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Objective: Immune checkpoint inhibitors (ICI) are recommended as the first‐line therapy for platinum‐refractory head and neck squamous cell carcinoma (HNSCC), a disease with a poor prognosis. However, biomarkers in this situation are rare. The objective was to identify radiomic features‐associated biomarkers to guide the prognosis and treatment opinions in the era of ICI. Methods: A total of 31 platinum‐refractory HNSCC patients were retrospectively enrolled. Of these, 65.5% (20/31) received ICI‐based therapy and 35.5% (11/31) did not. Radiomic features of the primary site at the onset of recurrent metastatic (R/M) status were extracted. Prognostic and predictive radiomic biomarkers were analysed. Results: The median overall survival from R/M status (R/M OS) was 9.6 months. Grey‐level co‐occurrence matrix‐associated texture features were the most important in identifying the patients with or without 9‐month R/M death. A radiomic risk‐stratification model was established and equally separated the patients into high‐, intermittent‐ and lower‐risk groups (1‐year R/M death rate, 100.0% vs. 70.8% vs. 27.1%, p = 0.001). Short‐run high grey‐level emphasis (SRHGE) was more suitable than programmed death ligand 1 (PD‐L1) expression in selecting whether patients received ICI‐based therapy. Conclusions: Radiomic features were effective prognostic and predictive biomarkers. Future studies are warranted. [ABSTRACT FROM AUTHOR]

Melanoma is rare in Taiwan. Asian melanoma is distinct from Western melanoma because acral and mucosal melanoma accounts for the majority of melanoma cases, leading to distinct tumor behaviors and genetic profiling. With consideration of the clinical guidelines in Western countries, Taiwanese experts developed a local clinical practice consensus guideline. This consensus includes diagnosis, staging, and surgical and systemic treatment, based only on clinical evidence, local epidemiology, and available resources evaluated by experts in Taiwan. This consensus emphasizes the importance of surgical management, particularly for sentinel lymph node biopsies. In addition, molecular testing for BRAF is mandatory for patients before systemic treatment. Furthermore, immunotherapy and targeted therapy are prioritized for systemic treatment. This consensus aimed to assist clinicians in Taiwan in diagnosing and treating patients according to available evidence. [ABSTRACT FROM AUTHOR]

Background: The incidence of nontuberculous mycobacterial lung disease (NTM-LD) is increasing worldwide. Immune exhaustion has been reported in NTM-LD, but T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a co-inhibitory receptor on T cells, has been scarcely studied. Methods: Patients with NTM-LD and healthy controls were prospectively recruited from July 2014 to August 2019 at three tertiary referral centers in Taiwan. We examined TIM3 expression on the T cells from the participants using flow cytometry. TIM3 expression was analyzed for different disease statuses and after treatment. The apoptosis and cytokine profiles were analyzed according to the TIM3 expression. Results: Among enrolled subjects (47 patients and 46 controls), TIM3 on CD4+ cells (6.44% vs. 4.12%, p = 0.028) and CD8+ cells (18.47% vs. 9.13%, p = 0.003) were higher in NTM-LD patients than in the controls. The TIM3 level on CD4+ and CD8+ T cells was positively associated with T-cell apoptosis in the NTM-LD patients. In stimulating peripheral blood mononuclear cells using PMA plus ionomycin, a high TIM3 level on T cells correlated with low interleukin-2 and tumor necrosis factor-alpha (TNF-α) on CD4+ cells and interferon-gamma and TNF-α on CD8+ T cells. For clinical manifestation, low body mass index (BMI), positive sputum acid-fast smear, and high radiographic score correlated with high TIM3 expression on T cells. After NTM treatment, TIM3+ decreased significantly on CD4+ and CD8+ T cells. Conclusions: In patients with NTM-LD, TIM3+ expression increased over CD4+ and CD8+ T cells and correlated with cell apoptosis and specific cytokine attenuation. Clinically, TIM3+ T cells increased in patients with low BMI, high disease extent, and high bacilli burden but decreased after treatment. [ABSTRACT FROM AUTHOR]

