The associates of anxiety among lung cancer patients: Dehydroepiandrosterone (DHEA) as a potential biomarker.

OBJECTIVE: Anxiety is a prevalent comorbidity in lung cancer (LC) patients associated with a decline in quality of life. Dehydroepiandrosterone (DHEA), a neuroactive steroid, levels rise in response to stress. Prior research on the association between DHEA and anxiety has yielded contradictory results and no study has investigated this association in LC patients. METHODS: A total of 213 patients with LC were recruited from a general hospital. Data on demographic and cancer-related variables were collected. Using the Chinese version of the Hospital Anxiety and Depression Scale (HADS), the degree of anxiety was determined. Cortisol, DHEA, and Dehydroepiandrosterone sulfate (DHEA-S) levels in saliva were measured. Adjusting for confounding variables, a multivariate regression analysis was conducted. RESULTS: 147 men and 66 women comprised our group with an average age of 63.75 years. After accounting for demographic and treatment-related factors, anxiety levels were significantly correlated with, post-traumatic stress symptoms (PTSSs) (ß = 0.332, p < 0.001) and fatigue (ß = 0.247, p = 0.02). Association between anxiety and three factors, including DHEA, PTSSs, and fatigue, was observed in patients with advanced cancer stages (III and IV) (DHEA ß = 0.319, p = 0.004; PTSS ß = 0.396, p = 0.001; fatigue ß = 0.289, p = 0.027) and those undergoing chemotherapy (DHEA ß = 0.346, p = 0.001; PTSS ß = 0.407, p = 0.001; fatigue ß = 0.326, p = 0.011). CONCLUSIONS: The association between anxiety and DHEA remained positive in advanced cancer stages and chemotherapy patients. Further study is necessary to determine whether DHEA is a potential biomarker of anxiety in LC patients.

Investigation of anxiety and depressive disorders and psychiatric medication use before and after cancer diagnosis.

OBJECTIVE: Data regarding the prevalence of depression and anxiety among cancer patients, especially before cancer diagnosis, remains scarce. This study investigated the prevalence of these conditions and associated drug use among cancer patients pre- and post-diagnosis. METHODS: This population-based cohort study using data from Taiwan's National Health Insurance Research Database recruited patients with a registered cancer diagnosis and matched control between January 1, 2000, and December 31, 2011. We compared the prevalence of anxiety and depressive disorders between cancer patients and non-cancer participants during a 2-year period both pre- and post-diagnosis by Pearson's chi-square test. Psychiatric medication use was also examined for the associated mental condition. RESULTS: We examined participants diagnosed with liver (N = 17,154), colorectal (N = 30,391), breast (N = 40,036), gynecological (N = 23,218), and lung (N = 15,671) cancer. Before the cancer diagnosis, the prevalence of depression was higher in non-cancer participants than in gynecological cancer patients (p = 0.018) but anxiety is higher in liver, colorectal, and lung cancer patients when compared to non-cancer participants (p < 0.05). After the cancer diagnosis, the prevalence of anxiety and depression became significantly higher in all enrolled cancer patients than non-cancer participants (p < 0.05). Similar results were observed in psychiatric medication use trends. CONCLUSIONS: This study proposed that patients with liver, colorectal, and lung cancer had an increased risk of developing anxiety, which might be a sentinel diagnosis. The participants had a significantly higher level of anxiety and depressive disorder post-diagnosis, which highlights the importance of the care for both mental and physical conditions in cancer management.

Artificial neural networks improve LDCT lung cancer screening: a comparative validation study.

