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Different approaches to endoscopic thyroidectomy utilize incisions that result in inevitable physical trauma to patients since postoperative tissue fibrosis and scars will influence their quality of life for a lifetime. Over the past few years, most studies have discussed the safety concerns of different kinds of endoscopic thyroidectomy; conversely, there has been less discussion on postoperative quality of life. Because most patients undergoing thyroidectomy for cancer or benign diseases are likely to have long-term survival, it is essential to study the cosmetic outcome of patients' scars from minimally invasive video-assisted thyroidectomy (MIVAT) and bilateral axillo-breast approach (BABA) robotic thyroidectomy on quality of life. From July 2015 to December 2017, 95 patients-60 who underwent MIVAT and 35 who underwent BABA robotic thyroidectomy-were retrospectively studied. Patient demographics, operative indications, pathologic findings, pain scores after surgery, complications, perception of scars, and overall satisfaction were compared between the two groups. The cosmetic outcome and overall satisfaction were evaluated at least 2 years after the operation using the patient scar assessment questionnaire and the 36-item short form health survey (SF-36). There was no statistically significant difference in scar perception between the two groups. However, in the SF-36, the MIVAT group had better satisfaction than the BABA robotic group regarding general health, vitality, mental health, and health change. MIVAT and BABA robotic thyroidectomy can be safely performed in selected patients, and patients who underwent MIVAT had better postoperative qualities of life than those who underwent the BABA robotic approach.

Synthetic bone graft has gained considerable attention because of an increase in the aged population. In the present study, a biphasic bone graft composed of hydroxyapatite (HAp) and calcium sulfate (CS) is prepared using a gel-foaming technique. The gel is prepared at a temperature as low as 35 °C; many pores are introduced into the gel through an agitation process. The foamed gel can be cut into any shape and size. After sintering, the porosity of the biphasic bone graft is approximately 70%. Depending on the HAp/CS ratio, the amount of macropores and micropores can be tailored. The macropores of approximately 130 μm diameter are interconnected with each other through openings of 40 μm size. The biphasic bone graft exhibits no cytotoxicity; preosteoblast cells can adhere and proliferate on the surface of the fabricated bone graft. However, migration of these cells into the bone graft is considerably limited in the in vitro study. When the biphasic bone graft is implanted into the distal femur of rats, with the combined effect of osteoblast and osteoclast cells, more than 90% of the bone graft is degraded after 3 months. New trabeculae bone and bone marrow are observed within the bone defect. The HAp/CS composite can thus be used as degradable bone grafts.

Background The human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene encodes a DNA glycosylase that removes 8-hydroxy-2-deoxyguanine (8-OH-dG) DNA damage to protect against gene mutations. The association of hOGG1 Ser326Cys polymorphism with lung cancer risk has predicted that hOGG1-Cys variants are less effective at removing 8-OH-dG damage from DNA; therefore, these variants might show an increased occurrence of tumor suppressor gene and oncogene mutations. However, no evidence has yet supported this hypothesis. Methods Direct sequencing was performed to examine the mutations of p53 and EGFR genes in lung tumors from patients with non-small cell lung cancer (NSCLC). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to examine hOGG1 Ser326Cys polymorphism in this study population. Results A total of 99 p53-mutated and 99 EGFR-mutated patients with NSCLC were selected to explore the possible associations of these mutations with hOGG1 Ser326Cys polymorphism. The p53-mutated and EGFR-mutated patients were divided into nondeletion and deletion subgroups. P53 deletion mutations were more commonly observed in male than in female patients (P = 0.030). However, EGFR exon 19 deletion mutations were more prevalent in female and adenocarcinoma patients than in male and squamous cell carcinoma patients (P = 0.028 for genders, P = 0.017 for tumor histology). Interestingly, p53 and EGFR exon 19 deletion mutations were more frequent in patients with hOGG1 Ser/Cys + Cys/Cys hOGG1-Cys variants than with the hOGG1 Ser/Ser genotype (P = 0.010 for p53, P = 0.032 for EGFR). Conclusions We suggest that the association of hOGG1 Ser326Cys polymorphism with lung cancer risk could be partially explained by increases in p53 and EGFR deletion mutations. Key points SIGNIFICANT FINDINGS OF THE STUDY: NSCLC patients with hOGG1-Cys variants may have a higher risk of p53 and EGFR deletion mutations than with hOGG1 Ser/Ser genotype. What this study adds NSCLC patients with hOGG1-Cys variants might be helpful to predict patients having higher risk of EGFR exon 19 deletion mutations and these patients who were treated with gefitinib or erlotinib could be a higher risk to occur EGFR T790M mutation.

Background Several studies have previously indicated that nuclear factor erythroid 2‐related factor 2 (Nrf2) expression may promote tumor progression when the Keap1/Nrf2 pathway is activated, but few reports have demonstrated the role of cytoplasmic Nrf2 on tumorigenesis. Methods Immunohistochemistry was conducted to evaluate Nrf2 expression in 167 tumors from surgically‐resected patients with non‐small cell lung cancer (NSCLC). Univariate and multivariate analyses were performed to examine the association of Nrf2 expression with patients' prognosis. This study was conducted to examine the association of Nrf2 expression with tumor response to cisplatin‐based chemotherapy. Results Among these tumors, 56 and 32 of 167 tumors expressed Nrf2 in the cytoplasm (34% for C+/N‐) and in the cytoplasm/nucleus (19% for C+/N+), but not in the nucleus of tumor cells. Nrf2 was negatively expressed in the remainder of the tumor samples (C‐/N‐, 79 of 167, 47%). Univariate analysis indicated that patients with Nrf2 positive tumors (C+/N‐ plus C+/N+) had worse overall survival (OS), but not relapse‐free survival (RFS) than with Nrf2 negative tumors (C‐/N‐). However, patients with C+/N‐ tumors possessed worse OS and RFS than those with Nrf2 negative tumors (C‐/N‐). Multivariate analysis further confirmed the prognostic significance of patients with Nrf2 positive and C+/N‐ tumors on OS and RFS, but not on RFS for patients with Nrf2 positive tumors. Patients with Nrf2 positive and C+/N‐ tumors were determined to more frequently have an unfavorable response to cisplatin‐based chemotherapy than those with Nrf2 negative tumors. Conclusions Cytoplasmic Nrf2 expression might potentially be used to predict poor prognosis and unfavorable response to cisplatin‐based chemotherapy in patients with NSCLC. Key points The expression of cytoplasmic Nrf2 showed a significant relationship with patients' response to cisplatin‐based chemotherapy and influenced NSCLC prognosis. A proteasomal inhibitor such as carfilzomib might be used to improve the outcomes and therapeutic response to cisplatin‐based chemotherapy in patients with tumors showing cytoplasmic Nrf2 expression.

