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Background:The novel coronavirus disease 2019 (COVID-19) has been a global pandemic health issue since 30, January, 2020. Mortality rate was as high as more than 50% in critically ill patients. The Stem cell treatment is effective in refractory severe critically ill COVID-19 patients, but immune regulation mechanisms have not been reported well. Therefore, we evaluate the clinical efficacy and immune modulation of placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) in severe critically ill COVID-19 infection who are refractory to current standard therapies.Methods:Intravenous infusion of 1 × 107 MatriPlax was given to five severe COVID-19 patients at Day 0 and day 4. Serum inflammatory markers and immune profiles were studied at Day 0, 4 and 8. Clinical parameters and 28-days mortality were compared between treated group and control group.Results:The treatment group had no 28-days mortality and Murray’s lung injury score was significantly improved compared with control group. After treatment, Ferritin, C-reactive protein (CRP) and Lactate dehydrogenases (LDH) were significantly reduced and lymphopenia was improved. IL-6, IL-1β, IFN-γ and IL-2 were significantly decreased together with decrease in IL-10 reflecting decreasing intensity of inflammation. Immune cell profiles showed increase in CD4+ T cells (CD4+ naïve T cells, CD4+ memory T cells subtypes), Treg cells, CD19+ B cells (and CD19+ naive B cells, CD27+ switched B cells subtypes) and dendritic cells, and a significant decrease in CD14+ monocytes (and CD16- classical, CD16+ non-classical subtypes) monocytes as well as plasma/plasmablast cells. pc-MSCs treatment suppressed hyper-inflammatory states of innate immune responses to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoted CD4+ T cells and CD19+ B cells towards adaptive immune responses.Conclusion:The intravenous transplantation of Matriplax was safe and effective for severe critically ill COVID-19 patients, especially those who were refractory to current standard care and immunosuppressive therapies

Objectives The coronavirus disease 2019 pandemic has affected countries around the world since 2020, and an increasing number of people are being infected. The purpose of this research was to use big data and artificial intelligence technology to find key factors associated with the coronavirus disease 2019 infection. The results can be used as a reference for disease prevention in practice. Methods This study obtained data from the "Imperial College London YouGov Covid-19 Behaviour Tracker Open Data Hub", covering a total of 291,780 questionnaire results from 28 countries (April 1~August 31, 2020). Data included basic characteristics, lifestyle habits, disease history, and symptoms of each subject. Four types of machine learning classification models were used, including logistic regression, random forest, support vector machine, and artificial neural network, to build prediction modules. The performance of each module is presented as the area under the receiver operating characteristics curve. Then, this study further processed important factors selected by each module to obtain an overall ranking of determinants. Results This study found that the area under the receiver operating characteristics curve of the prediction modules established by the four machine learning methods were all >0.95, and the RF had the highest performance (area under the receiver operating characteristics curve is 0.988). Top ten factors associated with the coronavirus disease 2019 infection were identified in order of importance: whether the family had been tested, having no symptoms, loss of smell, loss of taste, a history of epilepsy, acquired immune deficiency syndrome, cystic fibrosis, sleeping alone, country, and the number of times leaving home in a day. Conclusions This study used big data from 28 countries and artificial intelligence methods to determine the predictors of the coronavirus disease 2019 infection. The findings provide important insights for the coronavirus disease 2019 infection prevention strategies.

Background Family caregivers play an important role for patients admitted to the intensive care unit (ICU), and delirium is a common clinical syndrome. Little is known about the experiences of family caregivers when a relative is a patient with delirium, especially for caregivers in Asian cultures. Aims and objective To understand the experience of family caregivers with a family member as a patient with delirium in the ICU in Taiwan. Design A descriptive qualitative study with in-depth face-to-face semi-structured interviews. Methods Interviews were conducted with 20 family caregivers of 20 patients with delirium in the ICU of a hospital in northern Taiwan. Results The core theme describing the phenomenon of family caregivers of a patient with delirium was "Sailing in a sea of perplexity," which described family caregivers' uncertainty of navigating the ICU and providing support for a relative. Three subthemes described the core theme: (a) perplexity of the ICU environment, (b) perplexity of making decisions, and (c) perplexity of Chinese cultural constraints. Conclusion "Sailing in a sea of perplexity" underscores how uncertainty among family caregivers of patients with delirium in ICUs can lead to feelings of fear and anxiety. Therefore, nursing professionals should not only focus on patient care but also be sensitive to caregivers' feelings of uncertainty and their cultural beliefs. Relevance to clinical practice Unfamiliarity and lack of knowledge about intensive care and patient treatments were a source of family caregivers' perplexity. To reduce uncertainty, we recommend increased communication between staff and caregivers. Hospitals can also provide information on their websites, including treatment of delirium and visitation hours. Information access could be enhanced by developing a smartphone app linked to a QR code that families can scan to obtain information, which would be useful during restricted visitation.

For undiagnosed pleural effusion, diagnostic yields and safety were similar between pleuroscopic cryobiopsy and forceps biopsy, but cryobiopsy obtained a larger pleural tissue sample than forceps biopsy.

