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Purpose: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs)., Methods: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H 2 -receptor antagonists (H 2 RAs)., Results: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively., Conclusion: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

For rapid and unlimited cell growth and proliferation, cancer cells require large quantities of nutrients. Many metabolic pathways and nutrient uptake systems are frequently reprogrammed and upregulated to meet the demand from cancer cells, including the demand for lipids. The lipids for most adult normal cells are mainly acquired from the circulatory system. Whether different cancer cells adopt identical mechanisms to ensure sufficient lipid supply, and whether the lipid demand and supply meet each other, remains unclear, and was investigated in lung cancer cells. Results showed that, despite frequent upregulation in de novo lipogenesis and the lipid transporter system, different lung cancer cells adopt different proteins to acquire sufficient lipids, and the lipid supply frequently exceeds the demand, as significant amounts of lipids stored in the lipid droplets could be found within lung cancer cells. Lipid droplet surface protein, PLIN3, was found frequently overexpressed since the early stage in lung cancer tissues. Although the expression is not significantly associated with a specific gender, age, histology type, disease stage, and smoking habit, the frequently elevated expression of PLIN3 protein indicates the importance of lipid droplets for lung cancer. These lipid droplets are not only for nutrient storage, but are also crucial for tumor growth and proliferation, as well as survival in starvation. These results suggest that manipulation of lipid droplet formation or TG storage in lung cancer cells could potentially decrease the progression of lung cancer. Further exploration of lipid biology in lung cancer could help design novel treatment strategies.

Background: Studies have indicated that individuals taking aspirin have a reduced risk of cancers and have also established chemo-preventive benefit of aspirin in colorectal cancer. However, research on the association between aspirin use and the survival in patients with lung cancer has revealed inconsistent results. In this study, we investigated the effect of aspirin use on the survival of inoperable non-small cell lung cancer (NSCLC) patients., Methods: We identified a cohort of 38,842 patients diagnosed with NSCLC between 2000 and 2012 using the Taiwan's National Health Insurance Research Database and used propensity score matching to reduce possible confounding factors. In total, 9864 patients (4932 matched pairs) were included in the matched cohort. Aspirin exposure was analyzed to identify a possible association with mortality in patients with inoperable NSCLC. Time-dependent Cox regression models were used to calculate the hazard ratios (HRs) and the 95% confidence intervals (95% CIs) that corresponded with aspirin exposure., Results: A total of 4979 patients used aspirin at the time of diagnosis of NSCLC. The median overall survival (OS) of the aspirin users was 1.73 (interquartile range, 0.94-3.53) years compared with the 1.30 (interquartile range, 0.69-2.62) years of the non-aspirin users. The Cox proportional hazard model with the time-dependent covariate revealed that aspirin use was associated with a significantly longer OS (HR: 0.83, 95.0% CI: 0.80-0.86). After controlling the sociodemographic characteristics (age, sex, income, and level of urbanization) and lung cancer treatments by propensity score matching, the aspirin users still had a significantly longer OS than the non-aspirin users (HR: 0.79, 95.0% CI: 0.75-0.83)., Conclusion: Aspirin use is associated with a longer OS in patients with inoperable NSCLC, suggesting that aspirin has a potential anticancer effect. These results warrant further randomized clinical trials to evaluate the actual role of aspirin in the treatment of NSCLC patients., (© 2021. The Author(s).)

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.

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.

