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BACKGROUND: Associations between air pollution and morbidity/mortality from cardiovascular disease are recognized in epidemiologic and clinical studies, but the mechanisms by which inhaled fibers or particles mediate the exacerbation of atherosclerosis are unclear. OBJECTIVE AND METHODS: To determine whether lung inflammation after inhalation of a well-characterized pathogenic particulate, chrysotile asbestos, is directly linked to exacerbation of atherosclerosis and the mechanisms involved, we exposed apolipoprotein E--deficient (ApoE--/--) mice and ApoE--/-- mice crossed with CD4--/-- mice to ambient air, NIEHS (National Institute of Environmental Health Sciences) reference sample of chrysotile asbestos, or fine titanium dioxide (TiO2), a nonpathogenic control particle, for 3, 9, or 30 days. RESULTS: ApoE--/-- mice exposed to inhaled asbestos fibers had approximately 3-fold larger atherosclerotic lesions than did TiO2-exposed ApoE--/-- mice or asbestos-exposed ApoE--/--/CD4--/-- doubleknockout (DKO) mice. Lung inflammation and the magnitude of lung fibrosis assessed histologically were similar in asbestos-exposed ApoE--/-- and DKO mice. Monocyte chemoattractant protein-1 (MCP-1) levels were increased in bronchoalveolar lavage fluid and plasma, and plasma concentrations correlated with lesion size (p < 0.04) in asbestos-exposed ApoE--/-- mice. At 9 days, activator protein-1 (AP-1) and nuclear factor-[kappa]B (NF-[kappa]B), transcription factors linked to inflammation and found in the promoter region of the MCP-1 gene, were increased in aortas of asbestos-exposed ApoE--/-- but not DKO mice. CONCLUSION: Our findings show that the degree of lung inflammation and fibrosis does not correlate directly with cardiovascular effects of inhaled asbestos fibers and support a critical role of CD4+ T cells in linking fiber-induced pulmonary signaling to consequent activation of AP-1-- and NF-[kappa]B--regulated genes in atherogenesis. [ABSTRACT FROM AUTHOR]

Giant cell pneumonia secondary to human parainfluenza virus 3 has been reported only rarely in immunocompromised hosts. The few cases documented after bone marrow transplant have resulted in significant morbidity and mortality. To our knowledge, this entity has not been described following umbilical cord blood transplant. Pulmonary alveolar proteinosis, a rare condition that has been reported with increasing frequency in association with immunocompromise and infections, has not been documented in the setting of either umbilical cord blood transplant or human parainfluenza viral infection. We report what we believe is the first documented case of giant cell pneumonia caused by human parainfluenza virus 3 in an umbilical cord blood transplant recipient. To our knowledge, a unique associated feature of this case, a pulmonary alveolar proteinosis--like reaction, has not been reported previously in association with human parainfluenza virus pneumonia. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer related deaths worldwide, although some patients with early-stage disease can be cured with surgical resection. Standardised reporting of all clinically relevant pathological parameters is essential for best patient care and is also important for ongoing data collection and refinement of important pathological features that impact patient prognosis, staging and clinical care. Using the established International Collaboration on Cancer Reporting (ICCR) procedure, a representative international expert panel of nine lung pathologists as well as an oncologist was convened. Essential core elements and suggested non-core elements were identified for inclusion in the resected lung cancer pathology data set based on predetermined levels of evidence as well as consensus expert opinion. A lung cancer histopathology reporting guide was developed that includes relevant clinical, macroscopic, microscopic and ancillary testing. Critical review and discussion of current evidence was incorporated into the new data set including changes from the 2021 World Health Organisation (WHO) Classification of Thoracic Tumours, fifth edition, new requirements for grading invasive non-mucinous adenocarcinomas, assessment of response to neoadjuvant therapy and requirements for molecular testing in early-stage resected lung carcinomas. This ICCR data set represents incorporation of all relevant parameters for histology reporting of lung cancer resection specimens. Routine use of this data set is recommended for all pathology reporting of resected lung cancer and it is freely available worldwide on the ICCR website (https://www.iccr-cancer.org/datasets/published-datasets/). Widespread implementation will help to ensure consistent and comprehensive pathology reporting and data collection essential for lung cancer patient care, clinical trials and other research., (© 2024 John Wiley & Sons Ltd.)

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., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.

Objectives: Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM., Methods: Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions., Results: Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens., Conclusions: Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS., (Copyright © 2021. Published by Elsevier B.V.)

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age <60 years (P = 0.0001), ECOG performance status 0 or 1 (P = 0.01), absence of radiographic lymph-node metastasis (P = 0.04), cytoreduction surgery (P < 0.0001), hyperthermic intraperitoneal chemotherapy (P = 0.0001), peritoneal carcinomatosis index <27 (P = 0.01), absence of necrosis (P = 0.007), and epithelioid histotype (P < 0.0001). Among epithelioid malignant mesotheliomas only, longer overall survival was further associated with female sex (P = 0.03), tubulopapillary architecture (P = 0.005), low nuclear pleomorphism (P < 0.0001), low mitotic index (P = 0.0007), and low composite nuclear grade (P < 0.0001). On multivariate analyses, the low composite nuclear grade was independently associated with longer overall and disease-free survival (P < 0.0001). Our data further clarify the interactions of clinical and pathologic features in peritoneal mesothelioma prognosis and validate the prognostic significance of a standardized nuclear-grading system in epithelioid malignant mesothelioma of the peritoneum.

