Publications by authors named "Anjana Yeldandi"

59 Publications

Lung donation following SARS-CoV-2 infection.

Am J Transplant 2021 Jul 31. Epub 2021 Jul 31.

Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

There have been over 177 million cases of COVID-19 worldwide, many of whom could be organ donors. Concomitantly, there is an anticipated increase in the need for donor lungs due to expanding indications. Given that the respiratory tract is most commonly affected by COVID-19, there is an urgent need to develop donor assessment criteria while demonstrating safety and "efficacy" of lung donation following COVID-19 infection. Accordingly, we report an intentional transplant using lungs from a donor with recent, microbiologically confirmed, COVID-19 infection into a recipient suffering from COVID-19 induced ARDS and pulmonary fibrosis. In addition to the standard clinical assays, both donor and recipient lungs were analyzed using RNAscope, which confirmed that tissues were negative for SARS-CoV-2. Immunohistochemistry demonstrated colocalized KRT17+ basaloid-like epithelium and COL1A1+ fibroblasts, a marker suggestive of lung fibrosis in COVID-19 associated lung disease, in the explanted recipient lungs but absent in the donor lungs. We demonstrate that following a thorough assessment, lung donation following resolved COVID-19 infection is safe and feasible.
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http://dx.doi.org/10.1111/ajt.16777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441925PMC
July 2021

Liver Pathology and SARS-CoV-2 Detection in Formalin-Fixed Tissue of Patients With COVID-19.

Am J Clin Pathol 2021 05;155(6):802-814

Departments of Pathology, Chicago, IL, USA.

Objectives: The novel coronavirus, severe acute respiratory syndrome coronavirus 2, causing coronavirus disease 2019 (COVID-19) remains a global health threat and a significant source of human morbidity and mortality. While the virus primarily induces lung injury, it also has been reported to cause hepatic sequelae.

Methods: We aimed to detect the virus in formalin-fixed tissue blocks and document the liver injury patterns in patients with COVID-19 compared with a control group.

Results: We were able to detect viral RNA in the bronchioalveolar cell blocks (12/12, 100%) and formalin-fixed, paraffin-embedded tissue of the lung (8/8, 100%) and liver (4/9, 44%) of patients with COVID-19. Although the peak values of the main liver enzymes and bilirubin were higher in the patients with COVID-19 compared with the control group, the differences were not significant. The main histologic findings were minimal to focal mild portal tract chronic inflammation (7/8, 88%, P < .05) and mild focal lobular activity (6/8, 75%, P = .06).

Conclusions: We found that most patients who died of COVID-19 had evidence of mild focal hepatitis clinically and histologically; however, the virus was detected in less than half of the cases.
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http://dx.doi.org/10.1093/ajcp/aqab009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135761PMC
May 2021

A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection.

bioRxiv 2021 Mar 15. Epub 2021 Mar 15.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2), which is membrane bound, as its initial cell contact receptor preceding viral entry. Here we report a human soluble ACE2 variant fused with a 5kD albumin binding domain (ABD) and bridged via a dimerization motif hinge-like 4-cysteine dodecapeptide, which we term ACE2 1-618-DDC-ABD. This protein is enzymatically active, has increased duration of action in vivo conferred by the ABD-tag, and displays 20-30-fold higher binding affinity to the SARS-CoV-2 receptor binding domain than its des-DDC monomeric form (ACE2 1-618-ABD) due to DDC-linked dimerization. ACE2 1-618-DDC-ABD was administered for 3 consecutive days to transgenic k18-hACE2 mice, a model that develops lethal SARS-CoV-2 infection, to evaluate the preclinical preventative/ therapeutic value for COVID-19. Mice treated with ACE2 1-618-DDC-ABD developed a mild to moderate disease for the first few days assessed by a clinical score and modest weight loss. The untreated control animals, by contrast, became severely ill and had to be sacrificed by day 6/7 and lung histology revealed extensive pulmonary alveolar hemorrhage and mononuclear infiltrates. At 6 days, mortality was totally prevented in the treated group, lung histopathology was improved and viral titers markedly reduced. This demonstrates for the first time in vivo the preventative/ therapeutic potential of a novel soluble ACE2 protein in a preclinical animal model.
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http://dx.doi.org/10.1101/2021.03.12.435191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987000PMC
March 2021

Lung transplantation for patients with severe COVID-19.

Sci Transl Med 2020 12 30;12(574). Epub 2020 Nov 30.

Division of Pulmonary and Critical Care Medicine, Northwestern Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Lung transplantation can potentially be a life-saving treatment for patients with nonresolving COVID-19-associated respiratory failure. Concerns limiting lung transplantation include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and the potential risk for allograft infection by pathogens causing ventilator-associated pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to those of transplant. Here, we report the results of lung transplantation in three patients with nonresolving COVID-19-associated respiratory failure. We performed single-molecule fluorescence in situ hybridization (smFISH) to detect both positive and negative strands of SARS-CoV-2 RNA in explanted lung tissue from the three patients and in additional control lung tissue samples. We conducted extracellular matrix imaging and single-cell RNA sequencing on explanted lung tissue from the three patients who underwent transplantation and on warm postmortem lung biopsies from two patients who had died from COVID-19-associated pneumonia. Lungs from these five patients with prolonged COVID-19 disease were free of SARS-CoV-2 as detected by smFISH, but pathology showed extensive evidence of injury and fibrosis that resembled end-stage pulmonary fibrosis. Using machine learning, we compared single-cell RNA sequencing data from the lungs of patients with late-stage COVID-19 to that from the lungs of patients with pulmonary fibrosis and identified similarities in gene expression across cell lineages. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is their only option for survival.
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http://dx.doi.org/10.1126/scitranslmed.abe4282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050952PMC
December 2020

Lung transplantation for pulmonary fibrosis secondary to severe COVID-19.

medRxiv 2020 Oct 27. Epub 2020 Oct 27.