Acquired resistance is unavoidable with the approval of third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for first-line therapy of advanced non small cell lung cancer (NSCLC). Some studies have found that combining antiangiogenesis medicines with EGFR-TKI may benefit clinical outcomes in EGFR-mutant NSCLC. However, it is unclear whether EGFR-TKI paired with antiangiogenesis therapy could further improve survival for patients with gradual progression. Thus, we comprised the clinical effectiveness and safety of continuous EGFR-TKI in combination with anlotinib and EGFR-TKI alone in patients who had gradual progression on third-generation EGFR-TKI treatment. The comparison of progression-free survival (PFS) and overall survival(OS) between two groups used the Kaplan-Meier method. Our study comprised 121 eligible patients in total. The objective response rates were 25.0% and 0%, and the disease response rate was 91.7% and 86.9% in the combination group and EGFR-TKIs monotherapy group. The median PFS of combined anlotinib and EGFR-TKI treatment was 6.7 months and the median PFS was 3.6 months in the EGFR-TKI monotherapy group ( P  < 0.001). There were no significant differences between the two groups in OS. The common adverse reactions were diarrhea (21.7%), hypertension (21.6%) and proteinuria (20.0%) in the combination group. Seven patients experienced a grade 3 or higher adverse event, no patients discounted the treatment or died due to the toxicity. Our study indicated that, when combined with anlotinib following gradual progression on EGFR-TKIs, it was more efficacious for EGFR-mutant NSCLC patients than EGFR-TKI monotherapy. And the toxicity was clinically manageable., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: This meta-analysis compared radiotherapy (RT) versus concurrent chemoradiotherapy (RT+CT) in treating patients with inoperable stage III non-small-cell lung cancer (NSCLC)., Methods: Medline, Cochrane, EMBASE, Google Scholar databases were searched until July 28, 2015 using the following keywords non-small cell lung cancer, advanced cancer, incurable/inoperable/unresectable, chemotherapy, radiotherapy, chemoradiotherapy/chemoradiation. Randomized controlled trials (RCTs) and two-armed prospective studies that compared combined RT+CT with RT alone in patients with locally advanced (stage III) nonresectable NSCLC were eligible for inclusion. Treatment effect on overall survival, progression-free survival (PFS), and objective response rate (ORR) were evaluated., Results: Ultimately, 13 RCT studies were included in the systematic review and meta-analysis. The 13 studies included a total of 1936 patients with incurable/inoperable stage III NSCLC, of which 975 received RT alone and 961 received RT+CT combination therapy. The average age ranged from 54 to 77 years. At 1 and 2 years after treatment, the pooled data reveal that patients receiving CT+RT combination therapy had higher overall survival (pooled hazard ratio (HR), 0.72; 95% CI, 0.62-0.84; P < .001; 1-yr: HR, 0.67; 95% CI, 0.54-0.84; P < .001; 2-year: HR, 0.57; 95% CI, 0.45-0.73; P < .001), higher PFS (pooled HR, 0.73, 95% CI, 0.60-0.89; P = .002; 1-year: HR, 0.36; 95% CI, 0.24-0.53; P < .001; 2-year: HR, 0.38; 95% CI, 0.23-0.63; P < .001)., Conclusion: Our findings show higher efficacy for concurrent CT+RT over RT alone in treating locally-advanced, unresectable stage III NSCLC.

Background: Metformin use reportedly reduces cancer risk and improves survival in lung cancer patients. This study aimed to investigate the effect of metformin use in patients with diabetes mellitus (DM) and lung cancer receiving epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Methods: A nationwide, population-based cohort study was conducted using the Taiwan National Health Insurance Research Database. From January 1, 2004, to December 31, 2012, a total of 373 metformin and 1260 non-metformin lung cancer cohorts with type 2 DM and EGFR-TKI treatment were studied. Results: Metformin use was significantly associated with a reduced risk of death (hazard ratio: 0.73, 95% confidence interval [CI]: 0.62-0.85, P < .001), as well as a significantly longer median progression-free survival (9.2 months, 95% CI: 8.6-11.7, vs 6.4 months, 95% CI: 5.9-7.2 months, P < .001) and median overall survival (33.4 months, 95% CI: 29.4-40.2, vs 25.4 months, 95% CI: 23.7-27.2 months, P < 0.001). Conclusions: In conclusion, metformin may potentially enhance the therapeutic effect and increase survival in type 2 DM patients with lung cancer receiving EGFR-TKI therapy.