Introduction: We describe post-mortem pulmonary histopathologic findings of COVID-19 pneumonia in patients with a spectrum of disease course, from rapid demise to prolonged hospitalisation., Methods and Results: Histopathologic findings in post-mortem lung tissue from eight patients who died from COVID-19 pneumonia were reviewed. Immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed to detect virus. Diffuse alveolar damage (DAD) was seen in all cases with a spectrum of acute phase and/or organising phase. IHC with monoclonal antibodies against SARS-CoV-2 viral nucleoprotein and spike protein detected virus in areas of acute but not organising DAD, with intracellular viral antigen and RNA expression seen predominantly in patients with duration of illness less than 10 days. Major vascular findings included thrombi in medium- and large-calibre vessels, platelet microthrombi detected by CD61 IHC and fibrin microthrombi., Conclusions: Presence of SARS-CoV-2 viral RNA by NGS early in the disease course and expression of viral antigen by IHC exclusively in the acute, but not in the organising phase of DAD, suggests that the virus may play a major role in initiating the acute lung injury of DAD, but when DAD progresses to the organising phase the virus may have been cleared from the lung by the patient's immune response. These findings suggest the possibility of a major change during the disease course of COVID-19 pneumonia that may have therapeutic implications. Frequent thrombi and microthrombi may also present potential targets for therapeutic intervention., (© 2020 John Wiley & Sons Ltd.)

Exposure to polytetrafluoroethylene (PTFE), a compound used in nonstick cookware coating and a variety of other applications, is known to cause acute lung injury and granulomatous pneumonitis. It is uncertain whether PTFE and compounds used in its manufacture, such as perfluorooctanoic acid (PFOA), cause chronic lung disease. Here we report a case of interstitial pulmonary fibrosis in a 71-year-old man who died following a brief illness clinically suspected to be acute respiratory distress syndrome. He had a 25-year history of occupational exposure to PTFE and PFOA. At postmortem examination, the lungs demonstrated diffuse alveolar damage (DAD) superimposed on interstitial pulmonary fibrosis. The interstitial fibrosis lacked fibroblast foci and exhibited basilar and subpleural accentuation with focal microscopic honeycombing. Within the fibrotic lung parenchyma were scattered giant cells containing birefringent translucent particles. Scanning electron microscopy and energy-dispersive x-ray spectroscopy (SEM-EDS) were performed. A majority of the birefringent particles demonstrated a prominent peak for fluorine by EDS analysis. This is the first report to document the presence of fluorine, an elemental constituent of PTFE and PFOA, in fibrotic lung tissue. Careful evaluation of other individuals with long-term exposure to PTFE and/or PFOA appears warranted to better elucidate the spectrum of pulmonary disease associated with these compounds.

Lung adenocarcinomas differ in prognosis based on their histologic growth pattern. Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) both have an excellent prognosis when completely resected, whereas solid and micropapillary-predominant adenocarcinomas do not, with other patterns falling in between. In recent years, it has become apparent that even within histologic patterns, there are differences in appearance that are clinically important, such as complex acinar formations and highly variable-sized papillae. This review highlights prognostically important histologic features in lung adenocarcinoma that have emerged since implementation of the current World Health Organization (WHO) classification of lung adenocarcinoma., Competing Interests: Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr.2019.12.30). The series “Selected Highlights of the 2019 Pulmonary Pathology Society Biennial Meeting” was commissioned by the editorial office without any sponsorship or funding. The author has no other conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Patients undergoing transthoracic needle core lung biopsy (TTNB) are at risk for biopsy-related pneumothorax. Instilling pleural sealant at the pleural puncture site reduces this risk. The impact of histologic changes associated with pleural sealant on assessing the histologic type and pathologic stage in lung cancer resection specimens has not been previously evaluated. All lung cancer resection specimens from 2015 to 2018 in which polyethylene glycol hydrogel pleural sealant was instilled during TTNB were reviewed. Thirty-three cases were identified. TTNB preceded lobectomy by an average of 35 days. Amphophilic, weakly polarizable, crinkled pleural sealant material was associated with tumor in 11 cases (33%), including 8 adenocarcinomas, 2 squamous cell carcinomas, and 1 pleomorphic carcinoma that averaged 1.7 cm in greatest dimension. Surrounding the sealant material was a 0.25 to 1.0 cm in greatest dimension pseudocystic space with a thin granulomatous rim of macrophages and multinucleated giant cells that occupied on average 17% of the tumoral area. Pleural sealant could have impaired assessment of pathologic stage in 1 case by obscuring the visceral pleural elastic layer, but definitive visceral pleural invasion was present nearby. Although hydrogel pleural sealant instilled during TTNB has the potential to obscure important histologic features, in practice, it appears to have little or no adverse impact on the assessment of histologic type and pathologic stage in subsequent lung cancer resection specimens. Recognition of the histologic appearance of hydrogel pleural sealant and its associated tissue response is important for avoiding diagnostic misinterpretation.

Introduction: Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma where pathologic diagnosis has been essentially limited to three histologic subtypes., Methods: A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists, and oncologists), sponsored by European Network for Rare Adult Solid Cancers/International Association for the Study of Lung Cancer, met in 2018 to critically review the current classification., Results: Recommendations include: (1) classification should be updated to include architectural patterns and stromal and cytologic features that refine prognostication; (2) subject to data accrual, malignant mesothelioma in situ could be an additional category; (3) grading of epithelioid malignant pleural mesotheliomas should be routinely undertaken; (4) favorable/unfavorable histologic characteristics should be routinely reported; (5) clinically relevant molecular data (programmed death ligand 1, BRCA 1 associated protein 1 [BAP1], and cyclin dependent kinase inhibitor 2A) should be incorporated into reports, if undertaken; (6) other molecular data should be accrued as part of future trials; (7) resection specimens (i.e., extended pleurectomy/decortication and extrapleural pneumonectomy) should be pathologically staged with smaller specimens being clinically staged; (8) ideally, at least three separate areas should be sampled from the pleural cavity, including areas of interest identified on pre-surgical imaging; (9) image-acquisition protocols/imaging terminology should be standardized to aid research/refine clinical staging; (10) multidisciplinary tumor boards should include pathologists to ensure appropriate treatment options are considered; (11) all histologic subtypes should be considered potential candidates for chemotherapy; (12) patients with sarcomatoid or biphasic mesothelioma should not be excluded from first-line clinical trials unless there is a compelling reason; (13) tumor subtyping should be further assessed in relation to duration of response to immunotherapy; and (14) systematic screening of all patients for germline mutations is not recommended, in the absence of a family history suspicious for BAP1 syndrome., Conclusions: These multidisciplinary recommendations for pathology classification and application will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials., (Copyright © 2019 International Association for the Study of Lung Cancer. All rights reserved.)

