Osimertinib is an effective epidermal growth factor receptor-tyrosine kinase inhibitor choice for lung cancer with epidermal growth factor receptor exon 18-25 kinase domain duplication: report of two cases.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are an effective treatment for common EGFR mutations in non-small-cell lung cancer (NSCLC). Rarer EGFR mutations such as kinase domain duplications (KDDs) have been identified, but the optimal therapy following treatment resistance remains unknown. We report two patients who were diagnosed with NSCLC including KDD. For case 1, afatinib (40 mg once daily) was at first effective but then became ineffective. Consequently, osimertinib therapy (80 mg once daily) was administered. As of 26 May 2021, the osimertinib therapy achieved a stable disease state according to the chest computed tomography scan. As for case 2, the patient received second-line chemotherapy and anlotinib (12 mg once daily) for 6 months and died in May 2020. Here, we describe osimertinib as an effective therapy for EGFR-KDD positive lung adenocarcinoma and thereby provide a new alternative for further treatment following resistance to first- and second-generation EGFR-TKIs.

Differentiation and recruitment of Th9 cells stimulated by pleural mesothelial cells in human Mycobacterium tuberculosis infection.

Newly discovered IL-9-producing CD4(+) helper T cells (Th9 cells) have been reported to contribute to tissue inflammation and immune responses, however, differentiation and immune regulation of Th9 cells in tuberculosis remain unknown. In the present study, our data showed that increased Th9 cells with the phenotype of effector memory cells were found to be in tuberculous pleural effusion as compared with blood. TGF-ß was essential for Th9 cell differentiation from naïve CD4(+) T cells stimulated with PMA and ionomycin in vitro for 5 h, and addition of IL-1ß, IL-4 or IL-6 further augmented Th9 cell differentiation. Tuberculous pleural effusion and supernatants of cultured pleural mesothelial cells were chemotactic for Th9 cells, and this activity was partly blocked by anti-CCL20 antibody. IL-9 promoted the pleural mesothelial cell repairing and inhibited IFN-γ-induced pleural mesothelial cell apoptosis. Moreover, pleural mesothelial cells promoted Th9 cell differentiation by presenting antigen. Collectively, these data provide new information concerning Th9 cells, in particular the collaborative immune regulation between Th9 cells and pleural mesothelial cells in human M. tuberculosis infection. In particular, pleural mesothelial cells were able to function as antigen-presenting cells to stimulate Th9 cell differentiation.

Diagnosis of invasive fungal disease using serum (1→3)-ß-D-glucan: a bivariate meta-analysis.

BACKGROUND: The (1→3)-ß-D-Glucan (BG) assay has been approved for diagnosing invasive fungal disease (IFD). However, the test performance has been variable. We conducted a meta-analysis to determine the overall accuracy of BG assay for diagnosing IFD. METHODS: The sensitivity, specificity, and positive and negative likelihood ratios (PLR and NLR, respectively) of BG for diagnosing IFD were pooled using a bivariate meta-analysis. We also performed subgroup analyses. RESULTS: Twelve reports, including 15 studies, were included for the analysis (proven and probable IFD vs possible or no IFD). The sensitivity, specificity, PLR and NLR were 0.76 (95% CI, 0.67-0.83), 0.85 (95% CI, 0.73-0.92), 5.05 (95% CI, 2.71-9.43), and 0.28 (95% CI, 0.20-0.39), respectively. Subgroup analyses showed that the BG assay had higher specificities for patients with hematological disorders and a positive BG result with two consecutive samples. The combination of galactomannan and BG increased the specificity value to 0.98 (95% CI, 0.95-0.99) for diagnosing invasive aspergillosis. CONCLUSION: Serum BG determination is clinically useful for diagnosing IFD in at-risk patients, especially for hematology patients. The combination of galactomannan and BG was sufficient for diagnosing invasive aspergillosis. Since the BG assay is not absolutely sensitive and specific for IFD, the BG results should be interpreted in parallel with clinical findings.

CD39+ regulatory T cells suppress generation and differentiation of Th17 cells in human malignant pleural effusion via a LAP-dependent mechanism.