Objective To compare the effects of computerized cognitive training (CCT) and tai chi (TC) with usual care (UC) on cognitive functions and secondary outcomes in older adults with traumatic brain injury. Participants and settings Ninety-six patients aged 55 years and older who had a diagnosis of traumatic brain injury requiring hospital admission. Design Randomized controlled trial. Main measures The Mattis Dementia Rating Scale (MDRS), Mini-Mental State Examination, modified Telephone Interview of Cognitive Status, and Trail Making Tests A and B. Results Compared with UC, CCT increased scores on the MDRS's total, attention, and memory and those on the Mini-Mental State Examination and Telephone Interview of Cognitive Status over the 6-month intervention; TC increased scores on the MDRS's total and conceptualization and those on the Mini-Mental State Examination over the 6-month intervention, while it also increased scores on the MDRS's total and initiation/preservation and those on the Telephone Interview of Cognitive Status and reduced the time to complete the Trail Making Test B over the 12-month study. Furthermore, compared with UC, CCT increased handgrip strength and TC reduced the time to complete 5 sit-to-stands over the 6-month intervention. Conclusion Both CCT and TC may improve global cognition and different specific cognitive domains in older traumatic brain injury patients; the TC's effect may last for at least an additional 6 months.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

The nasopharyngeal tract traps mainly coarse particles in inhaled air. Soluble carcinogenic compounds, endotoxins, and trace metals contained in these particles are potential causes of inflammation and oxidative stress which could enhance carcinogenesis. The aim of this study was to determine the association between coarse particulate matter (PM10-2.5) and nasopharyngeal cancer (NPC). A total of 521,098 men (355 cases and 520,743 non-cases), aged ≥40 years were included in this study. Data were retrieved from the Taiwan Cancer Registry, the Adult Preventive Medical Services Database, and the Air Quality Monitoring Database. PM10-2.5 was significantly associated with a higher risk of NPC after adjusting for SO2, NOx, O3, age, body mass index, smoking, alcohol drinking, betel nut chewing, exercise, hypertension, diabetes, and hyperlipidemia. With PM10-2.53 as the reference, the ORs and 95% CIs were 1.47; 1.03–2.11, 1.34; 0.94–1.91, and 1.68; 1.16–2.44 for 20.44≤PM10-2.510-2.510-2.5≥29.27 μg/m3, respectively. PM10-2.5 remained significantly associated with a higher risk of NPC after further adjustments were made for the aforementioned covariates and PM2.5. The ORs; 95% CIs were 1.42; 0.96 to 2.12, 1.41; 0.94 to 2.10, and 1.71; 1.10 to 2.66 for 20.44≤PM10-2.510-2.510-2.5≥29.27 μg/m3, respectively. In conclusion, PM10-2.5 was significantly associated with a higher risk of NPC in Taiwanese men.

Background: High disease burden suggests the desirability to identify high-risk Asian never-smoking females (NSF) who may benefit from low-dose CT (LDCT) screening. In North America, one is eligible for LDCT screening if one satisfies the U.S. Preventive Services Task Force (USPSTF) criteria or has model-estimated 6-year risk greater than 0.0151. According to two U.S. reports, only 36.6% female patients with lung cancer met the USPSTF criteria, while 38% of the ever-smokers ages 55 to 74 years met the USPSTF criteria. Methods: Using data on NSFs in the Taiwan Genetic Epidemiology Study of Lung Adenocarcinoma and the Taiwan Biobank before August 2016, we formed an age-matched case–control study consisting of 1,748 patients with lung cancer and 6,535 controls. Using these and an estimated age-specific lung cancer 6-year incidence rate among Taiwanese NSFs, we developed the Taiwanese NSF Lung Cancer Risk Models using genetic information and simplified questionnaire (TNSF-SQ). Performance evaluation was based on the newer independent datasets: Taiwan Lung Cancer Pharmacogenomics Study (LCPG) and Taiwan Biobank data after August 2016 (TWB2). Results: The AUC based on the NSFs ages 55 to 70 years in LCPG and TWB2 was 0.714 [95% confidence intervals (CI), 0.660–0.768]. For women in TWB2 ages 55 to 70 years, 3.94% (95% CI, 2.95–5.13) had risk higher than 0.0151. For women in LCPG ages 55 to 74 years, 27.03% (95% CI, 19.04–36.28) had risk higher than 0.0151. Conclusions: TNSF-SQ demonstrated good discriminative power. The ability to identify 27.03% of high-risk Asian NSFs ages 55 to 74 years deserves attention. Impact: TNSF-SQ seems potentially useful in selecting Asian NSFs for LDCT screening.

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.

Background: Although left-lobe donation is considered safer, right-sided donor hepatectomy predominates in adult living donor liver transplantation (LDLT). We hypothesized that bilateral proficiency with donor hepatectomy reduces overall donor complications. Methods: A retrospective review of 834 adult LDLT donors (221 left lobes) from January 2004 to December 2014 was performed, dividing cases into two eras based on left-graft experience. Donor complications within 6 months were investigated, focusing on graft side and surgical era. Results: The overall complication rate was 17.6%, and was higher in right-lobe donors. In Era 2, during which left-lobe donation rates were three times higher, total complications decreased (14.7% vs. 20.9%, P=0.02). A significant reduction in postoperative ascites accounted for the lower overall complication rate. The proportion of major biliary complications (BCs) was halved from 62.5% to 25.0%. Right-lobe donor complications also decreased significantly (15.8% vs. 22.9%, P=0.032), demonstrating that it was not only increased left-lobe donations leading to lowered complication rates, but also greater experience with donor hepatectomy in general. Conclusions: Accumulating experience with bilateral donor hepatectomy leads to decreased donor morbidity and comparable outcomes for right and left lobes, further enhancing the goal of donor safety while balancing recipient needs.

BACKGROUND Formation of intraperitoneal adhesions is one of the major complications after abdominal surgery, which may lead to bowel obstruction. Thrombospondin 1 (TSP-1) is an extracellular matrix modulating glycoprotein during tissue regeneration and collagen deposition. AIM To evaluated the therapeutic potential of overexpressed TSP-1 in suppressing pelvic adhesion formations in rat models. METHODS Pelvic adhesion was induced in anesthetized rats by laparotomy cecal abrasion. The animals were randomly assigned to treatment of local application with Seprafilm (an antiadhesive bioresorbable membrane) or adenoviral vectors encoding mouse TSP-1 (AdTSP-1) on the surfaces of the injured cecum. The severity of the peritoneal adhesions was evaluated by blinded observers 14 d later. RESULTS Compared with control (no treatment) group, the application of Sperafilm significantly reduced the formation of adhesion band, and local administration of AdTSP-1 on the injured cecum the also attenuated the severity of peritoneal adhesion score. However, systemic delivery of AdTSP-1 did not affect the formation of adhesion. CONCLUSION We conclude that therapeutic approaches in inducing regional overexpression of TSP-1 may serve as alternative treatment strategies for preventing postoperative peritoneal adhesion.

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.