Malignant mesothelioma (MM) arising from the serosal membranes of the tunica vaginalis testis (TVT) is rare. Most examples in the published medical literature are individual case reports. This study presents the clinicopathological findings of mesothelioma of the TVT in one of the largest series to date. Individuals with mesothelioma of the TVT were identified from a database of more than 4000 mesothelioma cases, and their clinicopathological features were recorded. Eighteen men with MM and 2 with well-differentiated papillary mesothelioma of the TVT were identified, which represented 0.6% of males with mesothelioma in study population. The median age at diagnosis was 72 years (range, 32-85 years). A neoplasm was not suspected preoperatively in 12 of the 17 (71%) men whose clinical presentation was known, 7 of whom presented with hydrocele and 5 with inguinal hernia. The other 5 had a clinically recognized mass. Seven of the men underwent herniorrhaphy; 7, radical orchiectomy; 3, hydrocelectomy; and 3, paratesticular mass biopsy or excision as the initial diagnostic procedure. Twelve of the MM cases were epithelioid and 6 were biphasic. Among the 6 men with MM who had ≥6 months of follow-up, 1 was alive with no evidence of disease at 6 months, and 5 were known to have died of disease 8-74 months (median = 31.5 months) following diagnosis. Three men with MM had received either chemotherapy or radiation therapy. Of the 2 men initially diagnosed with well-differentiated papillary mesothelioma, 1 was alive without evidence of disease 5 years after diagnosis, while the other had findings more compatible with MM with peritoneal involvement 2 years following initial diagnosis. In 15 of the 18 cases of MM (83%), there was documented occupational or paraoccupational exposure to asbestos, the average duration of which was 33 years (range, 2-46 years). Information regarding the presence or absence of pleural plaques was available in 5 of the MM cases, and pleural plaques had been found in 4. Lung tissue was not available for fiber analysis in any of the cases. One additional case originally diagnosed at another institution as MM of the TVT was reclassified as adenocarcinoma following performance of additional immunohistochemical testing. TVT is a rare site of MM, the diagnosis of which is often unsuspected preoperatively. Like its counterparts at other serosal sites, MM of the TVT is an aggressive tumor with a poor prognosis that evidence would suggest is etiologically associated with asbestos in at least some cases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: Florid mesothelial hyperplasia is known to result from endometriosis. Well-differentiated papillary mesothelioma and multiloculated peritoneal inclusion cysts have also been described in women with endometriosis. To our knowledge, peritoneal diffuse malignant mesothelioma (MM) arising in the setting of endometriosis has not been reported. The purpose of this study is to report the clinicopathological characteristics of women with MM and endometriosis., Methods: The surgical pathology files of a tertiary academic medical centre and the consultation files of one of the study authors were reviewed for cases of MM in females with and without endometriosis., Results: Six women with MM and endometriosis ranging in age from 29 to 55 years (median=45 years) were identified. All had peritoneal MM and endometriosis involving the peritoneum and/or adnexa. Five had epithelioid MM and one had biphasic MM. Two had paraoccupational exposure to asbestos. The median age of women with MM and endometriosis (44.5 years) was significantly less than the median age of cases without endometriosis (58.0 years) (p value=0.01)., Conclusions: To our knowledge, this is the first report of MM in women with endometriosis. Interestingly, MM in the setting of endometriosis has only been observed in the peritoneum and not in other serosal cavities. The findings in the present study suggest that chronic serosal inflammation secondary to endometriosis may be an inducing factor in rare cases of MM of the peritoneum., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death 1-3 . Oxidative stress is believed to be critical in this disease pathogenesis 4-6 , although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modification of proteins that can be reversed by glutaredoxin-1 (GLRX) 7 . It remains unknown whether GLRX and PSSG play a role in lung fibrosis. Here, we explored the impact of GLRX and PSSG status on the pathogenesis of pulmonary fibrosis, using lung tissues from subjects with idiopathic pulmonary fibrosis, transgenic mouse models and direct administration of recombinant Glrx to airways of mice with existing fibrosis. We demonstrate that GLRX enzymatic activity was strongly decreased in fibrotic lungs, in accordance with increases in PSSG. Mice lacking Glrx were far more susceptible to bleomycin- or adenovirus encoding active transforming growth factor beta-1 (AdTGFB1)-induced pulmonary fibrosis, whereas transgenic overexpression of Glrx in the lung epithelium attenuated fibrosis. We furthermore show that endogenous GLRX was inactivated through an oxidative mechanism and that direct administration of the Glrx protein into airways augmented Glrx activity and reversed increases in collagen in mice with TGFB1- or bleomycin-induced fibrosis, even when administered to fibrotic, aged animals. Collectively, these findings suggest the therapeutic potential of exogenous GLRX in treating lung fibrosis.