BACKGROUND: Both regulatory T cells (Tregs) and T helper IL-17-producing cells (Th17 cells) have been found to be involved in human malignancies, however, the possible implication of Tregs in regulating generation and differentiation of Th17 cells in malignant pleural effusion remains to be elucidated. METHODS: The numbers of both CD39(+)Tregs and Th17 cells in malignant pleural effusion and peripheral blood from patients with lung cancer were determined by flow cytometry. The regulation and mechanism of Tregs on generation and differentiation of Th17 cells were explored. RESULTS: Both CD39(+)Tregs and Th17 cells were increased in malignant pleural effusion when compared with blood, and the numbers of CD39(+)Tregs were correlated negatively with those of Th17 cells. It was also noted that high levels of IL-1ß, IL-6, and TGF-ß1 could be observed in malignant pleural effusion when compared the corresponding serum, and that pleural CD39(+)Tregs could express latency-associated peptide on their surface. When naïve CD4(+) T cells were cocultured with CD39(+)Tregs, Th17 cell numbers decreased as CD39(+)Treg numbers increased, addition of the anti-latency-associated peptide mAb to the coculture reverted the inhibitory effect exerted by CD39(+)Tregs. CONCLUSIONS: Therefore, the above results indicate that CD39(+)Tregs inhibit generation and differentiation of Th17 cells via a latency-associated peptide-dependent mechanism.

Diagnostic accuracy of T-cell interferon-γ release assays in tuberculous pleurisy: a meta-analysis.

BACKGROUND AND OBJECTIVE: The diagnosis of tuberculous pleurisy by analysis of pleural fluid using standard diagnostic tools is difficult. Recently, T-cell interferon-γ release assays (IGRA) have been introduced for the diagnosis of tuberculous pleurisy. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of IGRA on both pleural fluid and peripheral blood, for diagnosing tuberculous pleurisy. METHODS: A systematic review was performed of English language publications. Sensitivity, specificity and other measures of the accuracy of IGRA for the diagnosis tuberculous pleurisy using both pleural fluid and blood were pooled using a random-effects model or a fixed-effects model. Receiver operating characteristic curves were used to summarize overall test performance. RESULTS: Seven out of eight studies met the inclusion criteria. The summary estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value, negative predictive value and diagnostic odds ratio were, for pleural fluid: 0.75, 0.82, 3.49, 0.24, 0.85, 0.70 and 19.04, respectively; and for blood: 0.80, 0.72, 2.86, 0.28, 0.78, 0.74 and 11.06, respectively. CONCLUSIONS: As almost 20% of non-tuberculosis patients would be erroneously treated for tuberculosis and 25% of patients with tuberculous pleurisy would be missed, pleural fluid IGRA are not useful for the clinical diagnosis of tuberculous pleurisy.

Generation and differentiation of IL-17-producing CD4+ T cells in malignant pleural effusion.

IL-17-producing CD4(+) T (Th17) cells have been found to be increased in some human cancers; however, the possible implication of Th17 cells in regulating antitumor responses in malignant pleural effusion (MPE) remains to be elucidated. In the current study, distribution and phenotypic features of Th17 cells in both MPE and peripheral blood from patients with lung cancer were determined by flow cytometry or double immunofluorescence staining. The impacts of cytokines on Th17 cell generation and differentiation were explored. The chemoattractant activity of chemokines CCL20 and CCL22 for Th17 cells in vitro was also observed. It was found that the increased Th17 cells could be found in MPE compared with blood. The in vitro experiments showed that IL-1ß, IL-6, IL-23, or their various combinations could promote Th17 cell generation and differentiation from naive CD4(+) T cells. MPE was chemotactic for Th17 cells, and this activity was partly blocked by anti-CCL20 and/or CCL22 Abs. Our data also showed that the accumulation of Th17 cells in MPE predicted improved patient survival. It could be concluded that the overrepresentation of Th17 cells in MPE might be due to Th17 cell differentiation and expansion stimulated by pleural proinflammatory cytokines and to recruitment of Th17 cells from peripheral blood induced by pleural chemokines CCL20 and CCL22. Furthermore, the accumulation of Th17 cells in MPE predicted improved patient survival. These data provide the basis for developing immune-boosting strategies based on ridding the cancer patient of this cell population.

Effects of the TREM-1 pathway modulation during empyema in rats.

