Update on cryptogenic organizing pneumonia.

Cryptogenic organizing pneumonia (COP) is a form of idiopathic interstitial pneumonia that results from the pulmonary reaction to various unidentified injuries. Secondary organizing pneumonia is diagnosed when the triggering factor has been identified; it is mainly caused by infections, toxic substance exposure, drugs, connective tissue diseases, malignancies, autoimmune diseases, bone marrow, or organ transplantation, and radiotherapy. There has been an increase in the number of reports of drug-induced organizing pneumonia (OP). New biological therapies, interferon, monoclonal antibodies, anti-interleukin antibodies, and PD1/PDL-1 inhibitors may induce this specific pulmonary reaction. The classical form of COP is usually subacute and does not manifest as severe disease. Patients maintain sufficient respiratory function, and treatment with steroids is usually effective. Several specific forms of OP (e.g., the cicatricial variant or acute fibrinous type) have distinct clinical and histological features, require higher doses of immunosuppressive drugs, and have a worse prognosis. In the era of administering steroid-sparing therapies for the treatment of interstitial lung diseases, connective tissue dases, and other conditions, it is important to emphasize this type of therapy for patients with COP.

Eosinophilic granulomatosis with polyangiitis - Advances in pathogenesis, diagnosis, and treatment.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease characterized by eosinophil-rich granulomatous inflammation and necrotizing vasculitis, pre-dominantly affecting small-to-medium-sized vessels. It is categorized as a primary antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) but also shares features of hypereosinophilic syndrome (HES); therefore, both vessel inflammation and eosinophilic infiltration are suggested to cause organ damage. This dual nature of the disease causes variable clinical presentation. As a result, careful differentiation from mimicking conditions is needed, especially from HES, given the overlapping clinical, radiologic, and histologic features, and biomarker profile. EGPA also remains a diagnostic challenge, in part because of asthma, which may pre-dominate for years, and often requires chronic corticosteroids (CS), which can mask other disease features. The pathogenesis is still not fully understood, however, the interaction between eosinophils and lymphocytes B and T seems to play an important role. Furthermore, the role of ANCA is not clear, and only up to 40% of patients are ANCA-positive. Moreover, two ANCA-dependent clinically and genetically distinct subgroups have been identified. However, a gold standard test for establishing a diagnosis is not available. In practice, the disease is mainly diagnosed based on the clinical symptoms and results of non-invasive tests. The unmet needs include uniform diagnostic criteria and biomarkers to help distinguish EGPA from HESs. Despite its rarity, notable progress has been made in understanding the disease and in its management. A better understanding of the pathophysiology has provided new insights into the pathogenesis and therapeutic targets, which are reflected in novel biological agents. However, there remains an ongoing reliance on corticosteroid therapy. Therefore, there is a significant need for more effective and better-tolerated steroid-sparing treatment schemes.

COVID-19 in patients with pulmonary alveolar proteinosis: a European multicentre study.

Adult PAP patients experience similar #COVID19 rates to the general population, and high rates of hospitalisation and deaths, underscoring their vulnerability and the need for measures to prevent infection. The impact of iGM-CSF must be considered. https://bit.ly/3M0wKnZ.

