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Abstract Large cohort studies have disclosed the association between obesity and rheumatoid arthritis (RA) risk. The sarcopenia prevalence in RA patients can be up to 31%. However, there is little information linking adipokines to sarcopenia in RA, so this study aimed to investigate whether adipokines were indeed involved in secondary sarcopenia in RA with a focus on non‐obese females. Sixty‐four female patients and 36 controls were included in this study. The serum adipokine levels (leptin and adiponectin) were determined by ELISA kits. The impacts of adipokines on muscle atrophy and potential autophagy were examined in mouse myoblasts, C2C12, upon treatment with recombinant leptin and adiponectin agonist (AdipoRan). Interestingly, serum adiponectin was significantly increased but the ratio of leptin/adiponectin was dramatically decreased in the RA patients with sarcopenia. After normalization by body mass, serum leptin was positively associated but adiponectin was negatively associated with muscle mass respectively, even after adjustment for fat mass. Treating C2C12 cells with leptin and AdipoRan inhibited proliferation of mature myotube respectively, as did treatment with the serum from RA patients. A combination of low leptin and high AdipoRan greatly decreased myogenin, but instead increased MAFbx and MuRF‐1 as well as increased Beclin 1, Atg5, and LC3β. Taken together, our study reveals that secondary sarcopenia of RA females may be an imbalance of RA‐related, but not obesity‐related, increase in adipokine production; additionally, the reduced leptin/adiponectin ratio could be a better indicator in monitoring sarcopenia in non‐obese RA females. Moreover, adipokine imbalance may promote muscle atrophy through inducing autophagy.

Abstract Background DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are “non-atopic”, lacking a clear etiology. Methods In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman’s rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. Results Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. Conclusion The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

IntroductionAnaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients. The association of smoking and ALK-tyrosine kinase inhibitors (TKIs) on overall survival (OS) of treatment-naïve ALK-positive advanced lung adenocarcinoma remains unclear in real-world.MethodsThis retrospective study evaluated all 33170 lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2019, of whom 9575 advanced stage patients had ALK mutation data.ResultsAmong the 9575 patients, 650 (6.8%) patients had ALK mutation with the median follow-up survival time 30.97 months (median age, 62 years; 125 [19.2%] were aged ≥75 years; 357 (54.9%) females; 179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status; and 544 (83.7%) with first-line ALK-TKI treatment). Overall, of 535 patients with known smoking status who received first-line ALK-TKI treatment, never-smokers and smokers had a median OS of 40.7 months (95% confidence interval (CI), 33.1-47.2 months) and 23.5 months (95% CI, 11.5-35.5 months) (P=0.015), respectively. Among never-smokers, those who received first-line ALK-TKI treatment had a median OS of 40.7 months (95% CI, 22.7-57.8 months), while those ALK-TKI not as first-line treatment had a median OS of 31.7 months (95% CI, 15.2-42.8 months) (P=0.23). In smokers, the median OS for these patients was 23.5 months (95% CI, 11.5-35.5 months) and 15.6 months (95% CI, 10.2-21.1 months) (P=0.026), respectively.Conclusions and relevanceFor patients with treatment-naïve advanced lung adenocarcinoma, the ALK test should be performed irrespective of smoking status and age. Smokers had shorter median OS than never-smokers among treatment-naïve-ALK-positive patients with first-line ALK-TKI treatment. Furthermore, smokers not receiving first-line ALK-TKI treatment had inferior OS. Further investigations for the first-line treatment of ALK-positive smoking advanced lung adenocarcinoma patients are needed.

Aberrant metabolism has been proposed as one of the emerging hallmarks of cancer. However, the interplay between metabolic disorders and cancer metastasis remains to be defined. To explore the sophisticated metabolic processes during metastatic progression, we analyzed differentially expressed metabolic genes during the epithelial-mesenchymal transition (EMT) of lung cancer cells and defined the EMT-associated metabolic gene signature in lung adenocarcinoma patients. We found that the glycosaminoglycan (GAG)-chondroitin sulfate (CS) biosynthesis pathway was upregulated in the mesenchymal state of lung cancer and associated with poor prognosis. Notably, carbohydrate sulfotransferase 11 (CHST11), a crucial CS biosynthetic enzyme, was confirmed as a poor prognosis marker in non-small cell lung cancer (NSCLC) by immunohistochemical analysis. Moreover, forced CHST11 expression promoted invasion and metastasis, which was abolished by depleting the final product of CS biosynthesis by chondroitinase ABC treatment or active-domain negative CHST11. In vivo metastasis mouse models showed that CHST11 increased lung colonies number and sulfated mucosubstance expression. Furthermore, microarray analysis revealed ceruloplasmin (CP), which facilitated iron metabolism, was the downstream effector of CHST11. CP was upregulated by CHST11 through interferon-γ signaling pathway stimulation and related to unfavorable prognosis. Both forced CP expression and long-term iron treatment increased invasion and lung colony formation. Furthermore, we found 3-AP, an iron chelator, hampered the CHST11-induced metastasis. Our findings implicate that the novel CHST11-CP-iron axis enhances EMT and may serve as a new therapeutic target to treat NSCLC patients.

