classify a pulmonary lymphoid process.
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Theories of disease pathogenesis following asbestos exposure have focused on the participation of iron. After exposure, an open network of negatively charged functional groups on the fiber surface complexes host metals with a preference for iron. Competition for iron between the host and the asbestos results in a functional metal deficiency. The homeostasis of iron in the host is modified by the cell response, including increased import to correct the loss of the metal to the fiber surface. The biological effects of asbestos develop in response to and are associated with the disruption of iron homeostasis. Cell iron deficiency in the host following fiber exposure activates kinases and transcription factors, which are associated with the release of mediators coordinating both inflammatory and fibrotic responses. Relative to serpentine chrysotile, the clearance of amphiboles is incomplete, resulting in translocation to the mesothelial surface of the pleura. Since the biological effect of asbestos is dependent on retention of the fiber, the sequestration of iron by the surface, and functional iron deficiency in the cell, the greater clearance (i.e., decreased persistence) of chrysotile results in its diminished impact. An inability to clear asbestos from the lower respiratory tract initiates a host process of iron biomineralization (i.e., asbestos body formation). Host cells attempt to mobilize the metal sequestered by the fiber surface by producing superoxide at the phagosome membrane. The subsequent ferrous cation is oxidized and undergoes hydrolysis, creating poorly crystalline iron oxyhydroxide (i.e., ferrihydrite) included in the coat of the asbestos body.
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Acute respiratory distress syndrome (ARDS) is a leading cause of respiratory failure and death in patients in the intensive care unit. Experimentally, acute lung injury resolution depends on the repair of mitochondrial oxidant damage by the mitochondrial quality control (MQC) pathways, mitochondrial biogenesis, and mitophagy, but nothing is known about this in the human lung. In a case-control autopsy study, we compared the lungs of subjects dying of ARDS (n = 8; cases) and age-/gender-matched subjects dying of nonpulmonary causes (n = 7; controls). Slides were examined by light microscopy and immunofluorescence confocal microscopy, randomly probing for co-localization of citrate synthase with markers of oxidant stress, mitochondrial DNA damage, mitophagy, and mitochondrial biogenesis. ARDS lungs showed diffuse alveolar damage with edema, hyaline membranes, and neutrophils. Compared with controls, a high degree of mitochondrial oxidant damage was seen in type 2 epithelial (AT2) cells and alveolar macrophages by 8-hydroxydeoxyguanosine and malondialdehyde co-staining with citrate synthase. In ARDS, antioxidant protein heme oxygenase-1 and DNA repair enzyme N-glycosylase/DNA lyase (Ogg1) were found in alveolar macrophages but not in AT2 cells. Moreover, MAP1 light chain-3 (LC3) and serine/threonine-protein kinase (Pink1) staining were absent in AT2 cells, suggesting a mitophagy failure. Nuclear respiratory factor-1 staining was missing in the alveolar region, suggesting impaired mitochondrial biogenesis. Widespread hyperproliferation of AT2 cells in ARDS could suggest defective differentiation into type 1 cells. ARDS lungs show profuse mitochondrial oxidant DNA damage but little evidence of MQC activity in AT2 epithelium. Because these pathways are important for acute lung injury resolution, our findings support MQC as a novel pharmacologic target for ARDS resolution.
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Lesão Pulmonar Aguda , Síndrome do Desconforto Respiratório , Humanos , Citrato (si)-Sintase/metabolismo , Pulmão/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Lesão Pulmonar Aguda/metabolismo , Oxidantes/metabolismo , Oxidantes/farmacologiaRESUMO
We tested the hypothesis that (1) mucus production can be included in the cell response to iron deficiency; (2) mucus binds iron and increases cell metal uptake; and subsequently (3) mucus impacts the inflammatory response to particle exposure. Using quantitative PCR, RNA for both MUC5B and MUC5AC in normal human bronchial epithelial (NHBE) cells decreased following exposures to ferric ammonium citrate (FAC). Incubation of mucus-containing material collected from the apical surface of NHBE cells grown at air-liquid interface (NHBE-MUC) and a commercially available mucin from porcine stomach (PORC-MUC) with iron demonstrated an in vitro capacity to bind metal. Inclusion of either NHBE-MUC or PORC-MUC in incubations of both BEAS-2B cells and THP1 cells increased iron uptake. Exposure to sugar acids (N-acetyl neuraminic acid, sodium alginate, sodium guluronate, and sodium hyaluronate) similarly increased cell iron uptake. Finally, increased metal transport associated with mucus was associated with a decreased release of interleukin-6 and -8, an anti-inflammatory effect, following silica exposure. We conclude that mucus production can be involved in the response to a functional iron deficiency following particle exposure and mucus can bind metal, increase cell uptake to subsequently diminish or reverse a functional iron deficiency and inflammatory response following particle exposure.
