Clinical features of cryptococcosis in patients with different immune statuses: a multicenter study in Jiangsu Province-China.

BACKGROUND: Current guidelines support different management of cryptococcosis between severely immunodeficient and immunocompetent populations. However, few studies have focused on cryptococcosis patients with mild-to-moderate immunodeficiency. We performed this study to determine the clinical features of pulmonary (PC) and extrapulmonary cryptococcosis (EPC) and compared them among populations with different immune statuses to support appropriate clinical management of this public health threat. METHODS: All cases were reported by 14 tertiary teaching hospitals in Jiangsu Province, China from January 2013 to December 2018. The trends in incidence, demographic data, medical history, clinical symptoms, laboratory test indicators, imaging characteristics and diagnostic method of these patients were then stratified by immune status, namely immunocompetent (IC, patients with no recognized underlying disease or those with an underlying disease that does not influence immunity, such as hypertension), mild-to-moderate immunodeficiency (MID, patients with diabetes mellitus, end-stage liver or kidney disease, autoimmune diseases treated with low-dose glucocorticoid therapy, and cancer treated with chemotherapy) and severe immunodeficiency (SID, patients with acquired immunodeficiency syndrome, haematologic malignancies, solid organ transplantation or haematologic stem cell transplantation, idiopathic CD4 lymphocytosis, agranulocytosis, aggressive glucocorticoid or immunosuppressive therapy and other conditions or treatments that result in severe immunosuppression). RESULTS: The clinical data of 255 cryptococcosis patients were collected. In total, 66.3% of patients (169) were IC, 16.9% (43) had MID, and 16.9% (43) had SID. 10.1% of the patients (17) with IC were EPC, 18.6% of the patients (8) with MID were EPC, and 74.4% of patients (32) were EPC (IC/MID vs. SID, p < 0.001). Fever was more common in the SID group than in the IC and MID groups (69.8% vs. 14.8% vs. 37.2%, p < 0.001). Of chest CT scan, most lesions were distributed under the pleura (72.7%), presenting as nodules/lumps (90.3%) or consolidations (10.7%). Pleural effusion was more common in SID group compared to IC group (33.3% vs. 2.4%, p < 0.001). Positivity rate on the serum capsular polysaccharide antigen detection (CrAg) test was higher in the SID group than in the other two groups [100.0% vs. 84.4% (MID) vs. 78.2% (IC), p = 0.013]. Positivity rate on the serum CrAg test was also higher in cryptococcal meningitis patients than in PC patients (100.0% vs. 79.5%, p = 0.015). CONCLUSIONS: The clinical presentation of MID patients is intermediate between SID and IC patients and is similar to that of IC patients. The serum CrAg test is more sensitive for the identification of SID or EPC patients.

Tumor Location and Survival Outcomes in Lung Adenosquamous Carcinoma: A Propensity Score Matched Analysis.

BACKGROUND There is little information in the literature available on lung adenosquamous carcinoma (LASC). The association between tumor location and survival outcomes in LASC is poorly understood. Our study was designed to probe the effect of tumor location on survival outcomes of LASC. MATERIAL AND METHODS Patients with LASC between 2004 and 2015 were identified using the Surveillance, Epidemiology and End Results (SEER) databases. The patients were divided into 2 groups, a main bronchus group and a peripheral group, according to their primary sites. The Propensity Score Matching (PSM) method was used to reduce possible bias between groups. The primary endpoints were overall survival (OS) and cancer-specific survival (CSS). RESULTS A total of 3176 patients, afflicted with LASC between 2004 and 2015, were extracted from the SEER databases. Of these, 212 patients were found to be eligible for analysis after a propensity 1: 1 nearest neighbor matched analysis. After PSM, multivariate Cox regression analysis showed that primary site, American Joint Committee on Cancer (AJCC) stage, T stage and surgery were independent predictors of LASC in both OS and CSS. Kaplan-Meier survival analysis showed that patients with LASC located in a peripheral site had better survival outcomes than those with LASC located in the main bronchus. In subgroup analysis, the advantages of tumor located in a peripheral site were more pronounced in female patients and AJCC stage I patients. CONCLUSIONS Tumor location may have an impact on the survival outcomes of patients with LASC. Patients with LASC located in a peripheral site had better survival outcomes than patients with LASC located in the main bronchus, particularly in female patients and AJCC stage I patients.