Nontuberculous mycobacterial lung disease (NTM-LD) prevalence has been increasing over the recent decades. Numerous host factors are associated with NTM-LD development, including susceptible phenotypes such as ciliary defect and lung structural change, pulmonary clearance defect with poor clearance of secretions, and immune suppression. Specifically, regarding the susceptible host phenotypes without clear pathogenesis, a slender body, pectus excavatum, and postmenopausal female status are common. Also, decreased host immunity to NTM, especially T helper 1 cell responses is frequently observed. Even so, the underlying mechanisms remain unclear and relevant large-scale studies are lacking. Infections due to host genetics associated defects are mostly untreatable but rare in Asia, particularly Taiwan. Nevertheless, some risks for NTM-LD are controllable over disease progression. We suggest that clinicians first manage host factors and deal with the controllable characteristics of NTM-LD, followed by optimizing anti-NTM treatment. Further researches focusing on NTM-LD pathogenesis, especially the host-NTM interaction may advance understanding the nature of the disease and develop efficient therapeutic regimens. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the prevalence of pain in cancer outpatients in Taiwan and to investigate the impact of pain on quality of life (QoL) and patient satisfaction. Results were compared to those of a similarly designed study conducted in 2008 to identify trends. Methods: Adult patients with cancer treated as outpatients in hospitals throughout Taiwan were recruited. Pain intensity and the extent to which pain interfered with QoL were self‐reported using a modified version of the Brief Pain Inventory. Patients also indicated their level of satisfaction with their physician, as well as with their pain control. Results: A total of 2652 patients were enrolled from 16 sites. Of these, 1167 (44.0%) patients reported experiencing pain during the previous week. Prevalence and severity of pain were highest in patients with progressive disease. A higher pain severity score was significantly associated with greater interference in both physical and psychological functions. Overall, 86.0% of all participants expressed satisfaction with their physician and 84.8% were satisfied with their pain control; satisfaction rates were associated with pain severity. Compared with the findings from the 2008 study, pain prevalence was notably lower and patient satisfaction was significantly greater in the current study. Conclusions: Prevalence and severity of pain were associated with disease stage. Pain interference on QoL correlated significantly with pain severity. Treatment of pain in cancer patients in Taiwan seems to have improved from 2008 to 2014, possibly attributable to new cancer pain treatment guidelines and the wider availability of novel analgesic therapies. [ABSTRACT FROM AUTHOR]

Purpose: Poor adherence to analgesic drugs is one of the most common barriers to adequate pain management. This prospective, cross-sectional, patient-oriented observational study aimed to explore the adherence rate, clinical factors, and impact of adherence to analgesic drugs on the quality of life (QoL) among cancer outpatients in Taiwan.Methods: Eight hundred ninety-seven consecutive adult outpatients with cancer who had reported tumor pain and received regular analgesic drug treatment were enrolled from 16 medical centers across Taiwan. The Brief Pain Inventory was used to assess pain intensity and QoL. Morisky's four-item medication adherence scale was used to assess adherence to analgesic drugs. Clinical factors possibly associated with good adherence to analgesic drugs were analyzed using multivariate logistic regression analyses.Results: Of the 897 patients, 26.9% met criteria for the good, 35.5% for the moderate, and 37.6% for the poor adherence groups. The good adherence group had significantly better QoL outcomes than the moderate and poor adherence groups (all p < 0.05). Age ≥ 50 years, head and neck or hematological malignancies, cancer-related pain, patients who agreed or strongly agreed that the side effects of analgesic drugs were tolerable, and patients who disagreed or strongly disagreed that the dosing schedule could be flexibly self-adjusted to deal with the actual pain were predictors of good adherence to analgesic drugs.Conclusions: Awareness of the clinical factors associated with adherence to analgesic drugs may help clinicians to identify cancer patients at a greater risk of non-adherence, reinforce optimal pain management, and improve the QoL by enhancing adherence to pain medications. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to investigate the prevalence of pain, pain management, and impact of recent pain on daily functioning in patients with head and neck cancer (HNC) and patients with other cancers.Methods: This multi-center survey was conducted by using Brief Pain Inventory questionnaire to evaluate pain status and its impact on daily functioning.Results: A total of 3289 patients were analyzed including 708 HNC patients and 2581 patients with other cancers. The overall pain prevalence was 69.17%. A higher percentage of HNC patients had recent pain (60.59 vs. 44.01%, P < 0.001), required pain management (86.29 vs. 72.03%, P < 0.001), and used any analgesics (53.81 vs. 34.52%, P < 0.001). HNC patients with pain management had a higher prevalence of recent pain (85.83 vs. 81.14%, P = 0.044) and a slightly lower satisfaction rate (74.00 vs. 79.70%, P = 0.070). Regarding the impact of pain on daily functioning, HNC patients had a lower mean interference score for general activity such as walking, normal work, sleep, and life enjoyment.Conclusions: The HNC patients may need more intensive pain management to achieve optimal pain control and maintain daily functioning. [ABSTRACT FROM AUTHOR]