This study aimed to explore the incidence and risk factors of depression after lung cancer diagnosis. Using the Taiwan National Health Insurance Research Database (NHIRD), incidences and risk factors of depression in lung cancer and nonlung cancer cohorts were analyzed.From 1998 to 2006, a total of 22,125 patients were included in each matched cohort of lung cancer and nonlung cancer patients from NHIRD. The incidence of depression was higher in the lung cancer cohort than in the nonlung cancer cohort (1545.8 vs 1366.6 per 100,000 person-years). An increased risk of depression was observed in the lung cancer cohort [adjusted hazard ratio (aHR): 1.16, 95% confidence interval (95% CI): 1.01-1.34, P = .0377]. In lung cancer patients, age ≤50 years (aHR: 2.72, 95% CI: 2.02-3.66, P < .0001), age 50 to 69 years (aHR: 2.34, 95% CI: 1.87-2.94, P < .0001), female gender (aHR: 1.50, 95% CI: 1.26-1.80, P < .0001), coronary artery disease (CAD) (aHR: 1.40, 95% CI: 1.08-1.82, P = .0113), and operation (aHR: 1.78, 95% CI: 1.46-2.16, P < .0001) were associated with an increased risk of depression. In addition, higher incidences of emergency room (ER) visit (4.76 vs 2.82, per person-year) and admission (5.73 vs 4.33, per person-year) were observed in lung cancer patients with depression than those without depression.Our results showed that early surveillance and intervention of depression should be advocated after a diagnosis of lung cancer.

Long-term use of statins has been reported to reduce the risk of death in patients with lung cancer. This study investigated the effect of statin use among patients with lung cancer receiving epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKIs) therapy. A nationwide, population-based case-control study was conducted using the Taiwan National Health Insurance Research Database. From January 1, 1997 to December 31, 2012, a total of 1,707 statin and 6,828 non-statin matched lung cancer cohorts with EGFR-TKIs treatment were studied. Statin use was associated with a reduced risk of death (HR: 0.58, 95% CI: 0.54-0.62, p < 0.001). In addition, statin use was associated with a significantly longer median progression-free survival (8.3 months, 95% CI: 7.6-8.9 vs. 6.1 months, 95% CI: 6.0-6.4, p < 0.001) and median overall survival (35.5 months, 95% CI: 33.8-38.1 vs. 23.9 months, 95% CI: 23.4-24.7, p < 0.001). In conclusion, statins might potentially enhance the therapeutic effect and increase survival in patients with lung cancer receiving EGFR-TKI therapy., Competing Interests: All authors declare no conflicts of interest.

Cullin 4A (Cul4A) has been observed to be overexpressed in various cancers. In this study, the role of Cul4A in the growth and chemosensitivity in lung cancer cells were studied. We showed that Cul4A is overexpressed in lung cancer cells and tissues. Knockdown of the Cul4A expression by shRNA in lung cancer cells resulted in decreased cellular proliferation and growth in lung cancer cells. Increased sensitivity to gemcitabine, a chemotherapy drug, was also noted in those Cul4A knockdown lung cancer cells. Moreover, increased expression of p21, transforming growth factor (TGF)-β inducible early gene-1 (TIEG1) and TGF beta-induced (TGFBI) was observed in lung cancer cells after Cul4A knockdown, which may be partially related to increased chemosensitivity to gemcitabine. G0/G1 cell cycle arrest was also noted after Cul4A knockdown. Notably, decreased tumour growth and increased chemosensitivity to gemcitabine were also noted after Cul4A knockdown in lung cancer xenograft nude mice models. In summary, our study showed that targeting Cul4A with RNAi or other techniques may provide a possible insight to the development of lung cancer therapy in the future., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Epidermal growth factor receptor (EGFR) activation has been shown to play a critical role in tumor angiogenesis. In this study, we investigate the correlation between EGFR mutations and cadherin-5 (CDH5), which is an angiogenic factor, in lung cancer cells. Increased expression CDH5 is observed in lung cancer cells with EGFR mutations. Stable lung cancer cell lines expressing mutant (exon 19 deletion E746-A750, and exon 21 missense mutation L858R) and wild type EGFR genes are established. A significantly higher expression of CDH5 is observed in exon 19 deletion stable lung cancer cells and mouse xenografts. Further studies show that expression of CDH5 is decreased after the inhibition of EGFR and downstream Akt pathways in lung cancer cells with EGFR mutation. In addition, mutant EGFR genes potentiates angiogenesis in lung cancer cells, which is inhibited by CDH5 siRNA, and potentiates migration and invasion in lung cancer cells. Our study shows that mutant EGFR genes are associated with overexpression of CDH5 through increased phosphorylation of EGFR and downstream Akt pathways. Our result may provide an insight into the association of mutant EGFR and CDH5 expression in lung cancer and aid further development of target therapy for NSCLC in the future.