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Deficiências de Ferro , Ferro , Humanos , Ferro/metabolismo , Interleucina-6/metabolismo , Células Epiteliais/metabolismo , Muco/metabolismo , Mucina-5AC/metabolismoRESUMO
This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed. Some practical implications of recent developments are that: (1) Asbestos-cancer exposure-response relationships should be expected to have non-zero background rates; (2) Evidence from inflammation biology and other sources suggests that there are exposure concentration thresholds below which exposures do not increase inflammasome-mediated inflammation or resulting inflammation-mediated cancer risks above background risk rates; and (3) The size of the suggested exposure concentration threshold depends on both the detailed time patterns of exposure on a time scale of hours to days and also on the composition of asbestos fibers in terms of their physiochemical properties. These conclusions are supported by complementary strands of evidence including biomathematical modeling, cell biology and biochemistry of asbestos-cell interactions in vitro and in vivo, lung fiber burden analyses and epidemiology showing trends in human exposures and MM rates.
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Amianto , Neoplasias Pulmonares , Mesotelioma , Humanos , Amianto/toxicidade , Mesotelioma/induzido quimicamente , Mesotelioma/epidemiologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/epidemiologia , Pulmão/patologia , Amiantos Anfibólicos/toxicidade , Inflamação/metabolismoRESUMO
It is proposed that the mechanistic basis for non-neoplastic lung injury with cigarette smoking is a disruption of iron homeostasis in cells after exposure to cigarette smoke particle (CSP). Following the complexation and sequestration of intracellular iron by CSP, the host response (eg, inflammation, mucus production, and fibrosis) attempts to reverse a functional metal deficiency. Clinical manifestations of this response can present as respiratory bronchiolitis, desquamative interstitial pneumonitis, pulmonary Langerhans' cell histiocytosis, asthma, pulmonary hypertension, chronic bronchitis, and pulmonary fibrosis. If the response is unsuccessful, the functional deficiency of iron progresses to irreversible cell death evident in emphysema and bronchiectasis. The subsequent clinical and pathological presentation is a continuum of lung injuries, which overlap and coexist with one another. Designating these non-neoplastic lung injuries after smoking as distinct disease processes fails to recognize shared relationships to each other and ultimately to CSP, as well as the common mechanistic pathway (ie, disruption of iron homeostasis).
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Fumar Cigarros , Doenças Pulmonares Intersticiais , Lesão Pulmonar , Doença Pulmonar Obstrutiva Crônica , Homeostase , Humanos , Ferro , Doenças Pulmonares Intersticiais/patologia , Lesão Pulmonar/induzido quimicamenteRESUMO
Substantial changes in the 2021 WHO Classification of Tumors of the Pleura and Pericardium since the 2015 WHO Classification include the following: (1) pleural and pericardial tumors have been combined in one chapter whereas in the 2015 WHO, pericardial tumors were classified with cardiac tumors; (2) well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumor given growing evidence that these tumors exhibit relatively indolent behavior; (3) localized and diffuse mesothelioma no longer include the term "malignant" as a prefix; (4) mesothelioma in situ has been added to the 2021 classification because these lesions can now be recognized by loss of BAP1 and/or MTAP by immunohistochemistry and/or CDKN2A homozygous deletion by fluorescence in situ hybridization; (5) the three main histologic subtypes (i.e., epithelioid, biphasic, and sarcomatoid) remain the same but architectural patterns and cytologic and stromal features are more formally incorporated into the 2021 classification on the basis of their prognostic significance; (6) nuclear grading for epithelioid diffuse mesothelioma is introduced, and it is recommended to record this and other histologically prognostic features in pathology reports; (7) BAP1, EZH2, and MTAP immunohistochemistry have been found to be useful in separating benign mesothelial proliferations from mesothelioma; (8) biphasic mesothelioma can be diagnosed in small biopsies having both epithelioid and sarcomatoid components even if the amount of one component is less than 10%; and (9) the most frequently altered genes in diffuse pleural mesothelioma include BAP1, CDKN2A, NF2, TP53, SETD2, and SETDB1.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Biomarcadores Tumorais/genética , Homozigoto , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Pleura/patologia , Neoplasias Pleurais/patologia , Deleção de Sequência , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Organização Mundial da SaúdeRESUMO