To examine postural control of anteroposterior (AP) and mediolateral sway of children with probable developmental coordination disorder (pDCD) and children with typical development (TD).Forty-eight children (24 in each group) aged 11 to 12 years performed an aiming task, maintaining a laser beam within targets placed in 2 locations (front/side). Precision was compromised primarily by the control of mediolateral sway for the front target and by the control of AP sway for the side target. The task was performed with large and small targets.In the side target condition, only (1) the TD group showed reduced AP sway in response to reduced target size, whereas the pDCD group increased AP sway, and (2) aiming performance for reduced target sizes deteriorated to a greater degree in the pDCD group than in the TD group.These findings suggest children with pDCD have specific deficits in controlling AP sway.

Severe H1N1 pneumonia with acute respiratory failure results in infiltration of lungs due to the presence of hyperactive immune cells. Rapamycin and corticosteroids inhibit this immune response by blocking the activation of T and B cells.Open-label prospective randomized controlled trial.A tertiary medical center, Chang Gung Memorial Hospital, located in Taiwan.Between 2009 and 2011, of 4,012 H1N1-infected patients, 38 patients with severe H1N1 pneumonia and acute respiratory failure were enrolled.Thirty-eight patients with confirmed H1N1 pneumonia and on mechanical ventilatory support were randomized to receive adjuvant treatment of corticosteroids with an mTOR inhibitor, either with sirolimus (Rapamune 2 mg/d) (sirolimus group, n = 19) for 14 days or without sirolimus (nonsirolimus group, n = 19). The clinical values measured included PaO2/FIO2, Sequential Organ Failure Assessment score, duration of ventilatory support, and mortality. The baseline demography was similar between the two groups. After treatment, the PaO2/FIO2 values on day 3 (167.5 [95% CI, 86.7-209.2 mm Hg], n = 19 vs 106.8 [95% CI, 73.0-140.7 mm Hg], n = 19; p = 0.025] and day 7 (241.6 [95% CI, 185.2-297.9 mm Hg], n = 19 vs 147.0 [95% CI, 100.7-193.7 mm Hg], n = 17; p = 0.008) in the sirolimus group were significantly better over the nonsirolimus group. Similarly, the Sequential Organ Failure Assessment score on day 3 (4.3 [95% CI, 3.1-5.5]; p = 0.029) and day 7 (5.9 [95% CI, 4.8-6.9], n = 19 and 6.2 [95% CI, 4.7-7.8], n = 17, respectively) significantly improved in the sirolimus group. The liberation from a mechanical ventilator at 3 months was also better in the sirolimus combined with corticosteroids treatment. Similarly, the duration of ventilator use was significantly shorter in the sirolimus group (median, 7 vs 15 d; p = 0.03 by log-rank test). In the sirolimus combined with corticosteroids treatment group, a rapid clearance of virus also occurred after 7 days of treatment.In patients with severe H1N1 pneumonia, early adjuvant treatment with corticosteroids and an mTOR inhibitor was associated with improvement in outcomes, such as hypoxia, multiple organ dysfunction, virus clearance, and shortened liberation of ventilator and ventilator days.

Objectives: To present the complications of Ultraflex Self-Expandable Metallic Stents (SEMSs) applied in patients with benign tracheobronchial diseases. Methods: Eighty patients received 124 SEMSs were retrospectively reviewed in a tertiary hospital. Results: The baseline characteristics of patients received SEMS implantation including age (mean + standard deviation: 62.5 + 14.8 years), gender (male, 60.5%), smoking (46.8%), forced expiratory volume in first one second (FEV1) (mean + standard deviation, 0.92 +0.41 L/s), follow-up days after SEMS implantation (median (interquartile range); 457 (131 - 897)) and covered SEMS (33.9%) were listed. Symptoms improved after SEMS implantation among 95 patients (76.6%). Time to complications developed was 236 (median; interquartile range, 59 - 672) days. The overall complication rate was 41.9% after SEMS implantation. The complications included SEMS migration (6.5%), granuloma (19.3%) and SEMS fracture (16.1%). Successful management rates of SEMS migration, granuloma and SEMS fracture were up to 100%, 83.3%, and 85% respectively. Conclusions: Patients received SEMS implantation due to benign conditions had poor lung function and were old. The complication rate in patients with benign conditions was high after longer follow-up period, however, successful management achieved in most patients with complications.

Magnolol has shown inhibitory effects on NO production and TNF-alpha production in lipopolysaccharide (LPS)-activated macrophages and LPS-induced acute lung injury; however, the poor solubility of magnolol has hindered its clinical success. In this study, magnolol-loaded microparticles were prepared via single emulsion method from a polyketal polymer, termed PK3. The particle sizes of magnolol-loaded PK3 microparticle is 3.73 ± 0.41 μm, and was suitable for phagocytosis by macrophages and pulmonary drug delivery. PK3 microparticles exhibited excellent biocompatibility both in vitro and in vivo. More importantly, intratracheal delivery of these magnolol-loaded microparticles significantly reduced the lung inflammatory responses at low dosage of magnolol (0.5 mg/kg), and have great clinical potential in treating acute lung injury.

Rationale: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear.Objectives: To identify subtypes of myeloid-derived suppressor cells in patients with non–small cell lung cancer (NSCLC) and their clinical relevance.Methods: CD11b+CD14− and CD11b+CD14+ cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b+CD14+S100A9+ cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy.Measurements and Main Results: Patients with NSCLC...