Abstract Background Afatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib. Methods We designed a retrospective study, enrolling all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg daily afatinib as their initial treatment in three Kaohsiung Medical University-affiliated hospitals in Taiwan. Results A total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (75% vs. 83%, p = 0.1672), median PFS (14.5 vs. 14.8 months, log-rank p = 0.4649), and median OS (34.0 vs. 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients initially receiving 30 mg afatinib daily had fewer ADRs compared with those using 40 mg daily. The overall incidence of moderate and severe ADRs was significantly lower in patients receiving 30 mg afatinib daily compared with those using 40 mg daily (49% vs. 77%, p = 0.002); similar findings was observed in terms of severe ADRs (7% vs. 24%, p

Abstract Background The number of people aged greater than 65 years is growing in many countries. Taiwan will be a superaged society in 2026, and health care utilization will increase considerably. Our study aimed to evaluate the efficacy of the geriatric integrated outpatient clinic model for reducing health care utilization by older people. Methods This was a retrospective case-control study. Patients aged greater than 65 years seen at the geriatric outpatient clinic (Geri-OPD) and non-geriatric outpatient clinic (non-Geri-OPD) at a single medical centre were age and sex matched. Data on the number of outpatient clinic visits, emergency department visits, hospitalizations and medical expenditures were collected during the first and second years. A subgroup analysis by Charlson comorbidity index (CCI) and older age (age≧80 years) was performed, and the results were compared between the Geri-OPD and non-Geri-OPD groups. Results A total of 6723 patients were included (3796 women and 2927 men). The mean age was 80.42 ± 6.39 years. There were 1291 (19.2%) patients in the Geri-OPD group and 5432 (80.8%) patients in the non-Geri-OPD group. After one year of regular follow-up, the Geri-OPD patients showed a significant reduction in the types of drugs included in each prescription (5.62 ± 10.85) and the number of clinic visits per year (18.18 ± 48.85) (P

Abstract Background Elevated Staphylococcus aureus and oral bacterial concentrations are known to correlate with pneumonia hospitalization in nursing home residents. However, the effects of a professional oral care intervention on these factors remain unclear. The aims of this quasi-experimental study were to compare bacterial concentrations in saliva and sputum, oral health status, distribution of Staphylococcus aureus, and pneumonia status before and after a professional oral care intervention. Methods A purposive sample of residents from two nursing homes was divided into an intervention group that received a weekly professional oral care intervention and a control group. Oral bacterial concentration was determined by real-time polymerase chain reaction. The Staphylococcus aureus distribution was determined by bacterial culture and matrix-assisted laser desorption/ionization–time of flight mass spectrometry. After data collection, a statistical analysis was performed to evaluate the effect of the intervention. Results Most residents were unconscious (80%), and most had a history of pneumonia (76%). Baseline demographic data did not significantly differ between the two groups. After the intervention, the intervention group had significant improvements in plaque index (1.66 ± 0.78 vs. 0.94 ± 0.64, p

ObjectivesLung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1) and its ligands, programmed death ligand 1 (CD274) and 2 (PDCD1LG2), associated with lung cancer risk in never-smoking women.Materials and MethodsDuring September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs.ResultsA total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 (p < 0.001), rs12237624 (p = 0.019), and rs78096119 (p = 0.019) were associated with the expression levels of programed death ligand 2.ConclusionsNovel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening.

Abstract Background Adenylate kinase 4 (AK4) has been identified as a biomarker of metastasis in lung cancer. However, the impacts of AK4 on metabolic genes and its translational value for drug repositioning remain unclear. Methods Ingenuity upstream analyses were used to identify potential transcription factors that regulate the AK4 metabolic gene signature. The expression of AK4 and its upstream regulators in lung cancer patients was examined via immunohistochemistry. Pharmacological and gene knockdown/overexpression approaches were used to investigate the interplay between AK4 and its upstream regulators during epithelial-to-mesenchymal transition (EMT). Drug candidates that reversed AK4-induced gene expression were identified by querying a connectivity map. Orthotopic xenograft mouse models were established to evaluate the therapeutic efficacy of drug candidates for metastatic lung cancer. Results We found that HIF-1α is activated in the AK4 metabolic gene signature. IHC analysis confirmed this positive correlation, and the combination of both predicts worse survival in lung cancer patients. Overexpression of AK4 exaggerates HIF-1α protein expression by increasing intracellular ROS levels and subsequently induces EMT under hypoxia. Attenuation of ROS production with N-acetylcysteine abolishes AK4-induced invasion potential under hypoxia. Pharmacogenomics analysis of the AK4 gene signature revealed that withaferin-A could suppress the AK4-HIF-1α signaling axis and serve as a potent anti-metastatic agent in lung cancer. Conclusions Overexpression of AK4 promotes lung cancer metastasis by enhancing HIF-1α stability and EMT under hypoxia. Reversing the AK4 gene signature with withaferin-A may serve as a novel therapeutic strategy to treat metastatic lung cancer.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase overexpressed in various cancer types that plays a critical role in tumor progression. Accumulating evidence suggests that targeting FAK, either alone or in combination with other agents, may serve as an effective therapeutic strategy for numerous cancers. In addition to retarding proliferation, metastasis, and angiogenesis, FAK inhibition triggers cellular senescence in lung cancer cells. However, the detailed mechanism remains enigmatic. In the present study, we found that FAK inhibition not only elicits DNA-damage signaling but also downregulates enhancer of zeste homolog 2 (EZH2) expression. The manipulation of FAK expression influences EZH2 expression and corresponding signaling in vitro. Immunohistochemistry shows that active FAK signaling corresponds with the activation of the EZH2-mediated signaling cascade in lung-cancer-cells-derived tumor tissues. We also found that ectopic EZH2 expression attenuates FAK-inhibition-induced cellular senescence in lung cancer cells. Our results identify EZH2 as a critical downstream effector of the FAK-mediated anti-senescence pathway. Targeting FAK-EZH2 axis-induced cellular senescence may represent a promising therapeutic strategy for restraining tumor growth.