Lung transplantation can potentially be a life-saving treatment for patients with non-resolving COVID-19 acute respiratory distress syndrome. Concerns limiting transplant include recurrence of SARS-CoV-2 infection in the allograft, technical challenges imposed by viral-mediated injury to the native lung, and potential risk for allograft infection by pathogens associated with ventilator-induced pneumonia in the native lung. Additionally, the native lung might recover, resulting in long-term outcomes preferable to transplant. Here, we report the results of the first two successful lung transplantation procedures in patients with non-resolving COVID-19 associated acute respiratory distress syndrome in the United States. We performed smFISH to detect both positive and negative strands of SARS-CoV-2 RNA in the explanted lung tissue, extracellular matrix imaging using SHIELD tissue clearance, and single cell RNA-Seq on explant and warm post-mortem lung biopsies from patients who died from severe COVID-19 pneumonia. Lungs from patients with prolonged COVID-19 were free of virus but pathology showed extensive evidence of injury and fibrosis which resembled end-stage pulmonary fibrosis. Single cell RNA-Seq of the explanted native lungs from transplant and paired warm post-mortem autopsies showed similarities between late SARS-CoV-2 acute respiratory distress syndrome and irreversible end-stage pulmonary fibrosis requiring lung transplantation. There was no recurrence of SARS-CoV-2 or pathogens associated with pre-transplant ventilator associated pneumonias following transplantation in either patient. Our findings suggest that some patients with severe COVID-19 develop fibrotic lung disease for which lung transplantation is the only option for survival.

Single Sentence Summary: Some patients with severe COVID-19 develop end-stage pulmonary fibrosis for which lung transplantation may be the only treatment.
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http://dx.doi.org/10.1101/2020.10.26.20218636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605582PMC
October 2020

Malignant melanoma arising in a primary mediastinal germ cell tumor.

Pathol Res Pract 2020 Nov 11;216(11):153210. Epub 2020 Sep 11.

Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL, 60611, USA.

Primary mediastinal germ cell tumors with somatic malignancies are rare. We report a case of a 34-year old man with melanoma arising in a primary mediastinal mixed germ cell tumor. On initial biopsy, the patient was found to have a germ cell tumor containing yolk sac and embryonal components only. After chemotherapy, histopathological evaluation of the residual tumor in the wide local resection specimen revealed a mature teratoma with melanoma. Molecular studies demonstrated that the residual germ cell tumor harbored KIT and NRAS mutations associated with malignant melanoma.
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http://dx.doi.org/10.1016/j.prp.2020.153210DOI Listing
November 2020

The diagnostic utility of PRAME and p16 in distinguishing nodal nevi from nodal metastatic melanoma.

Pathol Res Pract 2020 Sep 11;216(9):153105. Epub 2020 Jul 11.

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

The status of the sentinel lymph node is the strongest predictor of recurrence in patients with malignant melanoma, making accurate distinction between nodal metastases and nodal nevi of paramount importance. We explored the utility of p16 and PRAME in differentiating nodal nevi from metastatic melanoma by immunohistochemistry. We searched our institutional database for cases of nodal nevi and nodal metastatic melanoma. p16 and PRAME expression were assessed with immunolabeling quantified by extent of nuclear positivity (0-25 %, >25 %-50 %, >50 %-75 % and >75 %). Sensitivities and specificities were calculated, and discrimination assessed using the area under the receiver operating characteristic curve (AUC). Forty-nine cases out of 51 nevi and 56/56 melanoma cases had lesional tissue present for p16, while 44/51 nevi and 54/56 melanoma cases had lesional tissue present for PRAME. 43 nodal nevi (88 %) had >50 % nuclear staining for p16, while none had >50 % staining for PRAME. More than half (55 %) of melanoma cases had complete loss of nuclear staining for p16, while majority (94 %) had >50 % nuclear staining for PRAME. Using a cut-off value of 50 %, higher PRAME expression had a sensitivity and specificity of 94 % and 100 %, respectively, while lower p16 expression had a sensitivity and specificity of 66 % and 88 %, respectively, for detecting metastatic melanoma. PRAME showed significantly better discrimination (AUC = 0.97, 95 % CI 0.94-1.00) than p16 (AUC = 0.77, 95 % CI 0.68-0.86) for differentiating nodal nevi from nodal melanoma (P < 0.001). Our findings suggest that PRAME is more accurate than p16 in discriminating between the two entities, with excellent sensitivity and specificity.
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http://dx.doi.org/10.1016/j.prp.2020.153105DOI Listing
September 2020

The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes.

Int J Mol Sci 2020 Aug 5;21(16). Epub 2020 Aug 5.