Introduction Esophagorespiratory fistula (ERF) caused by esophageal cancer has a poor prognosis. This study describes the clinical effects of airway ultraflex stenting as an alternative method for ERF caused by esophageal cancer. Methods In an university-affiliated hospital, consecutive patients with ERF caused by esophageal cancer and confirmed by bronchoscopy were included. The demography, clinical manifestations and survival between groups with and without airway stenting were compared by case-control study. Results From 2001 to 2007, 817 patients with esophageal cancer received bronchoscopy. Among these patients, 59 patients with ERF were included in this study. The demography and clinical manifestations between groups with and without airway stenting were similar, but survival improved in group with airway stenting, which was compared using log-rank test [ P = 0.04; hazard ratio, 0.56; 95% confidence interval (CI), 0.31–0.99]. After adjusted with age and gender by multinominal logistic regression, airway stenting [adjusted odds ratio (OR), 5.2; P = 0.01; 95% CI, 1.4–18.8], performance status (adjusted OR, 6.1; P = 0.004; 95% CI, 1.8–20.8), further treatment (adjusted OR, 8.7; P = 0.001; 95% CI, 2.3–32.8) and prolonged pneumonia (adjusted OR, 0.14; P = 0.008; 95% CI, 0.03–0.59) remained as significant factors that impacted survival. Conclusions Surgical treatment remains the first choice in patients with esophageal cancer with ERF; however, the authors provided an alternative airway stenting for those patients whom surgery is unsuitable. It improved survival in the group with airway stenting than those without. Performance status improvement and further treatment for esophageal cancer may improve survival, but prolonged pneumonia may worsen survival.

Introduction Despite removal of airway metallic stents by rigid bronchoscope was presented, there are few reports describing such removal by flexible bronchoscope. Methods 36 patients who had airway Ultraflex stents removed by flexible bronchoscope from 2002 to 2009 were reviewed. Factors contributing to removal method and complications during and after removal were analyzed by multinomial logistic regression. Results Among 36 patients with stent extraction; 17 stents (47.2%) were removed by a single procedure and 19 (52.8%) by multiple procedures. There was no mortality or severe morbidity during or after stent removal. There were 21 complications after stent removal, including retained stent pieces (n = 9), mucosal tear with bleeding (n = 5), and re-obstruction requiring silicone stent placement (n = 7). Stent indwelling time > 10 months (adjusted odds ratio: 9.5; 95% confidence interval: 7.9–11.1, P=0.01), obstructive granulation tissue formation before stent removal (adjusted odds ratio: 5.2; 95% confidence interval: 2.2–8.6, P=0.01), and stent fracture before removal (adjusted odds ratio: 3.5; 95% confidence interval: 1.8–15.4, P=0.04) were independent predictors of the need for multiple procedures for stent removal. Stent indwelling time > 10 months (adjusted odds ratio: 4.2; 95% confidence interval: 2.1–8.9, P=0.01), obstructive granulation tissue formation before stent removal (adjusted odds ratio: 16.5; 95% confidence interval, 1.8–49.6, P=0.01), and multiple procedures required for removal (adjusted odds ratio: 6.9; 95% confidence interval, 1.1–43.5, P=0.04) were independent predictors of removal complications. Conclusions A flexible bronchoscope can be used to remove stents in patients with central airway obstruction and stent-related complications. This procedure should be performed in centers with experienced multidisciplinary teams.

Our study investigated whether tumor-associated macrophages (TAMs) in advanced non-small cell lung cancer (NSCLC) are related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and may be a predictor of survival. Of 206 advanced NSCLC patients treated (first-line) with an EGFR-TKI at the study hospital from 2006 to 2009, 107 with adequate specimens for assessing CD68 immunohistochemistry as a marker of TAMs were assessed. After EGFR-TKI treatment, response was observed in 55 (51%) patients, and the median follow-up period was 13.5 months. Most TAMs were located in the tumor stroma (>95%) and positively costained with the M2 marker CD163. TAM counts were significantly higher in patients with progressive disease than in those without (p < 0.0001), a trend that remained in patients with known EGFR mutation status (n = 59) and those with wild-type EGFR (n = 20). High TAM counts, among other factors (e.g., wild-type EGFR), were significantly related to poor progression-free survival (PFS) and overall survival (OS) (all p < 0.0001 for TAMs). Multivariate Cox analyses showed that high TAM counts and EGFR mutations were both independent factors associated with PFS [odds ratio (OR), 8.0; 95% confidence interval (CI), 2.87-22.4; p = 0.0001 and OR, 0.03; 95% CI, 0.003-0.31; p = 0.003, respectively] and OS (OR, 2.641; 95% CI, 1.08-6.5; p = 0.03 and OR, 0.14; 95% CI, 0.03-0.56; p = 0.006, respectively). TAMs are related to treatment response irrespective of EGFR mutation and can independently predict survival in advanced NSCLC treated with an EGFR-TKI.