This study aimed to elucidate the association of the content of mutant epidermal growth factor receptor (EGFR) deoxyribonucleic acid (DNA) with the treatment response to EGFR-tyrosine kinase inhibitor (TKI) and survival in patients with lung cancer.This retrospective cohort study included 77 lung adenocarcinoma patients with common EGFR mutations from December 2012 to February 2015. The content of mutant EGFR DNA in lung cancer tissues was determined using an Amplification Refractory Mutation System. The association of the amount of mutant EGFR DNA with treatment response, the clinical variables, and the progression-free survival (PFS) after EGFR-TKI therapy were evaluated.Using the amount of mutant EGR DNA above 4.77% as the cut-off value, the sensitivity to predict EGFR-TKI responder is 82.0% and the specificity is 75.0% (area under the curve [AUC]: 0.734, P = 0.003). The high content of mutant EGFR DNA is an independent factor associated with the response to EGFR-TKIs (odds ratio: 13.07, 95% confidence interval [CI]: 3.23-52.11, P = 0.0003). A significantly longer PFS was observed in the group with the high content of mutant EGFR DNA (26.3 months, 95% CI: 12.2-26.3) compared with the low content of mutant EGFR DNA groups (12.3 months, 95% CI: 5.7-14.8, P = 0.0155). A better predictive value of the content of mutant EGFR DNA was noted in patients with exon 19 deletions (AUC: 0.892, P < 0.0001) than exon 21 L858R mutations (AUC: 0.675, P = 0.0856).Our results show that the content of mutant EGFR DNA is associated with the clinical response to EGFR-TKIs, especially in patients with exon 19 deletions mutation.

Objectives: ALK fusion gene is an oncogenic driver in lung cancer with low prevalence, which can be ameliorated by crizotinib. Currently, ALK fusion gene can be diagnosed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), but inconstistnt results between the two methods are encountered regularly. To make the ALK fusion gene screening more efficient and to provide a simple solution to clarify the discrepancy between FISH and IHC results, a sensitive TaqMan-based reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay was established., Materials and Methods: The 3-plex TaqMan-based RT-qPCR assay was established and performed on 102 archived formalin-fixed, paraffin-embedded (FFPE) NSCLC samples to detect ALK rearrangement and overexpression. Break-apart FISH and automatic immunohistochemistry based ALK assays were performed side by side using tissue microarray., Results: The RT-qPCR was performed successfully for 80 samples and 10 of them showed positive signals. Three out of the 10 qPCR positive cases were further confirmed by FISH and IHC test. Two others were IHC positive and FISH negative, and expressed full-length ALK transcript. The rest were neither FISH nor IHC positive and their ALK expression level was significantly lower than those FISH or IHC positive cases., Conclusion: Our RT-qPCR assay demonstrates that the capability and reliability of ALK detection is comparable to FISH and IHC, but it is more effective at discriminating ALK rearrangement from overexpression. The RT-qPCR assay easily clarifies the discrepancy between FISH and IHC, and can be incorporated into routine ALK screening for lung cancer., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Cullin 4A (Cul4A) promotes oncogenesis through overexpression and then ubiquitination‑mediated proteolysis of tumor suppressors in various types of cancers. Transforming growth factor β‑induced (TGFBI) has been implicated as a tumor suppressor, which enhances gemcitabine chemosensitivity in lung cancer cells. The present study aimed to investigate the association of TGFBI and Cul4A and the mechanism by which Cul4A regulates TGFBI. In addition, we also evaluated the therapeutic value of Cul4A RNAi using adenoviral transfection of Cul4A RNAi in nude mouse xenograft models. We observed that knockdown of Cul4A was associated with increased sensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Cul4A regulated TGFBI through direct interaction and then ubiquitin‑mediated protein degradation. In the nude mouse xenograft models, adenoviral transfection of Cul4A RNAi in combination with gemcitabine chemotherapy inhibited lung cancer tumor growth. As the result, combination of Cul4A RNAi with chemotherapy may provide a new approach to lung cancer treatment.

