Mononuclear Inflammatory Cells Research Articles

Tumor-infiltrating lymphocytes in tissue material combined with systemic lymphocyte inflammation in patients with colorectal cancer.

The efficacy of cancer immunotherapy has been actively explored in the treatment of various malignant neoplasms of the gastrointestinal tract. In light of recent reports, the present study aimed to investigate the combination of the absolute lymphocyte count (ALC), percentage of tumor-infiltrating lymphocyte (TILs) and tumor progression status in patients with colorectal cancer (CRC) who underwent surgery. The medical records of 160 patients diagnosed with CRC were retrospectively reviewed. TILs were determined as a percentage of mononuclear inflammatory cells in the total intratumoral or stromal area as determined in five high power fields (magnification, x200-400), at the invasive front and in the centre of the tumour. Blood samples were obtained within 3 days prior to and 7 days following the surgical treatment. The assessment of the TIL percentage was performed in the tissue at the invasive front and in the centre of the primary tumour mass in combination with the determination of ALC in whole blood samples. The samples were obtained prior to and after surgery from patients with CRC, and the tumour progression status was also assessed (TILs/ALC/tumour progression status). A significant association was observed between the percentage of TILs in the main mass of tumour and the tumour size (P=0.031), the pT stage (P=0.049) and the incidence of necrosis (P=0.037) following surgery. The histological type was associated with the evaluated combined parameters prior to surgery (P=0.046). Lymph node pouch invasion was associated with TILs at the invasive front of tumour and with ALC prior to and after surgery (P=0.006 and P=0.037). Furthermore, the data indicated that the percentage of TILs located on the invasive front and centre of the tumour, and the ALC prior to and following surgery correlated with the treatment status (P=0.032, P=0.018, P≤0.001 and P≤0.001). A significant association was noted between eight features and evaluated combined parameters following surgery. These included the tumour size (P=0.021), TNM stage (P<0.001), tumour deposits (P=0.001), incidence of necrosis (P=0.042) and lymph node metastasis (P<0.001). Furthermore, the degree of invasion of venous (P<0.001), lymphatic (P<0.001) and perineural (P<0.001) sites was also significantly associated with TILs, ALC obtained after surgical treatment and tumor progression status. The data demonstrated that local and systemic chronic inflammation was associated with tumour progression in patients with CRC.

A porcine model of subcutaneous Staphylococcus aureus infection: a pilot study

In this descriptive pilot study, we aim to establish a porcine Staphylococcus aureus skin infection model by subcutaneous injection (s.c.) of the porcine S54F9 S. aureus strain in the groin area. Six pigs were used in the study: Five pigs were injected with S. aureus, inocula ranging from 7 × 103 to 5 × 107 colony-forming units per kg bodyweight; one pig was injected with saline exclusively. Lesions were recorded up to 6 days postinoculation using clinical evaluation, ultrasound evaluation, microbiology, flow cytometry, and pathology. Inoculation gave rise to lesions ranging from localized skin infection, that is, minute histological changes, intracellular infection, and macroscopic abscess formation with sequestration of soft tissue, to generalized infection and development of disseminated intravascular coagulation necessitating euthanasia only 10 h after inoculation. Ultrasound assessment of maximum width and characteristics was not able to disclose the progress of the local infection. Flow cytometry and immunohistochemistry revealed the participation of γδT cells in the immune response. In conclusion, we did see a graded inflammatory response associated with the dose of s.c. inoculated bacteria, which may be useful for studying, in particular, the interaction of bacteria and inflammatory mononuclear cell populations. It needs to be investigated if the model is discriminatory and robust.

The Impact of High Fat Diet and Flaxseed on Liver Histology, Histochemistry and Morphometry in Ovariectomized Albino Rat