ObjectiveSelf-expandable metallic stents are used to relieve airway stenosis in selected patients; however, fracture of these stents may occur. This analysis aims to investigate the extent of tracheal torsion, assessed by a computed-generated reformatted 3-dimensional tracheal reconstruction from 2-dimensional computed tomographic images in predicting fracture of tracheal self-expandable metallic stents.MethodsFrom 2001 to 2007, 32 patients (aged 62.8 ± 14.1 years) with benign tracheal diseases received chest computed tomographic evaluation and Ultraflex (Boston Scientific, Natick, Mass) self-expandable metallic stents. The bending angles of the central axis and peripheral wall of the trachea at choke point were measured from the computed-generated 3-dimensional tracheal images.ResultsSeventeen fractured stents were found among the patients. The median time for stent fracture was 865 days after implantation. Receiver operating characteristic curve analysis revealed that a 19° bending angle of the tracheal central axis (area under the curve, 0.929; 95% confidence interval, 0.847–1.012; P

Aims and objectives. To investigate the feasibility of a school-based asthma management programme for middle school children. Background. Asthma rates are increasing among school-aged children. Successful asthma treatment in children depends in part on clear communication and effective education. Design. This feasibility study employed a one-group only longitudinal design with four time points over 18 months. Methods. Nineteen female and twelve male (n = 31) seventh-grade children with asthma (13 SD 0·71 years) were identified using a six-stage asthma case-finding approach. Teachers and school staff were trained in the principles and methods of the proposed school-based asthma management programme. An individualised guided asthma self-management programme was developed for each child by a clinical team at a major academic medical centre. We assisted teachers in implementing the school programme; building a support network and monitoring children’s activities. Outcome measures included lung function tests (at 0, six, 12 and 18 months), disease-related symptoms, psychosocial status and impact of asthma on learning (at 0 and 18 months). School provided data on academic achievement and school absences at 0, six, 12 and 18 months. Results. Significant improvements were noted at six, 12 and 18 months on forced vital capacity (FVC)% of predicted (p = 0·001, 0·015, 0·015, respectively), forced expiratory volume in one second (FEV1)% of predicted (p = 0·001, 0·006, 0·088, respectively) and FEV1/FVC% of predicted (p = 0·001, 0·015, 0·099, respectively). There was a trend towards improved asthma symptoms (p = 0·050) and a significant decrease in positive perception of curriculum (p = 0·017) at 18 months after adjustment for covariates. Conclusions. This programme was associated with respiratory benefits on physiological asthma markers commonly, with a trend for symptom control. Academic and psychosocial outcomes are subject of further inquiry. Relevance to clinical practice. School-based asthma management holds promise as a feasible clinical option for middle school children with asthma in the Taiwanese school system.

Objective This retrospective study was to determine factors that contribute to self-expandable metallic stent fracture in patients with tracheobronchial disease. Methods From 2001 to 2006, 139 patients (age, 62.1 ± 15.4 years; range, 23–87 years) with benign (n = 62) and malignant (n = 77) tracheobronchial disease received 192 Ultraflex (Boston Scientific, Natick, Mass) self-expandable metallic stents (98 in patients with benign disease and 94 in patients with malignant disease). Results Seventeen fractured self-expandable metallic stents were found; the incidence was 12.2% (17/139 patients) among patients with tracheobronchial disease. Tortuous airway (odds ratio, 4.06; 95% confidence interval, 1.04–18.34; P = .04) independently predicted self-expandable metallic stent fracture. Most self-expandable metallic stent fractures (64.7%, 11/17) were detected 500 to 1000 days after self-expandable metallic stent implantation. Clinical presentations for patients with fractured self-expandable metallic stents included dyspnea exacerbation (70.6%, 12/17) and cough (23.5%, 4/17). Conclusions Self-expandable metallic stent fracture is not uncommon in patients with tracheobronchial disease. Tortuous airway is an independent predictor for it. Although management of the fractured self-expandable metallic stent in our study was feasible and safe, self-expandable metallic stents should be restricted to a more select population.

The phagocytic recognition and clearance of the recruited inflammatory cells with prolonged survival play a pivotal role in relieving tissue inflammation and maintaining tissue homeostasis. Transgenic mice expressing Bcl-2 in mature neutrophils demonstrated that Bcl-2 attenuated neutrophil apoptosis, while the homeostasis of the neutrophil population was essentially unaffected. This result suggests that clearance of neutrophils with prolonged survival operates independently from apoptosis. Owing to the constitutive and inducible expression of Bcl-2 homologue, A1 in human neutrophils and the intolerance of preparation for the isolated human neutrophils with prolonged survival, the human promyelocytic HL60-A1 transfectants were established to study the mechanism of phagocytic recognition/clearance of the cells with prolonged survival.The non-apoptotic cells with prolonged survival were enriched by serum withdrawal for five days and negatively isolated by annexin V-binding beads. Then, the cells were labeled with a fluorogenic marker. Monocyte-derived macrophages (MDM) were co-cultured to perform the phagocytosis assay, and flow cytometry was employed to determine the phagocytic index.In the serum-free condition, the phagocytic index of HL60-A1 transfectants was little different from that of the HL60-EGFP control, despite showing a significantly lower degree of apoptosis. While the phagocytic index of HL60-EGFP control was significantly correlated with the degree of apoptosis, the index of the HL60-A1 transfectants was less relevant to it. The phagocytic index for the annexin V-positive cells did not distinguish the two cell types. However, the phagocytic index for the annexin V-negative cells from the HL60-A1 transfectants was increased with age in days. Preincubation of MDM with the scavenger receptor inhibitor, Oxi-LDL, and the inhibitory antibodies against alphavbeta3, CD14 and CD36 surface molecules could attenuate the phagocytic recognition of the annexin V-positive HL60 cells but not the annexin V-negative A1 transfectants with prolonged survival.This study thus suggests that a mechanism unrelated to apoptosis exists, which mediates the phagocytic clearance of the non-apoptotic cells with prolonged survival and may be associated with A1 function in the myeloid cells.