Background: It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations. Methods: This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2). Results: From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age. Conclusion: This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: The correlation between cooking oil fumes, containing relatively higher amounts of heterocyclic amines, and female lung cancer has been revealed. The association of genetic polymorphisms of CYP1A2 and NAT2, two major enzymes responsible for the metabolism of heterocyclic amines, with lung cancer has been investigated with inconclusive results. In this study targeted on never-smoking population with 162 lung cancer patients and 208 non-cancer controls, while the distributions of CYP1A2 phenotypes in lung cancer patients were comparable to that in controls, NAT2 fast acetylators had an OR of 2.44 (95% CI 1.40–4.23, P=0.002) and 2.56 (95% CI 1.37–4.80, P=0.003) for lung cancer in overall and female cases, respectively, but not in males. These results suggested never-smoking females with NAT2 fast acetylator were more prone to lung cancer and reflected the possibility that exposure to heterocyclic amines may contribute to the female lung cancer development in Taiwan. [Copyright &y& Elsevier]

Background: DNA methylation is associated with cancer, metabolic, neurological, and autoimmune disorders. Hypomethylation of aryl hydrocarbon receptor repressor (AHRR) especially at cg05575921 is associated with smoking and lung cancer. Studies on the association between AHRR methylation at cg05575921 and sources of polycyclic aromatic hydrocarbon (PAH) other than smoking are limited. The aim of our study was to assess the pattern of blood DNA methylation at cg05575921 in non-smoking Taiwanese adults living in areas with different PM2.5 levels. Methods: Data on blood DNA methylation, smoking, and residence were retrieved from the Taiwan Biobank dataset (2008–2015). Current and former smokers, as well as individuals with incomplete information were excluded from the current study. The final analysis included 708 participants (279 men and 429 women) aged 30–70 years. PM2.5 levels have been shown to increase as one moves from the northern through central towards southern Taiwan. Based on this trend, the study areas were categorized into northern, north-central, central, and southern regions. Results: Living in PM2.5 areas was associated with lower methylation levels: compared with the northern area (reference area), living in north-central, central, and southern areas was associated with lower methylation levels at cg05575921. However, only methylation levels in those living in central and southern areas were significant (β= − 0.01003, P = 0.009 and β = − 0.01480, P < 0.001, respectively. Even though methylation levels in those living in the north-central area were not statistically significant, the test for linear trend was significant (P < 0.001). When PM2.5 was included in the regression model, a unit increase in PM2.5 was associated with 0.00115 (P < 0.001) lower cg05575921 methylation levels. Conclusion: Living in PM2.5 areas was inversely associated with blood AHRR methylation levels at cg05575921. The methylation levels were lowest in participants residing in southern followed by central and north-central areas. Moreover, when PM2.5 was included in the regression model, it was inversely associated with methylation levels at cg05575921. Blood methylation at cg05575921 (AHRR) in non-smokers might indicate different exposures to PM2.5 and lung cancer which is a PM2.5-related disease. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. Not much is known regarding the influence of non-smoking-related risk factors on COPD in Taiwan. We examined the relationship between exposure to particulate matter <2.5 μm (PM2.5) and COPD among nonsmokers in Taiwan.Methods: This population-based study involved 3941 nonsmoking Taiwanese adults who were recruited in the Taiwan Biobank project between 2008 and 2015. Air pollution data between 2006 and 2011 were obtained from the air quality monitoring database (AQMD). COPD was the outcome of interest and was identified using the National health insurance Research Database (NHIRD). The data were analyzed using multiple logistic regression models.Results: Compared with the lowest quartile (PM2.5 = 29.38), exposure to PM2.5 in the highest quartile (>38.98 μg/m3) was significantly associated with COPD (OR, 1.29; CI 1.01-1.65) after multivariate adjustments. However, exposures to concentrations of 32.07-38.98 μg/m3 (OR, 1.12 CI 0.88-1.44) and 29.38-32.07 μg/m3 (OR, 1.09 CI 0.84-1.41) showed positive but non-significant associations. However, the test for trend was significant (Ptrend = 0.043). The ORs for exposure to sulfur dioxide (SO2), ozone (O3), carbon monoxide (CO) and NOx (nitrogen monoxide (NO were not significant.Conclusions: Based on our data, exposure to PM2.5 at concentrations greater than 38.98 μg/m3 increased susceptibility to COPD among Taiwanese nonsmokers. Combatting COPD would involve integrating tobacco control and pollution management strategies. [ABSTRACT FROM AUTHOR]