BACKGROUND: This study proposes a prediction model for the automatic assessment of lung cancer risk based on an artificial neural network (ANN) with a data-driven approach to the low-dose computed tomography (LDCT) standardized structure report. METHODS: This comparative validation study analysed a prospective cohort from Chiayi Chang Gung Memorial Hospital, Taiwan. In total, 836 asymptomatic patients who had undergone LDCT scans between February 2017 and August 2018 were included, comprising 27 lung cancer cases and 809 controls. A derivation cohort of 602 participants (19 lung cancer cases and 583 controls) was collected to construct the ANN prediction model. A comparative validation of the ANN and Lung-RADS was conducted with a prospective cohort of 234 participants (8 lung cancer cases and 226 controls). The areas under the curves (AUCs) of the receiver operating characteristic (ROC) curves were used to compare the prediction models. RESULTS: At the cut-off of category 3, the Lung-RADS had a sensitivity of 12.5%, specificity of 96.0%, positive predictive value of 10.0%, and negative predictive value of 96.9%. At its optimal cut-off value, the ANN had a sensitivity of 75.0%, specificity of 85.0%, positive predictive value of 15.0%, and negative predictive value of 99.0%. The area under the ROC curve was 0.764 for the Lung-RADS and 0.873 for the ANN (P = 0.01). The two most important predictors used by the ANN for predicting lung cancer were the documented sizes of partially solid nodules and ground-glass nodules. CONCLUSIONS: Compared to the Lung-RADS, the ANN provided better sensitivity for the detection of lung cancer in an Asian population. In addition, the ANN provided a more refined discriminative ability than the Lung-RADS for lung cancer risk stratification with population-specific demographic characteristics. When lung nodules are detected and documented in a standardized structured report, ANNs may better provide important insights for lung cancer prediction than conventional rule-based criteria.

Spheroids Generated from Malignant Pleural Effusion as a Tool to Predict the Response of Non-Small Cell Lung Cancer to Treatment.

BACKGROUND: Spheroids generated by tumor cells collected from malignant pleural effusion (MPE) were shown to retain the characteristics of the original tumors. This ex vivo model might be used to predict the response of non-small cell lung cancer (NSCLC) to anticancer treatments. METHODS: The characteristics, epidermal growth factor receptor (EGFR) mutation status, and clinical response to EGFR-TKIs treatment of enrolled patients were recorded. The viability of the spheroids generated from MPE of enrolled patients were evaluated by visualization of the formazan product of the MTT assay. RESULTS: Spheroids were generated from 14 patients with NSCLC-related MPE. Patients with EGFR L861Q, L858R, or Exon 19 deletion all received EGFR-TKIs, and five of these seven patients responded to treatment. The viability of the spheroids generated from MPE of these five patients who responded to EGFR-TKIs treatment was significantly reduced after gefitinib treatment. On the other hand, gefitinib treatment did not reduce the viability of the spheroids generated from MPE of patients with EGFR wild type, Exon 20 insertion, or patients with sensitive EGFR mutation but did not respond to EGFR-TKIs treatment. CONCLUSION: Multicellular spheroids generated from NSCLC-related MPE might be used to predict the response of NSCLC to treatment.

An optimized ligation-mediated PCR method for chromosome walking and fusion gene chromosomal breakpoints identification.

Molecular techniques that recover unknown sequences next to a known sequence region have been widely applied in various molecular studies, such as chromosome walking, identification of the insertion site of transposon mutagenesis, fusion gene partner, and chromosomal breakpoints, as well as targeted sequencing library preparation. Although various techniques have been introduced for efficiency enhancement, searching for relevant single molecular event present in a large-sized genome remains challenging. Here, the optimized ligation-mediated polymerase chain reaction (PCR) method was developed and successfully identified chromosomal breakpoints far away from the exon of the new exon junction without the need for nested PCR. In addition to recovering unknown sequences next to a known sequence region, the high efficiency of the method could also improve the performance of targeted  next-generation sequencing (NGS).

Invasive pulmonary aspergillosis among patients with severe community-acquired pneumonia and influenza in ICUs: a retrospective cohort study.