Background: Postmenopausal weight gain sounds an alarm for women’s health and may lead to non-alcoholic fatty liver disease. Flaxseed is rich in antioxidants and may improve liver functions. However, the precise mechanisms remain unclear.Objective: This work was designed to evaluate the possible hepatoprotective role of flaxseed in ovariectomized obese female albino rat model.Materials & Methods: Adult female albino rats were divided into three groups: Group I (control), Group II (High fat diet group) and Group III (bilaterally ovariectomized group) which then subdivided equally into; GIIIa (ovariectomized only group), GIIIb (ovariectomized rats fed on a high fat diet) and GIIIc (ovariectomized rats fed on high-fat diet contained ground flaxseed) till the end of the experiment. After 12 weeks, body weight, serum lipid profiles and liver enzyme levels were estimated. liver specimens were processed for light and electron microscopic studies. Morphometric measurements and statistical analyses were done.Results: ovariectomy and high-fat diet caused a significant increase in body weight, lipid profiles and destructive changes within the liver tissue in the form of vacuolated cytoplasm, pyknotic nuclei, congested blood vessels and mononuclear inflammatory cells infiltration that was supported by a significant elevation in the liver enzymes coupled to a significant increase in the area percentage of collagen fibers and reduction in the Periodic-Acid-Schiff (PAS) reaction. The ultrastructural assessment confirmed these distortions. In contrast, flaxseed significantly corrected hyperlipidemia and hepatic biochemical parameters with critical improvement in the liver histopathological changes depicted previously.Conclusion: Flaxseed may have a hepatoprotective role against steatohepatitis and fibrosis in ovariectomized obese rat model.

Joint Tumor Bud-MMP/TIMP Count at the Invasive Front Improves the Prognostic Evaluation of Invasive Breast Carcinoma.

Background: Tumor budding is a histological phenomenon consisting of the formation of small clusters of one to five undifferentiated malignant cells detached from the main tumor mass which are observed in the tumor stroma. In the present study, we investigated the prognostic significance of tumor budding in breast cancer and its relationship with the expressions of matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs). Methods: The number of buds was counted in whole-tissue sections from 153 patients with invasive ductal carcinomas who underwent a long follow-up period. In addition, an immunohistochemical study of MMP-9, -11, and -14 TIMP-1 and -2 expression by cell types at the invasive tumor front was carried out. Results: There was a wide variability in the number of buds among tumors, ranging from 0 to 28 (median = 5). Tumor budding count ≥ 4 was the optimal cut-off to predict both relapse-free and overall survival. High-grade tumor budding was associated with MMP/TIMP expression by cancer-associated fibroblasts. In addition, we found that the combination of tumor budding grade with MMP/TIMP expression by stromal cells, and especially with MMP-11 expression by mononuclear inflammatory cells, significantly improved the prognostic evaluation. Conclusion: High-grade tumor budding is associated with a more aggressive tumor phenotype, which, combined with MMP/TIMP expression by stromal cells at the invasive front of the tumor, identifies patients with poor prognosis.

Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer

The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I–III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30–57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain–Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38–0.71) and 32% (95% CI: 0.12–0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.

Reduced Performance Due to Adenoviral Gizzard Erosion in 16-Day-Old Commercial Broiler Chickens in Iran, Confirmed Experimentally.

Adenoviral gizzard erosion (AGE) in broilers is an emerging infectious disease with negative impact on flock productivity. Despite of known primary etiological role of fowl adenovirus serotype 1 (FAdV-1) in AGE, there are a limited number of field reports worldwide, possibly because the disease is less noticeable and clinically difficult to assess. The present study documents an outbreak of AGE in 16-day-old broiler chickens on a farm in the north of Iran and the reproduction of the disease in an experimental setting. In the field, a sudden onset of mortality was noticed in affected broilers resulting in 6% total mortality and decreased weight gain leading to approximately 1-week delay to reach the target slaughter weight. Necropsy findings in dead broilers revealed black colored content in crop, proventriculus and gizzard together with severe gizzard erosions characterized by multiple black-brown areas of variable size in the koilin layer and mucosal inflammation. Microscopic examination revealed necrotizing ventriculitis marked with severe dissociation of koilin layer and degeneration of glandular epithelium with infiltration of mononuclear inflammatory cells. FAdV-1 was isolated from affected gizzards. Phylogenetic analysis of the hexon loop-1 (L1) sequence of the isolated virus showed 100% identity with pathogenic FAdV-1 strains previously reported from broiler chickens with AGE. Subsequently, an in vivo study infecting day-old commercial layer chickens with the field isolate demonstrated characteristic lesions and histopathological changes of AGE together with decreased weight gain in the infected birds. For the first time, the progress of a natural outbreak of AGE in Iran is described and experimental reproduction of the disease is demonstrated. The findings highlight the economic impact of the disease for regional poultry production due to mortality and impaired weight gain of the affected broilers.