Bioinformatics analysis of BTK expression in lung adenocarcinoma: implications for immune infiltration, prognostic biomarkers, and therapeutic targeting.

In recent years, as more and more lung-cancer patients have been treated with immunotherapeutic agents, their survival has been prolonged compared to before. It is well known that BTK (Bruton's tyrosine kinase) is predominantly found in cells of the hematopoietic system. However, there is a distinct lack of literature on BTK expression in lung adenocarcinoma (LUAD) patients and its effect on the immune microenvironment. Consequently, the main goal of this investigation was to analyze how BTK expression in lung adenocarcinoma affects its progression, along with its prognostic significance, through the utilization of bioinformatics online resources and publicly available databases. Data on the sequencing results and clinical records of lung adenocarcinoma patients were gathered from The Cancer Genome Atlas (TCGA) database. Based on the expression level of BKT, TCGA categorized lung adenocarcinoma patients into BTK high-expression and low-expression groups. We investigated the effects of BKT on clinicopathologic, genomic, and immunologic characteristics of lung adenocarcinoma patients. We analyzed BTK mRNA expression in tumors and normal tissues using two key resources: Tumor Immuno Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). We analyzed the prognosis of the patients using GEPIA2 and validated the results using univariate and multivariate analyses. In addition, we assessed BTK protein expression by Human Protein Atlas (HPA). We sought to elucidate the clinical prognostic significance of BTK in The TCGA using the online tool GEPIA 2. Furthermore, to clarify the biologic roles and pathways linked to BTK, we conducted a genomic enrichment analysis of the information. To predict the proportion of various immune cell infiltrations in the immune microenvironment of lung adenocarcinoma patients diagnosed in the TCGA database, we performed an analysis using the TIMER online tool. Using TIMER and CIBERSORT, the correlation between genes co-expressed with BTK and the corresponding tumor-infiltrating immune cells was explored; finally, the relationship between BTK expression and immune infiltration and immune checkpoints in the TMB group and the high and low groups was analyzed by R language analysis using the TCGA database. The expression of BTK provides some hints about the prognosis of the patients. The high expression of BTK is involved in immune response regulation signaling pathways, leukocyte-mediated immunity, leukocyte intercellular adhesion, graft rejection, and complement. Analysis of the GEPIA 2 database showed that BTK was co-expressed with the genes FGD2, SASH3, NCKAP1L, CD53, ARHGAP30 and LPXN. Increased expression of the above-mentioned genes resulted in increased proportions of CD8 + T cells, memory CD4 + T cells, B cells, macrophages, and dendritic cells, and decreased proportions of Treg cells and TH2 cells. In addition, our study revealed a strong positive correlation between various key immune checkpoints (e.g., PDCD1, CD274, PDCD1LG2, CTLA4, HAVCR2, LAG3, TIGIT, and SIGLEC15) and BTK expression. In conclusion, increased BTK expression in lung adenocarcinoma is closely associated with prolonged survival of lung-cancer patients. Moreover, the genes classified under the BTK high-expression group exhibit significant enrichment in immune-related pathways, suggesting a potential impact on the tumor microenvironment. We investigated the potential of BTK as a tumor suppressor gene in predicting prolonged patient survival. In addition, we further investigated the possibility that BTK further affects the immunotherapeutic response of patients by influencing the microenvironment of tumor immune infiltration, but the relevant mechanisms remain to be further studied.

