Misdiagnosis of lymphoma as vasculitis: A case report.

NK/T-cell lymphoma (NKTCL) is a highly aggressive malignant tumour with a very poor prognosis, which often poses diagnostic difficulties due to the non-specificity of its clinical presentation. NK/T-cell lymphoma with eosinophilic hyperplasia syndrome is extremely rare. This article describes a patient with NKTCL misdiagnosed as vasculitis who presented with sinusitis, abdominal pain, anorexia, and lung shadows. Additionally, the patient exhibited extremely high eosinophilia levels, which led to a further misdiagnosis of eosinophilic granuloma. We describe the clinical features, diagnostic methods and differential diagnosis of lymphoma and highlights the importance of a multidisciplinary approach in accurate diagnosis and treatment.

Retrospective comparison of high-resolution computed tomography of eosinophilic granulomatosis with polyangiitis with severe asthma.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often misdiagnosed as severe asthma due to their similar clinical presentations. We compared the pulmonary radiologic features of EGPA to those of severe asthma by high-resolution computed tomography (HRCT) in order to early diagnose EGPA. METHODS: We retrospectively reviewed clinical records and HRCT findings of 96 patients with EGPA and 82 patients with severe asthma who were seen at our hospital from 2011 to 2017. We used a semi-quantitative grading system to evaluate radiological findings. A radiological only and a clinical-radiological model were used to differentiate EGPA from severe asthma. RESULTS: Bronchial wall thickening, air trapping, tree-in-bud opacities, bronchial mucus plugging, bronchiectasis, diffuse ground-glass opacities (GGOs), consolidation, and increased small vascular markings were more common in EGPA patients than in severe asthmatics (P<0.05). The gradings of GGO (grade 2 vs. grade 1) and tree-in-bud opacities (grade 2 vs. grade 0) were higher in EGPA patients than in severe asthmatics. The total image score of EGPA patients was significantly higher than that of severe asthmatics (P<0.05). In the radiological only and the clinical-radiological model, the area under the receiver operating characteristic (ROC) curves (AUCs) for the identification of EGPA and severe asthma were 0.904 [95% confidence interval (CI): 0.860 to 0.948] and 0.974 (95% CI: 0.955 to 0.993), respectively. CONCLUSIONS: Lung HRCT scan is useful in differentiating EGPA from severe asthma. In patients with difficult-to-treat asthma, an HRCT scan of the thorax should be performed should there be features that raise the suspicion of EGPA.

Serum Cytokine Profiling Identifies Axl as a New Biomarker Candidate for Active Eosinophilic Granulomatosis With Polyangiitis.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) prognosis is generally favorable and is treated with combined corticosteroids/immunosuppressor(s) therapy. However, disease flares increase the number of clinical visits. Therefore, discovering new serum biomarkers for early identification of active EGPA is crucial. Objective: To identify reliable serum biomarkers to measure EGPA activity. Methods: The expression of 160 proteins was compared in sera from 15 inactive and 13 active EGPA patients by antibody-based microarray. Network-based analysis identified patterns in the different groups. Differentially expressed proteins (DEPs) in active disease were identified, and the correlation between their serum levels and clinical parameters was assessed. DEPs were further analyzed for GO enrichment and KEGG pathways. Finally, DEP marker candidates were validated by ELISA and Bio-plex as well as against a second cohort of 22 inactive and 18 active EGPA patients. Results: The active group presented higher peripheral and sputum eosinophil counts, FeNO, and FEV1 (% predicted) (P < 0.05). Network-based analysis showed scattered expression patterns in active subjects, but no significant bias in inactive subjects. Significant differences were observed in serum levels of 19 candidate markers, all of which were higher in active EGPA (P < 0.05). KEGG analysis indicated that DEPs were mainly involved in the MAPK, PI3K-Akt, RAS and Rap1 related pathways. Nine out of 19 candidate markers were positively correlated with peripheral eosinophil counts including FGF-7, SCF, GDNF, ß-NGF, IGFBP-4, Axl, PIGF, Insulin, NT-4, ErbB3, OPN and BMP-4 (r = 0.693, r = 0.692, r = 0.687, r = 0.683, r = 0.671, r = 0.606, r = 0.571, r = 0.570, r = 0.516, respectively; P < 0.05), while two, CD14 and MCP-3, were negatively correlated (r = -0.644 and r = -0.515; P < 0.05). The higher expression of Axl, OPN, HCC-4, GDNF, and MCP-3 in active EGPA subjects was confirmed by ELISA and Custom Multiplex Bio-plex analyses. Conclusion: The serum protein profiles were significantly different between active and inactive EGPA. The expression of the candidate proteins correlated with peripheral blood eosinophil count. Serum Axl, OPN, HCC-4, GDNF, and MCP-3 levels were consistently higher in active EGPA, independent of the assessment methods. Finally, Axl had the largest AUC, indicating that this cytokine may serve as novel biomarker for the diagnosis of active EGPA.