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Abstract Chronic exposure to ambient polycyclic aromatic hydrocarbons (PAHs) is associated with asthma, but its regulatory mechanisms remain incompletely defined. We report herein that elevated levels of urinary 1-hydroxypyrene, a biomarker of PAH exposure, were found in asthmatic subjects (n = 39) as compared to those in healthy subjects (n = 43) living in an industrial city of Taiwan, where indeno[1,2,3-cd]pyrene (IP) was found to be a prominent PAH associated with ambient PM2.5. In a mouse model, intranasal exposure of mice with varying doses of IP significantly enhanced antigen-induced allergic inflammation, including increased airway eosinophilia, Th2 cytokines, including IL-4 and IL-5, as well as antigen-specific IgE level, which was absent in dendritic cell (DC)-specific aryl hydrocarbon receptor (AhR)-null mice. Mechanistically, IP treatment significantly altered DC’s function, including increased level of pro-inflammatory IL-6 and decreased generation of anti-inflammatory IL-10. The IP’s effect was lost in DCs from mice carrying an AhR-mutant allele. Taken together, these results suggest that chronic exposure to environmental PAHs may pose a significant risk for asthma, in which IP, a prominent ambient PAH in Taiwan, was shown to enhance the severity of allergic lung inflammation in mice through, at least in part, its ability in modulating DC’s function in an AhR-dependent manner.

Abstract Background Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Compared to cytotoxic chemotherapy, afatinib has been shown to have better efficacy in the treatment of non-small cell lung cancer harboring EGFR mutations. However, 40 mg daily as the initial dose is often accompanied by serious adverse drug reactions (ADRs) and 28 to 53.3% of patients required a dose reduction. No previous study has compared the clinical efficacy and ADRs of different initial doses (40 mg vs. 30 mg daily) of afatinib in lung cancer treatment. Methods Patients with stage IV lung adenocarcinoma diagnosed and treated in two Kaohsiung Medical University-affiliated hospitals in Taiwan between May 2014 and August 2016 were identified and followed until December 2016. Demographic characteristics, responses, progression-free survival (PFS), overall survival (OS), and ADRs were recorded. Result A total of 48 patients with stage IV lung adenocarcinoma harboring susceptible EGFR mutations who received afatinib as their first-line therapy were enrolled. Patients using 30 mg daily as the initial dose tended to be older and female and have a smaller body size. The patients using 30 mg of afatinib daily as their initial dose had a similar response rate to those receiving 40 mg daily (76% vs. 95%, p = 0.0862) and the same disease control rate (100% vs. 100%, p = 0.1486). The PFS was similar between the patients receiving 30 mg or 40 mg of afatinib daily (median PFS: 469 vs. 443 days, log-rank p = 0.8418). Patients receiving 30 mg daily had a significantly lower incidence of diarrhea than those using 40 mg daily (41% vs. 100%, p

Abstract Background Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib can provide better efficacy and prolonged progression free survival (PFS) than cytotoxic chemotherapy for metastatic lung non-squamous cell carcinoma harboring susceptible EGFR mutations when used as first-line therapy. Cytotoxic chemotherapy is regarded as being the standard therapy to overcome acquired resistance to an initial EGFR TKI. However, there is currently no consensus on how best to treat patients who develop resistance to both an initial EGFR TKI and chemotherapy. Methods We enrolled stage IV lung adenocarcinoma patients with an EGFR mutation and who had developed acquired resistance to gefitinib and cytotoxic chemotherapy from two university-affiliated hospitals in Taiwan from June 2011 to December 2014. Basic demographic data, included Eastern Cooperative Oncology Group (ECOG) performance status were collected, and the response rate, progression-free survival (PFS) and overall survival (OS) were analyzed. Result Two hundred and nine patients with mutated EGFR and who took gefitinib as the first-line therapy were identified in the study period, of whom 86 received second-line cytotoxic chemotherapy, and 60 who received third-line therapy were eligible for this study. The patients who received cytotoxic chemotherapy had a significantly higher disease control rate than those who received erlotinib (73% vs. 46%, p = 0.0363), however there were no significant differences in PFS (2.9 months vs. 3.1 months, p = 0.9049) and OS (8.9 months vs. 7.9 months, p = 0.4956). Platinum- or pemetrexed-based chemotherapy provided similar PFS and OS as others did. The only significant poor prognostic factors for OS were old age (≥65 years) (HR = 5.97 [2.65–13.44], p

Focal adhesion kinase (FAK) is a non-receptor kinase that facilitates tumor aggressiveness. The effects of FAK inhibition include arresting proliferation, limiting metastasis, and inhibiting angiogenesis. PF-573228 is an ATP-competitive inhibitor of FAK. Treating lung cancer cells with PF-573228 resulted in FAK inactivation and changes in the expressions of lamin A/C and nuclear deformity. Since lamin A/C downregulation or deficiency was associated with cellular senescence, the senescence-associated β-galactosidase (SA-β-gal) assay was used to investigate whether PF-573228 treatment drove cellular senescence, which showed more SA-β-gal-positive cells in culture. p53 is known to play a pivotal role in mediating the progression of cellular senescence, and the PF-573228-treated lung cancer cells resulted in a higher p53 expression level. Subsequently, the FAK depletion in lung cancer cells was employed to confirm the role of FAK inhibition on cellular senescence. FAK depletion and pharmacological inhibition of lung cancer cells elicited similar patterns of cellular senescence, lamin A/C downregulation, and p53 upregulation, implying that FAK signaling is associated with the expression of p53 and the maintenance of lamin A/C levels to shape regular nuclear morphology and manage anti-senescence. Conversely, FAK inactivation led to p53 upregulation, disorganization of the nuclear matrix, and consequently cellular senescence. Our data suggest a new FAK signaling pathway, in that abolishing FAK signaling can activate the senescence program in cells. Triggering cellular senescence could be a new therapeutic approach to limit tumor growth.

Quality control is a crucial issue in the injection molding process with target of obtaining a high yield rate and reducing production cost. Consequently, effective methods for monitoring the injection conditions (e.g., pressure, velocity, and temperature) in real-time and adjusting these conditions adaptively as required to ensure a consistent part quality are essential. This study proposes a quality index based on the clamping force increment during the injection cycle, as determined by four strain gauges attached to the tie bars of the injection molding machine. Also, various quality indexes for online quality monitoring and prediction purposes based on the pressure, viscosity, and energy features extracted from the pressure profiles obtained at the load cell, nozzle, and molding cavity, respectively, are compared. The feasibility of the proposed quality indexes is investigated experimentally for various settings of the barrel temperature, back pressure, and rotational speed of the plasticizing screw. It is shown that all of the quality indexes are correlated with the injection-molded quality and hence provide a feasible basis for the realization of an on-line quality monitoring and control system. Particularly, the tie-bar elongation quality index requires no modification or invasion of the injection molding system or cavity and hence provides a particularly attractive solution for monitoring and controlling the part quality.