Background The role of radiotherapy for cT4bNanyM0 esophageal squamous cell carcinoma (ESqCC) is relatively unclear, with both chemotherapy (C/T) alone and definitive concurrent chemoradiotherapy (dCCRT) being treatment options in the current guidelines. We aimed to compare the survival of dCCRT versus C/T for these patients via a population-based approach. Methods Eligible cT4b ESqCC patients diagnosed between 2011 and 2017 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance the observable potential confounders between groups. The hazard ratio (HR) of death and incidence of esophageal cancer mortality (IECM) were compared between dCCRT and C/T. We also evaluated OS in subgroups of either low or standard radiotherapy doses. Results Our primary analysis consisted of 247 patients in whom covariates were well balanced after PS weighing. The HR for death when dCCRT was compared with C/T was 0.36 (95% confidence interval 0.24–0.53, P Conclusions In this population-based nonrandomized study of cT4bNanyM0 ESqCC patients from Asia (Taiwan), we found that the use of radiotherapy with chemotherapy was associated with better overall survival than chemotherapy alone. Further studies (especially RCTs) are needed to confirm our findings.

Situational factors might help explain why most vertebral fractures occur in older people without a previous osteoporosis diagnosis. After adjusting for predisposing risk factors, the activity before the fall, type of fall, and falling direction remained as strong determinants of fall-related vertebral fractures in older men and women. A matched case-control study was conducted to investigate the effects of situational factors, in addition to predisposing factors, on clinical vertebral fractures in older men and women in Taiwan. Cases were community-dwelling individuals aged ≥ 65 years who visited emergency departments (EDs) of two university-affiliated hospitals due to a fall and had a primary diagnosis of a vertebral fracture during a 1-year period in 2017. Five control patients per case, matched by the time of falling, gender, and age, who sought care in the same ED due to a fall resulting in a soft tissue injury were selected. A total of 64 men (age range: 65 ~ 99 years) and 194 women (age range: 65 ~ 100 years), diagnosed with a vertebral fracture, participated in the study. Multivariable logistic models were conducted separately for men and women. Results suggested that the following factors were significantly associated with an increased risk of vertebral fractures in men: a low educational level (adjusted odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.02 ~ 3.71), asthma (OR = 2.96; 95% CI, 1.35 ~ 6.92), depression (OR = 4.31; 95% CI, 1.03 ~ 17.5), toileting (OR = 2.30; 95% CI, 1.04 ~ 4.94), slipping (OR = 5.27; 95% CI, 1.80 ~ 15.4), stepping down (OR = 3.99; 95% CI, 1.40 ~ 11.4), sudden leg weakness (OR = 3.73; 95% CI, 1.13 ~ 12.4), and falling backwards (OR = 3.78; 95% CI, 1.83 ~ 7.80); and in women: a fracture history (OR = 2.00; 95% CI, 1.07 ~ 3.76), osteoporosis (OR = 1.94; 95% CI, 1.15 ~ 3.49), getting in/out of the bed/chair (OR = 1.90; 95% CI, 1.07 ~ 3.39), stepping down (OR = 2.10; 95% CI, 1.17 ~ 3.77), and falling backwards (OR = 4.00; 95% CI, 2.39 ~ 6.68) and sideways (OR = 2.61; 95% CI, 1.38 ~ 4.96). The combination of predisposing and situational risk factors may display a more comprehensive risk profile for the occurrence of VFs, and thus, interventions that add both types of risk factors may result in greater risk reduction of VFs, although those specifically targeted at situational risk factors during falls are limited and their effectiveness and efficiency remained to be explored.

The emergence of the coronavirus disease 2019 (COVID-19) caused a large-scale outbreak and has rapidly spread across China and multiple countries. We reported countermeasures in infection control for diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection and the experiences of point of care diagnostics and medical quarantine for presumed SARS-CoV-2-infected subjects. We conducted a retrospective cohort study on subjects came to Chung Shan Medical University Hospital with suspicion of SARS-CoV-2 infection during January to March, 2020. We performed the real-time reverse-transcription polymerase chain reaction testing (rRT-PCR) for SARS-CoV-2-infection and reported the results of testing and treatment. A total of 212 participants were enrolled due to suspicion of SARS-CoV-2 infection. Five of those were confirmed COVID-19 cases after monitoring for a period of 14 days and were cured. The time to rRT-PCR test conversion after treatment is variate. The infection control measures of home quarantine and mandatory medical quarantine combined with rapid diagnosis seem to postpone the speed of transmission of SARS-CoV-2 infection at once in Taiwan. Due to lack of vaccination and confirmed antiviral therapy, it is important to strictly abide by the infection control measures.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93&ndash, 28.32, p &lt, 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.

ObjectivesTo determine the influences of age and gender on the taste functions of healthy Taiwanese.MethodsWe evaluated taste functions of healthy Taiwanese using the whole mouth suprathreshold taste test, along with the taste quad test. In the whole-mouth test, we applied in a counterbalanced order sweet, sour, salty, and bitter solutions, each at 5 different suprathreshold concentrations to subjects, who were instructed to sip and swish in mouth twice. Each subject had to indicate the taste quality, and to rate the intensity and unpleasantness/pleasantness of each taste of the solutions. In the quad test, the 4 quadrants of the tongue surface were tested by dripping one concentration of sweet, sour, salty, or bitter solutions for 6 times. Subjects then indicated the taste quality, and rated the intensity of the solution.ResultsSubjects were divided into groups based on their gender and age: 20-39 years, 40-59 years, or ≥ 60 years. We found that in the whole mouth taste test, the total correct identification score dropped with age. But identifying sweet and salty qualities was not affected by age. No differences were found between male and female, except women scored better than men for sweet quality in the age group of 40-59 years. The total correct identification score of the taste quad test also decreased with an increased age of the taste quad test, without gender differences.ConclusionBoth age and gender affected the taste functions in healthy Taiwanese to some extent, and differences were dependent on age, tongue region, and taste quality.

The purpose of this study was to determine the influence of age and sex on the taste functions of healthy Taiwanese. Subjects were divided into groups based on their sex and age: 20-39 years, 40-59 years, or ≥ 60 years. We evaluated the taste functions of subjects using the whole mouth suprathreshold taste test and the taste quad test. For the whole-mouth test, subjects were instructed to sip and swish sweet, sour, salty, and bitter solutions, each at 5 different suprathreshold concentrations. Each subject was required to indicate the taste quality, and to rate the intensity and unpleasantness/pleasantness of each taste of the solutions. For the quad test, the 4 quadrants of the tongue surface were tested by applying a drop of one concentration of sweet, sour, salty, or bitter solutions 6 times. Subjects then indicated the taste quality and rated the intensity of the solution. We found that in the whole mouth test, the total correct identification score dropped with age, but the ability to identify sweet and salty qualities was not affected by age. No differences were found between males and females, except women scored better than men for sweetness in the 40-59 years age group. The intensity rating scores were higher in the 20-39 years age group, regardless of sex. With regard to the pleasantness of tastants, female subjects in the 20-39 years age group found sweet solution more pleasant than the older subjects did. In the quad test, the total correct identification score decreased with age, but there were no differences between males and females. Thus, our findings showed that both age and sex affected the taste functions of healthy Taiwanese to some extent, and differences were dependent on tongue region and taste quality.