Context: - Malignant mesothelioma (MM) is a component of the BAP1 tumor predisposition syndrome. Other than in BAP1 familial studies, nonmesothelial neoplasms in individuals with MM has not been comprehensively assessed., Objective: - To assess the spectrum and prevalence of nonmesothelial neoplasms in individuals with MM., Design: - Individuals with MM and second neoplasms were identified from a database of 3900 MM cases. The expected prevalence of each type of neoplasm was calculated and compared with the actual prevalence in the study population using available Surveillance, Epidemiology, and End Results data and other published data., Results: - Two hundred seventy nonmesothelial neoplasms were identified in 241 individuals (6% of the study population) with MM. Prostate adenocarcinoma was most common. Non-Hodgkin lymphoma, Hodgkin lymphoma, lung carcinoma, urothelial carcinoma, breast carcinoma, chronic lymphocytic leukemia, clear cell renal cell carcinoma, head and neck squamous cell carcinoma, papillary renal cell carcinoma, multiple myeloma/plasmacytoma, meningioma, pleomorphic undifferentiated sarcoma, chronic myelogenous leukemia, ocular melanoma, hepatocellular carcinoma, liposarcoma, and Wilms tumor all were more prevalent than expected., Conclusions: - Nonmesothelial neoplasms are uncommon in individuals with MM, but certain tumor types are increased in prevalence. In an unselected study population with respect to BAP1 status, the prevalence of several tumor types described in BAP1 mutation carriers, including lung carcinoma, clear cell renal cell carcinoma, breast carcinoma, meningioma, pleomorphic undifferentiated sarcoma, and ocular melanoma, was increased.

Postablation tubal sterilization syndrome (PATSS) is an uncommon complication of endometrial ablation in patients with antecedent tubal ligation characterized by cyclic pelvic pain. Recurrent tubal distention resulting from retrograde menstruation into occluded proximal fallopian tube segments by residual/regenerated cornual endometrial tissue is postulated to be the cause. Reports of PATSS have largely focused on the clinicoradiologic and operative findings. Detailed descriptions of the gross pathologic findings of PATSS are sparse and rarer still are examples in which the histologic manifestations are discussed. Three patients with a history of tubal ligation and subsequent endometrial ablation who underwent hysterectomy and bilateral salpingo-oophorectomy for pelvic pain were identified. A clinical suspicion of PATSS was conveyed to the pathologist at the time of initial pathologic examination in only 2 of the 3 cases. Pathologic findings in all 3 cases were similar and included hematosalpinx of the proximal fallopian tubes, intraluminal hemosiderotic material, mural hemosiderosis, and pseudoxanthomatous salpingitis featuring plical and mural lipofuscin-laden macrophages, along with inactive to attenuated endometrium with variable submucosal myometrial hyalinization/scarring compatible with postablative changes. The pathologic features, in conjunction with the appropriate clinicoradiologic findings, were interpreted as consistent with PATSS. PATSS complicates an estimated 5% to 10% of endometrial ablations, but is likely underreported due to a lack of awareness. Pathologists should consider PATSS in hysterectomy specimens that show postablative endometrial changes accompanied by hematosalpinx and pseudoxanthomatous salpingitis of the proximal segments of ligated fallopian tubes. To our knowledge, this is the first study to depict the histopathologic features of PATSS.

Context The Staging and Prognostic Factors Committee of the International Association for the Study of Lung Cancer, in conjunction with the International Mesothelioma Interest Group, the International Thymic Malignancy Interest Group, and the Worldwide Esophageal Cancer Collaboration, developed proposals for the 8th edition of their respective tumor, node, metastasis (TNM) staging classification systems. Objective To review these changes and discuss issues for the reporting pathologist. Data Sources Proposals were based on international databases of lung (N = 94 708), with an external validation using the US National Cancer Database; mesothelioma (N = 3519); thymic epithelial tumors (10 808); and epithelial cancers of the esophagus and esophagogastric junction (N = 22 654). Conclusions These proposals have been mostly accepted by the Union for International Cancer Control and the American Joint Committee on Cancer and incorporated into their respective staging manuals (2017). The Union for International Cancer Control recommended implementation beginning in January 2017; however, the American Joint Committee on Cancer has deferred deployment of the eighth TNM until January 1, 2018, to ensure appropriate infrastructure for data collection. This manuscript summarizes the updated staging of thoracic malignancies, specifically highlighting changes from the 7th edition that are relevant to pathologic staging. Histopathologists should become familiar with, and start to incorporate, the 8th edition staging in their daily reporting of thoracic cancers henceforth.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

Context: - Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose., Objective: - To provide updated, practical guidelines for the pathologic diagnosis of MM., Data Sources: - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks., Conclusions: - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

Aims: Mesothelial reaction simulating peritoneal diffuse malignant mesothelioma (MM) has been reported in the setting of Crohn ileitis. To our knowledge, peritoneal MM arising in patients with inflammatory bowel disease (IBD) has not been reported. The purpose of this study is to report the clinicopathological characteristics of patients with peritoneal MM and IBD., Methods: A database of approximately 3800 MM was reviewed for cases of MM in patients with IBD., Results: Three patients (0.08%) with peritoneal MM and Crohn disease (CD) were identified, including two women and one man ranging in age from 56 to 65 years. All had a long-standing history of diarrhoea and an established diagnosis of CD of 3 years or greater duration. Two had epithelial MM and one had biphasic MM. Only one had documented asbestos exposure., Conclusions: Peritoneal MM occurs rarely in patients with IBD, but interestingly, has only been observed in the setting of CD and not in patients with ulcerative colitis. Chronic inflammation has been associated with the development of MM in rare instances and these three cases suggest that CD with transmural inflammation may also be a precursor. The precise role of CD-related transmural inflammation in the carcinogenesis of peritoneal MM remains to be determined., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Idiopathic pulmonary fibrosis (IPF) is a debilitating lung disease characterized by excessive collagen production and fibrogenesis. Apoptosis in lung epithelial cells is critical in IPF pathogenesis, as heightened loss of these cells promotes fibroblast activation and remodeling. Changes in glutathione redox status have been reported in IPF patients. S-glutathionylation, the conjugation of glutathione to reactive cysteines, is catalyzed in part by glutathione- S -transferase π (GSTP). To date, no published information exists linking GSTP and IPF to our knowledge. We hypothesized that GSTP mediates lung fibrogenesis in part through FAS S-glutathionylation, a critical event in epithelial cell apoptosis. Our results demonstrate that GSTP immunoreactivity is increased in the lungs of IPF patients, notably within type II epithelial cells. The FAS-GSTP interaction was also increased in IPF lungs. Bleomycin- and AdTGFβ-induced increases in collagen content, α-SMA, FAS S-glutathionylation, and total protein S-glutathionylation were strongly attenuated in Gstp -/- mice. Oropharyngeal administration of the GSTP inhibitor, TLK117, at a time when fibrosis was already apparent, attenuated bleomycin- and AdTGFβ-induced remodeling, α-SMA, caspase activation, FAS S-glutathionylation, and total protein S-glutathionylation. GSTP is an important driver of protein S-glutathionylation and lung fibrosis, and GSTP inhibition via the airways may be a novel therapeutic strategy for the treatment of IPF.