RATIONALE: The prevalence, clinical characteristics, and outcomes of invasive pulmonary aspergillosis in patients with severe community-acquired pneumonia (CAP) in intensive care units remain underestimated because of the lack of a disease-recognition scheme and the inadequacy of diagnostic tests. OBJECTIVES: To identify the prevalence, risk factors, and outcomes of severe CAP complicated with invasive pulmonary aspergillosis (IPA) in intensive care units (ICUs). METHODS: We conducted a retrospective cohort study including recruited 311 ICU-hospitalized patients with severe CAP without influenza or with influenza. Bronchoalveolar lavage fluid (BALF) samples were from all patients and subjected to mycological testing. Patients were categorized as having proven or probable Aspergillus infection using a modified form of the AspICU algorithm comprising clinical, radiological, and mycological criteria. MEASUREMENTS AND MAIN RESULTS: Of the 252 patients with severe CAP and 59 influenza patients evaluated, 24 met the diagnostic criteria for proven or probable Aspergillus infection in the CAP group and 9 patients in the influenza group, giving estimated prevalence values of 9.5% and 15.3%, respectively. COPD and the use of inhaled corticosteroids were independent risk factors for IPA. IPA in patients with severe CAP was significantly associated with the duration of mechanical support, the length of ICU stay, and the 28-day mortality. CONCLUSIONS: An aggressive diagnostic approach for IPA patients with severe CAP and not only influenza or COVID-19 should be pursued. Further randomized controlled trials need to evaluate the timing, safety, and efficacy of antifungal therapy in reducing IPA incidence and improving clinical outcomes.

Dual-Ion Co-intercalation Mechanism on a Na2V6O16·3H2O Cathode with a Commercial-Level Mass Loading for Aqueous Zinc-Ion Batteries with High Areal Capacity.

A proton (H+) and zinc ion (Zn2+) co-insertion model is put forward in this study to elucidate the capacity origin of an aqueous zinc ion battery (ZIB) based on a heavily loaded (∼15 mg cm-2) cathode, which consists of Na2V6O16·3H2O (NVO) embedded particularly in the macropores of activated carbon cloth (ACC), coupled with a highly stable Zn/In anode. The confinement effect of these porous channels not only prevents the detachment of NVO from ACC but also well mitigates its volume change resulting from H+ and Zn2+ co-intercalation, which collectively render the stability of NVO/ACC markedly enhanced. Moreover, the bicontinuous structure of NVO/ACC, as a result of the self-interlacing of intrapore NVO, which is first engineered into the nanobelts, and their interlocking with the carbon fibers of ACC, simultaneously giving rise to a solid and a holey framework, is favorable to the electron and ion transport throughout the entire electrode. The synergistic effect of such facile charge transfer kinetics and the high packing density of NVO in the cathode endows ZIBs with not only a good rate performance but also an exceptional areal capacity amounting to 4.6 mAh cm-2, far surpassing those reported for additional vanadium-based counterparts reported in the literature.

Serum vascular endothelial growth factor affects tissue fluid accumulation and is associated with deteriorating tissue perfusion and oxygenation in severe sepsis: a prospective observational study.

BACKGROUND: Positive fluid balance and tissue fluid accumulation are associated with adverse outcomes in sepsis. Vascular endothelial growth factor (VEGF) increases in sepsis, promotes vascular permeability, and may affect tissue fluid accumulation and oxygenation. We used near-infrared spectroscopy (NIRS) to estimate tissue hemoglobin (Hb) oxygenation and water (H2O) levels to investigate their relationship with serum VEGF levels. MATERIAL AND METHODS: New-onset severe sepsis patients admitted to the intensive care unit were enrolled. Relative tissue concentrations of oxy-Hb ([HbO2]), deoxy-Hb ([HbR]), total Hb ([HbT]), and H2O ([H2O]) were estimated by near-infrared spectroscopy (NIRS) for three consecutive days and serum VEGF levels were measured. Comparisons between oliguric and non-oliguric patients were conducted and the correlations between variables were analyzed. RESULTS: Among 75 eligible patients, compared with non-oliguric patients, oliguric patients were administrated more intravascular fluids (median [IQR], 1926.00 [1348.50-3092.00] mL/day vs. 1069.00 [722.00-1486.75] mL/day, p < 0.001) and had more positive daily net intake and output (mean [SD], 1,235.06 [1303.14] mL/day vs. 313.17 [744.75] mL/day, p = 0.012), lower [HbO2] and [HbT] over the three-day measurement (analyzed by GEE p = 0.01 and 0.043, respectively) and significantly higher [H2O] on the third day than on the first two days (analyzed by GEE p = 0.034 and 0.018, respectively). Overall, serum VEGF levels were significantly negatively correlated with [HbO2] and [HbT] (rho = - 0.246 and - 0.266, p = 0.042 and 0.027, respectively) but positively correlated with [H2O] (rho = 0.449, p < 0.001). Subgroup analysis revealed a significant correlation between serum VEGF and [H2O] in oliguric patients (rho = 0.532, p = 0.003). Multiple regression analysis determined the independent effect of serum VEGF on [H2O] (standardized coefficient = 0.281, p = 0.038). CONCLUSIONS: In severe sepsis, oliguria relates to higher positive fluid balance, lower tissue perfusion and oxygenation, and progressive tissue fluid accumulation. Elevated serum VEGF is associated with worsening tissue perfusion and oxygenation and independently affects tissue fluid accumulation.