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

BACKGROUND:The goals of this multinational retrospective study were to describe treatment patterns and survival outcomes by receipt of molecular testing and molecular status of patients with advanced non-small cell lung cancer (NSCLC). METHODS:This chart review study, conducted in Italy, Spain, Germany, Australia, Japan, Korea, Taiwan, and Brazil, included 1440 patients with newly diagnosed advanced (stage IIIB/IV) NSCLC initiating systemic therapy from January 2011 through June 2013, with follow-up until July 2016. We evaluated treatment patterns and survival by histology, line of therapy, molecular testing, and test results for epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma kinase (ALK) rearrangement. Country-specific data were analyzed descriptively and presented as ranges (lowest to highest country). Overall survival (OS) was estimated using Kaplan-Meier method. RESULTS:Patients with ≥1 molecular test varied from 43% (Brazil) to 85% (Taiwan). Numerically greater proportions of patients who were female, Asian, or never/former-smokers, and those with nonsquamous histology or stage-IV NSCLC, received a test. Testing was common for nonsquamous NSCLC (54%, Brazil, to 91%, Taiwan), with positive EGFR and ALK tests from 17% (Brazil and Spain) to 67% (Taiwan) and from 0% (Brazil) to 60% (Taiwan), respectively. First-line treatment regimens for nonsquamous NSCLC with positive EGFR/ALK tests included targeted therapy for 30% (Germany) to 89% (Japan); with negative/inconclusive test results, platinum-based combinations for 88% (Japan) to 98% (Brazil); and if not tested, platinum-based combinations for 80% (Australia) to 95% (Japan), except in Taiwan, where 44% received single agents. Median OS from first-line therapy initiation was 10.0 (Japan) to 26.7 (Taiwan) months for those tested and 7.6 (Australia/Brazil) to 19.3 (Taiwan) months for those not tested. CONCLUSIONS:We observed substantial variation among countries in testing percentages, treatment patterns, and survival outcomes. Efforts to optimize molecular testing rates should be implemented in the context of each country's health care scenario.

Toona sinensis (TS) leaves are used as a vegetable and in traditional Chinese medicine. However, in vivo experiments regarding the anti-inflammatory function of TS leaves have not previously been conducted. The aim of this study was to investigate the potential role of TS leaf extract (TSL) in the prevention of sepsis-induced lung injury in vivo and on macrophage activation in vitro. The results showed that oral gavage pretreatment with TSL in rats for 30 days improved the survival of cecal ligation and puncture-induced sepsis, potentially by attenuating sepsis-induced histological lung damage rather than inflammatory cell infiltration. Furthermore, we demonstrated that pretreatment with TSL attenuated the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase, thereby inhibiting nitric oxide production and release in murine macrophage-like RAW 264.7 cells. Interestingly, TSL did not affect the LPS-induced release of other cytokines (e.g., tumor necrosis factor α and interleukin 1β) but increased LPS-induced heme-oxygenase-1 expression. In conclusion, the study provides preliminary data for TSL on cecal ligation and puncture-induced sepsis. The beneficial impact of TSL needs extensive study to get solid evidence.

Five new eunicellin-based diterpenoids, krempfielins E–I (1–5) and seven known compounds (6–12) were isolated from the organic extract of a Taiwanese soft coral Cladiella krempfi. The structures of the new metabolites were elucidated on the basis of extensive spectroscopic analysis. Metabolites 5, 6, 10 and 12 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines. Furthermore, compounds 6 and 10 could potently inhibit the accumulation of the pro-inflammatory iNOS protein, and 6 and 12 could significantly reduce the expression of COX-2 protein in LPS-stimulated RAW264.7 macrophage cells.

Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation.

The purpose of this study was to validate the Impact of Event Scale-Revised (IES-R) for adolescents who had experienced the floods and mudslides caused by Typhoon Morakot in Taiwan. The internal consistency, construct validity, and criteria validity of the instrument were examined. Principal component analysis followed by an oblique rotation was used to derive a three-factor solution. These factors were labeled intrusion, hyperarousal, and avoidance; all three factors together accounted for 58.1% of the variance. The total Cronbach’s alpha of 0.94 reflected the good internal consistency of the instrument. With reference to diagnosis of posttraumatic stress disorder, the IES-R cutoff point for posttraumatic stress disorder was 19 of 20 with a sensitivity of 85.7% and specificity of 84.1%. In conclusion, the IES-R can be used as a reliable and valid instrument when evaluating psychological distress among adolescents who have experienced a natural disaster, such as flooding and mudslides.

Four new eunicellin-based diterpenoids, krempfielins A–D (1–4), along with two known compounds (5 and 6) have been isolated from a soft coral Cladiella krempfi. The structures of the new metabolites were elucidated by extensive spectroscopic analysis and by comparison with spectroscopic data of related known compounds. Compounds 5 and 6 were shown to exhibit cytotoxicity against a limited panel of cancer cell lines. Furthermore, compounds 2, 3, 5 and 6 were shown to exert significant in vitro anti-inflammatory activity against LPS-stimulated RAW264.7 macrophage cells.