Objectives: To examine the clinicopathologic characteristics of individuals with diffuse malignant mesothelioma (DMM) occurring concurrently with lung cancer (LC)., Materials and Methods: A database of approximately 3800 patients with DMM was reviewed, from which 18 patients (0.5%) who had synchronous LC were identified. The clinicopathologic features, as well as the occupational exposure history and fiber burden analysis data were examined., Results: The patient median age was 68 years (range 58-84 years). Of the 18 patients (14 male, 4 female), 11 (61%) had epithelial, 5 (28%) had biphasic, and 2 (11%) had sarcomatoid DMM, with the majority (16 cases; 89%) originating in the pleura and only 2 were peritoneal. Among the histologic types of LC, adenocarcinoma was most frequent (12 cases; 67%), while 5 cases of squamous cell carcinoma, and 1 case of small cell carcinoma were observed. Three patients also had a history of prior malignancy (1 with testicular seminoma and bladder carcinoma and 2 with prostate carcinoma). Fifteen patients had a positive smoking history. All but 3 had documented asbestos exposure. Three had histologic features of asbestosis. Mineral analysis performed in 8 showed an elevated asbestos fiber burden in 4 (22%). Amosite was detected in 4 patients, crocidolite in 3, and non-commercial amphiboles in 5., Conclusion: The finding of simultaneous carcinoma of the lung and DMM is distinctly unusual. The majority of patients are male smokers with pleural epithelial DMM and lung adenocarcinoma. This study represents the largest cohort of patients reported to date with synchronous malignant mesothelioma and lung cancer, and we propose guidelines for making a diagnosis of synchronous malignant mesothelioma and primary lung cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Context: Although epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-directed therapies are not approved for patients with early-stage non-small cell lung carcinoma (NSCLC), many institutions perform EGFR and ALK testing for all patients with NSCLC at the time of initial diagnosis. Current consensus guidelines recommend EGFR testing and suggest ALK testing at the time of initial diagnosis for patients with advanced disease., Objectives: To examine the cost and clinical impact of EGFR and ALK testing of patients with early-stage NSCLC., Design: Records from all patients with a diagnosis of NSCLC made on a nonresection specimen at our institution during a single calendar year (2012) were reviewed, and a cost analysis was performed., Results: Of 133 total patients, 47 (35%) had early-stage (stage I or II) disease and 86 (65%) had locally advanced (stage III) or advanced (stage IV) disease at presentation. Eight of 47 patients with early-stage disease (17%) had progression/recurrence during 18 to 30 months of follow-up, 6 of 8 (75%) of whom had pathologic confirmation of progression/recurrence. The estimated additional cost of EGFR and ALK testing for all newly diagnosed patients with NSCLC at our institution is $75,200 per year, compared to testing only patients with locally advanced and advanced-stage disease., Conclusions: The cost of universal molecular testing of NSCLC is substantial. EGFR and ALK testing of patients with early-stage disease appears to have negligible clinical impact, as most patients do not have disease recurrence/progression. Those whose disease recurs/progresses typically undergo rebiopsy. Our findings do not support the practice of universal EGFR and ALK testing in NSCLC at the time of initial diagnosis.

Aims: The utility of routine histological examination of clinically primary spontaneous pneumothorax (SPTX) specimens has been questioned. In this retrospective study, we aimed to assess the clinical significance of unexpected SPTX histopathological findings, to determine whether such findings justify routine histological examination of SPTX specimens., Methods and Results: Records and slides from all SPTX resections at our institution from 2002-2012 were reviewed. Clinically significant unexpected histological findings were identified in 8.3% of 72 patients, including: one patient with lung cancer, one with endometriosis, one with Birt-Hogg-Dubé (BHD) syndrome, and three with 'bong lung'. Detection of BHD syndrome has the potential to avert advanced renal carcinoma by identifying individuals who should undergo periodic abdominal CT screening. The cost of treating a case of advanced renal carcinoma far exceeds that of histologically examining all SPTX specimens received in a 10-year period at our institution., Conclusions: Gross examination alone is an inadequate evaluation of SPTX specimens. This is the first study to demonstrate that routine histological examination of SPTX specimens is justified, in that it discloses unexpected findings that are clinically significant and impact on patient management., (© 2014 John Wiley & Sons Ltd.)