Combination Use of First-Line Afatinib and Proton-Pump Inhibitors Reduces Overall Survival Among Patients with EGFFR Mutant Lung Cancer.

Purpose: Previous retrospective studies reported that proton-pump inhibitors (PPIs) may decrease the efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) including gefitinib and erlotinib. Afatinib had a wider soluble pH range, with possible fewer interactions with antacids. However, clinical data were limited. Thus, this study aimed to evaluate the negative impact of PPIs on afatinib. Patients and Methods: This retrospective cohort study included patients who are newly diagnosed with non-small cell lung cancer (NSCLC) from 2014 to 2019 using the Chang Gung Research Database. We identified patients who were treated with first-line afatinib and analyzed the association between the PPI and afatinib treatment outcomes. Results: A total of 1418 patients were treated with first-line afatinib and followed up for 6 years. First-line afatinib was administered to 918 eligible patients, and 330 had afatinib with PPIs. The combination use of PPIs and afatinib significantly decreased the overall survival (OS) compared with that of patients using afatinib only (median OS: 33.2 and 25.1 months, p < 0.01) and multivariate analyses (Combination use: hazard ratio: 1.29; 1.05-1.59, p = 0.01). The percentages of patients who were able to receive 2nd line therapy also significantly decreased in afatinib with PPI cohort. Conclusion: The concurrent use of PPIs was associated with lower OS in patients with EGFR-mutant lung cancer under the first-line afatinib treatment but not associated with TTF.

Clinical Impact of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Associated Clostridioides difficile Infection Among Patients with Lung Cancer.

Aim: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs)-associated Clostridioides difficile infection (CDI) among lung cancer patients have been reported in case reports and adverse events reporting system databases in the United States and Japan, but clinical data remained insufficient. This study aims to evaluate CDI in lung cancer patients receiving EGFR-TKIs. Methods: We conducted a retrospective cohort study using multi-institutional electronic medical records database. We included patients aged older than 20 years diagnosed with lung cancer and treated with EGFR-TKIs (gefitinib, erlotinib, afatinib). We defined EGFR-TKI initiation date as the index date and occurrence of diarrhea with CDI or without CDI as the event date. We followed patients from the index date until the event date, ICU admission, death, or 12/31/2019. Results: We included 2242 diarrhea patients, 51 were EGFR-TKI with CDI cohort, and 2191 were diarrhea without CDI cohort. Patients who were concurrently taking antibiotics (hazard ratio [HR], 3.30; 95% CI, 1.67-6.5) and systemic steroids (HR, 4.9; 95% CI, 2.65-9.06) had an increased risk of CDI. First-generation EGFR-TKIs tended to be associated with an increased risk of CDI compared with afatinib (HR, 1.81, 95% CI, 0.94-3.47). EGFR-TKI with CDI had a higher ICU admission rate (HR, 3.42, 95% CI, 1.98-5.91) and mortality rate (HR, 2.34, 95% CI, 1.67-3.28) than diarrhea without CDI. Conclusion: Patients with CDI had higher ICU admission rates and mortality rates than those without CDI. Concurrent use of antibiotics and systemic steroids were risk factors for CDI among patients with lung cancer receiving EGFR-TKIs. Afatinib was not associated with a higher risk of CDI than first-generation EGFR-TKIs.