Department of Medicine, Division of Pulmonary & Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL 60611, USA.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease for which novel approaches are urgently required. We reported increased sphingosine kinase 1 (SPHK1) in IPF lungs and that SPHK1 inhibition using genetic and pharmacologic approaches reduces murine bleomycin-induced pulmonary fibrosis. We determined whether PF543, a specific SPHK1 inhibitor post bleomycin or asbestos challenge mitigates lung fibrosis by reducing mitochondrial (mt) DNA damage and pro-fibrotic monocyte recruitment-both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) or controls was intratracheally instilled in Wild-Type ( mice. PF543 (1 mg/kg) or vehicle was intraperitoneally injected once every two days from day 7-21 following bleomycin and day 14-21 or day 30-60 following asbestos. PF543 reduced bleomycin- and asbestos-induced pulmonary fibrosis at both time points as well as lung expression of profibrotic markers, lung mtDNA damage, and fibrogenic monocyte recruitment. In contrast to human lung fibroblasts, asbestos augmented lung epithelial cell (MLE) mtDNA damage and PF543 was protective. Post-exposure PF543 mitigates pulmonary fibrosis in part by reducing lung epithelial cell mtDNA damage and monocyte recruitment. We reason that SPHK1 signaling may be an innovative therapeutic target for managing patients with IPF and other forms of lung fibrosis.
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http://dx.doi.org/10.3390/ijms21165595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460639PMC
August 2020

Mitochondrial 8-oxoguanine DNA glycosylase mitigates alveolar epithelial cell PINK1 deficiency, mitochondrial DNA damage, apoptosis, and lung fibrosis.

Am J Physiol Lung Cell Mol Physiol 2020 05 25;318(5):L1084-L1096. Epub 2020 Mar 25.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.

Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased lung fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene () are protected against lung fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mice have diminished asbestos- and bleomycin-induced pulmonary fibrosis that was accompanied by reduced lung and AEC mtDNA damage and apoptosis. Asbestos and HO promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, -knockout () mice are more susceptible to asbestos-induced lung fibrosis and have increased lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and lung fibrosis. Given the key role of AEC apoptosis in pulmonary fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.
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http://dx.doi.org/10.1152/ajplung.00069.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272732PMC
May 2020

Pulmonary Mucormycosis: Risk Factors, Radiologic Findings, and Pathologic Correlation.

Radiographics 2020 May-Jun;40(3):656-666. Epub 2020 Mar 20.

From the Departments of Radiology (R.A., H.S., N.D.P., P.J.L., E.M.H.) and Pathology (A.Y.), Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Ste 800, Chicago, IL 60611.

Pulmonary mucormycosis (PM) is an uncommon fungal infection most often seen in immunocompromised patients. The fungus grows on decaying food, soil, and animal excrement. Patients usually become infected by inhalation of spores. The most common risk factors include diabetes mellitus, hematologic malignancy, and solid organ or stem cell transplant. PM can have a nonspecific appearance at imaging. For example, early imaging may show peribronchial ground-glass opacity. Later, the disease progresses to consolidation, nodules, or masses. Because patients are usually immunocompromised, the differential diagnosis often includes invasive pulmonary aspergillosis (IPA). Various radiologic findings suggestive of PM have been identified to help differentiate it from IPA. For example, the reverse halo sign is more closely associated with PM than with IPA. The reverse halo sign is an area of ground-glass opacity surrounded by a rim of consolidation. In addition, the presence of pleural effusions and more than 10 nodules is more suggestive of PM than it is of IPA. PM can progress rapidly in neutropenic patients. Identification of the hyphae in tissue by using endobronchial or percutaneous sampling can allow differentiation from IPA and help confirm the diagnosis of mucormycosis. Because of the high mortality rate associated with PM, early identification of the disease is critical for an improved likelihood of survival. A multimodality treatment approach with antifungal agents and surgical débridement has been shown to improve outcomes. The authors review the risk factors for PM, describe its imaging appearance and disease process, and describe the treatment of the disease. RSNA, 2020.
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http://dx.doi.org/10.1148/rg.2020190156DOI Listing
April 2021

Delivery of Immunotherapeutic Nanoparticles to Tumors via Enzyme-Directed Assembly.

Adv Healthc Mater 2019 12 30;8(23):e1901105. Epub 2019 Oct 30.

Departments of Chemistry, Materials Science & Engineering, Biomedical Engineering, International Institute for Nanotechnology, Chemistry of Life Processes Institute, Simpson-Querrey Institute, Lurie Cancer Center, Northwestern University, Evanston, IL, 60208, USA.

Amphiphilic diblock copolymers are prepared by ring opening metathesis polymerization, with one block containing hydrophobic Toll-like receptor 7 (TLR7) agonists and one block containing hydrophilic peptides as substrates for matrix metalloproteinases (MMPs). A fluorescent label is incorporated into the polymer chains for in vivo imaging. Upon dialysis against aqueous solution, polymers form 15 nm spherical micelles. Subsequent exposure to MMP-9 elicits a morphological change to yield immunostimulatory microscale assemblies. The intravenous (IV) administration of the formulation to mice bearing 4T1 breast cancer tumors results in nanoparticle accumulation in tumors, reduction in primary tumor growth, and inhibition of lung metastases, as compared to saline-treated animals. Mice administered the parent immunotherapeutic small molecule (1V209) experience significantly increased plasma levels of proinflammatory cytokines IL-6, IP-10, and MCP-1 at 2 h following IV administration, whereas the nanomaterial shows no increase over saline-treated controls. These data suggest that covalently packaging low molecular weight immunotherapeutics at high weight percent loadings in enzyme-responsive nanoparticles maintains drug efficacy while decreasing immunotoxicity, providing a platform for cancer immunotherapeutic delivery.
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http://dx.doi.org/10.1002/adhm.201901105DOI Listing
December 2019

Ectopic hamartomatous thymoma in an immunocompromised male.

Pathol Res Pract 2019 Sep 10;215(9):152497. Epub 2019 Jun 10.

Northwestern University, 303 E Chicago Ave Ward 3-140 W127, Chicago, 60611, United States.