Context: Undertreatment of cancer pain among outpatient cancer patients needs to be addressed to enhance care and improve patients' quality of life (QoL).Objectives: This prospective, cross-sectional, patient-focused study aimed to explore the prevalence of pain and undertreatment of cancer pain in outpatients in Taiwan.Methods: A total of 2652 non-selected outpatients with cancer and aged 20 years or older from 16 medical centers across Taiwan were included in this survey. All patients completed a questionnaire based on the Brief Pain Inventory. Pain management index (PMI) was used to evaluate the adequacy of pain management. Possible clinical variables of patients with positive PMI were examined by univariate and multivariate logistic regressions.Results: A total of 1659 (62.6%) outpatients had experienced some degree of pain; among these, 32.4% had negative PMI. Patients with a negative PMI score had significantly poor outcomes of QoL and a significantly higher tendency toward dissatisfaction with pain control by the physician and with the prescribed analgesic drugs. Female gender, primary tumor from breast, non-cancer-related cause of pain, and hospital locations from north Taiwan were independent variables that predicated patients with undertreatment of cancer pain. Most importantly, a forward trend of undertreatment of pain among patients who presented with lower prevalent rate of pain was observed.Conclusion: One-third of Taiwanese outpatients experienced pain because of undertreatment. Awareness of the prevalence of undertreatment of cancer pain and identification of the vulnerable subjects may assist in enhancing patient care and improving patient's QoL. [ABSTRACT FROM AUTHOR]

Background: DNA methylation is associated with cancer, metabolic, neurological, and autoimmune disorders. Hypomethylation of aryl hydrocarbon receptor repressor (AHRR) especially at cg05575921 is associated with smoking and lung cancer. Studies on the association between AHRR methylation at cg05575921 and sources of polycyclic aromatic hydrocarbon (PAH) other than smoking are limited. The aim of our study was to assess the pattern of blood DNA methylation at cg05575921 in non-smoking Taiwanese adults living in areas with different PM 2.5 levels., Methods: Data on blood DNA methylation, smoking, and residence were retrieved from the Taiwan Biobank dataset (2008-2015). Current and former smokers, as well as individuals with incomplete information were excluded from the current study. The final analysis included 708 participants (279 men and 429 women) aged 30-70 years. PM 2.5 levels have been shown to increase as one moves from the northern through central towards southern Taiwan. Based on this trend, the study areas were categorized into northern, north-central, central, and southern regions., Results: Living in PM 2.5 areas was associated with lower methylation levels: compared with the northern area (reference area), living in north-central, central, and southern areas was associated with lower methylation levels at cg05575921. However, only methylation levels in those living in central and southern areas were significant (β = - 0.01003, P = 0.009 and β = - 0.01480, P < 0.001, respectively. Even though methylation levels in those living in the north-central area were not statistically significant, the test for linear trend was significant (P < 0.001). When PM 2.5 was included in the regression model, a unit increase in PM 2.5 was associated with 0.00115 (P < 0.001) lower cg05575921 methylation levels., Conclusion: Living in PM 2.5 areas was inversely associated with blood AHRR methylation levels at cg05575921. The methylation levels were lowest in participants residing in southern followed by central and north-central areas. Moreover, when PM 2.5 was included in the regression model, it was inversely associated with methylation levels at cg05575921. Blood methylation at cg05575921 (AHRR) in non-smokers might indicate different exposures to PM 2.5 and lung cancer which is a PM 2.5 -related disease.