Biological behavior of magnesium-substituted hydroxyapatite during bone repair.

The aim of this study was to analyze the biological behavior and osteogenic potential of magnesium (Mg) substituted hydroxyapatite (HA) microspheres, implanted in a critical bone defect, considering that this ion is of great clinical interest, since it is closely associated with homeostasis and bone mineralization. For the purpose of this study, 30 rats were used to compose three experimental groups: GI - bone defect filled with HA microspheres; GII - bone defect filled with HA microspheres replaced with Mg; GIII - empty bone defect; evaluated at biological points of 15 and 45 days. The histological results, at 15 days, showed, in all the groups, a discrete chronic inflammatory infiltrate; biomaterials intact and surrounded by connective tissue; and bone neoformation restricted to the borders. At 45 days, in the GI and GII groups, an inflammatory response of discrete granulomatous chronic type was observed, and in the GIII there was a scarce presence of mononuclear inflammatory cells; in GI and GII, the microspheres were seen to be either intact or fragmented, surrounded by fibrous connective tissue rich in blood vessels; and discrete bone neoformation near the edges and surrounding some microspheres. In GIII, the mineralization was limited to the borders and the remaining area was filled by fibrous connective tissue. It was concluded that the biomaterials were biocompatible and osteoconductive, and the percentage of Mg used as replacement ion in the HA did not favor a greater bone neoformation in relation to the HA without the metal.

BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics.

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple ("uncomplicated") increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.

Expression and clinical significance of circular RNAs related to immunity and inflammation in patients with rheumatoid arthritis

The aim of this study was to investigate the changes in and clinical significance of circular RNAs (circRNAs) expression related to immunity and inflammation in patients with rheumatoid arthritis (RA). We analyzed the circRNAs related to immunity and inflammation in peripheral blood mononuclear cells (PBMCs) from three RA patients and three healthy controls using high-throughput sequencing and bioinformatics analysis. Subsequently, four differentially expressed circRNAs were verified by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). We selected hsa_circ_0003353 for functional phenotype analysis in fibroblast-like synoviocytes (FLS) according to correlation tests and logistic regression analysis. The results identified and verified the expression of circRNAs (0003353, 0005732, 0072428, 0091685) that were significantly changed in PBMCs from RA patients. ROC analysis suggested that these circRNAs have significant value in RA diagnosis. Spearman analysis revealed that significant relationships between these circRNAs and clinical indicators as well as SPP. The logistic regression analysis showed that clinical indicators and SPP were risk factors for hsa_circ_0003353 expression, which is worthy of further investigation. As predicted, hsa_circ_0003353 had significantly higher expression in RA-FLS. The cell proliferation, migration, invasion, apoptosis, and inflammatory cytokine production of RA-FLS showed significant alterations after hsa_circ_0003353 suppression and overexpression. Our results indicate that hsa_circ_0003353 may play an essential role in promoting immunity, inflammation, synovial invasion, and joint destruction and that hsa_circ_0003353 may act as a biomarker of RA.

Sub-acute oral toxicity study of aqueous extract of tobacco leaves (Nicotiana tabacum L.) on lipid profile, the tissue, and serum of the liver and kidney of male Wistar rats

Context Tobacco consumption may pose a very serious threat to the physiological state of the body; yet, fewer records have been documented in that regard. Objective We investigated the impact of aqueous extract of tobacco leaves on the lipid profile, the tissue, and serum levels of the liver and kidney of male Wister rats. Materials and methods Rats (n = 52; weight = 33 − 47 g; ∼ 2½ weeks old) were acclimatised for 7 days and administered aqueous extract of tobacco leaves at 100, 200, 400, 0 mg/kg of body weight (to group A, B, C, D) for 30 days. Results Compared with the control group, the kidney tissue and serum (i.e., urea and creatinine) were not influenced, in contrast, indices of the liver such as AST, ALT, and ALP, dose-dependently increased. Changes such as coagulative necrosis resulted in the infiltration of mononuclear inflammatory cells and the vacuolar degeneration of the liver. Beside the reduction in the high-density lipoprotein of the rats, there was an increase in the concentration of triglycerides, very low-density lipoprotein, low-density lipoprotein, and the total cholesterol. Conclusion Thus, extract of tobacco leaves can greatly influence the body lipid profile, beside the serum and tissues of the liver.