Purpose: To assess the diagnostic performance of computed tomography (CT)-guided transthoracic needle aspiration biopsy (TNAB) in the evaluation of persistent subsolid lung lesions., Materials and Methods: A retrospective review of all CT-guided TNABs performed at a single institution from January 2002 to November 2012 was conducted to identify patients with persistent subsolid lung lesions. The diagnostic performance of CT-guided TNAB was assessed through comparison of cytologic diagnoses with core needle biopsy, surgical resection, or imaging and clinical follow-up. The cytologic, histologic, and imaging features of each lesion were characterized, and CT-guided TNAB complications were recorded., Results: In 32 patients, a diagnosis of benign or malignant disease was identified through evaluation of pathologic or follow-up data. There were 18 men and 14 women, with a mean age of 67.1 years ± 9.6 (range, 52-86 y). The mean lesion diameter was 21 mm ± 11 (range, 8-62 mm). A final diagnosis of malignancy was made in 28 cases (87.5%); four benign lesions were also diagnosed. The overall sensitivity of CT-guided TNAB in the evaluation of these lesions was 89.2%, and the specificity and positive predictive value were 100%. Two pneumothoraces (6.3%) were identified., Conclusions: Among patients with subsolid lung lesions, CT-guided TNAB is safe and shows high sensitivity. The high specificity and positive predictive value of the procedure allow for definitive treatment decisions to be made for most patients., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Malignant mesotheliomas (MMs) are chemoresistant tumors related to exposure to asbestos fibers. The long latency period of MM (30-40 yrs) and heterogeneity of tumor presentation make MM difficult to diagnose and treat at early stages. Currently approved second-line treatments following surgical resection of MMs include a combination of cisplatin or carboplatin (delivered systemically) and pemetrexed, a folate inhibitor, with or without subsequent radiation. The systemic toxicities of these treatments emphasize the need for more effective, localized treatment regimens., Methods: Acid-prepared mesoporous silica (APMS) microparticles were loaded with doxorubicin (DOX) and modified externally with a mesothelin (MB) specific antibody before repeated intraperitoneal (IP) injections into a mouse xenograft model of human peritoneal MM. The health/weight of mice, tumor volume/weight, tumor necrosis and cell proliferation were evaluated in tumor-bearing mice receiving saline, DOX high (0.2 mg/kg), DOX low (0.05 mg/kg), APMS-MB, or APMS-MB-DOX (0.05 mg/kg) in saline., Results: Targeted therapy (APMS-MB-DOX at 0.05 mg/kg) was more effective than DOX low (0.05 mg/kg) and less toxic than treatment with DOX high (0.2 mg/kg). It also resulted in the reduction of tumor volume without loss of animal health and weight, and significantly decreased tumor cell proliferation. High pressure liquid chromatography (HPLC) of tumor tissue confirmed that APMS-MB-DOX particles delivered DOX to target tissue., Conclusions: Data suggest that targeted therapy results in greater chemotherapeutic efficacy with fewer adverse side effects than administration of DOX alone. Targeted microparticles are an attractive option for localized drug delivery.

Sarcina are gram-positive anaerobic bacteria found to be associated with delayed gastric emptying and gastric outlet obstruction. We describe two cases of Sarcina co-existing with Helicobacter pylori organisms in pediatric siblings presenting within four months of each other with pyloric obstruction secondary to severe gastritis/duodenitis. The co-existence of Sarcina and Helicobacter pylori has not, to our knowledge, been previously reported. Its characteristic tetrad packeted morphology permits Sarcina to be readily identified on routine sections. Detection of these organisms in gastric biopsies should prompt consideration of gastric outlet obstruction and/or delayed gastric emptying as a possible etiologic factor.

Context: The International Collaboration on Cancer Reporting (ICCR) is a quadripartite alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, and the Canadian Partnership Against Cancer. The ICCR was formed with a view to reducing the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish, and maintain standardized cancer-reporting data sets. The resultant standardization of cancer reporting would be expected to benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets., Objectives: To develop an evidence-based reporting data set for each cancer site., Design: A project to develop data sets for prostate, endometrium, and lung cancers and malignant melanoma was piloted by the quadripartite group., Results: A set of required and recommended data elements and appropriate responses for each element were agreed upon for the reporting of lung cancer., Conclusions: This review describes the process of development of the lung cancer data set.

The use of p63 has been advocated for separating small cell lung carcinoma from poorly differentiated non-small cell lung carcinoma, in particular, squamous cell lung carcinoma. However, p63 is not entirely specific in this distinction, as several studies have demonstrated p63 immunoreactivity in a proportion of small cell lung carcinomas. p40 (ΔNp63) has recently been purported to be a highly specific marker for squamous cell lung carcinoma, but data regarding p40 (ΔNp63) in small cell lung carcinoma, a key differential diagnostic consideration in biopsy samples of squamous cell lung carcinoma, are lacking. In this study, a total of 34 previously confirmed small cell lung carcinomas (27 bronchoscopic biopsy samples and 7 large specimens) were immunostained for p40 (ΔNp63), p63, and keratin 34βE12. All 34 small cell lung carcinomas were negative for p40 (ΔNp63) and keratin 34βE12. Although none of the large small cell lung carcinoma specimens exhibited p63 immunoreactivity, 12 (44.4%) of 27 biopsy samples of small cell lung carcinoma were positive for p63. The rate of p63 staining in small cell lung carcinoma biopsy samples differed significantly from that of p40 (ΔNp63) and keratin 34βE12 (P = .005). Ten cases of squamous cell lung carcinoma were also tested, all of which were positive for all 3 markers. These findings confirm that p63 immunoexpression is not uncommon in biopsy samples of small cell lung carcinoma. Positive p63 staining may be mistakenly interpreted as supportive of squamous differentiation and result in misclassification of small cell lung carcinoma as squamous cell lung carcinoma, a diagnostic error that has important therapeutic and prognostic consequences. To provide greater diagnostic accuracy, p40 (ΔNp63) or keratin 34βE12 should be used instead of p63 in the distinction of small cell lung carcinoma from non-small cell lung carcinoma in biopsy samples., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Pleural and peritoneal mesotheliomas (MMs) are chemoresistant tumors with no effective therapeutic strategies. The authors first injected multifunctional, acid-prepared mesoporous spheres (APMS), microparticles functionalized with tetraethylene glycol oligomers, intraperitoneally into rodents. Biodistribution of APMS was observed in major organs, peritoneal lavage fluid (PLF), and urine of normal mice and rats. After verification of increased mesothelin in human mesotheliomas injected into severe combined immunodeficient (SCID) mice, APMS were then functionalized with an antibody to mesothelin (APMS-MB) or bovine serum albumin (BSA), a nonspecific protein control, and tumor targeting was evaluated by inductively coupled plasma mass spectrometry and multifluorescence confocal microscopy. Some APMS were initially cleared via the urine over a 24 hr period, and small amounts were observed in liver, spleen, and kidneys at 24 hr and 6 days. Targeting with APMS-MB increased APMS uptake in mesenteric tumors at 6 days. Approximately 10% to 12% of the initially injected amount was observed in both spheroid and mesenteric MM at this time point. The data suggest that localized delivery of APMS-MB into the peritoneal cavity after encapsulation of drugs, DNA, or macromolecules is a novel therapeutic approach for MM and other tumors (ovarian and pancreatic) that overexpress mesothelin.