There is now increasing evidence from the experimental and clinical setting that therapeutic hypercapnia from intentionally inspired carbon dioxide (CO2) or lower tidal volume might be a beneficial adjunct to the strategies of mechanical ventilation in critical illness. Although previous reports indicate that CO2 exerts a beneficial effect in the lungs, the pulmonary vascular response to hypercapnia under various conditions remains to be clarified. The purpose of the present study is to characterize the pulmonary vascular response to CO2 under the different conditions of pulmonary hypertension secondary to increased pulmonary blood flow and secondary to hypoxic pulmonary vasoconstriction. Isolated rat lung (n = 32) was used to study (1) the vasoactive action of 5% CO2 in either N2 (hypoxic-hypercapnia) or air (normoxic-hypercapnia) at different pulmonary arterial pressure levels induced by graded speed of perfusion flow and (2) the role of nitric oxide (NO) in mediating the pulmonary vascular response to hypercapnia, hypoxia, and flow-associated pulmonary hypertension. The results indicated that inhaled CO2 reversed pulmonary hypertension induced by hypoxia but not by flow alteration. Endogenous NO attenuates hypoxic pulmonary vasoconstriction but does not augment the CO2-induced vasodilatation. Acute change in blood flow does not alter the endogenous NO production.

Self-contained underwater breathing apparatus (scuba) diving is increasingly popular in Taiwan. There are few references in the literature regarding pulmonary hemorrhage as the sole manifestation of pulmonary barotrauma in scuba divers, and no study from Taiwan was found in the literature. We present the case of a 25-year-old man who suffered alveolar hemorrhage related to pulmonary barotrauma as a complication of scuba diving. To our knowledge, this is the first case report describing a Taiwanese subject suffering from non-fatal pulmonary hemorrhage after scuba diving.

Our study aimed to understand the characteristics of ventilator dependence in patients at a respiratory care center and the potential effects of physical therapy on ventilator weaning and patients' functional status. Prospective data collection consisted of the following: (1) demographic data, including name, gender, age, diagnosis, the Acute Physiology and Chronic Health Evaluation as a severity of the disease, modified Glasgow Coma Scale, mobility at the time of admission, and days of hospitalization; (2) Rapid shallow breathing index (RSBI) as a predictive indicator of ventilator weaning, including indicators of ventilator weaning were collected from the respiratory flow sheet; and (3) Barthel index. Between July 1 and December 31, 2007, 126 patients were admitted to the respiratory care center, and those who required mechanical ventilation for more than 14 days were enrolled. Fifty-five subjects received physical therapy. The RSBI in patients who received physical therapy was 75.7 ± 37.9 before therapy and 80.0 ± 48.5 afterwards, while the Barthel index increased from 0.8 ± 1.4 to 1.9 ± 2.5 (p < 0.05). The RSBI decreased as time of physical therapy lengthened, but not significantly (r = 0.12, p = 0.44). The success rate of ventilator weaning in patients receiving physical therapy intervention versus non-physical therapy intervention was 58.2% and 40.9%, respectively. The results indicated that lengthening the physical therapy intervention time enhanced the ventilator weaning success rate while mobility was not affected (r = −0.11, p = 0.41). Physical therapy may be offered to ventilator-dependent patients in line with their individual needs to improve or maintain basic mobility.

In-hospital diagnosis delay (IHDD) of pulmonary tuberculosis (TB) has a significant impact on nosocomial TB transmission. We investigated the risk factors associated with prolonged IHDD in Taiwan, a high-resource, mid-incidence area. Methods: Between January 2005 and August 2006, we retrospectively enrolled 193 consecutive hospitalized patients. All of them had culture-proven pulmonary TB and did not receive antitubercular treatment at admission. IHDD was defined as the interval between admission and initiation of antitubercular treatment. Patients were grouped according to the median value of IHDD. Results: The median IHDD was 7 days. Patients with IHDD > 7 days were considered the prolonged-delay group, and those with IHDD £ 7 days, the short-delay group. Independent risk factors [with adjusted odd ratios (95% confidence intervals)] for prolonged IHDD were: negative sputum smear [47.53 (13.20–171.18), p < 0.001]; non-cavitary lesions on chest radiographs [14.90 (3.46–64.14), p < 0.001]; admission to hospital departments other than chest medicine/infectious diseases [6.60 (1.95–22.41), p = 0.002]; exposure to fluoroquinolones before antitubercular treatment [5.29 (1.13–24.75), p = 0.034]; underlying malignancy [4.59 (1.13–18.67), p = 0.033); and age > 65 years [3.19 (1.01–10.05), p = 0.048]. Death attributed to tuberculosis was associated with positive sputum smear (hazard ratio = 21.85; 95% CI = 2.74–174.44; p = 0.004) but not prolonged IHDD (p = 0.325). Conclusion: To minimize IHDD, clinicians should carefully manage hospitalized patients with risk factors for prolonged delay, such as those with negative sputum smears, non-cavitary lesions on chest radiographs, admission to departments other than chest medicine/infectious diseases, exposure to fluoroquinolones before antitubercular treatment, underlying malignancy, and age > 65 years.

Toona sinensis extracts have been shown to exhibit anti-cancer effects in human ovarian cancer cell lines, human promyelocytic leukemia cells and human lung adenocarcinoma. Its safety has also been confirmed in animal studies. However, its anti-cancer properties in human lung large cell carcinoma have not been studied. Here, we used a powder obtained by freeze-drying the super-natant of centrifuged crude extract from Toona sinensis leaves (TSL-1) to treat the human lung carcinoma cell line H661. Cell viability was evaluated by the 3-(4-,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Flow cytometry analysis revealed that TSL-1 blocked H661 cell cycle progression. Western blot analysis showed decreased expression of cell cycle proteins that promote cell cycle progression, including cyclin-dependent kinase 4 and cyclin D1, and increased the expression of proteins that inhibit cell cycle progression, including p27. Furthermore, flow cytometry analysis showed that TSL-1 induced H661 cell apoptosis. Western blot analysis showed that TSL-1 reduced the expression of the anti-apoptotic protein B-cell lymphoma 2, and degraded the DNA repair protein, poly(ADP-ribose) polymerase. TSL-1 shows potential as a novel therapeutic agent or for use as an adjuvant for treating human lung large cell carcinoma.