Immune checkpoint inhibitors (ICIs) ± chemotherapy is the standard treatment for driver mutation-negative non-small cell lung cancer (NSCLC). However, accessibility to ICIs in LMICs is limited due to high cost, and platinum-based chemotherapy remains the mainstay of treatment. Metformin has anticancer properties, and studies suggest synergism between metformin and pemetrexed. Based on preclinical evidence, this combination may be more beneficial for STK11-mutated NSCLC, a subgroup, inherently resistant to ICIs. In this Simon two-stage, single-arm phase 2 trial, we investigated metformin with pemetrexed-carboplatin (PC) in patients with treatment-naive stage IV non-squamous NSCLC. The primary outcome was 6-month progression-free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK11 mutation, and effect of STK11 mutation on 6-month PFS rate. The study was terminated for futility after interim analysis. The median follow-up was 34.1 months. The 6-month PFS rate was 28% (95% CI 12.4-0.46). The median PFS and OS were 4.5 (95% CI 2.2-6.1) and 7.4 months (95% CI 5.3-15.3), respectively. The ORR was 72%. Gastrointestinal toxicities were the most common. No grade 4/5 toxicities were reported. Targeted sequencing was possible in nine cases. Two patients had STK11 mutation and a poor outcome (PFS < 12 weeks). We could not demonstrate the benefit of metformin with CP in terms of improvement in 6-month PFS rate; however, the combination was safe (CTRI/2019/02/017815)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A., (Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2α in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer.

Background: Wnt-2 plays an oncogenic role in cancer, but which Frizzled receptor(s) mediates the Wnt-2 signaling pathway in lung cancer remains unclear. We sought to (1) identify and evaluate the activation of Wnt-2 signaling through Frizzled-8 in non-small cell lung cancer, and (2) test whether a novel expression construct dominant negative Wnt-2 (dnhWnt-2) reduces tumor growth in a colony formation assay and in a xenograft mouse model., Methods: Semi-quantitative RT-PCR was used to identify the expression of Wnt-2 and Frizzled-8 in 50 lung cancer tissues from patients. The TCF reporter assay (TOP/FOP) was used to detect the activation of the Wnt canonical pathway in vitro. A novel dnhWnt-2 construct was designed and used to inhibit activation of Wnt-2 signaling through Frizzled-8 in 293T, 293, A549 and A427 cells and in a xenograft mouse model. Statistical comparisons were made using Student's t-test., Results: Among the 50 lung cancer samples, we identified a 91% correlation between the transcriptional increase of Wnt-2 and Frizzled-8 (p<0.05). The Wnt canonical pathway was activated when both Wnt-2 and Frizzled-8 were co-expressed in 293T, 293, A549 and A427 cells. The dnhWnt-2 construct we used inhibited the activation of Wnt-2 signaling in 293T, 293, A549 and A427 cells, and reduced the colony formation of NSCLC cells when β-catenin was present (p<0.05). Inhibition of Wnt-2 activation by the dnhWnt-2 construct further reduced the size and mass of tumors in the xenograft mouse model (p<0.05). The inhibition also decreased the expression of target genes of Wnt signaling in these tumors., Conclusions: We demonstrated an activation of Wnt-2 signaling via the Frizzled-8 receptor in NSCLC cells. A novel dnhWnt-2 construct significantly inhibits Wnt-2 signaling, reduces colony formation of NSCLC cells in vitro and tumor growth in a xenograft mouse model. The dnhWnt-2 construct may provide a new therapeutic avenue for targeting the Wnt pathway in lung cancer.

CK2 interacts and phosphorylates >300 proteins, including Stat3, and is linked to a number of human cancers. Constitutively activated Stat3 has been reported in 50% of human lung cancers. Inhibition of CK2 activity can induce apoptosis and suppression of Stat3 activation in cancer cells. This study examined the effects of CK2 inhibitors on growth inhibition of lung cancer cells and the therapeutic potential on lung cancer. The CK2 inhibitor and radiation both suppressed cancer cell growth in a dose-dependent manner. Besides, the cytotoxic effect of irradiation could be augmented by CK2 inhibitors (p<0.05, two-way analysis of variance and Tukey's Honestly Significant Difference). Moreover, the growth inhibition of CK2 inhibitor and irradiation was both associated with suppression of Stat3 activation. Taken together, inhibition of CK2 activity appears to be a promising treatment strategy for non-small cell lung cancer and CK2 inhibition results in reduced Stat3 activation. Our data warrant further effort to develop CK2-targeted radiosensitizer for lung cancer treatment.