Localization of interleukin-6 signaling complex in epithelialized apical lesions of endodontic origin.

We aimed to determine the immunolocalization patterns of the interleukin (IL)-6 signaling complex in epithelialized and non-epithelialized apical lesions of endodontic origin (ALEOs). Epithelialized (n = 8) and non-epithelialized (n = 7) ALEOs were obtained from teeth with indication of extraction in patients with clinical diagnosis of apical periodontitis. All tissues were subjected to routine processing for histopathologic examination and primary antibodies for IL-6, IL-6 receptor (R), and glycoprotein (gp)-130 were used for immunohistochemistry and double immunofluorescence co-localization. IL-6, IL-6R, and gp-130 were immunolocalized in endothelial cells and mononuclear leukocytes in a diffuse pattern within the connective tissue of epithelialized and non-epithelialized ALEOs. In the epithelialized lesions, two different patterns were identified: IL-6 signaling complex was localized within the proliferating epithelium in a diffuse intracellular pattern and in a cell membrane localization pattern within the mature epithelial lining, showing a decreased intensity towards the surface layers. IL-6, IL-6R, and gp-130 localized to mononuclear inflammatory cells, vascular endothelial cells, and immature proliferating epithelia in a diffuse pattern and in mature lining epithelia in a localized cell membrane pattern, supporting a role for epithelial proliferation during cyst formation. Additional cell membrane co-localization of IL-6 receptor complex suggests classic signaling involvement in addition to trans-signaling.

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.

A Rat Model of Frozen Shoulder Demonstrating the Effect of Transcatheter Arterial Embolization on Angiography, Histopathology, and Physical Activity

PurposeTo assess the angiographic findings and the effects of transcatheter arterial embolization on physical activity and histopathology using a frozen shoulder rat model. Materials and MethodsFirst, the angiographic and histopathologic findings of rats in which the shoulder was immobilized with molding plaster for 6 weeks (n = 4) were compared to control rats with normal non-immobilized shoulders (n = 4). Next, a total of 16 frozen shoulder rats were divided into 2 groups. In the transcatheter arterial embolization group (n = 8), imipenem/cilastatin was injected into the left thoracoacromial artery. The changes of physical activity before and after procedures were evaluated and compared with a saline-injected control group (n = 8). Histopathologic findings were also compared between the 2 groups. ResultsAngiography revealed abnormal shoulder staining in all of the rats with a frozen shoulder. On histopathology, the numbers of microvessels and mononuclear inflammatory cells in the synovial membrane of the joint capsule were significantly higher compared with the control rats (both P = .03). In the transcatheter arterial embolization group, the running distance and speed were improved (P = .03 and P = .01, respectively), whereas there were no significant differences in the control group. The number of microvessels and mononuclear inflammatory cells in the transcatheter arterial embolization group were significantly lower than the control group (P = .002 and P = .001, respectively). ConclusionsThe rat frozen shoulder model revealed the development of neovascularization. Transcatheter arterial embolization decreased the number of blood vessels and inflammatory changes in the frozen shoulder and increased the moving distance and speed of the rats.

Preclinical Safety Assessment of 2 Inhaled Single-Domain Antibodies in the Cynomolgus Monkey.

The safety of 2 single domain antibodies (dAbs) was evaluated by inhalation toxicology studies in the cynomolgus monkey. In the first case study, a 14-day repeat-dose study evaluating an anti-thymic stromal lymphopoietin (anti-TSLP) dAb resulted in minimal mononuclear inflammatory cell infiltrates in the lungs, increases in lymphocytes in bronchoalveolar lavage fluid, and development of antidrug antibodies (ADAs). In a 6-week inhalation study, there was an increase in incidence and/or severity of mononuclear cell infiltrates in the lung, increased cellularity in the tracheobronchial lymph node (TBLN), and development of ADA. The second case study evaluated a change in duration of inhalation dosing, a different route of exposure (intravenous or IV), and recovery following an off-dose period with an anti-tumor necrosis factor receptor 1 dAb. A 7-day repeat-dose inhalation study and a 14-day IV study produced no microscopic effects in the lung, whereas a 14-day inhalation study resulted in moderate increases in pulmonary perivascular/peribronchiolar/alveolar lymphocytic infiltrates and increased cellularity in the TBLN, with partial and full recovery, respectively, after 14 days. The lung and lymph node findings seen after inhalation of either dAb were considered secondary to the immunogenic response to a human protein and were considered nonadverse.