This study aimed to identify the clinical characteristics of culture-positive pulmonary tuberculosis (TB) patients from a southern Taiwan hospital-based survey between August 1, 2003 and July 31, 2006. Demographics, symptoms, susceptibility patterns, sputum acid-fast bacilli (AFB) stain status and treatment outcomes were recorded. The medical records of 154 patients who presented to the Kaohsiung Municipal Hsiao-Kang Hospital were analyzed retrospectively. The mean age of patients was 59.5 years; 115 patients were male and 39 were female. Diabetes mellitus (48/154; 31.2%) was the most frequent risk factor for pulmonary TB infection. Nearly all patients (139/154; 90.3%) had a cough. Fever was only seen in 27.9% and hemoptysis in 14.9% of patients. The combined resistance rates of Mycobacterium tuberculosis to the tested first-line agents were as follows: isoniazid, 3.2%; rifampin, 7.8%; ethambutol, 5.8%; and streptomycin, 2.6%. The combined resistance rate to any one of four first-line drugs was 12.3%. The combined resistance rate to ofloxacin was 3.9%. The combined resistance rate of multidrug resistant-TB was 1.9%. Sputum AFB stains were positive in 68.2% of cases. Analysis of treatment outcomes showed overall treatment success at 76.6%. The proportions of patients who died, defaulted treatment or in whom treatment failed were 16.2%, 3.9% and 0.0%, respectively. In conclusion, our study showed: (1) a higher frequency of pulmonary TB in male subjects than in other areas of Taiwan; (2) a higher frequency of cough and lower frequency of fever and hemoptysis than previous studies; (3) that the combined resistance rates to isoniazid and streptomycin were lower than both average levels in Taiwan and the global combined drug resistance rate; and (4) a higher proportion of patients responding to treatment and lower proportions of patients suffering mortality, defaulting treatment or not responding to treatment compared with other areas of Taiwan. With regard to resistance rates, the combined resistance rate to ethambutol was similar to the average level in Taiwan and higher than the global combined drug resistance rate. However, the combined resistance rate to rifampin was higher than both the average level in Taiwan and the global combined drug resistance rate. The combined resistance rates to at least any one of four first-line drugs and multidrug resistant-TB were lower than the average levels in Taiwan and higher than the global combined drug resistance rate. Our results may help to identify local variations in the disease and improve the effectiveness of TB infection control programs.

Clinicians need to decide whether to begin isolation and empiric therapy for patients suspected of having infectious tuberculosis (TB). This study aimed to identify the demographic, clinical and radiographic characteristics of acid-fast bacilli (AFB) smear-positive patients and to create a smear-positive TB prediction rule, which clinicians may use to predict risk. Methods: This was a retrospective study involving 105 patients with AFB smear-positive TB and 52 patients with AFB smear-negative TB at Kaohsiung Municipal Hsiao-Kang Hospital in southern Taiwan from August 1, 2003 to July 31, 2006. All of the patients had at least one sputum culture that was positive for Mycobacterium tuberculosis. Demographic, clinical and radiographic data of patients with AFB smear-positive TB were compared to those of patients with AFB smear-negative TB. Results: On univariate analysis, young age (p = 0.033), alcoholism (p = 0.036), weight loss (p = 0.003), fever (p = 0.018), consolidation (p = 0.001), infiltration (p = 0.012), cavitary pattern (p = 0.005), right upper lung field (p < 0.001) and left upper lung field (p = 0.001) lesions on chest radiographs were found to be predictive of smear-positive TB patients. In contrast, end-stage renal disease (p = 0.035) and normal chest radiograph (p = 0.006) were predictive of smear-negative TB patients. On multivariate analysis, age less than 65 years (p = 0.004), fever (p = 0.004), right upper lung field (p = 0.044), left upper lung field (p = 0.041), consolidation (p = 0.018) and cavitary (p = 0.049) lesions on chest radiograph were independently associated with an increased risk of an AFB positive smear finding. The smear-positive TB prediction model was created based on the results of the multivariate analysis that had an area of 0.788 under the receiver operating characteristic curve. Conclusion: The smear-positive TB prediction model may help clinicians decide if a patient with pending sputum smear results should first be placed in isolation and empiric anti-tuberculous therapy started.

Studies have shown that weekend or night admissions to intensive care units (ICUs) are associated with increased mortality in critically ill patients. Our study aimed to evaluate the effects of admission time and day on patient outcomes in a medical ICU equipped with patient management guidelines, and staffed by intensivists on call for 24 hours, who led the morning rounds on all days of the week but did not stay in-house overnight. The study enrolled 611 consecutive patients admitted to a 26-bed medical ICU in a university hospital during a 7-month period. We divided them into two groups, which we labeled as “office hours” (08:00–18:00 on weekdays) and “non-office hours” (18:00–08:00 on weekdays, and all times on weekends) according to their ICU admission times. The clinical outcomes were compared between the groups. The effects of admission on weekends, at night, and various days of the week on hospital mortality were also evaluated. Our results showed that there were no significant differences in ICU and hospital mortalities between patients admitted during office hours and those admitted during non-office hours (27.2% vs. 27.4%, p = 1.000; 38.9% vs. 37.6%, p = 0.798). The ICU length of stay, ICU-free time within 21 days, and length of stay in the hospital were also comparable in both groups. Among the 392 patients requiring mechanical ventilation, the ventilator outcomes were not significantly different between those in the office-hour group and the non-office-hour group. Multivariate logistic regression analyses showed that the adjusted odds of hospital mortality were not significantly higher for patients admitted to our ICU on weekends, at night, or on any days of the week. In conclusion, our results showed that non-office-hour admissions to our medical ICU were not associated with poorer ICU, hospital, and ventilator outcomes, compared with office-hour admissions. Neither were time of day and day of the week admissions to our ICU associated with significant differences in hospital mortality.