OBJECTIVE: Several mechanisms have been proposed for the biological effect of diacetyl. We tested the postulate that animal and cell exposures to diacetyl are associated with a disruption in iron homeostasis. MATERIALS AND METHODS: Male, Sprague-Dawley rats were intratracheally-instilled with either distilled water or diacetyl. Seven days after treatment, animals were euthanized and the lungs removed, fixed, and embedded. Sections were cut and stained for iron, collagen, and ferritin. Human epithelial (BEAS-2B) and monocytic (THP-1) cells were exposed in vitro to ferric ammonium citrate (FAC), diacetyl, and both FAC and diacetyl. Cell non-heme iron concentrations and ferritin levels were quantified using inductively coupled plasma optical emission spectroscopy and an immunoassay respectively. RESULTS: After exposure of animals to diacetyl, there were airway polypoid lesions which stained positively for both iron and the intracellular storage protein ferritin. Trichrome stain showed a deposition of collagen immediately adjacent to accumulated metal following diacetyl exposure. In in vitro cell exposures, FAC increased non-heme iron concentration but co-incubations of FAC and diacetyl elevated levels to significantly greater values. Levels of ferritin were increased with exposures of BEAS-2B and THP-1 cells to FAC but were similarly greater after co-exposure with FAC and diacetyl. CONCLUSIONS: Results of animal and cell studies support a disruption of iron homeostasis by diacetyl. It is proposed that, following internalization, diacetyl complexes intracellular sources of iron. The cell recognizes a loss of its requisite iron to diacetyl and imports greater concentrations of the metal.
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Diacetil/efeitos adversos , Animais , Homeostase/efeitos dos fármacos , Humanos , Ferro/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Células THP-1RESUMO
Occupational exposure to diacetyl, a butter flavor chemical, can result in obliterative bronchiolitis. Obliterative bronchiolitis is characterized by exertional dyspnea, fixed airflow obstruction, and histopathologic constrictive bronchiolitis, with bronchiolar wall fibrosis leading to luminal narrowing and obliteration. We describe a case of advanced lung disease with histopathology distinct from obliterative bronchiolitis in a 37-year-old male coffee worker following prolonged exposure to high levels of diacetyl and the related compound 2,3-pentanedione, who had no other medical, avocational, or occupational history that could account for his illness. He began working at a coffee facility in the flavoring room and grinding area in 2009. Four years later he moved to the packaging area but continued to flavor and grind coffee at least 1 full day per week. He reported chest tightness and mucous membrane irritation when working in the flavoring room and grinding area in 2010. Beginning in 2014, he developed dyspnea, intermittent cough, and a reduced sense of smell without a work-related pattern. In 2016, spirometry revealed a moderate mixed pattern that did not improve with bronchodilator. Thoracoscopic lung biopsy results demonstrated focal mild cellular bronchiolitis and pleuritis, and focal peribronchiolar giant cells/granulomas, but no evidence of constrictive bronchiolitis. Full-shift personal air-samples collected in the flavoring and grinding areas during 2016 measured diacetyl concentrations up to 84-fold higher than the recommended exposure limit. Medical evaluations indicate this worker developed work-related, airway-centric lung disease, most likely attributable to inhalational exposure to flavorings, with biopsy findings not usual for obliterative bronchiolitis. Clinicians should be aware that lung pathology could vary considerably in workers with suspected flavoring-related lung disease.