Placental Pathology of COVID-19 with and without Fetal and Neonatal Infection: Trophoblast Necrosis and Chronic Histiocytic Intervillositis as Risk Factors for Transplacental Transmission of SARS-CoV-2.

The mechanism(s) by which neonates testing positive for coronavirus disease 2019 (COVID-19) acquire their infection has been largely unknown. Transmission of the etiological agent, SARS-CoV-2, from mother to infant has been suspected but has been difficult to confirm. This communication summarizes the spectrum of pathology findings from pregnant women with COVID-19 based upon the infection status of their infants and addresses the potential interpretation of these results in terms of the effects of SARS-CoV-2 on the placenta and the pathophysiology of maternal-fetal infection. Placentas from pregnant women with COVID-19 and uninfected neonates show significant variability in the spectrum of pathology findings. In contrast, placentas from infected maternal-neonatal dyads are characterized by the finding of mononuclear cell inflammation of the intervillous space, termed chronic histiocytic intervillositis, together with syncytiotrophoblast necrosis. These placentas show prominent positivity of syncytiotrophoblast by SARS-CoV-2, fulfilling the published criteria for transplacental viral transmission as confirmed in fetal cells through identification of viral antigens by immunohistochemistry or viral nucleic acid using RNA in situ hybridization. The co-occurrence of chronic histiocytic intervillositis and trophoblast necrosis appears to be a risk factor for placental infection with SARS-CoV-2 as well as for maternal-fetal viral transmission, and suggests a potential mechanism by which the coronavirus can breach the maternal-fetal interface.

Case Studies Discussing the Pathology, Immunogenicity, and Proposed Mechanism of Toxicity of an Inhaled Anti-TGFβ Humanized Fab Antibody in Non-Human Primates and Mice.

Treatment of nonhuman primates and mice with a humanized antigen-binding fragment (Fab) antibody (UCBFab) inhibiting transforming growth factor β via daily inhalation for up to 13 weeks resulted in low systemic exposure but high local exposure in the lung. Target engagement was demonstrated by reduced levels of signal transducers, phosphoSMAD and plasminogen activator inhibitor-1 in the bronchoalveolar lavage fluid (BALF). Treatment was associated with a high frequency and titer of antidrug antibodies, indicating high local immunogenicity, and local pathology within the lung and draining lymph nodes. Microscopic changes were characterized by perivascular (PV) and peribronchiolar (PB) mononuclear inflammatory cell (MIC) infiltrates that were principally lymphocytic in nature and mixed inflammatory cell infiltrates and/or inflammation within the alveoli. Immunohistochemical investigation revealed a predominantly CD68-positive macrophage and CD3- and CD8>CD4-positive T-cell response in the alveoli, whereas within the airways, there was a variable mixture of CD3-positive T cells, CD20-positive B cells, and CD68-positive macrophages. Increased cellularity of the draining lymph nodes was also noted, indicating the presence of an immune response to the inhaled test article. Morphologic changes did not progress over time, and all changes partially recovered. Increased leukocytes (principally macrophages) in BALF cytology correlated with the changes seen by histopathology.

Artificial intelligence identifies inflammation and confirms fibroblast foci as prognostic tissue biomarkers in idiopathic pulmonary fibrosis

A large number of fibroblast foci (FF) predict mortality in idiopathic pulmonary fibrosis (IPF). Other prognostic histological markers have not been identified. Artificial intelligence (AI) offers a possibility to quantitate possible prognostic histological features in IPF. We aimed to test the use of AI in IPF lung tissue samples by quantitating FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with a deep convolutional neural network (CNN). Lung tissue samples of 71 patients with IPF from the FinnishIPF registry were analyzed by an AI model developed in the Aiforia® platform. The model was trained to detect tissue, air spaces, FF, interstitial mononuclear inflammation, and intra-alveolar macrophages with 20 samples. For survival analysis, cut-point values for high and low values of histological parameters were determined with maximally selected rank statistics. Survival was analyzed using the Kaplan-Meier method. A large area of FF predicted poor prognosis in IPF (p=0.01). High numbers of interstitial mononuclear inflammatory cells and intra-alveolar macrophages were associated with prolonged survival (p=0.01 and p=0.01, respectively). Of lung function values, low diffusing capacity for carbon monoxide was connected to a high density of FF (p=0.03) and a high forced vital capacity of predicted was associated with a high intra-alveolar macrophage density (p=0.03). The deep CNN detected histological features that are difficult to quantitate manually. Interstitial mononuclear inflammation and intra-alveolar macrophages were novel prognostic histological biomarkers in IPF. Evaluating histological features with AI provides novel information on the prognostic estimation of IPF.