Early radiologic and bronchoscopic changes after bronchial thermoplasty in patients with severe asthma.

Bronchial thermoplasty (BT) is a treatment to reduce the airway smooth muscle mass by delivering radiofrequency thermal energy to the airways. BT is used in patients with severe asthma. The present study reported on cases of pneumothorax directly after BT and retrospectively analyzed early radiologic and bronchoscopic modifications after BT. The clinical data and radiologic and bronchoscopic findings of 12 patients with severe asthma who were subjected to BT between July 2014 and October 2017 were analyzed. A total of 33 chest radiographs were collected within 18-24 h after BT. Radiological abnormalities were observed in 32 radiographs as atelectasis (53.1%), peribronchial consolidations (84.4%), pleural effusion (18.8%), effusion in oblique fissures (3.1%), pleural thickening (6.3%) and pneumothorax (3.1%). Of note, one patient suffered pneumothorax after the third BT session and underwent chest drain insertion, followed by mechanical ventilation at the intensive care unit and multiple bronchoscopic interventions, which revealed extensive phlegm plugs. A total of six patients with worsened symptoms and lobar atelectasis also required bronchoscopic intervention, which revealed that phlegm plugs occluded the bronchus in the treated lobe. No bronchoscopic intervention was required in the remaining five patients. During 16-30 days of follow-up, 95.7% of the findings on chest radiography were resolved. To the best of our knowledge, the present study reported the first case of pneumothorax following BT. Early radiologic modifications such as atelectasis and peribronchial consolidations appear common after BT. However, whether bronchoscopic intervention is required for atelectasis following BT warrants further investigation. Of note, BT should be audited and recorded in detail to ideally contribute to a framework of clinical trials to improve risk-benefit evaluations and the selection of patients likely to benefit from treatment.

Hydrogen gas inhalation enhances alveolar macrophage phagocytosis in an ovalbumin-induced asthma model.

BACKGROUND: Maintaining an airway clear of bacteria, foreign particles and apoptotic cells by alveolar macrophages is very essential for lung homeostasis. In asthma, the phagocytic capacity of alveolar macrophages is significantly reduced, which is thought to be associated with increased oxidative stress. Hydrogen (H2) has been shown to exert potent antioxidant and anti-inflammatory effects, yet its effects on phagocytosis of alveolar macrophages are unknown. This study is aimed to evaluate the beneficial effects of hydrogen gas inhalation on alveolar macrophage phagocytosis in an ovalbumin (OVA)-induced murine asthma model. METHODS: Female C57BL/6 mice were intraperitoneally sensitized with OVA before they were subject to airway challenge with aerosolized OVA. Hydrogen gas was delivered to the mice through inhalation twice a day (2 h once) for 7 consecutive days. Phagocytic function of alveolar macrophages isolated from bronchoalveolar lavage fluid was assessed by fluorescence-labeled Escherichia coli as well as flow cytometry. RESULTS: Alveolar macrophages isolated from OVA-induced asthmatic mice showed decreased phagocytic capacity to Escherichia coli when compared with those of control mice. Defective phagocytosis in asthmatic mice was reversed by hydrogen gas inhalation. Hydrogen gas inhalation significantly alleviated OVA-induced airway hyperresponsiveness, inflammation and goblet cell hyperplasia, diminished TH2 response and decreased IL-4 as well as IgE levels, reduced malondialdehyde (MDA) production and increased superoxide dismutase (SOD) activity. Concomitantly, hydrogen gas inhalation inhibited NF-κB activation and markedly activated Nrf2 pathway in OVA-induced asthmatic mice. CONCLUSIONS: Our findings demonstrated that hydrogen gas inhalation enhanced alveolar macrophage phagocytosis in OVA-induced asthmatic mice, which may be associated with the antioxidant effects of hydrogen gas and the activation of the Nrf2 pathway.

Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model.

Multiple studies have addressed the vital role of Nod-like receptor protein 3(NLRP3)/caspase-1/IL-1ß signaling in asthma. Yet, the role of NLRP3/caspase-1 in toluene diisocyanate (TDI)-induced asthma is still obscure. The aim of this study is to investigate the role of the NLRP3/caspase-1 axis in TDI-induced asthma. Using an established murine model of TDI-induced asthma as described previously, we gave the asthmatic mice a highly selective NLRP3 inhibitor, MCC950, as well as the specific caspase-1 inhibitors VX-765 and Ac-YVAD-CHO for therapeutic purposes. Airway resistance was measured and bronchoalveolar lavage fluid was analyzed. Lungs were examined by histology, immunohistochemistry, Western blotting, and flow cytometry. TDI exposure elevated the expression of NLRP3 and caspase-1 that was coupled with increased airway hyperresponsiveness (AHR), neutrophil-dominated cell infiltration, pronounced goblet cell metaplasia, extensive collagen deposition, and increased TH2/TH17 responses. Both VX-765 and Ac-YVAD-CHO effectively inhibited the activation of caspase-1 in TDI-asthmatic mice that was accompanied by dramatic attenuation of AHR, airway inflammation, and airway remodeling, in addition to a decreased TH2 response and lower levels of IL-18 and IL-1ß. MCC950 blocked the activation of NLRP3 and downregulated protein expression of caspase-1, IL-1ß, and IL-18 in TDI-exposed mice. Furthermore, MCC950 remarkably alleviated AHR, airway inflammation, airway remodeling, and significantly suppressed TH2/TH17 responses. These findings suggested that blockade of the NLRP3/caspase-1 axis effectively prevents the progression of TDI-induced asthma and could be used as therapeutic targets for asthmatics.

IL-17F, rather than IL-17A, underlies airway inflammation in a steroid-insensitive toluene diisocyanate-induced asthma model.

Steroid insensitivity constitutes a major problem for asthma management. Toluene diisocyanate (TDI) is one of the leading allergens of asthma that induces both T-helper Th2 and Th17 responses, and is often associated with poor responsiveness to steroid treatment in the clinic.We sought to evaluate the effects of inhaled and systemic steroids on a TDI-induced asthma model and to find how interleukin (IL)-17A and IL-17F function in this model. BALB/c mice were exposed to TDI for generating an asthma model and were treated with inhaled fluticasone propionate, systemic prednisone, anti-IL-17A, anti-IL-17F, recombinant IL-17A or IL-17F.Both fluticasone propionate and prednisone showed no effects on TDI-induced airway hyperresponsiveness (AHR), bronchial neutrophilia and eosinophilia, and epithelial goblet cell metaplasia. TDI-induced Th2 and Th17 signatures were not suppressed by fluticasone propionate or prednisone. Treatment with anti-IL-17A after TDI exposure led to increased AHR, aggravated mucus production and airway eosinophil recruitment, accompanied by amplified Th2 responses, whereas anti-IL-17F ameliorated TDI-induced AHR and airway neutrophilia, with decreased Th17 responses. Recombinant IL-17A and IL-17F showed opposite effects to the monoclonal antibodies.IL-17A and IL-17F exert distinct biological effects during airway inflammation of a TDI-induced asthma model, which is unresponsive to both inhaled and systemic steroids.