The value of metagenomic next-generation sequencing with different nucleic acid extracting methods of cell-free DNA or whole-cell DNA in the diagnosis of non-neutropenic pulmonary aspergillosis.

Purpose: Metagenomic next-generation sequencing(mNGS) is a novel molecular diagnostic technique. For nucleic acid extraction methods, both whole-cell DNA (wcDNA) and cell-free DNA (cfDNA) are widely applied with the sample of bronchoalveolar lavage fluid (BALF). We aim to evaluate the clinical value of mNGS with cfDNA and mNGS with wcDNA for the detection of BALF pathogens in non-neutropenic pulmonary aspergillosis. Methods: mNGS with BALF-cfDNA, BALF-wcDNA and conventional microbiological tests (CMTs) were performed in suspected non-neutropenic pulmonary aspergillosis. The diagnostic value of different assays for pulmonary aspergillosis was compared. Results: BALF-mNGS (cfDNA, wcDNA) outperformed CMTs in terms of microorganisms detection. Receiver operating characteristic (ROC) analysis indicated BALF-mNGS (cfDNA, wcDNA) was superior to culture and BALF-GM. Combination diagnosis of either positive for BALF-mNGS (cfDNA, wcDNA) or CMTs is more sensitive than CMTs alone in the diagnosis of pulmonary aspergillosis (BALF-cfDNA+CMTs/BALF-wcDNA+CMTs vs. CMTs: ROC analysis: 0.813 vs.0.66, P=0.0142/0.796 vs.0.66, P=0.0244; Sensitivity: 89.47% vs. 47.37%, P=0.008/84.21% vs. 47.37%, P=0.016). BALF-cfDNA showed a significantly greater reads per million (RPM) than BALF-wcDNA. The area under the ROC curve (AUC) for RPM of Aspergillus detected by BALF-cfDNA, used to predict "True positive" pulmonary aspergillosis patients, was 0.779, with a cut-off value greater than 4.5. Conclusion: We propose that the incorporation of BALF-mNGS (cfDNA, wcDNA) with CMTs improves diagnostic precision in the identification of non-neutropenic pulmonary aspergillosis when compared to CMTs alone. BALF-cfDNA outperforms BALF-wcDNA in clinical value.

The clinical value of Aspergillus-specific IgG antibody test in the diagnosis of nonneutropenic invasive pulmonary aspergillosis.

OBJECTIVES: Aspergillus-specific IgG antibody (Asp IgG) has been successfully applied in the diagnosis of chronic pulmonary aspergillosis. We explored its value in nonneutropenic invasive pulmonary aspergillosis (IPA) by a multicenter, prospective, and controlled study. METHODS: We enrolled 372 clinically suspected nonneutropenic patients with IPA from February 2015 to August 2022. After excluding 4 cases with Aspergillus colonization, the remaining 368 cases were finally confirmed as patients with IPA (n = 99), or non-IPA patients (n = 269) consisting of community-acquired pneumonia (n = 206), tuberculosis (n = 22), nontuberculous mycobacteria (n = 5), lung abscess (n = 6), or noninfectious diseases (n = 30). Asp IgG in plasma samples was tested by enzyme-linked immunosorbent assay. RESULTS: At cut-off value of ≥80 AU/mL, Asp IgG had much higher sensitivity (59.6% vs. 19.2%, p < 0.0001), but lower specificity (77.0% vs. 96.3%, p < 0.0001) than serum galactomannan (GM) (cut-off value of ≥1.0), and similar sensitivity (59.6% vs. 55.6%, p = 0.611) but lower specificity (77.0% vs. 91.2%, p = 0.001) than bronchoalveolar lavage fluid (BALF) GM (cut-off value of ≥1.0), respectively. Combination diagnosis of either positive for Asp IgG or BALF GM had higher sensitivity (81.0% vs. 55.6%, p = 0.002), but lower specificity (75.2% vs. 91.2%, p = 0.001) than BALF GM alone. The receiver operating characteristic curve showed that Asp IgG had an optimal diagnostic value when the cut-off value was 56.6 AU/ml, and the sensitivity and specificity were 77.8% and 63.9%, respectively. DISCUSSIONS: The diagnostic value of Asp IgG for IPA is superior to serum GM, and a little inferior to BALF GM in nonneutropenic patients with IPA. Considering the convenience of taking blood samples, it is a good screening and diagnostic method for nonneutropenic patients with IPA, especially for those who cannot bear invasive procedures.