Background The optimal treatment for locally advanced esophageal squamous cell carcinoma remains unclear. We compared the clinical outcomes of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by esophagectomy [the surgery group] and CCRT without surgery [the CCRT group] in patients with squamous cell carcinoma from an Asian population. Methods Eligible patients diagnosed from 2008 to 2015 were identified through the Taiwan Cancer Registry. To balance observable potential confounders, we constructed a 1:1 propensity score-matched cohort [surgery vs CCRT]. We compared the hazard ratios between the surgery and CCRT groups for death using a robust variance estimator. We also evaluated the outcomes of patients for freedom from local regional recurrence (FFLRR) and esophageal cancer-specific survival (ECSS). Extensive supplementary analyses were performed to examine the robustness of our findings. Results Our study population included 298 patients balanced with respect to the observed covariables. The hazard ratio of death was 0.56 [95% confidence interval 0.42~0.75] when surgery was compared to CCRT. The results remained significant in the FFLRR and ECSS outcomes. In the supplementary analyses, our results also remained significant when additional covariables were taken into consideration or when the definition of the index date was changed. Conclusions When compared to definitive CCRT, neoadjuvant CCRT followed by esophagectomy was associated with improved overall survival for locally advanced esophageal squamous cell carcinoma. However, given the nonrandomized nature of the study and the sensitivity to potentially unmeasured confounders, our results should be interpreted cautiously.

Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells. Mechanistically, dioscin may down-regulate the expression of SH2 domain-containing phosphatase-2 (SHP2) at the transcription level by increasing p53 binding to the SHP2 promoter due to reactive oxygen species (ROS). Simultaneous inhibition of MEK/ERK and PI3K/AKT activation via decreased SHP2 expression and its interaction with GAB1 may be responsible for dioscin-mediated TKI sensitivity. A higher unfavorable response to TKI therapy occurred more commonly in patients with high SHP2 mRNA expression than in patients with low SHP2 mRNA expression. Therefore, we suggest that dioscin may act as a dual inhibitor of the MEK/ERK and PI3K/AKT signaling pathways to overcome TKI resistance via dysregulation of SHP2 expression in lung adenocarcinoma.

Purpose: MicroRNA-630 plays dual roles in apoptosis and drug resistance in human cancers. However, the role of miR-630 in resistance to tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma remains to be elucidated. Methods: Manipulation of miR-630 and its targeted gene YAP1 and/or combination of inhibitor treatments was performed to explore whether low miR-630 could confer TKI resistance due to de-targeting YAP1, and this could decrease proapoptotic protein Bad expression through the miR-630/YAP1/ERK feedback loop. A retrospective study was conducted to examine whether the expression of miR-630 and YAP1 could be associated with TKI therapeutic response in patients with lung adenocarcinoma. Results: Low miR-630 expression may confer TKI resistance via increased SP1 binding to the miR-630 promoter due to ERK activation by YAP1 de-targeting. Persistent activation of ERK signaling via the miR-630/YAP1/ERK feedback loop may be responsible for TKI resistance in EGFR-mutated cells. Moreover, a decrease in Bad expression by its phosphorylation at Serine 75 through ERK activation conferred low miR-630-mediated TKI resistance by modulating the apoptotic pathway. Xenographic tumors induced by miR-630-knockdown PC9 and PC9GR cells in nude mice were nearly suppressed by the combination of gefitinib with the YAP1 inhibitor verteporfin or an MEK/ERK inhibitor AZD6244. Patients with low miR-630 and high YAP1 expressing tumors had a higher prevalence of unfavorable responses to TKI therapy and poorer outcomes when compared with their counterparts. Conclusion: MiR-630 may be a potential biomarker for the prediction of TKI therapeutic response and outcome in patients with lung adenocarcinoma.

Purpose In the current targeted therapy era, information on the effect of smoking in epidermal growth factor receptor (EGFR)-mutant lung cancer patients is scarce. Results In total, 11,678 adenocarcinoma patients were enrolled. Of these, 33.3% and 91.8% of male and female patients were non-smokers, respectively. An increased amount of smoking (P < 0.001 for trend), fewer smoke-free years (P < 0.001 for trend), and younger age of smoking initiation (P = 0.034 for trend) were all associated with significantly lower EGFR mutation rates. Smokers had a shorter median overall survival (OS) among both EGFR-mutant and EGFR-wild type patients (17.8 vs. 21.1 months, and 7.9 vs. 11.4 months respectively; both P < 0.001). Among patients with EGFR-mutant adenocarcinoma, younger smokers were associated with shorter OS (P = 0.047). In multivariate analysis, female gender was an independent prognostic factor for OS (hazard ratio: 0.86 [95% confidence interval {CI}: 0.80-0.93]; P < 0.001 in the EGFR-mutant group and 0.88 [95% CI: 0.81-0.96]; P = 0.004 in the EGFR-wild type group). Materials and Methods We reviewed the National Lung Cancer database (Taiwan) to assess the impact of smoking on the EGFR mutation rate and survival in advanced lung adenocarcinoma patients during 2011 and 2014 retrospectively. Conclusions Smoking was associated with lower incidence of EGFR mutation rate and reduced OS of advanced lung adenocarcinoma patients in a dose-dependent manner. In addition to EGFR mutation and smoking, gender also plays an important role in survival among these patients.

The utility of induction therapy (IT) in patients with resectable esophageal cancer remains controversial, especially when clinical evidence of nodal metastases is lacking. We sought to compare the survival impact of IT versus upfront surgery (US) in patients with cT3N0 esophageal cancer. We searched the Taiwan Cancer Registry for patients with cT3N0 esophageal cancer who underwent US or IT between 2008 and 2013. Multivariate Cox regression analysis was used to analyze the potential benefits of IT in terms of overall survival (OS) and disease-free survival (DFS). Of the 11752 patients with esophageal cancer included in the nationwide database, 762 (6.5%) had cT3N0 disease. Most cases (720 [94.5%]) had a histological diagnosis of squamous cell carcinoma. Of them, 135 received IT (the IT group) and 237 received surgery first (the US group). In the US group, pretreatment clinical staging was accurate in 47.9% of patients. Twenty-one (8.97%) were clinically overstaged (pT1-2N0), whereas 101 (43.17%) were clinically understaged (pT4N0 or pTanyN1-3). The presence of unexpected nodal metastases was identified in 92.1% of clinically understaged patients. In the IT group, 28 (20.74%) patients did not proceed to surgery after IT. The use of IT was associated with higher R0 resection rates and fewer pathological nodal metastases, despite unexpected M1 disease being more common (all P

PD‐1/PD‐L1 immunotherapy is viewed as having clinical benefits in advanced cancers but is effective in only a few patients, suggesting that an efficient combination approach is needed to improve efficacy. Immunohistochemistry analysis indicated that PD‐L1 expression was correlated with the E6 expression in tumors from 122 lung cancer patients. The poorest survival occurred in PD‐L1‐positive/E6‐positive tumor. PD‐L1 expression was increased by the expression of E6, but not the E7, oncoprotein in lung and cervical cancer cells. PD‐L1 expression was responsible for E6‐mediated colony formation and soft agar growth. Therefore, PD‐L1 secreted from tumor cells may directly promote tumor progression, particularly in E6‐positive tumors. Immune deficiency nude mice were used to test the possibility that combining anti‐PD‐L1 mAb with Lm‐LLO‐E6 vaccine could have a higher antitumor activity compared with anti‐PD‐L1 mAb or Lm‐LLO‐E6 vaccine alone. A greater antitumor activity was obtained with anti‐PD‐L1 mAb + Lm‐LLO‐E6 vaccine than with anti‐PD‐L1 mAb or Lm‐LLO‐E6 alone in subcutaneous and metastatic tumors induced by TL‐1 and SiHa cells. The longest survival time for nude mice was observed in the anti‐PD‐L1 mAb + Lm‐LLO‐E6 vaccine group. In conclusion, an anti‐PD‐L1 mAb + Lm‐LLO‐E6 vaccine may be an efficient treatment for suppression of tumor growth and metastasis induced by HPV‐infected cells.