Novel folliculin gene mutations in Polish patients with Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare, autosomal dominant, inherited disease caused by mutations in the folliculin gene (FLCN). The disease is characterised by skin lesions (fibrofolliculomas, trichodiscomas, acrochordons), pulmonary cysts with pneumothoraces and renal tumours. We present the features of Polish patients with BHDS. MATERIALS AND METHODS: The first case of BHDS in Poland was diagnosed in 2016. Since then, 15 cases from 10 families have been identified. Thirteen patients were confirmed via direct FLCN sequencing, and two according to their characteristic clinical and radiological presentations. RESULTS: BHDS was diagnosed in 15 cases (13 women and 2 men) from 10 families. The mean ages at the time of first pneumothorax and diagnosis were 38.4 ± 13.9 and 47.7 ± 13 years, respectively. Five patients (33%) were ex-smokers (2.1 ± 1.37 packyears), and 10 (67%) had never smoked cigarettes. Twelve patients (83%) had a history of recurrent symptomatic pneumothorax. Three patients had small, asymptomatic pneumothoraces, which were only detected upon computed tomography examination. All patients had multiple bilateral pulmonary cysts, distributed predominantly in the lower and middle, peripheral, and subpleural regions of the lungs. Generally, patients exhibited preserved lung function. Skin lesions were seen in four patients (27%), one patient had renal angiomyolipoma, and one had bilateral renal cancer. Different mutations of the FLCN gene were identified (mainly in exon 6), with two novel heterozygous variants: c.490delA p.(Arg164GlyTer13) and c.40delC p.(His14ThrsfTer41). CONCLUSIONS: All analysed patients with BHDS presented with lung lesions and with less frequent skin and renal lesions than previously reported in other populations. In addition, more frequent mutations located in exon 6 were detected, and two novel FLCN gene mutations were identified.

Decreased Volume of Lateral and Medial Geniculate Nuclei in Patients with LHON Disease-7 Tesla MRI Study.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited genetic disorder leading to severe and bilateral loss of central vision, with a young male predilection. In recent years, multiple studies examined structural abnormalities in visual white matter tracts such as the optic tract and optic radiation. However, it is still unclear if the disease alters only some parts of the white matter architecture or whether the changes also affect grey matter parts of the visual pathway. This study aimed at improving our understanding of morphometric changes in the lateral (LGN) and medial (MGN) geniculate nuclei and their associations with the clinical picture in LHON by the application of a submillimeter surface-based analysis approach to the ultra-high-field 7T magnetic resonance imaging data. To meet these goals, fifteen LHON patients and fifteen age-matched healthy subjects were examined. A quantitative analysis of the LGN and MGN volume was performed for all individuals. Additionally, morphometric results of LGN and MGN were correlated with variables covering selected aspects of the clinical picture of LHON. In comparison with healthy controls (HC), LHON participants showed a significantly decreased volume of the right LGN and the right MGN. Nevertheless, the volume of the right LGN was strongly correlated with the averaged thickness value of the right retinal nerve fiber layer (RNFL). The abnormalities in the volume of the LHON patients' thalamic nuclei indicate that the disease can cause changes not only in the white matter areas constituting visual tracts but also in the grey matter structures. Furthermore, the correlation between the changes in the LGN volume and the RNFL, as well as the right optic nerve surface area located proximally to the eyeball, suggest some associations between the atrophy of these structures. However, to fully confirm this observation, longitudinal studies should be conducted.

Recommendations for Lung Ultrasound in Internal Medicine.

A growing amount of evidence prompts us to update the first version of recommendations for lung ultrasound in internal medicine (POLLUS-IM) that was published in 2018. The recommendations were established in several stages, consisting of: literature review, assessment of literature data quality (with the application of QUADAS, QUADAS-2 and GRADE criteria) and expert evaluation carried out consistently with the modified Delphi method (three rounds of on-line discussions, followed by a secret ballot by the panel of experts after each completed discussion). Publications to be analyzed were selected from the following databases: Pubmed, Medline, OVID, and Embase. New reports published as of October 2019 were added to the existing POLLUS-IM database used for the original publication of 2018. Altogether, 528 publications were systematically reviewed, including 253 new reports published between September 2017 and October 2019. The new recommendations concern the following conditions and issues: pneumonia, heart failure, monitoring dialyzed patients' hydration status, assessment of pleural effusion, pulmonary embolism and diaphragm function assessment. POLLUS-IM 2020 recommendations were established primarily for clinicians who utilize lung ultrasound in their everyday clinical work.

TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme-Future Perspectives.