Background: Both SOX2 promoter methylation and air pollution have been associated with lung cancer risk. However, little has been done to assess SOX2 promoter methylation in individuals living in air pollution areas. The aim of this study was to investigate SOX2 promoter methylation in non-smoking Taiwanese adults living in areas with different levels of air pollution especially particulate matter with diameter < 2.5 μm (PM 2.5 )., Methods: A total of 1142 individuals aged 30-70 years were recruited. Data on SOX2 methylation, residence, age, and exposure to second-hand smoke (SHS) among others were extracted from the Taiwan Biobank dataset (2008-2015). After excluding former and current smokers, alongside those with incomplete information, a total of 461 non-smokers comprising 176 men and 285 women were included in the study. Participants' residences were grouped under northern and central/southern areas because air pollution (PM 2.5 ) is lower in northern compared to central and southern areas., Results: The methylation levels in men (0.16310 ± 0.01230) and women (0.15740 ± 0.01240) were significantly different (P < .0001). In both sexes, the SOX2 promoter region was shown to be significantly hypermethylated in central and southern areas compared with the northern areas. The regression coefficient (β) was 0.00331 (P = 0.0257) in men and 0.00514 (P < .0001) in women., Conclusion: SOX2 was significantly hypermethylated in both men and women residing in central and southern areas. The consistency in the results for both sexes shows that SOX2 promoter methylation could serve as a potential biomarker for industrial air pollution exposure. Moreover, it might reflect predisposition to cancer. Hence, healthy non-smokers at precancerous stages who have not been clinically diagnosed could be identified.

CDKAL1 rs10946398 is a type 2 diabetes (T2D)-associated variant. It is a new body mass index (BMI)-associated variant in Asian populations. We investigated the association between rs10946398 and T2D among 9908 participants aged 30-70 years based on BMI: normal weight; 18.5 ≤ BMI < 24 kg/m 2 , overweight; 24 ≤ BMI < 27 kg/m 2 , and obesity; BMI ≥27 kg/m 2 . The CC genotype conferred a higher risk of T2D than the CA genotype. The odds ratios (ORs) were 1.83; 95% confidence interval (CI) 1.49-2.26 and 1.20; 95% CI 1.02-1.40, respectively. The C allele was the significant risk allele compared with A allele (OR = 1.32; 95% CI 1.19-1.47). For normal, overweight and obese participants with CC genotype, the ORs were respectively 1.69; 95% CI 1.02-2.81, 2.34; 95% CI 1.50-3.66, and 1.58; 95% CI 1.02-2.45 among men and 1.22; 95% CI 0.67-2.22, 2.42; 95% CI 1.30-4.52, and 2.3; 95% CI 1.19-4.50 among women. The C allele ORs were higher in obese and overweight women. In conclusion, the rs10946398 CC/CA genotypes, as well as the C allele increased the risk of T2D. The ORs were higher in women who were overweight and obese than in those with normal weight. Nonetheless, significant results were prominent only among those with CC genotype and C allele.

Background: Asthma and COPD (chronic obstructive pulmonary disease) lead to persistent airway inflammation and are associated with lung cancer. The objective of the study was to assess the relationship between inhaled (ICS) and oral corticosteroid (OCS) use, and risk of lung squamous cell carcinoma (SqCC)., Methods: This study was a nested case-control study. Patients with newly diagnosed asthma or COPD between 2003 and 2010 were identified from the National Health Insurance Database. Cases were defined as patients diagnosed with SqCC after enrollment. For each case, four control individuals who were randomly matched for sex and age and date diagnosis of asthma or COPD were selected., Results: From the 1,672,455 eligible participants, 793 patients with SqCC were matched with 3,172 controls. The odds ratios (ORs) of SqCC in men who received high and low-dose ICS were 2.18 (95 %CI, 1.56-3.04) and 1.77 (1.22-2.57), respectively. Similarly, the ORs were 1.46 (95 %CI, 1.16-1.84) and 1.55 (95 %CI, 1.22-1.98) for men who were placed on low and high dose OCS. However, there was no significant association between cumulative ICS and/or OCS and risk of SqCC in women. Recent dose increase in corticosteroid was significantly associated with risk of SqCC. Specifically, among men, the ORs for SqCC were 8.08 (95 %CI, 3.22-20.30) for high-dose ICS + OCS, 4.49 (95 % CI, 2.05-9.85) for high-dose ICS, and 3.54 (95 % CI, 2.50-5.01) for high-dose OCS treatments, respectively. The OR for SqCC in women who received high-dose OCS was 6.72 (95 %CI, 2.69-16.81)., Conclusion: Corticosteroid use did not decrease SqCC in patients with asthma or COPD. Recent dose increase in corticosteroids was associated with SqCC.