The potential and limitation of targeted chromosomal breakpoint sequencing for the ROS1 fusion gene identification in lung cancer.

ROS1 fusion genes are rare but important driver genes in lung cancer. Owing to their rarity, many clinicopathological features and treatment responses for each ROS1 fusion variant are still largely unknown and require further investigation. RNA is the preferable template for the ROS1 fusion gene screening, but deterioration of RNA in FFPE often makes the detection challenging. To resolve the difficulty, a targeted chromosomal breakpoint sequencing method was developed for searching the ROS1 fusion gene, and was compared with fluorescence in situ hybridization, immunohistochemistry, RT-qPCR using 260 lung cancer samples of Southern Taiwan. The results showed that ROS1-altered cases were present at low frequencies, did not share distinct clinicopathological features, and often carried other driver mutations. The performance of the targeted sequencing assay was superior to the RT-qPCR in ROS1 fusion gene identification when the cDNAs were from FFPE samples, but long-read DNA sequencing and fresh-frozen samples would be better to revolve all fusion genes. Precise determination of all ROS1 fusion variants and concomitant driver mutations using both genomic DNA and RNA would be required to help improve the treatment of patients with ROS1 alterations.

The impacts of bacterial co-infections and secondary bacterial infections on patients with severe influenza pneumonitis admitted to the intensive care units.

PURPOSES: This study investigated the prevalence and clinical outcomes of pulmonary bacterial co-infections and secondary bacterial infections in patients with severe influenza pneumonitis. METHODS: We retrospectively analyzed the data of adult patients with severe influenza pneumonitis admitted to medical ICUs. Bacterial co-infections and secondary bacterial infections were identified. The risk factors of bacterial infection were evaluated. The outcomes of patients regarding co-infection or secondary bacterial infection were analyzed. RESULTS: We identified 117 critically ill patients with laboratory-confirmed influenza pneumonitis admitted to the medical ICUs. Klebsiella pneumoniae (31.4%) and Staphylococcus aureus (22.8%) were the most identified bacteria in patients with bacterial co-infection. A high proportion of methicillin-resistant Staphylococcus aureus (17.1%) was noted. Liver cirrhosis and diabetes mellitus were the independent risk factors for bacterial co-infection. Acinetobacter baumannii (30.7%) and S. aureus (23.1%) were the most often identified bacteria in patients with secondary bacterial pneumonia. Patients with secondary bacterial infections had a longer duration of mechanical ventilation, and longer ICU and hospital stay. CONCLUSIONS: High rates of drug-resistant bacterial co-infections and secondary bacterial infections were identified in patients with severe influenza pneumonitis requiring ICU care and were associated with more morbidity in these patients.

Sleep Quality and Related Factors in Patients with Breast Cancer: A Cross-Sectional Study in Taiwan.