BACKGROUND: The activation of triggering receptor expressed on myeloid cells-1 (TREM-1) in the presence of microbial components amplifies the inflammatory response. The aim of the present study was to investigate the effect of the modulation of the TREM-1 pathway during empyema in rats. METHODS: Adult male Wistar rats were subjected to empyema induced by intrapleural injection of Pseudomonas aeruginosa and Staphylococcus aureus. The animals were treated with LP17 (a synthetic TREM-1 inhibitor), a control peptide, or a vehicle (normal saline). Differential cell count, flow cytometry and histological examination were performed to evaluate local inflammatory alterations. Concentrations of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in both pleural effusion and serum were measured by enzyme-linked immunosorbent assay. RESULTS: Although differential counts of each type of leukocytes in pleural effusion were not affected by LP17, a marked reduction in neutrophil numbers was seen in LP17 treated rats due to the reduction of both pleural effusion volume and total cell numbers. LP17 administration impaired concentration elevation in tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in both pleural effusion and serum. It was found that survival rate in LP17 treated rats was much higher than that in control rats. CONCLUSION: The modulation of the TREM-1 pathway by the use of LP17 appears to be beneficial during empyema in rats in attenuating pleural and systemic inflammatory responses.

Expression of soluble Toll-like receptors in pleural effusions.

BACKGROUND: The Toll-like receptors (TLRs) represent a group of single-pass transmembrane receptors expressed on sentinel cells that are central to innate immune responses.The aim of this study was to investigate the presence of soluble TLRs in pleural effusions, and the diagnostic values of TLRs for pleural effusion with various etiologies. METHODS: Pleural effusion and serum samples were collected from 102 patients (36 with malignant pleural effusion, 36 with tuberculous pleural effusion, 18 with bacterial pleural effusion, and 12 with transudative pleural effusion). The concentrations of TLR1 to TLR10 were determined in effusion and serum samples by enzyme linked immunosorbent assay. Four classical parameters (protein, lactate dehydrogenase, glucose and C-reactive protein (CRP)) in the pleural fluid were also assessed. Receiver-operating characteristic curves were used to assess the sensitivity and specificity of pleural fluid TLRs and biochemical parameters for differentiating bacterial pleural effusion. RESULTS: The concentrations of TLR1, TLR3, TLR4, TLR7 and TLR9 in bacterial pleural effusion were significantly higher than those in malignant, tuberculous, and transudative groups, respectively. Analysis of receiver operating characteristic curves revealed that the area under the curves of TLR1, TLR3, TLR4, TLR7 and TLR9 were 0.831, 0.843, 0.842, 0.883 and 0.786, respectively, suggesting that these TLRs play a role in the diagnosis of bacterial pleural effusion. Also, the diagnostic value of TLRs for bacterial pleural effusions was much better than that of biochemical parameters (protein, lactate dehydrogenase, glucose and CRP). CONCLUSIONS: The concentrations of TLR1, TLR3, TLR4, TLR7 and TLR9 appeared to be increased in bacterial pleural effusion compared to non-bacterial pleural effusions. Determination of these pleural TLRs may improve the ability of clinicians to differentiate pleural effusion patients of bacterial origin from those with other etiologies.

Accuracy of BAL galactomannan in diagnosing invasive aspergillosis: a bivariate metaanalysis and systematic review.

BACKGROUND: A serum galactomannan (GM) assay has been approved for diagnosing invasive aspergillosis (IA). However, the role of the BAL-GM assay has not been well established. Therefore, we conducted a metaanalysis to determine the overall accuracy of BAL-GM in the diagnosis of IA. METHODS: After a systematic review of English-language studies, the sensitivity (SEN), specificity (SPE), and positive and negative likelihood ratios (PLR and NLR, respectively) of BAL-GM for the diagnosis of IA were pooled using a bivariate metaanalysis. Hierarchic summary receiver operating characteristic curves were used to summarize overall test performance. Potential between-study heterogeneity was explored by subgroup analyses. We calculated posttest probability to evaluate clinical usefulness. RESULTS: Twelve reports, including 13 studies, met our inclusion criteria. The summary estimates of the BAL-GM assay for proven or probable IA were as follows: SEN, 0.90 (95% CI, 0.79-0.96); SPE, 0.94 (95% CI, 0.90-0.96); PLR, 14.87 (95% CI, 8.89-24.90); and NLR, 0.10 (95% CI, 0.04-0.24). The four summary estimates of the BAL-GM assay for proven IA were 0.94 (95% CI, 0.86-0.98), 0.79 (95% CI, 0.68-0.86), 4.41 (95% CI, 2.87-6.77), and 0.07 (95% CI, 0.03-0.09), respectively. Significant heterogeneity was present. CONCLUSIONS: BAL-GM determination is a sensitive and specific test for the diagnosis of proven and probable IA. The measurement of BAL-GM is thus likely to be a useful tool for diagnosing IA. Further studies focused on the impact of treatment agents are needed.