Pathogenicity of severe fever with thrombocytopenia syndrome virus in mice regulated in type I interferon signaling

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease, which causes high fever, thrombocytopenia, and death in humans and animals in East Asian countries. The pathogenicity of SFTS virus (SFTSV) remains unclear. We intraperitoneally infected three groups of mice: wild-type (WT), mice treated with blocking anti-type I interferon (IFN)-α receptor antibody (IFNAR Ab), and IFNAR knockout (IFNAR−/−) mice, with four doses of SFTSV (KH1, 5 × 105 to 5 × 102 FAID50). The WT mice survived all SFTSV infective doses. The IFNAR Ab mice died within 7 days post-infection (dpi) with all doses of SFTSV except that the mice were infected with 5 × 102 FAID50 SFTSV. The IFNAR−/− mice died after infection with all doses of SFTSV within four dpi. No SFTSV infection caused hyperthermia in any mice, whereas all the dead mice showed hypothermia and weight loss. In the WT mice, SFTSV RNA was detected in the eyes, oral swabs, urine, and feces at 5 dpi. Similar patterns were observed in the IFNAR Ab and IFNAR−/− mice after 3 dpi, but not in feces. The IFNAR Ab mice showed viral shedding until 7 dpi. The SFTSV RNA loads were higher in organs of the IFNAR−/− mice compared to the other groups. Histopathologically, coagulation necrosis and mononuclear inflammatory cell infiltration in the liver and white pulp atrophy in the spleen were seen as the main lesions in the IFN signaling lacking mice. Immunohistochemically, SFTSV antigens were mainly detected in the marginal zone of the white pulp of the spleen in all groups of mice, but more viral antigens were observed in the spleen of the IFNAR−/− mice. Collectively, the IFN signaling-deficient mice were highly susceptible to SFTSV and more viral burden could be demonstrated in various excreta and organs of the mice when IFN signaling was inhibited.

INFLAMMATORY MYOFIBROBLASTIC TUMOR OF PLEURA: A RARE BENIGN TUMOR

SESSION TITLE: Fellows Disorders of the Pleura Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Inflammatory myofibroblastic tumor (also known as plasma cell granuloma, inflammatory pseudotumor, fibrous histiocytoma, fibroxanthoma, xanthogranuloma) is a rare benign neoplasm which can also be locally invasive. The symptoms and radiological findings are mostly non-specific. It is occasionally reported in lungs with incidence of 0.04 - 0.7% of all lung tumors, whereas in pleura, it is rarely reported. CASE PRESENTATION: A 30yr female non-smoker presented with breathlessness, left sided chest pain for 2 months. CXR- large homogenous opacity in the left hemithorax sparing the left upper zone. HRCT chest - a large multiloculated, multiseptated cystic lesion was found in left pleural cavity with collapse of underlying left lung and mild pleural effusion. Thoracotomy was performed and a large fleshy highly vascular mass was noted of size 30cm x 20cm having variegated margins, adherent to lower lobe of left lung, diaphragm and postero-medial aspect of mediastinum. The tumor was resected in-toto weighing around 4.5kg. HPE of the tissue showed features of INFLAMMATORY MYOFIBROBLASTIC TUMOR. IHC analysis showed positive staining for vimentin and smooth muscle actin(SMA) confirming the diagnosis DISCUSSION: IMT was first described in lungs by Brunn in 1939. It is reported in other extrapulmonary sites like orbit, liver, spleen, thyroid, breast, lymph nodes, skull base and rarely in pleura. Pathogenesis of IMT is still unknown. One Hypothesis is that, IMTs are low grade mesenchymal neoplasms with a secondary inflammatory component. It is supported by the presence of a fusion gene ALK gene, a tyrosine kinase oncogene located on chromosome 2p23, initially found to be arranged in anaplastic large cell lymphomas, leading to overexpression of ALK gene. The cytoplasmic expression of ALK gene is found on immunohistochemistry in some cases of IMT. It is found less commonly in pulmonary IMT than in extrapulmonary IMT. The clinical findings and symptoms are largely non-specific. The symptoms may be cough, dyspnea, chest pain, hemoptysis, fever and fatigue. Weight loss and anorexia are rare. Approximately 70 percent of patients are asymptomatic and tumor discovered incidentally on chest x-ray. Approximately 50 percent of the patients have an elevated sedimentation rate, mild anemia and thrombocytosis can also occur. The diagnosis of IMT requires the presence of characteristic pathological features- a background proliferation of spindle cells associated with a variable dense polymorphic infiltrate of mononuclear inflammatory cells CONCLUSIONS: IMT is a rare benign tumor. Clinical and radiological presentation is variable and nonspecific and diagnosis can be made only by histopathological and immunohistochemical studies. Despite being benign, its potential for recurrence and local invasion requires complete surgical resection. 4.5 kg of IMT pleura was never reported in literature till now. Reference #1: R. J. Cerfolio, M. S. Allen, A. G. Nascimento et al., “Inflammatory pseudotumors of the lung,” Annals of Thoracic Surgery, vol. 67, no. 4, pp. 933–936, 1999. Reference #2: J. Loeffler-Ragg, J. Bodner, M. Freund et al., “Diagnostic and therapeutic challenges of a large pleural inflammatory myofibroblastic tumor,” Case Reports in Pulmonology, vol. 2012, Article ID 102196, 5 pages, 2012. Reference #3: C. M. Coffin, A. Patel, S. Perkins, K. S. J. Elenitoba-Johnson, E. Perlman, and C. A. Griffin, “ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor,” Modern Pathology, vol. 14, no. 6, pp. 569–576, 2001. DISCLOSURES: No relevant relationships by PRAPULLA CHANDRA DAVULURI, source=Web Response