Transient Receptor Potential Ion Channels Mediate Adherens Junctions Dysfunction in a Toluene Diisocyanate-Induced Murine Asthma Model.

Disruption of epithelial cell-cell junctions is essential for the initiation and perpetuation of airway inflammation in asthma. We've previously reported compromised epithelial barrier integrity in a toluene diisocyanate (TDI)-induced occupational asthma model. This study is aimed to explore the role of transient receptor potential vanilloid 4 (TRPV4) and transient receptor potential ankyrin 1 (TRPA1) in the dysfunction of adherens junctions in TDI-induced asthma. Mice were sensitized and challenged with TDI for a chemical-induced asthma model. Selective blockers of TRPV4 glycogen synthase kinase (GSK)2193874, 5 and 10 mg/kg) and TRPA1 (HC030031, 10 and 20 mg/kg) were intraperitoneally given to the mice. Immunohistochemistry revealed different expression pattern of TRPV4 and TRPA1 in lung. TDI exposure increased TRPV4 expression in the airway, which can be suppressed by GSK2193874, while treatment with neither TDI alone nor TDI together with HC030031 led to changes of TRPA1 expression in the lung. Blocking either TRPV4 or TRPA1 blunted TDI-induced airway hyperreactivity, airway neutrophilia and eosinophilia, as well as Th2 responses in a dose-dependent manner. At the same time, membrane levels of E-cadherin and ß-catenin were significantly decreased after TDI inhalation, which were inhibited by GSK2193874 or HC030031. Moreover, GSK2193874 and HC030031 also suppressed serine phosphorylation of glycogen synthase kinase 3ß, tyrosine phosphorylation of ß-catenin, as well as activation and nuclear transport of ß-catenin in mice sensitized and challenged with TDI. Our study suggested that both TRPV4 and TRPA1 contribute critically to E-cadherin and ß-catenin dysfunction in TDI-induced asthma, proposing novel therapeutic targets for asthma.

Bronchiectasis after bronchial thermoplasty.

Bronchial thermoplasty (BT) is used in the treatment of severe refractory asthma. It has been found to be beneficial to long-term improvements in the rate of asthma exacerbation, quality of life questionnaire answers (AQLQ), hospitalization, and emergency room visits. Atelectasis and lung abscess as direct complication of BT, but not bronchiectasis, have been reported previously. In this study, we report bronchiectasis after BT in what we believe may be the first case, combined with optical coherence tomography (OCT) and a 3-year follow-up of chest computed tomography (CT), to evaluate a patient with severe persistent asthma. We describe a 49-year-old Chinese male who complained of recurrent wheezing lasting over 5 years. His chest CT scan was normal before BT, but one month thereafter, he presented with mild central bronchiectasis on high-resolution CT, which persisted for more than 4 years. It remains unclear why this patient developed bronchiectasis so early post-BT treatment. This case highlights the need for short-term and long-term safety data on BT.

Rapamycin provides anti-epileptogenic effect in a rat model of post-traumatic epilepsy via deactivation of mTOR signaling pathway.

The mammalian target of rapamycin (mTOR) signaling pathway has attracted much attention in recent years. However, the contribution of mTOR activation to the development of post-traumatic epilepsy (PTE) remains largely unknown. The purpose of the present study was to investigate the activation of mTOR signaling in a rat model of FeCl2-induced PTE, and to explore the potential effect of its specific inhibitor rapamycin. The results indicated that the expression levels of p-mTOR and p-P70S6K, the overactivation biomarkers of mTOR signaling, increased significantly in hippocampal and perilesional cortex following PTE induction. Notably, they were significantly decreased in the aformementioned brain regions following rapamycin treatment. Furthermore, the frequency and number of behavioral seizures and epileptic brain injury were also greatly reduced. These results suggest that hyperactivation of the mTOR signaling pathway is a crucial mechanism of PTE development, and it may be considered a novel therapeutic target for PTE treatment.