CCL22 is involved in the recruitment of CD4+CD25 high T cells into tuberculous pleural effusions.

BACKGROUND AND OBJECTIVE: CD4(+)CD25(high) regulatory T cells are increased in tuberculous pleural effusions (TPE). However, the mechanism by which CD4(+)CD25(high) T cells infiltrate into the pleural cavity is unknown. The aim of this study was to investigate whether the chemokines CCL22 and CCL17 are present in TPE, and the chemoattractant activity of these chemokines for infiltration of CD4(+)CD25(high) T cells into the pleural space. METHODS: The concentrations of CCL22 and CCL17 were measured in pleural effusions from 33 patients with tuberculous pleurisy, 21 patients with pleural bacterial infections and 18 patients with transudative pleural effusions. T lymphocyte subsets in pleural effusions were assessed by flow cytometry. Pleural effusion cells were analysed for the expression of CCL22. The chemoattractant activity of CCL22 for CD4(+)CD25(high) T cells was assessed in vitro. RESULTS: The frequency of CD4(+)CD25(high) T cells was significantly higher in TPE than in blood. High concentrations of CCL22 were detected in tuberculous effusions, but not in bacterial effusions or transudates. Macrophages and T cells in TPE expressed CCL22. Tuberculous pleural fluid was chemotactic for CD4(+)CD25(high) T cells in vitro, and anti-CCL22 antibody partly inhibited this chemotactic activity. CONCLUSIONS: CCL22 appeared to be increased in TPE compared with bacterial pleural effusions or transudates. CCL22 may be responsible for the infiltration of CD4(+)CD25(high) T cells into the pleural space of patients with tuberculous pleurisy.

Diagnostic value of soluble mesothelin-related peptides for malignant mesothelioma: a meta-analysis.

BACKGROUND: Serum concentrations of soluble mesothelin-related peptides (SMRP) have been reported to be higher in patients with malignant mesothelioma than in healthy subjects and in patients with non-malignant mesothelioma diseases. The aim of the present meta-analysis was to establish the overall diagnostic accuracy of the measurement of SMRPs for diagnosing malignant mesothelioma. METHODS: After a systematic review of English language studies, sensitivity, specificity, and other measures of accuracy of serum SMRPs in the diagnosis of malignant mesothelioma were pooled using random-effects models. Summary receiver operating characteristic curves were used to summarize overall test performance. RESULTS: Eleven publications from 12 studies met our inclusion criteria. The summary estimates for SMRPs in the diagnosis of malignant mesothelioma in the studies included were sensitivity 0.64 (95% confidence interval 0.61-0.68), specificity 0.89 (0.88-0.90), positive likelihood ratio 7.10 (4.44-11.35), negative likelihood ratio 0.39 (0.31-0.48), and diagnostic odds ratio 19.35 (10.95-34.17). CONCLUSIONS: Serum SMRP determination plays a role in the diagnosis of malignant mesothelioma. The results of SMRP assays should be interpreted in parallel with clinical findings and the results of conventional tests.

Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis.