Toll-like-receptor (TLR) family members were detected in the central nervous system (CNS). TLR occurrence was noticed and widely described in glioblastomamultiforme (GBM) cells. After ligand attachment, TLR-4 reorients domains and dimerizes, activates an intracellular cascade, and promotes further cytoplasmatic signaling. There is evidence pointing at a strong relation between TLR-4 signaling and micro ribonucleic acid (miRNA) expression. The TLR-4/miRNA interplay changes typical signaling and encourages them to be a target for modern immunotherapy. TLR-4 agonists initiate signaling and promote programmed death ligand-1 (PD-1L) expression. Most of those molecules are intensively expressed in the GBM microenvironment, resulting in the autocrine induction of regional immunosuppression. Another potential target for immunotreatment is connected with limited TLR-4 signaling that promotes Wnt/DKK-3/claudine-5 signaling, resulting in a limitation of GBM invasiveness. Interestingly, TLR-4 expression results in bordering proliferative trends in cancer stem cells (CSC) and GBM. All of these potential targets could bring new hope for patients suffering from this incurable disease. Clinical trials concerning TLR-4 signaling inhibition/promotion in many cancers are recruiting patients. There is still a lot to do in the field of GBM immunotherapy.

Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer.

Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world's population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial-mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial-mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4ß, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.

Update on Pulmonary Langerhans Cell Histiocytosis.

Pulmonary Langerhans cell (LC) histiocytosis (PLCH) has unknown cause and is a rare neoplastic disorder characterized by the infiltration of lungs and various organs by bone marrow-derived Langerhans cells with an accompanying strong inflammatory response. These cells carry somatic mutations of BRAF gene and/or NRAS, KRAS, and MAP2K1 genes, which cause activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. PLCH occurs predominantly in young smokers, without gender predominance. Lungs might be involved as an isolated organ or as part of a multiorgan disease. High-resolution computed chest tomography plays an outstanding role in PLCH diagnosis. The typical radiological picture of PLCH is the presence of small intralobular nodules, "tree in bud" opacities, cavitated nodules, and thin- and thick-walled cysts, frequently confluent. Histological examination of the lesion and demonstration of characteristic eosinophilic granulomas with the presence of LCs that display antigen CD1a or CD207 in immunohistochemistry are required for definite diagnosis. Smoking cessation is the most important recommendation for PLCH patients, but treatment of progressive PLCH and multisystem disease is based on chemotherapy. Recently, new targeted therapies have been implemented.

Risk of breast cancer in patients with lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare metastasizing pulmonary disease that shares some clinical, cellular, and molecular similarities with metastatic breast cancer to lung. LAM cells have been identified circulating in various body fluids of patients and, intriguingly, diverse evidence indicates that these cells may originate from a different organ to the lung. Following on from these observations, we hypothesized the existence of a common risk basis between LAM and breast cancer, and suggested increased risk of breast cancer among LAM patients. Here, by studying two additional LAM cohorts with more detailed epidemiological, life-style, and disease-related data, we show consistent results; a potential excess of estrogen-receptor-positive young breast cancer cases in LAM. This observation further suggests the need of prospective studies to precisely assess the association between both diseases.

Interferon Gamma Release Assays in Patients with Respiratory Isolates of Non-Tuberculous Mycobacteria - a Preliminary Study.