This study aims to investigate the effects of treatments on the quality of life for patients with esophageal squamous cell carcinoma patients diagnosed at early and late stages. From a medical center in central Taiwan, patients who had been diagnosed with esophageal squamous cell carcinoma from February 2007 and March 2011 were recruited. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Oesophageal 18 (QLQ-OES18), quality of life scores for 105 esophageal squamous cell carcinoma patients were obtained and assessed. Multivariate analysis was performed on the quality of life scores after stratification by cancer stage. Among early-stage esophageal squamous cell carcinoma patients, those received only surgery (S-only) performed better in physical and social functioning compared with patients who underwent surgery and concurrent chemoradiotherapy (S+CCRT) (β = 9.0, P = 0.03; β = 12.1, P = 0.04, respectively). For those that received only concurrent chemoradiotherapy (CCRT-only), they performed worse in role and emotional functioning relative to S+CCRT patients (β = -17.2, P = 0.02; β = -15.7, P = 0.05, respectively). Among late-stage patients, CCRT-only treatment gave insignificantly better global health status and functional scale scores and less severe symptoms compared to the S+CCRT option. Better functional scores and less aggravated symptoms are observed in early-stage esophageal squamous cell carcinoma patients who received surgery-only treatment relative to those that underwent both surgery and chemoradiotherapy. For late-stage esophageal cancer patients, the measured difference of quality of life is not significant between CCRT-only and S+CCRT treatments.

All nontechnical factors were analyzed to predict nasal bacterial culture results in patients with chronic rhinosinusitis (CRS). Four hundred and ninety-six CRS patients, who underwent functional endoscopic sinus surgery (FESS), were enrolled. Prior to FESS, the severity of each patient’s CRS was evaluated using a questionnaire, endoscopic examination, acoustic rhinometry, smell test, saccharine transit test, and CT scan. Nasal bacterial cultures were collected from both middle meati using a cotton-tipped stick. Our results showed that the symptom severity complained of by patients and their loss of smell function did not influence the bacterial culture rate. We discovered that the bacterial culture rate was significantly higher in nostrils with nasal polyps than those without polyps, along with nostrils experiencing thick, purulent discharge as opposed to those without discharge. Additionally, this result also occurred in nostrils with a saccharin transit time of more than 30 min than it did in those with a saccharin transit time of less than or equal to 30 min. Both the total endoscopic score and anterior group CT score were significantly higher in nostrils with positive culture than those with negative culture, while the second minimal cross-sectional area (MCA2) of the nasal cavity was significantly lower in nostrils with positive culture than those with negative culture. Multiple logistic regression analysis showed that both nasal polyps and MCA2 were the predictors for positive nasal bacterial culture results. It was concluded that nasal polyps and MCA2 were the predictors for positive nasal bacterial culture results in CRS patients.

Purpose: EGFR mutation as a biomarker has documented that EGFR-mutant patients will derive clinical benefit from tyrosine kinase inhibitor (TKI) treatment. Unfortunately, most patients show TKI resistance and tumor recurrence after therapy. Therefore, we expected that an adjuvant biomarker other than EGFR mutation is needed for predicting TKI resistance. Experimental Design: Molecular manipulations were performed to verify whether TKI resistance mediated by p21-activated kinase (PAK1) could be through increasing Mcl-1 protein stability via the PI3K/AKT/C/EBP-β/miR-145 cascade. Xenograft mouse models were used to confirm the mechanistic action of PAK1 on TKI resistance. Forty-six tumor tissues from patients with lung adenocarcinoma who received TKI therapy were collected to evaluate PAK1 and E-cadherin mRNA expressions by real-time PCR. The association of PAK1 and E-cadherin mRNA expressions with tumor response to TKI treatment and outcomes was evaluated. Results: We demonstrate that PAK1 confers TKI resistance in EGFR-mutant cells as well as in EGFR–wild-type cells. Mechanistically, the positive feedback loop of PAK1/PI3K/AKT/C/EBP-β/miR-145 cascades persistently activates the PI3K/AKT signaling pathway to protect Mcl-1 degradation by Fbw7, which results, in turn, in TKI resistance and cell invasion via epithelial-to-mesenchymal transition due to a decrease in E-cadherin expression. The mechanism underlying the cell model is further confirmed in xenograft tumors. Among patients, high-PAK1 or low–E-cadherin tumors more commonly exhibited an unfavorable response to TKI and poorer outcome compared with low-PAK1 or low–E-cadherin tumors. Conclusions: The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in patients with lung adenocarcinoma who harbored high PAK1 mRNA–expressing tumors. Clin Cancer Res; 22(21); 5370–82. ©2016 AACR.

Environment radiations in vault rooms resulting from Axesse linac use was assessed at Medical University Hospital using Thermoluminescent dosimeters (TLDs) during the use of the new radiation treatment known as volumetric modulated arc therapy (VMAT) in the treatment of nasopharyngeal cancer (NPC). The TLD-100H was calibrated using linac 6 MV photons. A total of 75 measurement points of the TLD-100H were utilized for environmental monitoring. The measured environment radiations were then visualized as three-dimensional graphical representations. Environment radiations were visualized using colored three-dimentional graphical representations. The radiations in NPC treatment of Rando phantom was found to reach levels up to 370 mSv/treatment. Many researchers consider TLD, which is the most cost-effective method to environment radiations. The minimum detectable dose (MDD) was also identified to demonstrate the reliability of the TLD approach. Quantitative results that provide practical guidance with ...

Lung cancer is relatively rare in young patients as the median age at diagnosis is 65-70 years. The main objective of this nationwide study was to investigate the characteristics of young lung cancer in Taiwan, especially the relationships among smoking behavior, epidermal growth factor receptor (EGFR) mutation, and age. The National Taiwan Lung Cancer Registry, a database contain detailed cancer statistics, was analyzed in this study for the period 2011-2012. Young lung cancer was defined as age ≦ 45 years. There were 21,536 lung cancer patients (13,187 men and 8349 women). Among these patients, 1074 (5.0%) were in the younger group, and 20,462 patients (95.0%) were in the older group. Female gender (48.8% versus 38.2%, P < 0.001), never-smokers (47.3% versus 43.8%, P = 0.015), and adenocarcinoma (70.4% versus 58.1%, P < 0.001) were more frequent in the younger group. While the EGFR mutation rate was lower in the younger group (52.5% versus 60.6%, P = 0.001), the primary site of lung cancer and stage distribution were not significantly different. If only adenocarcinoma patients were included in the analysis, female gender, older age, and never-smokers were more likely to have EGFR mutation. In conclusion, lung cancer in young patients (≦ 45 year-old) was associated with unique characteristics, with greater percentages of female patients, adenocarcinoma, and never-smokers and a lower EGFR mutation rate compared with older patients.