Objective: Pulmonary carcinoid tumors are low-grade malignant neoplasms thought to arise primarily within the central airways in 85% of cases. The CT features of pulmonary carcinoid tumors that arise as solitary pulmonary nodules (SPNs) have not been well elucidated. We reviewed our experience with primary pulmonary carcinoid tumors to determine the distribution of lesions within the lung at diagnosis and to identify CT features that might aid in distinguishing these neoplasms from benign pulmonary nodules., Materials and Methods: CT scans, if available, of all patients with a primary pulmonary carcinoid tumor diagnosed by biopsy or surgical resection over the previous 15 years were reviewed. The CT scans were reviewed for the following features: lesion location; order of bronchus involved; lesion size, contour, and density; contrast enhancement; and the presence of peripheral atelectasis, hyperlucency, and bronchiectasis. We defined central lesions as those involved with a segmental or larger bronchus. Subsegmental bronchial involvement and tumors surrounded by lung parenchyma without direct airway involvement were defined as peripheral lesions. The final pathologic diagnosis for all cases was confirmed by review of cytologic or histologic specimens., Results: Twenty-eight carcinoid tumors were identified in 28 patients: 24 typical carcinoids and four atypical carcinoids. The study group was composed of 23 females and five males with a mean age of 52.4 years (range, 14-83 years). Twelve of the 28 lesions (43%) were central (i.e., involved a segmental or larger bronchus), and the remaining 16 lesions (57%) were peripheral. The mean tumor diameter for the 16 peripheral tumors was 14 mm (range, 9-28 mm); the majority (14/16, 88%) had a lobulated contour. Of six peripheral lesions with unenhanced and contrast-enhanced CT nodule enhancement studies, the mean maximal enhancement was 55.2 HU (range, 34-73 HU). Thirteen of the 16 peripheral carcinoid tumors (81%) involved a subsegmental bronchus, with 10 (63%) showing peripheral hyperlucency, bronchiectasis, or atelectasis., Conclusion: In our series, primary pulmonary carcinoid tumors presenting as peripheral SPNs were more common than central endobronchial lesions in contrast to the published literature. The CT features of peripheral carcinoid tumors presenting as SPNs that suggest the diagnosis include lobulated nodules of high attenuation on contrast-enhanced CT; nodules that densely enhance with contrast administration; the presence of calcification; subsegmental airway involvement on thin-section analysis; and nodules associated with distal hyperlucency, bronchiectasis, or atelectasis.

Members of the extracellular signal-regulated kinase (ERK) family may have distinct roles in the development of cell injury and repair, differentiation and carcinogenesis. Here, we show, using a synthetic small-molecule MEK1/2 inhibitor (U0126) and RNA silencing of ERK1 and 2, comparatively, that ERK2 is critical to transformation and homeostasis of human epithelioid malignant mesotheliomas (MMs), asbestos-induced tumors with a poor prognosis. Although MM cell (HMESO) lines stably transfected with shERK1 or shERK2 both exhibited significant decreases in cell proliferation in vitro, injection of shERK2 cells, and not shERK1 cells, into immunocompromised severe combined immunodeficiency (SCID) mice showed significant attenuated tumor growth in comparison to shControl (shCon) cells. Inhibition of migration, invasion and colony formation occurred in shERK2 MM cells in vitro, suggesting multiple roles of ERK2 in neoplasia. Microarray and quantitative real-time PCR analyses revealed gene expression that was significantly increased (CASP1, TRAF1 and FAS) or decreased (SEMA3E, RPS6KA2, EGF and BCL2L1) in shERK2-transfected MM cells in contrast to shCon-transfected MM cells. Most striking decreases were observed in mRNA levels of Semaphorin 3 (SEMA3E), a candidate tumor suppressor gene linked to inhibition of angiogenesis. These studies demonstrate a key role of ERK2 in novel gene expression critical to the development of epithelioid MMs. After injection of sarcomatoid human MM (PPMMill) cells into SCID mice, both shERK1 and shERK2 lines showed significant decreased tumor growth, suggesting heterogeneous effects of ERKs in individual MMs., (Copyright © 2010 UICC.)