Interferon gamma releasing assays (IGRAs) are extensively used in the diagnosis of latent tuberculosis infections. Comparing to tuberculin skin test (TST) they lack false positive results in the populations vaccinated with BCG, and in most non-tuberculous mycobacteria (NTM) infections. Nevertheless, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium szulgai may induce positive IGRAs due to RD1 homology with Mycobacterium tuberculosis. The aim of the study was to investigate the possible influence of NTM respiratory isolates on the results of IGRAs. 39 patients (23 females and 16 males) of median age 61 years, with negative medical history concerning tuberculosis, entered the study. Identification of NTM was performed using the niacin test and molecular method GenoType CM test (Hain Lifescience). QFT-Plus was performed in 17 patients, T-SPOT-Tb - in 23 patients. Chest X-rays and a high-resolution computed tomography of the chest have been reviewed by the experienced radiologist blinded to the results of IGRAs, in search of past tuberculosis signs. Positive IGRAs results were obtained in three out of 39 patients (8%): 22% of patients with M. kansasii isolates and 18% of patients with radiological signs on HRCT that might be suggestive of past tuberculosis. Positive IGRAs correlated with radiological signs suggestive of past tuberculosis (r = 0.32, p = 0.04), and on the borderline with isolation of M. kansasii (r = 0.29, p = 0.06). These findings may suggest that a positive IGRAs result, in our material, could depend mostly on asymptomatic past Tb infection. The cross-reactivity of M. kansasii isolates with IGRAs was less probable; nevertheless, it requires further investigations.Interferon gamma releasing assays (IGRAs) are extensively used in the diagnosis of latent tuberculosis infections. Comparing to tuberculin skin test (TST) they lack false positive results in the populations vaccinated with BCG, and in most non-tuberculous mycobacteria (NTM) infections. Nevertheless, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium szulgai may induce positive IGRAs due to RD1 homology with Mycobacterium tuberculosis. The aim of the study was to investigate the possible influence of NTM respiratory isolates on the results of IGRAs. 39 patients (23 females and 16 males) of median age 61 years, with negative medical history concerning tuberculosis, entered the study. Identification of NTM was performed using the niacin test and molecular method GenoType CM test (Hain Lifescience). QFT-Plus was performed in 17 patients, T-SPOT-Tb ­ in 23 patients. Chest X-rays and a high-resolution computed tomography of the chest have been reviewed by the experienced radiologist blinded to the results of IGRAs, in search of past tuberculosis signs. Positive IGRAs results were obtained in three out of 39 patients (8%): 22% of patients with M. kansasii isolates and 18% of patients with radiological signs on HRCT that might be suggestive of past tuberculosis. Positive IGRAs correlated with radiological signs suggestive of past tuberculosis (r = 0.32, p = 0.04), and on the borderline with isolation of M. kansasii (r = 0.29, p = 0.06). These findings may suggest that a positive IGRAs result, in our material, could depend mostly on asymptomatic past Tb infection. The cross-reactivity of M. kansasii isolates with IGRAs was less probable; nevertheless, it requires further investigations.

A genome-wide association study implicates NR2F2 in lymphangioleiomyomatosis pathogenesis.

INTRODUCTION: Lymphangioleiomyomatosis (LAM) occurs either associated with tuberous sclerosis complex (TSC) or as sporadic disease (S-LAM). Risk factors for development of S-LAM are unknown. We hypothesised that DNA sequence variants outside of TSC2/TSC1 might be associated with susceptibility for S-LAM and performed a genome-wide association study (GWAS). METHODS: Genotyped and imputed data on 5 426 936 single nucleotide polymorphisms (SNPs) in 426 S-LAM subjects were compared, using conditional logistic regression, with similar data from 852 females from COPDGene in a matched case-control design. For replication studies, genotypes for 196 non-Hispanic White female S-LAM subjects were compared with three different sets of controls. RNA sequencing and immunohistochemistry analyses were also performed. RESULTS: Two noncoding genotyped SNPs met genome-wide significance: rs4544201 and rs2006950 (p=4.2×10-8 and 6.1×10-9, respectively), which are in the same 35 kb linkage disequilibrium block on chromosome 15q26.2. This association was replicated in an independent cohort. NR2F2 (nuclear receptor subfamily 2 group F member 2), a nuclear receptor and transcription factor, was the only nearby protein-coding gene. NR2F2 expression was higher by RNA sequencing in one abdominal LAM tumour and four kidney angiomyolipomas, a LAM-related tumour, compared with all cancers from The Cancer Genome Atlas. Immunohistochemistry showed strong nuclear expression in both LAM and angiomyolipoma tumours. CONCLUSIONS: SNPs on chromosome 15q26.2 are associated with S-LAM, and chromatin and expression data suggest that this association may occur through effects on NR2F2 expression, which potentially plays an important role in S-LAM development.