BACKGROUND: Sleep disturbances are common and symptomatic burden in patients with breast cancer, but they are poorly documented and managed in routine clinical practice. This descriptive and cross-sectional study evaluated factors associated with post-treatment sleep disturbances in patients with breast cancer. PATIENTS AND METHODS: Patients with breast cancer who underwent standard treatment were enrolled and surveyed for their basic demographic data and precancerous and cancer treatment-related factors; they were also administered self-report questionnaires including the Family Adaptation, Partnership, Growth, Affection, Resolve questionnaire; Impact of Event Scale; Center for Epidemiologic Studies Depression Scale; and Maudsley Personality Inventory. Their sleep disturbances were evaluated using the Pittsburgh sleep quality index (PSQI). Independent sample t test and chi-square tests were used to compare the variables between patients with or without sleep disturbance, and multivariate logistic regression analyses were conducted to detect the independent factors. RESULTS: In total, 448 patients, including 145 with PSQI ≤ 5 and 303 with PSQI > 5, completed the investigation. Multiple logistic regression analysis revealed that significantly more patients with sleep disturbances demonstrated psychological distress, severe pain, depression, and impact of stress events than patients without sleep disturbances (adjusted odds ratios [95% confidence intervals]: 2.83 [1.135-7.067], P = 0.026; 1.14 [1.023-1.280], P = 0.018; 1.08 [1.036-1.133], P < 0.001; and 1.03 [1.002-1.051], P = 0.037, respectively). CONCLUSION: Patients with breast cancer showed 67.6% prevalence of sleep disturbances after treatment. The patients with sleep disturbances were more likely to have previously experienced psychological disturbances, severe pain, depression within 5 years after diagnosis. After diagnosis for more than 5 years, higher distress caused by traumatic events still associated with sleep disturbances.

Low Concentrations of Dehydroepiandrosterone Sulfate are Associated with Depression and Fatigue in Patients with Non-Small-Cell Lung Cancer After Chemotherapy.

BACKGROUND: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) concentrations were reported to decrease in patients with advanced cancer. However, the clinical significance of DHEA and DHEAS concentrations in patients with NSCLC receiving chemotherapy (CT) has not been sufficiently documented. OBJECTIVE: To evaluate the correlation between mental health and hormone concentrations on patients with advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: The present study was a cross-sectional analysis based on a self-reported psychological investigation. Salivary samples were collected from 22 patients with advanced NSCLC after CT and 17 healthy controls. The concentrations of DHEA, DHEAS, and cortisol were analyzed to investigate their associations with the results of self-reported questionnaires on psychological health. RESULTS: Patients with advanced NSCLC exhibited significantly higher Patient Health Questionnaire (PHQ-9) and Startle, Physiological arousal, Anger, and Numbness-Chinese version (SPAN-C) scores, poorer health conditions, lower sleep quality, and more severe fatigue after CT than did healthy controls, and salivary concentrations of DHEA and DHEAS were significantly lower among patients after CT than among controls. DHEAS concentrations were negatively associated with depression scores (PHQ-9, r = -0.496, P = 0.019) and fatigue scores (Brief Fatigue Inventory-Taiwan, r = -0.562, P = 0.006). CONCLUSION: Patients with advanced NSCLC after CT had lower DHEA and DHEAS concentrations than did controls. Lower DHEAS concentrations were associated with higher fatigue and depression scores.

A highly sensitive and specific real-time quantitative PCR for BRAF V600E/K mutation screening.

Mutations that lead to constitutive activation of key regulators in cellular processes are one of the most important drivers behind vigorous growth of cancer cells, and are thus prime targets in cancer treatment. BRAF V600E mutation transduces strong growth and survival signals for cancer cells, and is widely present in various types of cancers including lung cancer. A combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has recently been approved and significantly improved the survival of patients with advanced NSCLC harboring BRAF V600E/K mutation. To improve the detection of BRAF V600E/K mutation and investigate the incidence and clinicopathological features of the mutation in lung cancer patients of southern Taiwan, a highly sensitive and specific real-time quantitative PCR (RT-qPCR) method, able to detect single-digit copies of mutant DNA, was established and compared with BRAF V600E-specific immunohistochemistry. Results showed that the BRAF V600E mutation was present at low frequency (0.65%, 2/306) in the studied patient group, and the detection sensitivity and specificity of the new RT-qPCR and V600E-specific immunohistochemistry both reached 100% and 97.6%, respectively. Screening the BRAF V600E/K mutation with the RT-qPCR and V600E-specific immunohistochemistry simultaneously could help improve detection accuracy.

Concurrent proton-pump inhibitors increase risk of death for lung cancer patients receiving 1st-line gefitinib treatment - a nationwide population-based study.