Interleukin (IL)-5 plays an important role in maintaining the survival of eosinophils via the specific alpha-subunit of its receptor. Apoptosis, a form of programmed cell death, is thought to represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma. The aim of our present study is to investigate whether IL-5 acts in an autocrine fashion on eosinophil apoptosis in asthmatics. Immunoreactivities of intracellular IL-5 and IL-5 receptor alpha-subunit (Ralpha) were detected uniquely on the eosinophils. The magnitude of IL-5 and IL-5 Ralpha expression on eosinophils was significantly higher in asthmatics than that of normal subjects (p0.05) determined by flow cytometry. Apoptosis of eosinophils was measured by the propidium iodide staining method and DNA ladder. The percent of apoptotic eosinophils from asthmatics was significantly increased by coincubation with anti-hIL-5 Ralpha Ab (0.1, 0.5, and 2.5 microg/mL) for 1, 2, or 16 hours than was those of corresponding controls (p0.05, n=8). However, there was no significant effect of anti-hIL-5 Ralpha Ab on eosinophil apoptosis in normal subjects. Furthermore, the expression of B-cell lymphoma-2 (Bcl-2) proteins was significantly inhibited by the anti-hIL-5 Ralpha Ab or antisense IL-5 oligonucleotides in asthmatics (p0.05, n=8), but there was no significant change in eosinophils from normal subjects. This study demonstrates that eosinophils from asthmatics release IL-5 in an autocrine fashion to act on their own IL-5 receptors in prevention of apoptosis through the upregulation of Bcl-2 expression.

The ability to generate reactive oxidative intermediates is one of the quintessential properties of mature human neutrophils. Endogenously generated oxidants have been shown to be an important mechanism underlying neutrophil cell death. In acute lung inflammation, newly recruited neutrophils further encounter external oxidants, including reactive oxygen and nitrogen intermediates. In our present study, we showed that A1, a constitutive and inducible Bcl-2 homologue expressed in mature circulating human neutrophils, might confer the protection from hydrogen peroxide (H(2)O(2))- and peroxynitrite (ONOO)-induced cell death. Utilizing the myeloid precursor cell line, HL-60, we further examined the hypothesis that A1 was capable of conferring cytoprotective activity against these oxidative stresses. Whereas the control-transfected HL-60 cells expressed small amounts of A1 and were sensitive to the biologically relevant, cell death-inducing oxidants, H(2)O(2) and ONOO, the stable transfectants that overexpressed A1 were significantly more tolerant. Furthermore, there was a correlation between the level of A1 expression and the antiapoptotic activity. Thus, our results suggest a cytoprotective role of A1 in mature human neutrophils under oxidant stresses in host defense and inflammation.

Background Central airway obstruction related to endobronchial malignancy is one of the most difficult oncological complications and requires efficient palliative intervention. Methods Fifty-three consecutive patients with unresectable endobronchial malignancy receiving bronchoscopic cryotherapy as palliative treatment were retrospectively reviewed. Efficiency was evaluated by the improvement of performance status (PS), and the best achievement of tumor removal was assessed as complete or partial removal. Result Patients' PS after cryotherapeutic tumor removal improved from the baseline PS (P = 0.006). In multivariate logistic regression analysis, the compression part of the tumor (odds ratio [OR] 0.42; 95% confidence interval [CI] 0.23∼0.75, P = 0.004) and the thin tumor stalk (OR 87.86; 95% CI 2.31∼3337.37, P = 0.016) were independent predictors of complete tumor removal. Tumors larger than 9.3 cm, including compression and invasion parts, had the highest odds of being only partially removed (positive predictive value [PPV]: 88.2%, likelihood ratio [LR]+: 10.49); tumors smaller than 9.3 cm were likely to be completely removed (negative predictive value [NPV]: 80.6%, LR−: 0.34). After cryotherapy, re-obstruction was significantly associated with non-squamous cell carcinoma (65.7 vs. 16.7%, P = 0.001) and patients who had longer overall survival (11.7 vs. 1.5 months, P < 0.001). Odds of tumor re-obstruction increased 2.28-fold (PPV: 81.6%, LR+: 2.28) beyond two months; the odds decreased by 81% (NPV: 73.3%, LR−: 0.19) within two months. Conclusion Debulking of a tumor using cryotherapy is a useful palliative treatment for endobronchial obstruction secondary to a variety of malignancies.

Although malignant endobronchial mass (MEM) has poor prognosis, cryotherapy is reportedly a palliative treatment. Clinical data on postcryotherapy MEM patients in a university-affiliated hospital between 2007 and 2011 were evaluated. Survival curve with or without postcryotherapy chemotherapy and performance status (PS) improvement of these subjects were analyzed using the Kaplan-Meier method. There were 59 patients (42 males), with median age of 64 years (range, 51–76, and median performance status of 2 (interquartile range [IQR], 2-3). Postcryotherapy complications included minor bleeding (n=12) and need for multiple procedures (n=10), while outcomes were relief of symptoms (n=51), improved PS (n=45), and ability to receive chemotherapy (n=40). The survival of patients with chemotherapy postcryotherapy was longer than that of patients without such chemotherapy (median, 534 versus 106 days; log-rank test,P=0.007; hazard ratio, 0.25; 95% confidence interval, 0.10–0.69). The survival of patients with PS improvement postcryotherapy was longer than that of patients without PS improvement (median, 406 versus 106 days; log-rank test,P=0.02; hazard ratio, 0.28; 95% confidence interval, 0.10–0.81). Cryotherapy is a feasible treatment for MEM. With better PS after cryotherapy, further chemotherapy becomes possible for patients to improve survival when MEM caused dyspnea and poor PS.