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Bronquiolite Obliterante , Pneumopatias , Adulto , Bronquiolite Obliterante/induzido quimicamente , Café/efeitos adversos , Diacetil/efeitos adversos , Humanos , Pulmão/química , MasculinoRESUMO
Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to 1) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction and 2) test the safety and efficacy of a novel extracorporeal blood filter to remove proinflammatory molecules and improve organ function. After a dose-finding pilot study, 12 animals were inoculated with Streptococcus pneumoniae [5 × 109 colony-forming units (CFU)], given ceftriaxone at 24 h after inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate (n = 6) or sham treatment (n = 6) for 4 h at 30 h after inoculation. For safety analysis, four uninfected animals also underwent purification. At 48 h, necropsy was performed. Inoculated animals developed severe pneumonia and septic shock. Compared with sham-treated animals, septic animals treated with purification displayed significantly less kidney injury, metabolic acidosis, hypoglycemia, and shock (P < 0.05). Purification blocked the rise in peripheral blood S. pneumoniae DNA, attenuated bronchoalveolar lavage (BAL) CCL4, CCL2, and IL-18 levels, and reduced renal oxidative injury and classical NLRP3 inflammasome activation. Purification was safe in both uninfected and infected animals and produced no adverse effects. We demonstrate that heparin-based blood purification significantly attenuates levels of circulating S. pneumoniae DNA and BAL cytokines and is renal protective in baboons with severe pneumococcal pneumonia and septic shock. Purification was associated with less severe acute kidney injury, metabolic derangements, and shock. These results support future clinical studies in critically ill septic patients.
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Hemofiltração , Heparina/química , Pneumonia Pneumocócica/terapia , Choque Séptico/terapia , Streptococcus pneumoniae/metabolismo , Animais , Citocinas/metabolismo , Masculino , Papio , Projetos Piloto , Pneumonia Pneumocócica/sangue , Choque Séptico/sangueRESUMO
Perls' Prussian blue (PPB) stain recognizes Fe3+ associated with hemosiderin. The employment of this stain in clinical medicine and research has been extensive and novel applications continue to evolve. Ferruginous bodies are intracellular structures in lung tissue, bronchoalveolar lavage (BAL), and sputum that stain with PPB. Inhaled, insoluble, biopersistent particles and fibers are phagocytosed by lung macrophages and thought to be coated, either partially or completely, with an iron-containing protein at the interface forming a ferruginous body. These structures can be categorized as ferruginous bodies having either an inorganic or a carbonaceous core (e.g., asbestos and byssinotic bodies, respectively). In lung tissue, BAL, and sputum, the only cells that stain with PPB are macrophages. These are described as iron- and hemosiderin-laden macrophages and called either siderophages or sideromacrophages. Siderophages can be observed in the lung tissue, BAL, and sputum after various exposures and can also be associated with many different pulmonary and extrapulmonary diseases.
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Líquido da Lavagem Broncoalveolar/química , Corantes/metabolismo , Ferrocianetos/metabolismo , Pulmão/química , Macrófagos/química , Escarro/químicaRESUMO
Only 50% to 70% of patients with mesothelioma report asbestos exposure. Other exposures (eg, radiation) play a role in some cases, but some patients have no obvious cause. We describe a series of patients with long-standing indwelling intra-abdominal shunt catheters who developed malignant peritoneal mesothelioma, suggesting a novel association. We identified 7 patients who had shunts and subsequently developed mesothelioma (5 women; median age: 31 y, range: 18 to 45 y). Clinical history and pathology materials were reviewed, and RNA sequencing was performed. Clinical presentations varied; 6 patients had hydrocephalus and a ventriculoperitoneal shunt, and 1 patient had portal hypertension and a portoatrial shunt. The median duration of shunt therapy in 5 cases was 29 years (range: 12 to 35 y); the remaining 2 patients also had shunts for many years, but specific details were unavailable. Two patients had radiotherapy for malignancies in childhood. One had an alleged exposure to asbestos and 1 had prior exposure to talc. The rest had no known risk factors. Histologically, all tumors were purely epithelioid. Treatments included surgical debulking, chemotherapy, and palliative care. All 7 died of disease (median survival: 7 mo, range: 1 to 18 mo). Molecular testing showed loss of NF2 and CDKN2A/B and a BAP1 mutation in 1 case, and no genomic alterations associated with mesothelioma in 2 cases. Peritoneal mesothelioma may represent a complication of long-standing indwelling shunt catheters. The mechanism is unknown, but chronic peritoneal irritation may play a role. Albeit rare, mesothelioma should be considered in patients with a shunt who present with new ascites.