S2970 Epigastric Pain and Scarring of the Stomach Body Leading to a Rare Diagnosis of Collagenous Gastritis in an Adult

INTRODUCTION: Collagenous gastritis (CG) is a rare disease characterized by subepithelial deposition of collagen bands and infiltration of inflammatory mononuclear cells in the lamina propria. Since 1989, there have been approximately 100 reported cases, limiting understanding of disease management. We discuss a 55-year-old female in the hopes of providing more information regarding CG. CASE DESCRIPTION/METHODS: A 55-year-old Caucasian female with a history of hypothyroidism presented with a 6-month history of diarrhea, epigastric pain, and loss of appetite. The patient stated stools were up to 5 times a day; epigastric pain was described as a burning sensation. She was on a short course of antibiotics for an upper respiratory tract infection 2 months prior. C. difficile, stool culture, and stool white blood cell were collected and were negative. Bloodwork was obtained including CBC, CMP, lipids, TSH, vitamin D, and HbA1c and were within normal limits. The patient was referred to gastroenterology. Abdominal ultrasound was performed and noted no sonographic abnormality of the abdomen. EGD showed localized continuous petechiae of the antral mucosa; abnormal vascularity, as well as petechiae and scarring of the mucosa of the stomach body (Figure 1). Colonoscopy demonstrated moderate diverticulosis of the left side of the colon (Figure 2). Biopsies were performed of the duodenum, stomach body, rectal polyp, and colon. Immunohistochemical stain was negative for H. pylori. Biopsies of the colon and rectal polyp confirmed collagenous colitis. Gastric biopsy demonstrated impressive full thickness lamina propria dense fibrosis, mixed chronic inflammation, complete gland atrophy, metaplastic mucous glands, epithelial injury, necroinflammatory luminal debris, and intraepithelial neutrophils. Trichrome stain was performed that highlighted marked collagen deposition, confirming our diagnosis of collagenous gastritis. HHV8 immunohistochemical stain of gastric biopsy was completed, to exclude Kaposi sarcoma, and was negative. The patient was successfully initiated on 1 gram of sucralfate four times a day. DISCUSSION: CG is a rare disease, previous case reports have enabled physicians to characterize biopsy findings and we aim to add to that pool. No trials have been conducted with regards to treatment, therefore we hope our patient’s may be useful for physicians researching treatment strategies for both current and future patients.Figure 1.: Stomach Body Scarring and Petechiae.Figure 2.: Descending Colon Diverticulosis.