Inhaled corticosteroids (ICSs) are widely used in asthma control. Ciclesonide (CIC) is an ICS with on-site lung activation for potent anti-inflammatory activity. This study aimed to compare the clinical benefit of CIC with budesonide (BUD) in step-down therapy. A total of 150 patients with mild-to-moderate asthma well controlled by a combination of ICS and long-acting β2-agonist were randomised to receive either CIC 320 μg (n=75) once daily or 2 inhalations of BUD 200 μg (n=75) twice daily for 12 weeks. The forced expiratory volume in 1s (FEV1), maximum mid-expiratory flow (MMEF) and asthma control test (ACT) scores were measured. Ranked stratification of patients and physicians was assessed. Drug adherence was significantly higher in the CIC group than in the BUD group (76.0% vs. 58.7%, P=0.03). The FEV1 and MMEF remained stable throughout the 12-week CIC treatment. In the BUD group, FEV1 significantly decreased at weeks 4 and 12. MMEF had a higher value in the CIC group than in the BUD group. Both patients and physicians ranked CIC over BUD. CIC is more effective and has better drug adherence than BUD as step-down treatment when asthma is well controlled by combination therapy. Ciclesonide is more effective than budesonide in people seeking to reduce their asthma medications. Best-practice guidelines suggest that patients can take just one drug once they achieve reasonable asthma control for at least 3 months. This is known as step-down therapy. Researchers in Taiwan, led by Chun-Hua Wang and Han-Pin Kuo of Chang Gung Memorial Hospital, randomised 150 individuals with mild to moderate asthma well controlled by a combination of corticosteroid and β2 agonist to receive either ciclesonide or budesonide, both inhaled corticosteroid drugs. The study found that participants on a once-daily regimen of ciclesonide maintained a stable pulmonary function throughout the 12-week trial, whereas those receiving two doses of budesonide per day had smaller lung volumes. More research is needed to determine whether the benefit of ciclesonide is attributable to treatment compliance or drug efficacy.

BACKGROUND: Current staging system for small cell lung cancer (SCLC) categorizes patients into limited- or extensive-stage disease groups according to anatomical localizations. Even so, a wide-range of survival times has been observed among patients in the same staging system. This study aimed to identify whether endobronchial mucosa invasion is an independent predictor for poor survival in patients with SCLC, and to compare the survival time between patients with and without endobronchial mucosa invasion. METHODS: We studied 432 consecutive patients with SCLC based on histological examination of biopsy specimens or on fine-needle aspiration cytology, and received computed tomography and bone scan for staging. All the enrolled patients were assessed for endobronchial mucosa invasion by bronchoscopic and histological examination. Survival days were compared between patients with or without endobronchial mucosa invasion and the predictors of decreased survival days were investigated. RESULTS: 84% (364/432) of SCLC patients had endobronchial mucosal invasion by cancer cells at initial diagnosis. Endobronchial mucosal involvement (Hazard ratio [HR], 2.01; 95% Confidence Interval [CI], 1.30-3.10), age (HR, 1.04; 95% CI, 1.03-1.06), and extensive stage (HR, 1.39; 95% CI, 1.06-1.84) were independent contributing factors for shorter survival time, while received chemotherapy (HR, 0.32; 95% CI, 0.25-0.42) was an independent contributing factor better outcome. The survival days of SCLC patients with endobronchial involvement were markedly decreased compared with patients without (median 145 vs. 290, p

To investigate the feasibility of a school-based asthma management programme for middle school children.Asthma rates are increasing among school-aged children. Successful asthma treatment in children depends in part on clear communication and effective education.This feasibility study employed a one-group only longitudinal design with four time points over 18 months.Nineteen female and twelve male (n = 31) seventh-grade children with asthma (13 SD 0·71 years) were identified using a six-stage asthma case-finding approach. Teachers and school staff were trained in the principles and methods of the proposed school-based asthma management programme. An individualised guided asthma self-management programme was developed for each child by a clinical team at a major academic medical centre. We assisted teachers in implementing the school programme; building a support network and monitoring children's activities. Outcome measures included lung function tests (at 0, six, 12 and 18 months), disease-related symptoms, psychosocial status and impact of asthma on learning (at 0 and 18 months). School provided data on academic achievement and school absences at 0, six, 12 and 18 months.Significant improvements were noted at six, 12 and 18 months on forced vital capacity (FVC)% of predicted (p = 0·001, 0·015, 0·015, respectively), forced expiratory volume in one second (FEV(1) )% of predicted (p = 0·001, 0·006, 0·088, respectively) and FEV(1) /FVC% of predicted (p = 0·001, 0·015, 0·099, respectively). There was a trend towards improved asthma symptoms (p = 0·050) and a significant decrease in positive perception of curriculum (p = 0·017) at 18 months after adjustment for covariates.This programme was associated with respiratory benefits on physiological asthma markers commonly, with a trend for symptom control. Academic and psychosocial outcomes are subject of further inquiry.School-based asthma management holds promise as a feasible clinical option for middle school children with asthma in the Taiwanese school system.