Objectives To compare the effects of guided home-based tai chi chuan (TCC) and lower extremity training (LET) and of levels of self-practice on falls and functional outcomes in older fallers. Design Randomized controlled trial. Setting Taipei, Taiwan. Participants Individuals aged 60 and older who had fall-related emergency department visits at least 6 months before participating in the study and ambulated independently at baseline (N = 456). Intervention Six months of TCC or LET. Measurements Four types of fall measures (falls, time to first fall, fallers, recurrent fallers) and six functional measures (handgrip strength, balance, mobility, fear of falling, depression, cognitive function). Results The TCC group was significantly less likely than the LET group to experience any falls during the 6-month intervention (incidence rate ratio (IRR) = 0.30, 95% confidence interval (CI) = 0.15–0.60), and the effects remained significant after 12 months of follow-up (IRR = 0.32, 95% CI = 0.14–0.71). These effects remained significant for injurious falls during the 6-month intervention (IRR = 0.33, 95% CI = 0.16–0.68) and the entire 18-month study (IRR = 0.39, 95% CI = 0.18–0.83). Similar results were obtained when another two fall measures (time to first fall, number of fallers) were used. Moreover, participants who independently practiced TCC or LET seven times per week or more were significantly less likely to experience injurious falls during the 6-month intervention (IRR = 0.41, 95% CI = 0.20–0.83) and the 18-month study (IRR = 0.43, 95% CI = 0.21–0.87) than their counterparts, had a significantly longer time to first injurious fall, and were significantly less likely to have an injurious fall during the 6-month intervention. Cognitive function improved to a greater extent in the TCC group than in the LET group over the 18-month study. Conclusion Home-based TCC may reduce the incidence of falls and injurious falls more than conventional LET in older fallers, and the effects may last for at least 1 year.

// Ya-Wen Cheng 1,2 , Frank Cheau-Feng Lin 3,4 , Chih-Yi Chen 3,4 , Nan-Yung Hsu 1,2,5 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 2 Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan 3 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 4 Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan 5 Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan Correspondence to: Nan-Yung Hsu, e-mail: ywc@tmu.edu.tw Keywords: B[a]P, HPV, DNA repair, promoter hypermethylation, environmental exposure Received: November 02, 2015 Accepted: February 16, 2016 Published: February 23, 2016 ABSTRACT Most studies of lung tumorigenesis have focused on smokers rather than nonsmokers. In this study, we used human papillomavirus (HPV)-positive and HPV-negative lung cancer cells to test the hypothesis that HPV infection synergistically increases DNA damage induced by exposure to the carcinogen benzo[a]pyrene (B[a]P), and contributes to lung tumorigenesis in nonsmokers. DNA adduct levels induced by B[a]P in HPV-positive cells were significantly higher than in HPV-negative cells. The DNA adduct formation was dependent on HPV E6 oncoprotein expression. Gene and protein expression of two DNA repair genes, XRCC3 and XRCC5, were lower in B[a]P-treated E6-positive cells than in E6-negative lung cancer cells. The reduced expression was also detected immunohistochemically and was caused by increased promoter hypermethylation. Moreover, mutations of p53 and epidermal growth factor receptor (EGFR) genes in lung cancer patients were associated with XRCC5 inactivation. In sum, our study indicates that HPV E6-induced promoter hypermethylation of the XRCC3 and XRCC5 DNA repair genes and the resultant decrease in their expression increases B[a]P-induced DNA adducts and contributes to lung tumorigenesis in nonsmokers.

Smoking status is an important determinant of the prevalence of epidermal growth factor receptor (EGFR) mutations in lung cancer patients. However, it is unclear whether smoking status could also influence the spectrum of EGFR mutations.We enrolled patients with lung adenocarcinoma from three medical centers in Taiwan. EGFR mutations were assessed by Sanger direct sequencing. The objective of this study was to evaluate the influence of smoking status on both the frequency and patterns of EGFR mutations.From 2001 to 2013, a total of 1175 patients with lung adenocarcinoma were enrolled for EGFR mutation analysis. The overall EGFR mutation rate was 59.6%, which was significantly higher in females than males (69.1% vs. 49.8%) and in non-smokers than current/former smokers (73.8% vs. 29.8%) (both P0.001). Among patients harboring EGFR mutations, smokers expressed L858R mutation less frequently (35.2% vs. 50.2%, P=0.005) and exon 19 deletions more frequently (52.8% vs 38.8%, P=0.008) than non-smokers. Smokers and non-smokers also had divergent exon 19 deletions subtypes (Del E746-A750 82.5% vs. 57.6%, respectively, P0.001). Among subgroup patients harboring the L858R mutation, smokers were associated with a higher rate of complex mutations than non-smokers (34.2% vs. 8.4%, P0.001).Our results suggested that smoking status could influence not only the frequency but also the spectrum of EGFR mutations. These findings provide a clue for further investigation of EGFR mutagenesis.

The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer was introduced in 2017 and included major revisions, especially of stage III. For the subgroup stage IIIA-N2 non-small-cell lung cancer (NSCLC), surgical resection remains controversial due to heterogeneous disease entity. The aim of this study was to evaluate the clinicopathologic features and prognostic factors of patients with completely resected stage IIIA-N2 NSCLC. We retrospectively evaluated 77 consecutive patients with pathologic stage IIIA-N2 NSCLC (AJCC eighth edition) who underwent surgical resection with curative intent in China Medical University Hospital between 2006 and 2014. Survival analysis was conducted, using the Kaplan&ndash, Meier method. Prognostic factors predicting overall survival (OS) and disease-free survival (DFS) were analyzed, using log-rank tests and multivariate Cox proportional hazards models. Of the 77 patients with pathologic stage IIIA-N2 NSCLC examined, 35 (45.5%) were diagnosed before surgery and 42 (54.5%) were diagnosed unexpectedly during surgery. The mean age of patients was 59 years, and the mean length of follow-up was 38.1 months. The overall one-, three-, and five-year OS rates were 91.9%, 61.3%, and 33.5%, respectively. Multivariate analysis showed that tumor size &lt, 3 cm (hazards ratio (HR): 0.373, p = 0.003) and video-assisted thoracoscopic surgery (VATS) approach (HR: 0.383, p = 0.014) were significant predictors for improved OS. For patients with surgically treated, pathologic stage IIIA-N2 NSCLC, tumor size &lt, 3 cm and the VATS approach seemed to be associated with better prognosis.