Increased incidence of erectile dysfunction (ED) has been reported among patients with sleep apnea (SA). However, this association has not been confirmed in a large-scale study. We therefore performed a population-based cohort study using Taiwan National Health Insurance (NHI) database to investigate the association of SA and ED. From the database of one million representative subjects randomly sampled from individuals enrolled in the NHI system in 2010, we identified adult patients having SA and excluded those having a diagnosis of ED prior to SA. From these suspected SA patients, those having SA diagnosis after polysomnography were defined as probable SA patients. The dates of their first SA diagnosis were defined as their index dates. Each SA patient was matched to 30 randomly-selected, age-matched control subjects without any SA diagnosis. The control subjects were assigned index dates as their corresponding SA patients, and were ensured having no ED diagnosis prior to their index dates. Totally, 4,835 male patients with suspected SA (including 1,946 probable SA patients) were matched to 145,050 control subjects (including 58,380 subjects matched to probable SA patients). The incidence rate of ED was significantly higher in probable SA patients as compared with the corresponding control subjects (5.7 vs. 2.3 per 1000 patient-year; adjusted incidence rate ratio = 2.0 [95% CI: 1.8-2.2], p

In lung cancer, uPA, its receptor (uPAR), and the inhibitors PAI-1 and PAI-2 of the plasminogen activator family interact with MMP-2 and MMP-9 of the MMP family to promote cancer progression. However, it remains undetermined which of these markers plays the most important role and may be the most useful indicator to stratify the patients by risk.We determined the individual prognostic value of these 6 markers by analyzing a derivation cohort with 98 non-small cell lung cancer patients by immunohistochemical staining. The correlation between the IHC expression levels of these markers and disease prognosis was investigated, and an immunohistochemical panel for prognostic prediction was subsequently generated through prognostic model analysis. The value of the immunohistochemical panel was then verified by a validation cohort with 91 lung cancer patients.In derivation cohort, PAI-2 is the most powerful prognostic factor (HR = 2.30; P = 0.001), followed by MMP-9 (HR = 2.09; P = 0.019) according to multivariate analysis. When combining PAI-2 and MMP-9, the most unfavorable prognostic group (low PAI-2 and high MMP-9 IHC expression levels) showed a 6.40-fold increased risk of a poor prognosis compared to the most favorable prognostic group (high PAI-2 and low MMP-9 IHC expression levels). PAI-2 and MMP-9 IHC panel could more precisely identify high risk patients in both derivation and validation cohort.We revealed PAI-2 as the most powerful prognostic marker among PA and MMP protease family even after considering their close relationships with each other. By utilizing a combination of PAI-2 and MMP-9, more precise prognostic information than merely using pathological stage alone can be obtained for lung cancer patients.

Since its introduction in 1985 by Ciaglia et al, percutaneous dilational tracheostomy (PDT) has gradually become the procedure of choice in establishing a long-term airway in many intensive care units (ICU). However, the safety of performing PDT in patients with barotrauma is still unknown and has never been reported. We present the case of a 35-year-old man with AIDS, who was admitted to our medical ICU for pneumonia and acute respiratory distress syndrome. He developed subcutaneous emphysema and pneumomediastinum as complications of mechanical ventilation. After stabilization of the barotrauma, he underwent PDT with the standard Ciaglia Blue Rhino technique. However, rapid and extensive progression of preexisting barotrauma occurred shortly after PDT. This severe complication was nearly fatal. The prolonged procedure during which the susceptible lung was exposed to longer duration of high airway pressure was thought to be the mechanism of rapid deterioration of the preexisting barotrauma. With aggressive supportive care, the patient survived. To prevent further deterioration of preexisting barotrauma during and after PDT in future cases, we propose some principles that should be strictly followed. Under administration of these principles, we safely performed PDT in another case with preexisting barotrauma 1 month later.

Infective endocarditis has been the major cause of morbidity and mortality among intravenous drug users (IDUs) with infections, mostly involving the tricuspid valve and presenting multiple septic pulmonary embolisms. Numerous pulmonary complications of septic pulmonary embolism have been described, but only a few have reported spontaneous pneumothorax. Our patient, a 23-year-old heroin addict, was hospitalized for tricuspid endocarditis and septic pulmonary embolism. Acute onset of respiratory distress occurred on his seventh hospital day and rapidly resulted in hypoxemia. Immediate bedside chest radiograph demonstrated left pneumothorax. It was thought to be a spontaneous pneumothorax, because he had not undergone any invasive procedure before the occurrence of pneumothorax. His clinical condition improved after the insertion of an intercostal chest tube. He later underwent surgery to replace the tricuspid valve as a result of the large size of the vegetation and poor control of infection. He ultimately survived. Pneumothorax is a possible lethal complication of septic pulmonary embolism in IDUs with right-sided endocarditis and should be considered in such patients when respiratory distress occurs acutely during their hospitalization.

To compare the efficacy and safety of tiotropium and ipratropium in patients with chronic obstructive pulmonary disease (COPD) in Taiwan. Methods: This double-blind, randomized, placebo-controlled, parallel group study was conducted at six hospitals in Taiwan. COPD patients aged ≥ 40 years, with a forced expiratory volume in 1 second (FEV1) ≤65% of predicted and FEV1/forced vital capacity (FVC) ≤ 70% were enrolled. After a 2-week screening/baseline period, 132 patients were randomized to receive 4 weeks of treatment with either tiotropium 18 μg once daily from a dry powder inhaler (HandiHaler(r)) or two puffs of ipratropium 20 μg four times daily from a metered dose inhaler. The primary outcome was the change in trough FEV1 from baseline to week 4. The secondary outcome measures were trough FVC response, FEV1 and FVC responses at 2 hours postinhalation. Results: After 4 weeks, trough FEV1 had increased by 61.7 + 25.3 mL for tiotropium but decreased by 16.4 + 27.9 mL for ipratropium. The difference between groups was significant (p

Germ cell tumors occur mostly in the gonad. Extragonadal germ cell tumors are rare, and most occur in the retroperitoneum and mediastinum. Primary mediastinal germ cell tumors are often found in the anterior portion of the mediastinum and include teratomas and non-teratomatous tumors. Non-teratomatous tumors include seminomas and malignant non-seminomatous germ cell tumors (MNSGCTs). MNSGCTs include yolk sac tumors, choriocarcinomas, embryonal carcinomas, and mixed type germ cell tumors. Teratomas are the most common germ cell tumors of the mediastinum, and seminomas are the most common non-teratomatous germ cell tumors of the mediastinum. Cases of primary mediastinal MNSGCT reported in the literature are rare. In this report, we review all primary mediastinal germ cell tumors from a 10-year period at the Chung-Ho Memorial Hospital of Kaohsiung Medical University. A total of 14 cases were reviewed, including 11 patients with mature teratomas, two with yolk sac tumors, and one with seminoma. We discuss the differences in clinical presentation, histopathologic characteristics, treatment, and prognosis.