Objectives: Lung cancer and tuberculosis (TB) share common risk factors and are associated with high morbidity and mortality. Coexistence of lung cancer and TB were reported in previous studies, with uncertain pathogenesis. The association between lung cancer and latent TB infection (LTBI) remains to be explored., Methods: Newly diagnosed, treatment-naïve lung cancer patients were prospectively enrolled from four referral medical centers in Taiwan. The presence of LTBI was determined by QuantiFERON-TB Gold In-Tube (QFT-GIT). Demographic characteristics and cancer-related factors associated with LTBI were investigated. The survival status was also analyzed according to the status of LTBI., Results: A total of 340 lung cancer patients were enrolled, including 96 (28.2%) LTBI, 214 (62.9%) non-LTBI, and 30 (8.8%) QFT-GIT results-indeterminate cases. Non-adenocarcinoma cases had higher proportion of LTBI than those of adenocarcinoma, especially in patients with younger age. In multivariate analysis, COPD (OR 2.41, 95% CI 1.25-4.64), fibrocalcified lesions on chest radiogram (OR 2.73, 95% CI 1.45-5.11), and main tumor located in typical TB areas (OR 2.02, 95% CI 1.15-3.55) were independent clinical predictors for LTBI. Kaplan-Meier survival analysis demonstrated patients with indeterminate QFT-GIT results had significantly higher 1-year all-cause mortality than those with LTBI (p<0.001) and non-LTBI (p=0.003). In multivariate analysis, independent predictors for 1-year all-cause mortality included BMI<18.5 (HR 2.09, 95% CI 1.06-4.14, p=0.033), advanced stage of lung cancer (RR 7.76, 95% CI 1.90-31.78, p=0.004), and indeterminate QFT-GIT results (RR 2.40, 95% CI 1.27-4.54, p=0.007)., Conclusions: More than one-quarter of newly diagnosed lung cancer patients in Taiwan have LTBI. The independent predictors for LTBI include COPD, fibrocalcified lesions on chest radiogram, and main tumor located in typical TB areas. The survival rate is comparable between LTBI and non-LTBI cases. However, indeterminate QFT-GIT result was an independent predictor for all-cause mortality in lung cancer patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Inactivation of p16INK4a gene through promoter hypermethylation has been frequently observed in non small cell lung cancer; however, various studies have shown a controversial correlation between p16INK4a hypermethylation and cigarette smoking. Our recent report showed that human papillomarvirus (HPV) 16/18 infections were associated with the development of nonsmoking female lung cancer in Taiwan and we further speculated that HPV infection may be linked with p16INK4a hypermethylation. To verify the influence of environmental exposure, including cigarette smoking, environmental carcinogen exposure and HPV infections on p16INK4a hypermethylation, tumors from 162 lung patients, including 67 smoking males, 41 nonsmoking males and 58 nonsmoking females, were subjected to p16INK4a hypermethylation analysis by methylation-specific PCR. As the results showed, p16INK4a hypermethylation was detected in 40 (59.7%) of 67 smoking male, 15 (36.6%) of 41 nonsmoking male and 35 (60.3%) of 58 nonsmoking female lung tumors. This result seemed to reveal that gender and cigarette smoking both possess an equal influence on p16INK4a hypermethylation. This result also led to a speculation that HPV infection may promote p16INK4a hypermethylation in nonsmoking female lung cancer patients. From our data, p16INK4a hypermethylation frequency in nonsmoking female lung tumors with HPV infection was as high as 70% (30 of 43) compared to those without HPV infection (33%; 5 of 15). In fact, the correlation between HPV infection and p16INK4a hypermethylation was only observed in nonsmoking female lung tumors (p = 0.017), but not in smoking male or nonsmoking male lung tumors. Moreover, the reverse correlation between p16INK4a immunostaining and p16INK4a promoter hypermethylation was also only observed in nonsmoking female lung tumors. These results strongly suggested that the involvement of HPV infection in lung tumorigenesis of nonsmoking female cancer patients in Taiwan may be mediated at least in part through the increase of hypermethylation to cause p16INK4a inactivation.