BACKGROUND: Conventional tests are not always helpful in making a diagnosis of tuberculous pleurisy. Many studies have investigated the usefulness of adenosine deaminase (ADA) in pleural fluid for the early diagnosis of tuberculous pleurisy. We conducted a meta-analysis to determine the accuracy of ADA measurements in the diagnosis of tuberculous pleurisy. METHODS: After a systematic review of English language studies, sensitivity, specificity, and other measures of accuracy of ADA concentration in the diagnosis of pleural effusion were pooled using random effects models. Summary receiver operating characteristic curves were used to summarize overall test performance. RESULTS: Sixty-three studies met our inclusion criteria. The summary estimates for ADA in the diagnosis of tuberculous pleurisy in the studies included were sensitivity 0.92 (95% confidence interval 0.90-0.93), specificity 0.90 (95% confidence interval 0.89-0.91), positive likelihood ratio 9.03 (95% confidence interval 7.19-11.35), negative likelihood ratio 0.10 (95% confidence interval 0.07-0.14), and diagnostic odds ratio 110.08 (95% confidence interval 69.96-173.20). CONCLUSIONS: ADA determination is a relative sensitive and specific test for the diagnosis of tuberculous pleurisy. Measurement of ADA in pleural effusion is thus likely to be a useful diagnostic tool for tuberculous pleurisy. The results of ADA assays should be interpreted in parallel with clinical findings and the results of conventional tests.

Diagnostic value of interferon-gamma in tuberculous pleurisy: a metaanalysis.

BACKGROUND: Conventional tests are not always helpful in making a diagnosis of tuberculous pleurisy. Many studies have investigated the usefulness of interferon (IFN)-gamma measurements in pleural fluid for the early diagnosis of tuberculous pleurisy. We conducted a metaanalysis to determine the accuracy of IFN-gamma measurements in the diagnosis of tuberculous pleurisy. METHODS: After a systematic review of English-language studies, sensitivity, specificity, and other measures of accuracy of IFN-gamma concentrations in the diagnosis of pleural effusion were pooled using random-effects models. Summary receiver operating characteristic curves were used to summarize overall test performance. RESULTS: Twenty-two studies met our inclusion criteria. The summary estimates for IFN-gamma in the diagnosis of tuberculous pleurisy in the studies included were as follows: sensitivity, 0.89 (95% confidence interval [CI], 0.87 to 0.91); specificity, 0.97 (95% CI, 0.96 to 0.98); positive likelihood ratio, 23.45 (95% CI, 17.31 to 31.78); negative likelihood ratio, 0.11 (95% CI, 0.07 to 0.16); and diagnostic odds ratio, 272.7 (95% CI, 147.5 to 504.2). CONCLUSIONS: IFN-gamma determination is a sensitive and specific test for the diagnosis of tuberculous pleurisy. The measurement of IFN-gamma levels in pleural effusions is thus likely to be a useful tool for diagnosing tuberculous pleurisy. The results of IFN-gamma assays should be interpreted in parallel with clinical findings and the results of conventional tests.

[CD4+CD25+ T lymphocytes in peripheral blood from patients with asthma].

OBJECTIVE: To explore whether regulatory CD(4)(+)CD(25)(+) cells exist in patients with atopic asthma. METHODS: The numbers of peripheral blood CD(4)(+)CD(25)(+) cells in peripheral blood of atopic asthmatics and healthy nonatopic subjects were determined using flow cytometry. CD(4)(+)CD(25)(+) and CD(4)(+)CD(25)(-) cells from atopic asthmatics and normal donors were isolated, and were cultured to observe the effects of CD(4)(+)CD(25)(+) cells on proliferation response as well as Th1/Th2 cytokine production of CD(4)(+)CD(25)(-) cells in vitro. RESULTS: A significant increase in CD(4)(+)CD(25)(+) cell numbers was shown in atopic asthmatic patients during acute exacerbation [(14.9 +/- 1.8)%, P < 0.01], but not in patients with stable asthma [(11.8 +/- 0.7)%] and normal subjects [(11.2 +/- 0.8)%, P > 0.05]. The mean inhibition values of the proliferation response of CD(4)(+)CD(25)(-) cells by CD(4)(+)CD(25)(+) cells from normal controls [(72 +/- 8)%] and asthmatics [(74 +/- 9)%] were similar (P > 0.05). There was no difference in inhibitory effects on both Th1 and Th2 cytokine production of CD(4)(+)CD(25)(-) cells by CD(4)(+)CD(25)(+) cells in the two groups. CONCLUSION: Although CD(4)(+)CD(25)(+) cells increase in atopic asthma during exacerbation, these regulatory T cells appear to function normally with regard to their suppressive activities.