Malignant fibrous histiocytoma (MFH) is the most common soft tissue sarcoma in adults. However, primary MFH of the lung is rare, with only a few cases reported in the literature. Here, we report the case of an 86-year-old male who was admitted to our hospital with the chief complaint of exertional dyspnea and poor appetite. Chest roentgenography revealed a 9 × 15 cm, pleural-based opacity in the left lower lobe. Chest computerized tomography disclosed a well-defined mass with heterogeneous density in the left lower lung field. The diagnosis of MFH was confirmed by thoracoscopic lung biopsy and pathologic examination. Supportive care was given because of extreme old age and poor performance status (the patient's Karnofsky performance status was 30). The patient died from respiratory failure 2 months later.

Strongyloidiasis is endemic in tropic and subtropic areas, but is currently seldom encountered in developed area like Taiwan. We present an elder man with acute respiratory distress syndrome complicating Strongyloides stercoralis hyperinfection. There was no significant clue initially for diagnosing this patient as having S. stercoralis hyperinfection. Neither peripheral eosinophilia nor significant hemoptysis was noted. Bronchoscopy played a critical role to define the unexpected cause of his progressive pulmonary infiltrates. The correct diagnosis was soon made by recognition of the worm in bronchioloalveolar lavage cytology, and specific treatment was initiated promptly. For a septic patient with progressive pulmonary infiltrates, bronchoscopic studies including cytology may be necessary for defining the cause. Hyperinfection strongyloidiasis should be considered as a cause of acute respiratory distress syndrome in immunocompromised patient, especially with the presence of chronic gastrointestinal symptoms.

BackgroundBetel nut is commonly used in many countries. Despite evidence suggesting an association with asthma, few studies have investigated the connection between betel nut use and asthma; thus, the underlying mechanism for the association with asthma is also unclear. The aim of this study was to investigate the association between betel chewing and asthma as well as the associations of plasma arecoline (a biomarker for exposure) and eotaxin-1 (a potential mediator) with asthma and lung function.MethodsWe recruited 600 hospital-based asthmatic patients and 1200 age- and gender-matched community controls in southern Taiwan. To clarify the mechanism of action for eotaxin-1 in the association between betel chewing and asthma, we also designed an in vitro experiment to study the functional associations between arecoline exposure and eotaxin-1 levels.ResultsA significant association was found between asthma and current betel chewing (adjusted odds ratio 2.05, 95% CI = 1.12-3.76), which was independent of potential confounders but was attenuated following adjustment for eotaxin-1. Arecoline and eotaxin-1 levels were positively correlated (Spearman r = 0.303, p = 0.02), while arecoline and arecaidine were negatively correlated with lung function. Functionally, arecoline alone does not induce eotaxin-1 release in vitro from dermal and gingival fibroblasts. However, in the presence of IL-4 and TNF-alpha, arecoline at 100 μg/ml induced more eotaxin-1 release than arecoline at 0 μg/ml (2700±98 pg/ml vs 1850±142 pg/ml, p = 0.01 in dermal fibroblast cells, and 1489±78 pg/ml vs 1044±95 pg/ml, p = 0.03 in gingival fibroblast cells, respectively).ConclusionBetel chewing is associated with asthma in this population, with arecoline induction of eotaxin-1 supported as a plausible causal pathway.

IntroductionMethods used for epidermal growth factor receptor (EGFR) mutation testing vary widely. The impact of detection methods on the rates of response to EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-wild type (wt) lung adenocarcinoma patients is unknown.MethodsWe recruited the Group-I patients to evaluate the efficacy of erlotinib in patients with EGFR-wt lung adenocarcinoma by either direct sequencing (DS) or mutant type-specific sensitive (MtS) methods in six medical centers in Taiwan. Cross recheck of EGFR mutations was performed in patients who achieved objective response to erlotinib and had adequate specimens. The independent Group-II lung adenocarcinoma patients whose EGFR mutation status determined by DS were recruited to evaluate the potential limitations of three MtS methods.ResultsIn Group-I analysis, 38 of 261 EGFR-wt patients (14.6%) achieved partial response to erlotinib treatment. Nineteen patients (50.0%) had adequate specimens for cross recheck of EGFR mutations and 10 of them (52.6%) had changes in EGFR mutation status, 5 in 10 by DS and 5 in 9 by MtS methods originally. In Group-II analysis, 598 of 996 lung adenocarcinoma patients (60.0%) had detectable EGFR mutations. The accuracy rates of the three MtS methods, MALDI-TOF MS, Scorpions ARMS and Cobas, were 87.8%, 86.8% and 85.8%, respectively.ConclusionsA significant portion of the erlotinib responses in EGFR-wt lung adenocarcinoma patients were related to the limitations of detection methods, not only DS but also MtS methods with similar percentages. Prospective studies are needed to define the proper strategy for EGFR mutation testing.

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10(-7) or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30 x 10(-11)). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38 x 10(-11)). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60 x 10(-20), allelic risk = 1.54, 95% Confidence Interval (CI) 1.41-1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40-1.87), and 2.35 (95% CI: 1.95-2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.