Ectopic hamartomatous thymoma (EHT) is a rare benign neoplasm classically occurring in the lower neck of adult males. Here we present a case of EHT occurring in a 43-year-old immunocompromised male and a brief review of existing literature. The patient presented with a palpable mass overlying the left clavicle which, on imaging, showed a solitary nodule possibly eroding the cortical bone. A biopsy predominantly showed spindle cells that were immunopositive for keratin AE1/AE3 as well as weakly positive for CD99, SMA, and CD34. A diagnosis of synovial sarcoma was favored; at which point surgical resection was performed. The resected mass was well-demarcated with a tan-yellow cut surface. Microscopically, the lesion was composed of a mixture of spindle cells, glands, and mature adipose tissue. The spindle cells were plump with bland nuclei, and the epithelial component showed morphology similar to glands of salivary or breast tissue with a bilayered appearance (luminal and basal). No pleomorphism, mitotic figures, or necrosis was present. Immunohistochemical stains were performed and showed the spindle cells to express a myoepithelial phenotype (cytokeratin AE1/AE3, p63, calponin positive). The glands showed SMA and p63 positivity in the basal cells (similar to salivary gland and breast). Overall, given the clinical context, histomorphologic, and immunohistochemical profile, a diagnosis of EHT was made. At 12 months of follow-up there was no evidence of recurrence.
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http://dx.doi.org/10.1016/j.prp.2019.152497DOI Listing
September 2019

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 06;199(12):1517-1536

4 Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois; and.

The contributions of diverse cell populations in the human lung to pulmonary fibrosis pathogenesis are poorly understood. Single-cell RNA sequencing can reveal changes within individual cell populations during pulmonary fibrosis that are important for disease pathogenesis. To determine whether single-cell RNA sequencing can reveal disease-related heterogeneity within alveolar macrophages, epithelial cells, or other cell types in lung tissue from subjects with pulmonary fibrosis compared with control subjects. We performed single-cell RNA sequencing on lung tissue obtained from eight transplant donors and eight recipients with pulmonary fibrosis and on one bronchoscopic cryobiospy sample from a patient with idiopathic pulmonary fibrosis. We validated these data using RNA hybridization, immunohistochemistry, and bulk RNA-sequencing on flow-sorted cells from 22 additional subjects. We identified a distinct, novel population of profibrotic alveolar macrophages exclusively in patients with fibrosis. Within epithelial cells, the expression of genes involved in Wnt secretion and response was restricted to nonoverlapping cells. We identified rare cell populations including airway stem cells and senescent cells emerging during pulmonary fibrosis. We developed a web-based tool to explore these data. We generated a single-cell atlas of pulmonary fibrosis. Using this atlas, we demonstrated heterogeneity within alveolar macrophages and epithelial cells from subjects with pulmonary fibrosis. These results support the feasibility of discovery-based approaches using next-generation sequencing technologies to identify signaling pathways for targeting in the development of personalized therapies for patients with pulmonary fibrosis.
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http://dx.doi.org/10.1164/rccm.201712-2410OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580683PMC
June 2019

A Young Man with Fevers and an Invasive Mediastinal Mass.

Ann Am Thorac Soc 2018 12;15(12):1477-1482

Northwestern University Feinberg School of Medicine, Division of Pulmonary and Critical Care, Chicago, Illinois.

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http://dx.doi.org/10.1513/AnnalsATS.201806-378CCDOI Listing
December 2018

Pharmacological Inhibition of Toll-Like Receptor-4 Signaling by TAK242 Prevents and Induces Regression of Experimental Organ Fibrosis.

Front Immunol 2018 23;9:2434. Epub 2018 Oct 23.

Northwestern Scleroderma Program, Feinberg School of Medicine, Chicago, IL, United States.

Systemic sclerosis (SSc) is a poorly understood heterogeneous condition with progressive multi-organ fibrosis. Recent genetic and genomic evidence suggest a pathogenic role for dysregulated innate immunity and toll-like receptor (TLR) activity in SSc. Levels of both TLR4, as well as certain endogenous TLR ligands, are elevated in skin and lung tissues from patients with SSc and correlate with clinical disease parameters. Conversely, genetic targeting of TLR4 or its endogenous "damage-associated" ligands ameliorates progressive tissue fibrosis. Targeting TLR4 signaling therefore represents a pharmacological strategy to prevent intractable fibrosis. We examined the effect of TAK242, a small molecule TLR4 inhibitor, in preclinical fibrosis models and in SSc fibroblasts. TAK242 treatment prevented, promoted regression of, bleomycin-induced dermal and pulmonary fibrosis, and reduced the expression of several pro-fibrotic mediators. Furthermore, TAK242 ameliorated peritoneal fibrosis and reduced spontaneous hypodermal thickness in TSK/+ mice. Importantly, TAK242 abrogated collagen synthesis and myofibroblasts differentiation in explanted constitutively active SSc fibroblast. Altogether, these findings identify TAK242 as an anti-fibrotic agent in preclinical models of organ fibrosis. TAK242 might potentially represent a novel strategy for the treatment of SSc and other fibrotic diseases.
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http://dx.doi.org/10.3389/fimmu.2018.02434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207051PMC
September 2019

Surgical Treatment of Multifocal Pulmonary Mucormycosis.

Ann Thorac Surg 2018 08 31;106(2):e93-e95. Epub 2018 Jan 31.

Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address:

Mucormycosis is a devastating opportunistic fungal infection to which the immunosuppressed are particularly vulnerable. We report the case of a 60-year-old man who was found to have multifocal pulmonary mucormycosis 10 weeks after concomitant heart and kidney transplantation. Despite appropriate antifungal therapy, the infection progressed rapidly and soon involved critical pulmonary vasculature. He successfully underwent staged operative resection of his pulmonary mucormycosis without recurrence of infection. Although surgical debridement of pulmonary mucormycosis is typically reserved for localized disease, this case demonstrates that surgical intervention should be considered as an adjunct to antifungal therapy in multifocal disease.
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http://dx.doi.org/10.1016/j.athoracsur.2017.12.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085879PMC
August 2018

Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis.

Am J Physiol Lung Cell Mol Physiol 2017 07 20;313(1):L16-L26. Epub 2017 Apr 20.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois;

Alveolar epithelial cell (AEC) apoptosis and inadequate repair resulting from "exaggerated" lung aging and mitochondrial dysfunction are critical determinants promoting lung fibrosis. α-Klotho, which is an antiaging molecule that is expressed predominantly in the kidney and secreted in the blood, can protect lung epithelial cells against hyperoxia-induced apoptosis. We reasoned that Klotho protects AEC exposed to oxidative stress in part by maintaining mitochondrial DNA (mtDNA) integrity and mitigating apoptosis. We find that Klotho levels are decreased in both serum and alveolar type II (AT2) cells from asbestos-exposed mice. We show that oxidative stress reduces AEC Klotho mRNA and protein expression, whereas Klotho overexpression is protective while Klotho silencing augments AEC mtDNA damage. Compared with wild-type, Klotho heterozygous hypomorphic allele () mice have increased asbestos-induced lung fibrosis due in part to increased AT2 cell mtDNA damage. Notably, we demonstrate that serum Klotho levels are reduced in wild-type but not mitochondrial catalase overexpressing () mice 3 wk following exposure to asbestos and that EUK-134, a MnSOD/catalase mimetic, mitigates oxidant-induced reductions in AEC Klotho expression. Using pharmacologic and genetic silencing studies, we show that Klotho attenuates oxidant-induced AEC mtDNA damage and apoptosis via mechanisms dependent on AKT activation arising from upstream fibroblast growth factor receptor 1 activation. Our findings suggest that Klotho preserves AEC mtDNA integrity in the setting of oxidative stress necessary for preventing apoptosis and asbestos-induced lung fibrosis. We reason that strategies aimed at augmenting AEC Klotho levels may be an innovative approach for mitigating age-related lung diseases.
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http://dx.doi.org/10.1152/ajplung.00063.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538874PMC
July 2017

Pathologic and Radiologic Correlation of Adult Cystic Lung Disease: A Comprehensive Review.

Patholog Res Int 2017 8;2017:3502438. Epub 2017 Feb 8.

Northwestern University, Chicago, IL, USA.

The presence of pulmonary parenchymal cysts on computed tomography (CT) imaging presents a significant diagnostic challenge. The diverse range of possible etiologies can usually be differentiated based on the clinical setting and radiologic features. In fact, the advent of high-resolution CT has facilitated making a diagnosis solely on analysis of CT image patterns, thus averting the need for a biopsy. While it is possible to make a fairly specific diagnosis during early stages of disease evolution by its characteristic radiological presentation, distinct features may progress to temporally converge into relatively nonspecific radiologic presentations sometimes necessitating histological examination to make a diagnosis. The aim of this review study is to provide both the pathologist and the radiologist with an overview of the diseases most commonly associated with cystic lung lesions primarily in adults by illustration and description of pathologic and radiologic features of each entity. Brief descriptions and characteristic radiologic features of the various disease entities are included and illustrative examples are provided for the common majority of them. In this article, we also classify pulmonary cystic disease with an emphasis on the pathophysiology behind cyst formation in an attempt to elucidate the characteristics of similar cystic appearances seen in various disease entities.
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http://dx.doi.org/10.1155/2017/3502438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320373PMC
February 2017

SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.

FASEB J 2017 06 3;31(6):2520-2532. Epub 2017 Mar 3.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA;

Alveolar epithelial cell (AEC) mitochondrial dysfunction and apoptosis are important in idiopathic pulmonary fibrosis and asbestosis. Sirtuin 3 (SIRT3) detoxifies mitochondrial reactive oxygen species, in part, by deacetylating manganese superoxide dismutase (MnSOD) and mitochondrial 8-oxoguanine DNA glycosylase. We reasoned that SIRT3 deficiency occurs in fibrotic lungs and thereby augments AEC mtDNA damage and apoptosis. Human lungs were assessed by using immunohistochemistry for SIRT3 activity acetylated MnSOD Murine AEC SIRT3 and cleaved caspase-9 (CC-9) expression were assayed by immunoblotting with or without SIRT3 enforced expression or silencing. mtDNA damage was measured by using quantitative PCR and apoptosis ELISA. Pulmonary fibrosis after asbestos or bleomycin exposure was evaluated in 129SJ/wild-type and SIRT3-knockout mice ( ) by using fibrosis scoring and lung collagen levels. Idiopathic pulmonary fibrosis lung alveolar type II cells have increased MnSOD acetylation compared with controls. Asbestos and HO diminished AEC SIRT3 protein expression and increased mitochondrial protein acetylation, including MnSOD SIRT3 enforced expression reduced oxidant-induced AEC OGG1 acetylation, mtDNA damage, and apoptosis, whereas SIRT3 silencing promoted these effects. Asbestos- or bleomycin-induced lung fibrosis, AEC mtDNA damage, and apoptosis in wild-type mice were amplified in animals. These data suggest a novel role for SIRT3 deficiency in mediating AEC mtDNA damage, apoptosis, and lung fibrosis.-Jablonski, R. P., Kim, S.-J., Cheresh, P., Williams, D. B., Morales-Nebreda, L., Cheng, Y., Yeldandi, A., Bhorade, S., Pardo, A., Selman, M., Ridge, K., Gius, D., Budinger, G. R. S., Kamp, D. W. SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis.
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http://dx.doi.org/10.1096/fj.201601077RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434657PMC
June 2017

Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage.