BACKGROUND: This retrospective study aimed to determine the factors leading to obstructive granulation tissue formation after the placement of a self-expandable metallic stent (SEMS) in patients with benign tracheal disease. METHODS: From 2001 to 2007, a total of 67 patients (age: 62.1 ± 15.4 years; range: 23-87 years) with benign tracheal disease received 75 ultraflex SEMS in our institution. RESULTS: There were 35 SEMSs complicated by obstructive granulation tissue formation out of the 75 stents placed in patients with tracheal disease, giving an incidence of 47.8 % (32/67 patients). The median time until developing granulation tissue was 106 days (IQR, 46-396). Structural airway obstruction prior to SEMS implantation independently predicted obstructive granulation tissue formation after SEMS implantation (odds ratio: 3.84; 95 % CI: 1.01-8.7; P = 0.04). Time to granulation tissue detection was shorter in patients with structural airway obstruction before SEMS implantation (structural airway obstruction vs. dynamic collapse airway: median [IQR] 95 [38-224, n = 26] vs. 396 days [73-994, n = 9]; P = 0.02). CONCLUSIONS: Obstructive granulation tissue formation is not uncommon after SEMS implantation and structural airway obstruction prior to SEMS implantation is an independent predictor. Although SEMS implantation should be restricted to a select population, it may be placed in patients not suitable for surgical intervention or rigid bronchoscopy with anesthesia because of poor pulmonary function.

Erlotinib (Tarceva) is a human epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor used for treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Interstitial lung disease, associated with gefitinib (Iressa) use, has been reported in approximately 1% of patients worldwide. However, the adverse pulmonary effects of erlotinib remain poorly documented. Reviewed English language publications in MEDLINE and PubMed suggest that this report is to be the first case report in English of a histologically-confirmed case of near-fatal interstitial pneumonitis with acute lung injury, associated with erlotinib, in East Asian patients. Physicians are hereby encouraged to promptly evaluate new or worsening pulmonary symptoms so that they can detect early radiographic signs of pulmonary toxicity in patients on erlotinib. If toxicity is confirmed, erlotinib should be discontinued and the patient treated appropriately. The case presented suggests that the outcome of erlotinib-associated pulmonary toxicity with acute respiratory failure may be favorable with adequate early management.

Summary Purpose Failure to gefitinib is generally believed to be associated with cross-resistance to other epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Here we report a case whose active EGFR- mutant NSCLC responded to erlotinib treatment. Patient and methods Lung specimen was obtained during diagnostic procedures from a 41-year-old Taiwanese male smoker with adenocarcinoma. He received cisplatin-based chemotherapy following craniotomy to remove his brain metastasis. Tumor progressed in both lung and left adrenal gland. He underwent second-line docetaxel chemotherapy. Tumor progressed again 7 months later. He was subsequently treated with gefitinib 250mg QD. Complete regression of the lung tumor and partial response of the left adrenal gland mass was achieved. Nine months later, the left lower lobe lung tumor and left adrenal gland tumor progressed. A lung biopsy from the left lower lobe disclosed an adenocarcinoma which harbored an in-frame deletion in exon 19 (heterozygous delE746-A750) of EGFR without a second mutation such as T790M in exon 20. Subsequent erlotinib 150mg QD was administered. He experienced grade 1 skin rash, diarrhea and paronychia following erlotinib. Results This patient achieved a partial response to erlotinib treatment. He remained on erlotinib for a total of 18 months until the left adrenal gland tumor progressed. Conclusions This case demonstrated that NSCLC bearing in-frame deletion in exon 19 of EGFR may respond to erlotinib treatment following gefitinib failure.

Defensins play a pivotal role in antimicrobial reactions, inflammatory responses, wound repair, and specific immunity. In inflammatory and infectious lung diseases, alpha-defensins are released from recruited neutrophils, and modulate a variety of lung cell functions. We found that human bronchial and alveolar epithelial cells treated with low and moderate concentrations (5 and 10 micro g/ml) of purified neutrophil-derived alpha-defensin-1 secreted more interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 in a dose- and time-dependent manner. Under moderate and high concentrations (10 and 20 micro g/ml) of alpha-defensin-1, we observed typical apoptotic changes in the lung epithelial cells after stimulation for 24 h. Furthermore, alpha-defensin-1 triggered lung cell detachment in a time- and dose-dependent manner at moderate and high concentrations. Prior to the detachment, caspase-3 activity significantly increased. On confocal laser microscopy, rapid translocation of alpha-defensin-1 to the endoplasmic reticulum (ER) was noted. These findings suggest that neutrophil-derived alpha-defensin-1 has pro-inflammatory and apoptotic effects in human bronchial and alveolar epithelial cells, which are concentration-dependent and may be associated with ER activity.

Apoptosis mediated by caspase activation is important in the neutrophil homeostasis and resolution of tissue inflammation. Paradoxically, our previous study demonstrated that broad-spectrum caspase inhibition augmented tumor necrosis factor (TNF)- \(\alpha\)-induced cell death in the human neutrophils. Therefore, we further explored the mechanisms related to the caspase-independent cell death in the neutrophils. The cell apoptosis/necrosis was determined by annexin V and propidium iodide dual staining in flow cytometry. Their morphological changes were observed under light microscopy. Fluorogenic substrates were used to measure the intracellular oxidative reactions and the activities of proteinases, calpains. Calpain inhibitors and antioxidants were used to elucidate the relationship of calpains and oxidants with the neutrophil cell death. Our results verified the caspase-independent cell death pathway in the zVAD-sensitized, TNF- \(\alpha\)-stimulated neutrophils. Furthermore, the cell death was accompanied with increased calpain and oxidative activities in the cells. Calpain inhibitors, zLLY, as well as anti-oxidants, catalase and DMSO, were able to attenuate the cell death in the zVAD-sensitized, TNF- \(\alpha\)-induced neutrophils. Pretreating the neutrophils with G-CSF or GM-CSF was not able to reduce the cell death. These results demonstrate that, in human neutrophils, TNF- \(\alpha\)-induces a caspase-independent cell death signal, which is related to calpain and oxidative activities and cannot be rescued by the growth factor-related signaling mechanism.