Reduced nuclear p27 expression is associated with a poor outcome in various cancers, including non-small cell lung cancer (NSCLC). Cytoplasmic p27 expression was shown to be associated with an unfavorable response to chemotherapy and poor outcomes in some carcinomas, but it has not been well studied in NSCLC. Herein, p27 expression in 219 tumors surgically resected from NSCLC patients was evaluated by immunohistochemistry (IHC). The most common of p27 immunostaining in lung tumors was observed in the cytoplasm (N-/C+, 32 %), followed by negative (N-/C-, 29 %), nucleus (N+/C-, 24 %), and nucleus plus cytoplasm (N+/C+, 15 %). Kaplan-Meier and Cox regression models showed that p27 N-/C+ tumors exhibited the worst overall survival (OS) and relapse-free survival (RFS) among the four categories of tumors. Among 135 of 219 patients who received cisplatin-based chemotherapy, p27 N-/C+ tumors most commonly showed an unfavorable response to cisplatin-based chemotherapy, followed by p27 N-/C- tumors when p27 N+/C- tumors were used as a reference. IHC analysis for phosphorylated extracellular signal-regulated kinase (p-ERK) and Bcl-2 expression in the lung tumors was performed to test whether ERK activation could enhance p27 nuclear export and the expression of Bcl-2 to test whether ERK activation could enhance p27 nuclear export and Bcl-2 expression. The data showed that p-ERK expression was positively correlated with cytoplasmic p27 (N-/C+) and Bcl-2 expression in the lung tumors. Patients with high Bcl-2-expressing tumors treated with cisplatin-based chemotherapy showed unfavorable predictive values in a subset of this study population. Therefore, we suggest that cytoplasmic p27 (N-/C+) via ERK-activated Bcl-2 expression may predict an unfavorable response to cisplatin-based chemotherapy and poor outcomes in NSCLC.

Introduction: The association between estrogen receptor (ER) gene polymorphism and lung cancer risk is rarely studied. This study aimed to explore the ER gene polymorphisms associated with the lung adenocarcinoma risk in never-smoking women. Methods: This study evaluated 532 never-smoking female patients with lung adenocarcinoma and 532 healthy controls. The ESR1 and ESR2 single nucleotide polymorphism (SNP) data were retrieved from a genome-wide association study. Using a multivariate-adjusted logistic regression assay, the associations of ESR1 and ESR2 SNPs with the lung adenocarcinoma risk were estimated. Expression quantitative trait loci analysis was performed to investigate the possible functional roles of ER gene SNPs. Results: For ESR1, seven tagged SNPs were identified. Among them, rs7753153 and rs985192 were associated with lung adenocarcinoma risk (rs7753153: odds ratios [OR], 1.509; 95% confidence intervals [CI], 1.168–1.950; rs985192: OR, 1.309; 95% CI, 1.001–1.712). For ESR2, only rs3020450 was associated with lung adenocarcinoma risk (OR, 2.110; 95% CI, 1.007–4.422). Subjects without hormone replacement therapy (HRT) use carrying at-risk genotypes had a significantly higher lung adenocarcinoma risk than subjects with HRT carrying no at-risk genotypes (rs7753153 GG: OR, 2.133; 95% CI, 1.415–3.216; rs985192 AA/AC, OR: 1.752, 95% CI: 1.109–2.768; rs3020450 AG/GG, OR: 7.162, 95% CI: 1.608–31.90). Risk genotypes of rs7753153 ( p = 0.0248) and rs9479122 ( p = 0.0251) were associated with decreased ESR1 expression. Conclusions: ER gene SNPs are associated with lung adenocarcinoma risk in never-smoking women. The joint effects of ER gene SNPs and HRT use on lung adenocarcinoma risk highlight the importance of the gene–environment interaction in lung carcinogenesis.

MicroRNA (miR)-184 has been reported to have a dual role in human cancers. However, the role of miR-184 in non-small cell lung cancer (NSCLC) remains unclear. Wild-type or mutant CDC25A promoters were constructed by PCR and site-directed mutagenesis to verify whether miR-184 could inhibit CDC25A expression at post-transcription level. Boyden chamber assay was used to assess whether miR-184 could modulate cell invasiveness via targeting CDC25A and c-Myc. We utilized 124 tumors from NSCLC patients to determine miR-184, miR-21, PDCD4 mRNA, c-Myc mRNA, and CDC25A mRNA expression levels by means of real-time PCR analysis. The prognostic value of CDC25A, c-Myc, and miR-184 on overall survival (OS) and relapse-free survival (RFS) was evaluated by Kaplan–Meier and Cox regression analysis. MiR-184 suppressed CDC25A expression by enhancing the instability of its mRNA as a result of miR-184 binding to its coding region. An increase in CDC25A expression by means of a reduction in miR-184 promotes cell invasiveness. Moreover, a concomitant increase in CDC25A and c-Myc expression as a result of decreased miR-184 via the miR-21-mediated PDCD4 reduction is responsible for cell invasiveness. Among patients, miR-184 expression in lung tumors was found to correlate negatively with CDC25A mRNA, c-Myc mRNA, and miR-21 expression, but was positively related to PDCD4 mRNA expression. High-miR-184, High-CDC25A, or high-c-Myc mRNA tumors exhibited shorter OS and RFS periods than their counterparts. The worst OS and RFS were observed in low-miR-184/high-CDC25A/high-c-Myc tumors, followed by low-miR-184 /high-CDC25A, low-miR-184/high-c-Myc, high-c-Myc, and high-CDC25A tumors. MiR-184 as a tumor suppressor miR inhibits cell proliferation and invasion capability via targeting CDC25A and c-Myc. Low miR-184 level may predict worse prognosis in NSCLC patients.

NKX2-1 plays a dual role in lung adenocarcinoma progression, but the underling mechanism is not fully understood. In the present study, we provide evidence that NKX2-1 directly regulates p53 transcription, and in turn, NKX2-1 elevates the mutant p53/NF-Y complex to up-regulate IKKβ transcription in p53-mutant cells, but NKX2-1-mediated wild-type p53 down-regulates IKKβ transcription via decreased Sp1 binding to IKKβ promoter in p53-WT cells. The IKKβ-mediated p65 nuclear localization and epithelial-to-mesenchymal transition (EMT) modulated by the NKX2-1/p53 axis is responsible for soft-agar growth, invasion, and xenograft tumour formation. Among patients, high-IKKβ mRNA tumours had higher prevalence in p53-mutant or nuclear p65 tumours than their counterparts, but not related with NKX2-1 mRNA expression. However, when tumours were divided into p53-WT and p53-mutant subgroups, NKX2-1 mRNA expression was negatively correlated with IKKβ mRNA in p53-WT subgroup, but positively related with IKKβ mRNA expression in p53-mutant subgroup. Kaplan-Meier and Cox regression analysis indicated that high NKX2-1 mRNA tumours exhibited poorer overall survival and relapse free survival than low NKX2-1 mRNA tumours in p53-WT subgroup, but the opposite was observed in p53-mutant subgroup. Therefore, we suggest that NKX2-1 as a tumour suppressor or a tumour promoter in lung adenocarcinoma progression is dependent on p53 status.