Free Radic Biol Med 2016 12 11;101:482-490. Epub 2016 Nov 11.

Department of Medicine, Division of Pulmonary & Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, IL, United States; Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States. Electronic address:

Rationale: Alveolar epithelial cell (AEC) injury and mitochondrial dysfunction are important in the development of lung fibrosis. Our group has shown that in the asbestos exposed lung, the generation of mitochondrial reactive oxygen species (ROS) in AEC mediate mitochondrial DNA (mtDNA) damage and apoptosis which are necessary for lung fibrosis. These data suggest that mitochondrial-targeted antioxidants should ameliorate asbestos-induced lung.

Objective: To determine whether transgenic mice that express mitochondrial-targeted catalase (MCAT) have reduced lung fibrosis following exposure to asbestos or bleomycin and, if so, whether this occurs in association with reduced AEC mtDNA damage and apoptosis.

Methods: Crocidolite asbestos (100µg/50µL), TiO (negative control), bleomycin (0.025 units/50µL), or PBS was instilled intratracheally in 8-10 week-old wild-type (WT - C57Bl/6J) or MCAT mice. The lungs were harvested at 21d. Lung fibrosis was quantified by collagen levels (Sircol) and lung fibrosis scores. AEC apoptosis was assessed by cleaved caspase-3 (CC-3)/Surfactant protein C (SFTPC) immunohistochemistry (IHC) and semi-quantitative analysis. AEC (primary AT2 cells from WT and MCAT mice and MLE-12 cells) mtDNA damage was assessed by a quantitative PCR-based assay, apoptosis was assessed by DNA fragmentation, and ROS production was assessed by a Mito-Sox assay.

Results: Compared to WT, crocidolite-exposed MCAT mice exhibit reduced pulmonary fibrosis as measured by lung collagen levels and lung fibrosis score. The protective effects in MCAT mice were accompanied by reduced AEC mtDNA damage and apoptosis. Similar findings were noted following bleomycin exposure. Euk-134, a mitochondrial SOD/catalase mimetic, attenuated MLE-12 cell DNA damage and apoptosis. Finally, compared to WT, asbestos-induced MCAT AT2 cell ROS production was reduced.

Conclusions: Our finding that MCAT mice have reduced pulmonary fibrosis, AEC mtDNA damage and apoptosis following exposure to asbestos or bleomycin suggests an important role for AEC mitochondrial HO-induced mtDNA damage in promoting lung fibrosis. We reason that strategies aimed at limiting AEC mtDNA damage arising from excess mitochondrial HO production may be a novel therapeutic target for mitigating pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928521PMC
December 2016

Ectopic pleural thymoma in a 49-year-old woman: A case report.

Pathol Res Pract 2016 Nov 2;212(11):1076-1080. Epub 2016 Sep 2.

Department of Pathology, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, United States.

Ectopic pleural thymoma is an exceedingly uncommon clinical entity that has only been described sporadically. Because of their peculiar location and variety of histologic patterns manifested, pleural thymomas may be confused with other neoplasms and may cause diagnostic problems clinically, radiologically, and morphologically. We describe the case of a giant left-sided ectopic pleural thymoma, preoperatively suspected to be a solitary fibrous tumor. A complete surgical resection was achieved and a postoperative diagnosis of WHO Type AB, modified Masaoka stage I tumor was attained. Subsequent thymectomy demonstrated unremarkable thymic tissue. The possibility of ectopic thymoma should be considered when the morphology of the lesion reveals a dual population of epithelial cells without significant nuclear atypia and lymphoid cells. Immunohistochemical studies are helpful in supporting the morphologic impression, both by characterizing the epithelial component as thymic in origin and by demonstrating the immature T-cell phenotype of the admixed reactive lymphocytes.
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http://dx.doi.org/10.1016/j.prp.2016.08.011DOI Listing
November 2016

Primary Spontaneous Pneumothorax in Menstruating Women Has High Recurrence.

Ann Thorac Surg 2016 Oct 24;102(4):1125-30. Epub 2016 Jun 24.

Division of Thoracic Surgery, Department of Surgery, Northwestern Memorial Hospital, Chicago, Illinois. Electronic address:

Background: Primary spontaneous pneumothorax (PSP) is treated on the basis of studies that have predominantly consisted of tall male subjects. Here, we determined recurrence of PSP in average-statured menstruating women and studied prevalence of catamenial pneumothorax (CP) in this population.

Methods: Men and menstruating women, aged 18 to 55 years, without underlying lung disease or substance abuse were retrospectively studied between 2009 and 2015. A chest pathologist reviewed all specimens for thoracic endometriosis. Kaplan-Meier curves were constructed to determine recurrence.

Results: The median age of women (n = 33) and men (n = 183) was 33.4 and 31.6 years, respectively. In women, 9 (27%) had left-sided and 24 (73%) had right-sided PSP, treated with tube thoracostomy. Recurrence occurred in 21 women (64%) with median follow-up of 14 months, and they were treated with thoracoscopic pleurodesis. Right PSP had higher recurrence (70%) than left PSP (56%, p = 0.02). Four women (12%) presented with recurrent tension pneumothorax within 6 months. Eight patients (24%) had PSP within 72 hours of menses, meeting clinical criteria of CP. All these were placed on hormonal suppression after initial episode but went on to experience recurrence that was treated with pleurodesis. Classical endometrial glands were not found in any biopsy specimens obtained during the thoracoscopy. In contrast to female subjects, only 8 average-statured men (4.4%) had recurrence (p < 0.001) with a median follow-up of 16 months.