Based on SEER Database: Population Distribution, Survival Analysis, and Prognostic Factors of Organ Metastasis of Lung Large Cell Neuroendocrine Carcinoma.

Background: The incidence rate of lung large cell neuroendocrine carcinoma (LCNEC) in lung cancer is low, but the malignancy is high and the prognosis is poor. We used the Surveillance, Epidemiology, and End Results (SEER) database to determine the population distribution of organ metastasis in LCNEC, conduct survival analysis, judge prognostic factors, and provide direction for follow-up diagnosis and treatment. Materials and methods: By logging into the SEER database, the data of lung LCNEC were retrieved and the target population was selected. According to the presence or absence of organ metastasis (bone, brain, liver, and lung), we divided the target population into the no organ metastasis group (n = 1,202) and the organ metastasis group (n = 870). By analyzing the clinicopathological data of patients and using the survival function, the corresponding median survival time was obtained, and the influencing factors of each group were analyzed. Then, the significant influencing factors were analyzed by multivariate Cox regression analysis to screen out the independent influencing factors. Result: In the overall sample group, multivariate Cox regression analysis showed that sex, age, primary site surgery, bone metastasis, brain metastasis, liver metastasis, radiotherapy, and chemotherapy were independent prognostic factors. The 1-year survival rate was 13.8% in the bone metastasis group, 19.1% in the brain metastasis group, 13.8% in the liver metastasis group, and 20.3% in the intrapulmonary metastasis group. In the organ metastasis group, multivariate Cox regression analysis showed that sex, chemotherapy, radiotherapy sequence with surgery, primary site surgery, liver metastasis, and age at diagnosis were independent factors affecting the prognosis. Conclusion: In the overall sample of LCNEC, bone metastasis, brain metastasis, and liver metastasis all reduced the overall survival time, while the effect of intrapulmonary metastasis on the overall survival time was not statistically significant. Sex, chemotherapy, radiotherapy sequence with surgery, primary site surgery, liver metastasis, and age were independent factors affecting the prognosis of the LCNEC organ metastasis group. Women, chemotherapy, and radiotherapy sequence with surgery were favorable factors, while old age, liver metastasis, and male were unfavorable factors.

Monoamine Oxidase A Inhibits Lung Adenocarcinoma Cell Proliferation by Abrogating Aerobic Glycolysis.

Lung adenocarcinoma (LUAD) accounts for ~30% of all lung cancers and is one of the causes of cancer-related death worldwide. As the role of monoamine oxidase A (MAOA) in LUAD remains unclear, in this study, we examine how MAOA affects LUAD cell proliferation. Analyses of both public data and our data reveal that the expression of MAOA is downregulated in LUAD compared with non-tumor tissue. In addition, the expression of MAOA in tumors correlates with clinicopathologic features, and the expression of MAOA serves as an independent biomarker in LUAD. In addition, the overexpression of MAOA inhibits LUAD cell proliferation by inducing G1 arrest in vitro. Further mechanistic studies show that MAOA abrogates aerobic glycolysis in LUAD cells by decreasing hexokinase 2 (HK2). Finally, the expression of HK2 shows a negative correlation with MAOA in LUAD, and high HK2 predicts poor clinical outcome. In conclusion, our findings indicate that MAOA functions as a tumor suppressor in LUAD. Our results indicate that the MAOA/HK2 axis could be potential targets in LUAD therapy.