New and effective treatment strategies are desperately needed for malignant mesothelioma (MM), an aggressive cancer with a poor prognosis. We have shown previously that acid-prepared mesoporous microspheres (APMS) are nontoxic after intrapleural or intraperitoneal (IP) administration to rodents. The purpose here was to evaluate the utility of APMS in delivering chemotherapeutic drugs to human MM cells in vitro and in two mouse xenograft models of MM. Uptake and release of doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were evaluated in MM cells. MM cell death and gene expression linked to DNA damage/repair were also measured in vitro. In two severe combined immunodeficient mouse xenograft models, mice received saline, APMS, DOX or APMS-DOX injected directly into subcutaneous (SC) MM tumors or injected IP after development of human MMs peritoneally. Other mice received DOX intravenously (IV) via tail vein injections. In comparison to DOX alone, APMS-DOX enhanced intracellular uptake of DOX, MM death and expression of GADD34 and TP73. In the SC MM model, 3× weekly SC injections of APMS-DOX or DOX alone significantly inhibited tumor volumes, and systemic DOX administration was lethal. In mice developing IP MMs, significant (p < 0.05) inhibition of mesenteric tumor numbers, weight and volume was achieved using IP administration of APMS-DOX at one-third the DOX concentration required after IP injections of DOX alone. These results suggest APMS are efficacious for the localized delivery of lower effective DOX concentrations in MM and represent a novel means of treating intracavitary tumors., (Copyright © 2010 UICC.)

Inflammation and lung remodeling are hallmarks of asbestos-induced fibrosis, but the molecular mechanisms that control these events are unclear. Using laser capture microdissection (LCM) of distal bronchioles in a murine asbestos inhalation model, we show that osteopontin (OPN) is up-regulated by bronchiolar epithelial cells after chrysotile asbestos exposures. In contrast to OPN wild-type mice (OPN(+/+)) inhaling asbestos, OPN null mice (OPN(-/-)) exposed to asbestos showed less eosinophilia in bronchoalveolar lavage fluids, diminished lung inflammation, and decreased mucin production. Bronchoalveolar lavage fluid concentrations of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-12 subunit p40, MIP1α, MIP1β, and eotaxin) also were significantly less in asbestos-exposed OPN(-/-) mice. Microarrays performed on lung tissues from asbestos-exposed OPN(+/+) and OPN(-/-) mice showed that OPN modulated the expression of a number of genes (Col1a2, Timp1, Tnc, Eln, and Col3a1) linked to fibrosis via initiation and cross talk between IL-1β and epidermal growth factor receptor-related signaling pathways. Novel targets of OPN identified include genes involved in cell signaling, immune system/defense, extracellular matrix remodeling, and cell cycle regulation. Although it is unclear whether the present findings are specific to chrysotile asbestos or would be observed after inhalation of other fibers in general, these results highlight new potential mechanisms and therapeutic targets for asbestosis and other diseases (asthma, smoking-related interstitial lung diseases) linked to OPN overexpression., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived IL-6, IL-8, bFGF, and VEGF were observed in mice at 7 days postinjection of either MM line, and a striking neutrophilia was observed at all time points. Free-floating tumor spheroids developed in mice at 14 days, and both spheroids and adherent MM tumor masses occurred in all mice at 30 days. Results suggest that inflammation and cytokine production precede and may be critical to the development of MMs.

Tracheobronchial amyloidosis is a rare disorder of unknown cause associated with the extracellular deposition of amyloid protein in a characteristic spatial structure of β-sheet fibrils assembled into bundles. We present a case that represents the nodular form of tracheobronchial amyloidosis, which is the least common form of pulmonary amyloidosis with less than 20 cases reported so far. Patients with tracheobronchial amyloidosis may present with symptoms of dyspnea, localized wheezing, cough, hemoptysis, or recurrent pneumonias. The mainstay of the therapy is debridement of the symptomatic luminal obstruction with neodymium-doped yttrium aluminium garnet laser therapy. Other treatment strategies include airway stenting, external beam radiation therapy, bypass tracheostomy, or open surgical resection.

Little is known about the cellular mechanisms contributing to the development and chemoresistance of malignant mesothelioma (MM), an aggressive asbestos-associated tumor. A human mesothelial cell line (LP9/TERT-1) and isolated human pleural mesothelial cells showed rapid and protracted asbestos-induced cAMP response element binding protein (CREB1) phosphorylation, which was inhibited in LP9/TERT-1 cells by small molecule inhibitors of epidermal growth factor receptor phosphorylation and protein kinase A. Asbestos increased expression of several CREB target genes (c-FOS, EGR-1, MKP1, BCL2, and MMP13) and apoptosis, which was enhanced using small interfering CREB. Human MM tissue arrays showed elevated endogenous levels of phosphorylated nuclear CREB1 as compared with reactive mesothelial hyperplasias and normal lung tissue. Significantly increased phosphorylated CREB1 and mRNA levels of BCL2, c-FOS, MMP9, and MMP13 were also observed in MM cells in vitro, which were further augmented after addition of Doxorubicin (Dox). Small interfering CREB inhibited migration of MMs, increased apoptosis by Dox, and decreased BCL2 and BCL-xL expression, suggesting a role for these molecules in CREB-induced MM survival. These data indicate that CREB1 and its target genes are up-regulated in asbestos-exposed human mesothelial cells through an epidermal growth factor receptor/protein kinase A pathway. Since activated CREB1 also is increased endogenously in human MM and modifies migration and resistance to Dox-induced apoptosis, inhibition of CREB1 may be a new strategy for MM therapy.

Aim: To analyze the immunohistochemical expression of uroplakin (URO) in pleural malignant mesothelioma (PMM)., Methods and Results: We analyzed URO expression in PMM using similar immunohistochemical techniques at 2 separate institutions. At an antibody dilution of 1:10, 0/5 PMMs were immunoreactive for URO. At 1:8, diffuse weak cytoplasmic staining was seen in all 38 PMMs tested, but no membrane staining was observed. Adjacent nontumor tissue and positive control tissue showed cytoplasmic staining of equivalent intensity. Similar staining results were observed in 27 PMMs at a 1:5 dilution., Conclusions: At an antibody dilution for which positive and negative control tissues stain appropriately, PMM does not stain for URO. At higher antibody concentrations, PMM exhibits nonspecific cytoplasmic staining. We assert that URO is not a useful immunohistochemical marker for the detection of PMM. Further studies addressing whether URO is overexpressed at the mRNA level in PMM are warranted.