Conclusions: PSP in healthy average-statured menstruating women has high recurrence compared with male counterparts. CP is a clinical diagnosis and often recurs despite hormonal suppression therapy.
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http://dx.doi.org/10.1016/j.athoracsur.2016.04.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030123PMC
October 2016

Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation.

Am J Respir Cell Mol Biol 2016 Oct;55(4):532-541

4 Norton Thoracic Institute, St. Joseph's Hospital, Phoenix, Arizona.

Over one-third of lung recipients have preexisting antibodies against lung-restricted antigens: collagen (Col) type V and K-α1 tubulin (KAT). Although clinical studies have shown association of these antibodies with primary graft dysfunction (PGD), their biological significance remains unclear. We tested whether preexisting lung-restricted antibodies can mediate PGD and prevent allotolerance. A murine syngeneic (C57BL/6) or allogeneic (C57BL/6 to BALB/c) left lung transplantation model was used. Rabbit polyclonal antibodies were produced against KAT and Col-V and injected pretransplantation. T cell frequency was analyzed using enzyme-linked immunospot, whereas alloantibodies were determined using flow cytometry. Wet:dry ratio, arterial oxygenation, and histology were used to determine PGD. Preexisting Col-V or KAT, but not isotype control, antibodies lead to dose-dependent development of PGD after syngeneic lung transplantation, as evidenced by poor oxygenation and increased wet:dry ratio. Histology confirmed alveolar and capillary edema. The native right lung remained unaffected. Epitope spreading was observed where KAT antibody treatment led to the development of IL-17-producing CD4 T cells and humoral response against Col-V, or vice versa. In contrast, isotype control antibody failed to induce Col-V- or KAT-specific cellular or humoral immunity. In addition, none of the mice developed immunity against a non-lung antigen, collagen type II. Preexisting lung-restricted antibodies, but not isotype control, prevented development of allotolerance using the MHC-related 1 and cytotoxic T-lymphocyte-associated protein 4-Ig regimen. Lung-restricted antibodies can induce both early and delayed lung graft dysfunction. These antibodies can also cause spreading of lung-restricted immunity and promote alloimmunity. Antibody-directed therapy to treat preexisting lung-restricted antibodies might reduce PGD after lung transplantation.
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http://dx.doi.org/10.1165/rcmb.2016-0077OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070112PMC
October 2016

Plexiform fibromyxoma with cotyledon-like serosal growth: A case report of a rare gastric tumor and review of the literature.

Oncol Lett 2016 Mar 4;11(3):2189-2194. Epub 2016 Feb 4.

Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Plexiform fibromyxoma is a rare, benign mesenchymal neoplasm that predilects the gastric antrum and has potential for misdiagnosis as a gastrointestinal stromal tumor (GIST). The histology of the tumor is characterized by interwoven fascicular growth of cytologically bland spindled cells within a variably myxoid stroma. The current study reports the clinicopathological and immunohistochemical findings of a plexiform fibromyxoma resected from a 28-year-old Vietnamese female. The patient presented with acute, severe abdominal pain and worsening anemia. The initial fine-needle aspiration and needle core biopsy of the gastric antral mass led to an initial diagnosis of GIST. The subsequent distal partial gastrectomy revealed a 5.5-cm transmural antral mass that ulcerated the overlying mucosa and grew as variably elongated, myxoedematous, polypoid (cotyledon-like) excrescences from the serosal surface. Microscopically, the tumor demonstrated plexiform and multinodular growth of cytologically bland spindled cells proliferating in an abundant myxocollagenous stroma with a prominent capillary network. Tumor cells immunohistochemically expressed smooth muscle actin and CD10, but did not express CD117, Discovered on GIST-1 or nuclear β-catenin. Follow-up evaluation 23 months post surgery revealed no evidence of residual tumor. A review the cases of this rare entity reported in the English language literature is also provided.
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http://dx.doi.org/10.3892/ol.2016.4185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774512PMC
March 2016

Rare Middle Mediastinal Paraganglioma Mimicking Metastatic Neuroendocrine Tumor.

Ann Thorac Surg 2015 Aug;100(2):702-5

Department of Surgery, Division of Thoracic Surgery, Northwestern Memorial Hospital, Chicago, Illinois. Electronic address:

Mediastinal paragangliomas are rare neural crest derived tumors that may produce symptoms of excess catecholamine production or mass effect. Paragangliomas can histologically mimic neuroendocrine tumors. Further, both can arise in similar locations. We report a patient who presented with a right upper lobe as well as middle mediastinal lesion. Preoperative biopsy as well as intraoperative frozen section of these lesions failed to distinguish between paraganlioma or neuroendocrine tumor, necessitating a right upper lobectomy and complete mediastinal lymphadenectomy. Final pathology revealed carcinoid tumorlets in the right upper lobe and a middle mediastinal paraganglioma.
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http://dx.doi.org/10.1016/j.athoracsur.2014.09.068DOI Listing
August 2015

Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice.

Am J Respir Cell Mol Biol 2015 Jan;52(1):25-36

1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, Jesse Brown VA Medical Center, Chicago, Illinois.