Background: Lung cancer is the leading cause of cancer death in Taiwan, and the paucity of dependable risk markers has impeded the early management of lung cancer. An association of human papillomavirus (HPV) 16/18 infection with lung cancer among nonsmoking Taiwanese women was revealed in our previous study., Methods: Nested PCR was employed to detect HPV 16/18 DNA in the blood circulation of 149 lung cancer patients and 174 noncancer controls. In addition, correlation of prevalence of HPV DNA between the blood circulation and lung tumor tissue was compared from 70 sets of paired tumor tissues and peripheral blood samples available., Results: The results showed that the prevalence rate of HPV 16/18 in the blood circulation of lung cancer cases was significantly higher than that of noncancer controls (47.7% vs. 12.6% for HPV 16, P < 0.0001; 30.9% vs. 5.2% for HPV 18, P < 0.0001). A significantly higher HPV 16 prevalence was detected in female lung cancer patients than that of male (57.6% vs. 41.1%, P = 0.048), as well as in cases with tumor Stages III/IV than those with tumor Stages I/II (54.6% vs. 29.3%, P = 0.006). After adjusting the effects of age, gender, and smoking status, a 6.5-fold greater risk of lung cancer was demonstrated for those subjects with HPV Type 16 positive (95% CI 3.7-11.3, P < 0.0001), a 9.2-fold for HPV Type 18 positive (95% CI 4.2-20.2, P < 0.0001), and a 75.7-fold greatest risk for those with both HPV Type 16 and 18 positive (95% CI 9.8-582.1, P < 0.0001)., Conclusions: These results suggested that the presence of HPV DNA in the blood circulation may serve as a feasible risk marker of lung cancer., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11191)

Epidemiological studies have shown that the incidence of lung cancer was associated with exposure to cooking oil fumes (COF) in nonsmoking Taiwanese women. We suspect that quercetin may be a potent inhibitor for reduction of COF-induced DNA damage and prevention of lung cancer development. Comet assay was used to evaluate the DNA damage induced by a relatively low dose of COF (100 g/ml) in human lung adenocarcinoma CL-3 cells. To understand whether quercetin has the most potent protective effect on COF-induced DNA damage, the 50% inhibition concentration of quercetin for COF-induced DNA damage (IC50) was compared with IC50 values of alpha-naphthoflavone(alpha-NF), NS-398, and NaN3 (specific inhibitors) or scavengers of cytochrome P-450 1A1, cyclooxygenase-2 (COX-2),and reactive oxygen species. The IC50 of quercetin was only 1/2, 1/3, and 1/35 of IC50 values of alpha-NF, NS-398, and NaN3,respectively. Clearly, quercetin was the most effective inhibitor of COF-induced DNA damage, followed sequentially by kappa-NF, NS-398, and NaN3. To further elucidate whether inhibition of COF-induced DNA damage of quercetin is mediated through the inhibition of COX-2 gene expression by altering the nuclear factor-kappaB pathway, COX-2 mRNA and its protein expressions induced by COF were evaluated by reverse transcription-polymerase chain reaction and Western blot, respectively. Our data showed that COX-2 mRNA and protein levels were significantly repressed by addition of quercetin in a dose-dependent manner. Gel retardation assay showed that nuclear factor-kappaB DNA binding activity induced by COF was significantly inhibited by quercetin. From our previous and present studies, it is revealed that coexpression of COX-2 and cytochrome P-450 1A1 caused by COF may contribute to genomic instability in lung cancer development. Thus quercetin may act as a potent chemopreventive agent of lung cancer for nonsmoking Taiwanese women.