Manganese superoxide dismutase (MnSOD) has been shown to be associated with doxorubicin resistance in gastric cancer cells, but the underlying mechanism of MnSOD in drug resistance remains unclear. A recent study indicated that NF-κB activation by MnSOD promoted tumor malignancy in lung adenocarcinoma. Therefore, we hypothesized that MnSOD-mediated NF-κB activation might confer cisplatin resistance in lung adenocarcinoma via the NF-κB/Bcl-2/Snail pathway. Here, the inhibition concentration of cisplatin with 50% cell viability (IC50) was positively correlated with MnSOD expression and its activity in a panel of lung adenocarcinoma cells. The IC50 value was markedly increased and decreased by MnSOD overexpression and knockdown, respectively, in lung cancer cells. Mechanistically, an increase in Bcl-2 by MnSOD-mediated NF-κB activation confers greater cisplatin resistance than cIAP2, Bcl-xL, Mcl-1, and Snail. MnSOD-mediated cisplatin resistance can be overcome by a Bcl-2 antagonist (ABT-199) or IKKβ inhibitor (curcumin) in cells and xenograft tumors. MnSOD expression was positively correlated with nuclear p65 protein and Bcl-2 mRNA expression in tumors from patients with lung adenocarcinomas. A retrospective study indicated that it was more common for MnSOD-positive, nuclear p65-positive, or high Bcl-2 mRNA tumors to have an unfavorable response to cisplatin-based chemotherapy than their counterparts. Therefore, we suggest that ABT-199 or curcumin may be potentially useful to improve tumor regression and chemotherapeutic response in patients with MnSOD/Bcl-2-positive tumors.

We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene–HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30 % increased risk of lung cancer (OR 1.3, 95 % CI 1.0–1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.

Stereotactic body radiation therapy (SBRT) plays an important role in early stage non-small cell lung cancer. Tumor growth before radiotherapy planning (RTP) or during SBRT has been reported in lung cancer patients; however, little is known of growth during the period in-between (i.e. after RTP but before SBRT). An 83-year-old man referred to our hospital and diagnosed with medically inoperable non-small cell lung cancer was noted to have significant tumor progression on day 1 of cone beam computed tomography just before the planned SBRT delivery. Because of uncertainty of the underlying etiology and unfamiliarity with this phenomenon, we made a clinical decision to arrange re-simulation and revise our treatment to conventional fractionated radiotherapy (CFRT). After an initial response, distant metastases occurred eight months after CFRT. The patient received best supportive care and was under hospice care at the last follow-up (27 months after CFRT). We report a case with significant tumor growth just before planned SBRT. Optimal management in this scenario requires further investigation.

Nickel compounds have been classified as carcinogens and shown to be associated with induction of epithelial-mesenchymal transition (EMT) in fibrogenesis and tumorigenesis, as well as the crucial role of microRNAs (miRNAs) and their related genes in controlling EMT and cancer metastasis. Thus, the mechanisms involved in the regulation of EMT in nickel-treated cells are of potential interest in understanding lung fibrosis and tumor progression. We investigated the miRNA-dependent mechanisms involved in nickel-induced EMT in lung epithelial cells. Nickel increased miR-4417 expression and decreased its target gene TAB2 expression. Treatment of cells with TGF-β inhibitor SB525334 significantly blocked NiCl2 and TGF-β-induced EMT. The expression of miR-4417 was abolished by SB525334 in TGF-β-treated cells, but not in nickel-treated cells. Both overexpression of miR-4417 and silencing of TAB2 induced fibronectin expression, but did not reduce E-cadherin expression. Moreover, oral administration of nickel promoted lung tumor growth in nude mice that had received BEAS-2B transformed cells by intravenous injection. The induction of EMT by nickel is mediated through multiple pathways. Induction of abundant miR-4417 and reduction of TAB2 expression following nickel exposure and may be involved in nickel-induced fibronectin. These findings provide novel insight into the roles of nickel in fibrogenesis and tumor progression.

Pneumocytoma, former known as sclerosing hemangioma, is a rare and benign tumor in lung which derived from primitive respiratory epithelium. It’s usually a single tumor, size from 0.3–7 cm (70% of patient

A prospective cohort study was conducted to identify risk and protective factors for crash involvement in older motorcyclists. Over a 1-year study period from August 2013 to July 2014, study participants were recruited from local community centers of five cities in Taiwan. People aged ≥60 years who rode a motorcycle at least once per week were eligible and were invited to participate in the study. Among 256 older riders who completed the baseline assessment and at least one of the four follow-up assessments, 79 (33.7%) experienced a motorcycle crash over the study period. Results of the proportional hazards model showed that after controlling for age, gender, and riding distance, older riders who had sustained hearing impairment (hazard ratio (HR)=2.58; 95% confidence interval (CI), 1.30-5.15), rode a motorcycle at speeds of ≥41km/h (HR=2.31; 95% CI, 1.26-4.23), and had experienced a motorcycle crash in the past year (HR=1.81; 95% CI, 1.06-3.09) were more likely to be involved in a crash, compared to their counterparts. Conversely, older riders who were obese (HR=0.43; 95% CI, 0.22-0.82) were less likely to be involved in a crash than those with a normal weight, while longer functional reach distances (HR=0.96; 95% CI, 0.93-0.99) and higher Tinetti balance scores (HR=0.79; 95% CI, 0.69-0.91) were associated with a reduced risk of crash involvement. Among older people riding a motorcycle as their primary source of transportation, several factors associated with the occurrence of motorcycle crashes were identified. Restrictions and modifications of these risk factors may help design effective safety interventions for reducing crash and injury risks of this increasing riding population.

Objective To examine the level of agreement between patients and their proxies on a measure of health-related quality of life (HRQL) 1 year after traumatic brain injury (TBI). Design A cross-sectional study. Setting Four hospitals in Taipei. Participants Participants (N=176) were patients with TBI (n=88) identified from discharge records of 4 hospitals in Taiwan and family members or friends (n=88) who could answer questions regarding the patient's health and HRQL 1 year after the injury. Interventions Not applicable. Main Outcome Measures A health profile of the brief Taiwanese version of the World Health Organization Quality of Life (WHOQOL-BREF) and 2 health utility measures of the time tradeoff (TTO) and standard gamble (SG). Results Compared with proxy responses, patients provided higher ratings on the domains of the WHOQOL-BREF and lower ratings on the TTO and SG. Intraclass correlation coefficients between patient and proxy ratings varied among the 4 domains of the WHOQOL-BREF, in which levels of agreement were moderate or good for physical capacity (.69) and low for psychological well-being (.45), social relationships (.24), and the environment (.32). Levels of agreement were extremely low for the TTO (0.0) and SG (.10). A profile analysis showed that patients' ratings on the WHOQOL-BREF, on average, were significantly greater than those of their proxies (mean difference, 3.07), with a similar distribution of scatter responses (mean difference, .002) and shape agreement (mean difference, .57). Greater variations in the patient-proxy level of agreement appeared in patients who were younger and had more severe injuries, and also with parent and child proxies. Conclusions To assess the HRQL of patients with a TBI, the level of patient-proxy agreement was adequate for the physical domain but was lower for the social and environmental domains, and the agreement was very low for the TTO and SG. Furthermore, a patient's age and injury severity, and the patient-proxy' relationship may affect the agreement.