Asbestos causes asbestosis and malignancies by mechanisms that are not fully established. Alveolar epithelial cell (AEC) injury and repair are crucial determinants of the fibrogenic potential of noxious agents such as asbestos. We previously showed that mitochondrial reactive oxygen species mediate asbestos-induced AEC intrinsic apoptosis and that mitochondrial human 8-oxoguanine-DNA glycosylase 1 (OGG1), a DNA repair enzyme, prevents oxidant-induced AEC apoptosis. We reasoned that OGG1 deficiency augments asbestos-induced pulmonary fibrosis. Compared with intratracheal instillation of PBS (50 μl) or titanium dioxide (100 μg/50 μl), crocidolite or Libby amphibole asbestos (100 μg/50 μl) each augmented pulmonary fibrosis in wild-type C57BL/6J (WT) mice after 3 weeks as assessed by histology, fibrosis score, lung collagen via Sircol, and type 1 collagen expression; these effects persisted at 2 months. Compared with WT mice, Ogg1 homozygous knockout (Ogg1(-/-)) mice exhibit increased pulmonary fibrosis after crocidolite exposure and apoptosis in cells at the bronchoalveolar duct junctions as assessed via cleaved caspase-3 immunostaining. AEC involvement was verified by colocalization studies using surfactant protein C. Asbestos increased endoplasmic reticulum stress in the lungs of WT and Ogg1(-/-) mice. Compared with WT, alveolar type 2 cells isolated from Ogg1(-/-) mice have increased mtDNA damage, reduced mitochondrial aconitase expression, and increased P53 and cleaved caspase-9 expression, and these changes were enhanced 3 weeks after crocidolite exposure. These findings suggest an important role for AEC mtDNA integrity maintained by OGG1 in the pathogenesis of pulmonary fibrosis that may represent a novel therapeutic target.
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http://dx.doi.org/10.1165/rcmb.2014-0038OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370253PMC
January 2015

Correlation of EGFR mutation status with predominant histologic subtype of adenocarcinoma according to the new lung adenocarcinoma classification of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society.

Arch Pathol Lab Med 2014 Oct 26;138(10):1353-7. Epub 2014 Feb 26.

From the Department of Pathology (Drs Villa, Yeldandi, and Raparia), the Division of Medical Oncology, and Robert H. Lurie Comprehensive Cancer Center (Drs Johnson and Patel), the Division of Pulmonary, and Critical Care Medicine (Dr Raj); and the Division of Thoracic Surgery, and Robert H. Lurie Comprehensive Cancer Center (Dr DeCamp), Northwestern University Feinberg School of Medicine, Chicago, Illinois; and the Department of Pathology & Genomic Medicine, The Methodist Hospital, Houston, Texas (Dr Cagle).

Context: Epidermal growth factor receptor (EGFR) mutations have been identified as predictors of response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer.

Objective: To investigate the relationship of EGFR mutation status to the histologic subtype of adenocarcinoma according to the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification.

Design: We screened EGFR mutation in 200 consecutive lung adenocarcinoma resection specimens diagnosed between 2008 and 2011.

Results: Among 200 lung adenocarcinomas, EGFR mutations were identified in 41 tumors (20.5%). The mean age in the EGFR-mutant group was 64.8 years and this group consisted of 78% females and 22% males. Most patients with EGFR-positive lung cancers were never-smokers (51%) as compared to 8% with EGFR-negative cancers (P < .001). The most common mutations identified in our population were deletions in exon 19 (22 patients) and L858R in exon 21 (12 patients). Five patients had double mutations. The predominant pattern of adenocarcinoma was lepidic (44%) in EGFR-mutant lung cancers as compared to 69% with acinar pattern in EGFR wild-type lung cancers (P < .001). Of 22 minimally invasive adenocarcinomas, 8 (36%) had EGFR mutations, accounting for 20% of adenocarcinomas with EGFR mutations (P < .05).

Conclusions: Based on the new IASLC/ATS/ERS classification, the predominant subtype of adenocarcinoma was lepidic (44%) in EGFR-mutant lung cancers (P < .001). However, histologic subtype should not be used to exclude patients from tyrosine kinase inhibitor therapy, since EGFR mutations are found in lung adenocarcinomas of other subtypes.
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http://dx.doi.org/10.5858/arpa.2013-0376-OADOI Listing
October 2014

Sarcomatoid (spindle cell) carcinoma of the pancreas: A case report and review of the literature.

Oncol Lett 2014 Jan 14;7(1):245-249. Epub 2013 Nov 14.

Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.

Sarcomatoid (spindle cell) carcinoma of the pancreas is a rare, high-grade epithelial malignancy composed predominantly or exclusively of spindle cells demonstrating evidence of epithelial derivation, but no features indicative of a specific line of mesenchymal differentiation. The current study presents the case of an 85-year-old Caucasian male with a tumor mass in the body of the pancreas. The individual subsequently underwent a distal pancreatectomy, splenectomy and partial gastrectomy. Microscopic examination of the 3.3-cm mass located in the body of the pancreas revealed a small, but high-grade, adenocarcinomatous component that blended imperceptibly with malignant spindle cells. No light microscopic or immunohistochemical evidence of specific mesenchymal differentiation was identified, and the spindle cells, as in the case of the carcinoma, were diffusely keratin-positive. Sarcomatoid (spindle cell) carcinoma defined in this way rarely presents in the pancreas, with, to the best of our knowledge, only six cases reported in the English literature.
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http://dx.doi.org/10.3892/ol.2013.1683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861608PMC
January 2014

Cytology of the lung.

Cancer Treat Res 2014 ;160:59-82

Office of the Medical Examiner, District 9, 2350 E. Michigan St, Orlando, FL, 32806, USA.

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http://dx.doi.org/10.1007/978-3-642-38850-7_4DOI Listing
April 2014
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