BackgroundDuring the acute phase of severe acute respiratory syndrome (SARS), mononuclear cells infiltration, alveolar cell desquamation and hyaline membrane formation have been described, together with dysregulation of plasma cytokine levels. Persistent high-resolution computed tomography (HRCT) abnormalities occur in SARS patients up to 40 days after recovery.MethodsTo determine further the time course of recovery of lung inflammation, we investigated the HRCT and inflammatory profiles, and coronavirus persistence in bronchoalveolar lavage fluid (BALF) of 12 patients at recovery at 60 and 90 days.ResultsAt 60 days, compared to normal controls, SARS patients had increased cellularity of BALF with increased alveolar macrophages (AM) and CD8 cells. HRCT scores were increased and correlated with T-cell numbers and their subpopulations, and inversely with CD4/CD8 ratio. TNF-α, IL-6, IL-8, RANTES and MCP-1 levels were increased. Viral particles in AM were detected by electron microscopy in 7 of 12 SARS patients with high HRCT score. On day 90, HRCT scores improved significantly in 10 of 12 patients, with normalization of BALF cell counts in 6 of 12 patients with repeat bronchoscopy. Pulse steroid therapy and prolonged fever were two independent factors associated with delayed resolution of pneumonitis, in this non-randomized, retrospective analysis.ConclusionResolution of pneumonitis is delayed in some patients during SARS recovery and may be associated with delayed clearance of coronavirus, Complete resolution may occur by 90 days or later.

The diagnostic yield of flexible fiberoptic bronchoscopy for peripheral lung cancers is still limited. This study evaluated whether endobronchial ultrasound (EBUS) may help localize and improve the diagnostic yield of bronchoscopic transbronchial lung biopsy in peripheral lung cancer.Between July 2001 and May 2002, 218 patients received transbronchial lung biopsy during bronchoscopic examinations with (n = 122) or without EBUS guidance (n = 96) and had the presence of peripheral lung cancers subsequently confirmed. These 218 patients were included in this retrospective analysis.The diagnostic accuracy of transbronchial lung biopsy was significantly increased under EBUS guidance for small cell carcinoma (65.6%) and for non-small cell carcinoma (42.7%) [p0.01]. For peripheral lung cancer either smaller than 2 cm or larger than 2 cm, the diagnostic yield of transbronchial lung biopsy with EBUS guidance was significantly higher (66.0% vs 42.3%, p0.002 for mass larger than 2 cm; 54.5% vs 0%, p0.04 for mass smaller than 2 cm). EBUS provided a better diagnostic yield (p = 0.014; odds ratio, 0.219) for lesions localized at the left upper lobe, which are generally thought to be more difficult to approach through bronchoscopy. There were no significant differences in complications between patients who underwent bronchoscopy with or without EBUS guidance.Under EBUS guidance, the diagnostic yield of transbronchial lung biopsy in peripheral lung cancer by bronchoscopic examination was significantly improved without difference in the complication rate.

Neutrophils and their derived elastase are abundant in chronic inflammatory responses of asthma. This study aimed to investigate the mitogenic effect of elastase on airway smooth muscle (ASM) cells and the implicated signal transduction pathway. Near confluent cultured human ASM cells were treated with human neutrophil elastase (HNE, 0.01 to 0.5 microg/ml) or vehicle for 24 hours with or without extracellular signal-regulated kinase (ERK) inhibitor (PD98059, 30 microM), p38 kinase inhibitor (SB203580, 10 microM) or elastase inhibitor II (100 microg/ml). The ASM cell numbers were counted by a hemocytometer and DNA synthesis was assessed by flowcytometry. Western blots analysis for the expression of ERK, p38 and cyclin D1 was determined. HNE dose-dependently increased ASM cell numbers and the percentage of cells entering S-phase of cell cycle. This response was abolished by neutrophil elastase inhibitors and attenuated by PD98059, but not SB203580. HNE increased ERK phosphorylation and cyclin D1 expression. Pretreatment with PD98059 significantly inhibited elastase-induced cyclin D1 activity. The increased ASM cellular gap and cell shape change by proteolytic activity of HNE may be contributory to ERK activation and therefore cell proliferation. Our results demonstrate that HNE is mitogenic for ASM cells by increasing cyclin D1 activity through ERK signaling pathway.

To the Editors: Advanced, unresectable oesophageal cancer with airway invasion has a very poor prognosis. For tumours extending into the airway lumen, the primary goals of therapy are for the palliative relief of the malignant obstruction of the oesophageal lumen and central airway and to close the fistula between the oesophagus and central airway. Palliative options include mechanical core-out, dilatation, laser ablation, electrocautery, cryotherapy, photodynamic therapy and brachytherapy 1, 2. However, satisfactory results may not be immediate or lasting. Endoscopic stenting is effective for airway stenosis from both extrinsic compression and direct tumour invasion, and has also been shown to be useful in the treatment of tracheo-oesophageal fistulas 3. …