PURPOSE: Concurrent proton pump inhibitor (PPI) use might reduce the plasma concentration of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Clinically, the adverse effect of PPIs on patients with non-small cell lung cancer (NSCLC) treated with first-line EGFR TKIs remains controversial. This study was conducted to evaluate whether the combined use of gefitinib with PPIs affected NSCLC outcomes. PATIENTS AND METHODS: We performed a nationwide cohort study of patients newly diagnosed with NSCLC between 1997 and 2013 using the Taiwan Cancer Registry and Taiwan National Health Insurance databases. We identified patients who were treated with first-line EGFR TKIs and analyzed the association between use of PPIs and TKI treatment outcome. We defined the coverage ratio of PPIs as duration of PPI treatment in days divided by duration of TKIs in days. Patients who exhibited an overlap of >20% between PPI and TKI usage days were defined as having a high coverage ratio. RESULTS: A total of 1278 patients were treated with first-line gefitinib, 309 of which took PPIs at the same time and 145 had a high PPI coverage ratio. Patients had similar time to failure regardless of their PPI coverage ratio during gefitinib treatment. However, higher PPI coverage ratio significantly decreased overall survival (OS) compared with that of patients with a lower PPI coverage ratio or no PPI treatment in univariate analysis (median OS, 13.5, 16.7, and 21.8 months, respectively, p<0.01) and multivariate analyses (high coverage ratio HR: 1.67; low coverage ratio HR: 1.29). Exposure to PPIs during first line gefitinib treatment significantly decreased overall survival of patients with NSCLC. CONCLUSION: Concurrent use of PPIs was associated with lower overall survival in patients with EGFR-mutant NSCLC under first-line gefitinib treatment.

Comparative Analysis of Two Methods for the Detection of EGFR Mutations in Plasma Circulating Tumor DNA from Lung Adenocarcinoma Patients.

Mutations in the epidermal growth factor receptor (EGFR) are associated with various solid tumors. This study aimed to compare two methods for the detection of EGFR mutations in circulating tumor DNA (ctDNA) from lung adenocarcinoma (LUAD) patients and to evaluate the clinical significance of EGFR mutations in ctDNA. In this prospective cohort study, the EGFR mutation status of 77 patients with stage IIIB or IV LUAD was first determined using lung cancer tissue. The amplification refractory mutation system (ARMS) and single allele base extension reaction combined with mass spectroscopy (SABER/MassARRAY) methods were also used to detect EGFR mutations in plasma ctDNA from these patients and then compared using the EGFR mutation status in lung cancer tissue as a standard. Furthermore, the relationship between the presence of EGFR mutations in ctDNA after receiving first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and survival was evaluated. The overall sensitivity and specificity for the detection of EGFR mutations in plasma ctDNA by ARMS and SABER/MassARRAY were 49.1% vs. 56% and 90% vs. 95%, respectively. The agreement level between these methods was very high, with a kappa-value of 0.88 (95% CI 0.77-0.99). Moreover, 43 of the patients who carried EGFR mutations also received first-line EGFR-TKI therapy. Notably, patients with EGFR mutations in plasma ctDNA had significantly shorter progression-free survival (9.0 months, 95% CI 7.0-11.8, vs. 15.0 months, 95% CI 11.7-28.2; p = 0.02) and overall survival (30.6 months, 95% CI 12.4-37.2, vs. 55.6 months, 95% CI 25.8-61.8; p = 0.03) compared to those without detectable EGFR mutations. The detection of EGFR mutations in plasma ctDNA is a promising, minimally invasive, and reliable alternative to tumor biopsy, and the presence of EGFR mutations in plasma ctDNA after first-line EGFR-TKI therapy is associated with poor prognosis.

MET exon 14 skipping mutations and gene amplification in a Taiwanese lung cancer population.