Pretreatment elevated serum lactate dehydrogenase as a significant prognostic factor in malignant mesothelioma: A meta-analysis.

BACKGROUND: Lactate dehydrogenase (LDH) as a hypoxia-regulator plays a vital role in alternative metabolic pathways of cancer cells. Numerous studies have assessed the prognostic value of elevated pretreatment LDH in malignant mesothelioma (MM). However, the results have been largely inconsistent. Hence, the aim of current study was to investigate the prognostic value of pretreatment LDH levels in patients with MM by performing a meta-analysis of relevant studies. METHODS: A literature search for English language studies, which investigated the association of LDH levels with overall survival (OS) in malignant mesothelioma, was performed in the electronic databases, PubMed, Medline, Embase, and Web of Science. Pooled hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were calculated. Heterogeneity was assessed using Cochran Q and I statistics. Sensitivity analysis, meta-regression model, and subgroup analysis were performed to trace the source of heterogeneity, if applicable. RESULTS: A total of 9 studies with a combined study population of 1977 patients came within the purview of this meta analysis. Pooled HR for OS in patients with high LDH level was 1.68 (95% CI = 1.36-2.00). Significant heterogeneity was observed in the included studies (I = 54.1%, P = 0.026). Sensitivity analysis after sequential exclusion of 1 study at a time, and meta-regression with inclusion of 6 confounding factors failed to identify the source of heterogeneity. However, in the subgroup analysis, it was found that the publication of Nojiri et al was the origin of heterogeneity. When omitted the publication of Nojiri et al, the pooled HR of the rest 8 studies was 1.83 (95% CI = 1.45-2.20, I = 0.0%, P = 0.723). Egger test and funnel plots excluded the possibility of publication bias affecting the results of the current meta-analysis. CONCLUSION: A negative association was observed between high LDH levels and poor overall survival in the current study. Our findings suggest that pretreatment LDH level could serve as a useful predictor of prognosis in patients with malignant mesothelioma.

Prognostic significance of pretreated serum lactate dehydrogenase level in nasopharyngeal carcinoma among Chinese population: A meta-analysis.

BACKGROUND: A large number of studies have investigated the prognostic value of pretreated lactate dehydrogenase (LDH) level in nasopharyngeal carcinoma (NPC) patients while the role of it was inconsistent and inconclusive. Hence, the aim of the current study was to conduct a meta-analysis of all published studies to quantify the prognostic impact of pretreated serum LDH in NPC for Chinese population. OBJECTIVES: The aim of the current study was to conduct a meta-analysis of all published studies to quantify the prognostic impact of pretreated serum lactate dehydrogenase (LDH) in nasopharyngeal carcinoma (NPC) for Chinese population. METHODS: The PubMed, Medline, Embase, and Web of Science databases were searched for studies that assessed survival outcome and LDH in NPC. Overall survival (OS) was the primary survival outcome. Distant metastasis-free survival (DMFS) and disease-free survival (DFS) were secondary outcomes. The pooled hazard ratios (HRs), associated with 95% confidence intervals (95% CIs), were combined to calculate overall effects. The Cochran Q and I statistics were used to assess heterogeneity. When apparent heterogeneity was observed, sensitivity and meta-regression analyses were performed to explore its origin. RESULTS: Sixteen studies, which included 14,803 patients, were enrolled in the current meta-analysis to yield statistics. Overall, the pooled HR for OS in 11 eligible studies with high LDH level was 1.79 (95% CI = 1.47-2.12), and the pooled HR for DMFS in 9 eligible studies with high LDH level was 1.85 (95% CI = 1.48-2.22). Meanwhile, the pooled HR for DFS in 5 eligible studies with high LDH level was 1.63 (95% CI = 1.34-1.91). Egger test and funnel plots revealed that the publication bias in the current meta-analysis was insignificant. CONCLUSIONS: The present meta-analysis demonstrated that high pretreated LDH level is significantly associated with poorer OS, DMFS, and DFS, suggesting that pretreated LDH could sever as a prognostic factor in NPC among Chinese population.