Somatic mutations of MET gene are emerging as important driver mutations for lung cancers. To identify the common clinicopathological features of MET exon 14 skipping mutations and amplification and clarify whether the two MET gene alterations cause protein overexpression were investigated using 196 lung cancer samples of Taiwan through real time-qPCR/sequencing, fluorescence in situ hybridization, and immunohistochemistry. The two MET gene alterations are both present in low frequency, ~1%, in the studied lung cancer population of Taiwan. MET exon 14 skipping mutations were identified from two early-stage patients, who were both relatively advanced in age, and did not carry other driver mutations. One was an adenocarcinoma and the other was a rare carcinosarcoma. Three gene amplifications cases were identified. Neither of the two MET gene alterations would lead to protein overexpression; hence, direct detection in nucleic acid level would be a preferred and straightforward solution for the identification of skipping mutations. The presence of MET exon 14 mutations in minor histological types of lung cancers urge to extend screening scope of this mutation in lung cancer and treatment response evaluation in clinical trials. These would be important next steps for the success of MET target therapy in clinical practice.

Survival-associated factors of first-line EGFR-tyrosine kinase inhibitor responders and non-responders in lung adenocarcinoma patients with common EGFR mutations.

The aim of the present retrospective cohort study was to elucidate the clinical presentation of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) responders and non-responders in lung adenocarcinoma patients with common EGFR mutations. The cohort included 131 lung adenocarcinoma patients with common exon 19 or exon 21 EGFR mutations, who were receiving first-line EGFR-TKI therapy. The patient characteristics, treatment regimen and outcomes were recorded and analyzed. Of the 131 patients, 104 (79.3%) responded to treatment, while 27 (20.7%) did not. A significantly longer median progression-free survival (PFS) [14.3, 95% confidence interval (CI): 12.2-18.4 vs. 5.7, 95% CI: 2.7-9.9 months; P<0.001] and overall survival (OS) (42.2, 95% CI: 28.1-58.1 vs. 11.5, 95% CI: 8.3-19.7 months; P<0.001) were observed in responders compared with non-responders. In responders, bone [hazard ratio (HR)=1.87, 95% CI: 1.11-3.20, P=0.021] and pleural (HR=2.40, 95% CI: 1.37-4.22, P=0.002) metastasis were independent factors of PFS. Exon 19 mutations (HR=0.38, 95% CI: 0.19-0.76, P=0.006), Eastern Cooperative Oncology Group performance status score ≥2 (HR=3.53, 95% CI: 1.42-8.75, P=0.007) and bone metastasis (HR=2.01, 95% CI: 1.05-3.85, P=0.034), were independent factors of OS. In non-responders, smoking (HR=3.97, 95% CI: 1.13-13.91, P=0.031) was an independent factor of PFS. Different survival-associated factors were observed between EGFR-TKI responders and non-responders. The development of new treatment strategies should be advocated in EGFR-TKI non-responders.

Impact of hypertrophic pulmonary osteoarthropathy on patients with lung cancer.

PURPOSE: Hypertrophic pulmonary osteoarthropathy (HPOA) is a rare disease that most commonly occurs secondary to lung cancer. However, the clinical significance of HPOA remains unclear. The aim of this study was to evaluate the impact of HPOA on patients with lung cancer in Taiwan. PATIENTS AND METHODS: Data regarding lung cancer patients who demonstrated findings of HPOA on bone scintigraphy between 2010 and 2016 were retrospectively analyzed. Pathological confirmation of cases was conducted at Chiayi and Kaohsiung Chang Gang Memorial Hospital. Clinical characteristics, including gender, smoking status, histology subtype, clinical stage, and epidermal growth factor receptor (EGFR) status were investigated. RESULTS: We identified 69 lung cancer patients with typical HPOA findings on bone scintigraphy. Among them, 56 were male (81.2%) and 51 were ex-smokers or current smokers (73.9%). Adenocarcinoma was the most common histology subtype (n=42, 60.9%). Of 34 patients subjected to EGFR mutation analysis, only 4 (11.8%) had EGFR-tyrosine kinase inhibitor (EGFR-TKI)-sensitive mutations. CONCLUSION: Male, smoking, and adenocarcinoma were the most common clinical characteristics of lung cancer patients with HPOA in our cohort. However, the proportion of EGFR-TKI-sensitive mutation cases was extremely low.