Protein kinase CK2 is frequently up-regulated in human cancers, although the mechanism of CK2 activation in cancer remains unknown. In this study, we investigated the role of the CK2alpha intronless gene (CSNK2A1P, a presumed CK2alpha pseudogene) in the pathogenesis of human cancers. We found evidence of amplification and over-expression of the CSNK2A1P gene in non-small cell lung cancer and leukemia cell lines and 25% of the lung cancer tissues studied. The mRNA expression levels correlated with the copy numbers of the CSNK2A1P gene. We also identified a novel polymorphic variant (398T/C, I133T) of the CSNK2A1P gene and showed that the 398T allele is selectively amplified over the 398C allele in 101 non-small cell lung cancer tissue samples compared to those in 48 normal controls (p = 0.013<0.05). We show for the first time CSNK2A1P protein expression in transfected human embryonic kidney 293T and mouse embryonic fibroblast NIH-3T3 cell lines. Both alleles are transforming in these cell lines, and the 398T allele appears to be more transforming than the 398C allele. Moreover, the 398T allele degrades PML tumor suppressor protein more efficiently than the 398C allele and shows a relatively stronger binding to PML. Knockdown of the CSNK2A1P gene expression with specific siRNA increased the PML protein level in lung cancer cells. We report, for the first time, that the CSNK2A1P gene is a functional proto-oncogene in human cancers and its functional polymorphism appears to degrade PML differentially in cancer cells. These results are consistent with an important role for the 398T allele of the CSNK2A1P in human lung cancer susceptibility.

Secreted Wingless type (Wnt) ligands have previously been shown to be involved in tumor developmental processes and oncogenesis. Aberrant promoter methylation of Wnt inhibitory factor-1 (WIF-1) is a fundamental mechanism of epigenetic silencing in human cancers. Procaine, a local anesthetic drug, and procainamide, a drug for the treatment of cardiac arrhythmias, have been reported as inhibitors of DNA methylation, causing demethylation and reactivation of methylation-silenced genes such as RARbeta and GSTP1. The promoter demethylation of WIF-1 has not previously been reported on. We demonstrated previously that WIF-1 is silenced due to promoter hypermethylation in lung cancer cell lines. In this study, we demonstrate promoter demethylation of WIF-1; restoration of WIF-1 expression, and underexpression of cytosolic beta-catenin protein and TCF reporter activity, after procaine and procainamide treatment in H460 and A549 cell lines. Our results provide the first evidence that procaine and procainamide reactivate WIF-1 in these cancer cells and downregulate the Wnt canonical pathway. These results further suggest that procaine and procainamide may have a potential use for preventing the development of lung cancer.

Purpose: Malignant pleural effusion is an important staging criterion in non-small cell lung cancer (NSCLC). Although cytologic examination remains the major diagnostic tool for NSCLC-related malignant pleural effusion, sometimes other invasive methods maybe required. Aberrant activation of Wnt signaling pathway due to Wnt inhibitory factor-1 (WIF-1) promoter region hypermethylation is common in NSCLC, and can be specifically detected by methylation-specific polymerase chain reaction (MSP). We hypothesized that WIF-1 promoter region MSP can be used to improve the diagnostic yield of NSCLC-related malignant pleural effusion., Methods: We performed WIF-1 promoter region MSP in 36 definite malignant pleural effusions from consecutive NSCLC patients and 35 pleural effusion specimens of benign origin. Pleural effusion cells were collected for DNA extraction. After bisulfite treatment, DNA was amplified by methylation-specific and unmethylation-specific primers, respectively, to identify the methylation status of WIF-1 promoter region., Results: The results of WIF-1 promoter region MSP were positive in 25 (69.4%) of 36 NSCLC patients with malignant pleural effusion. In addition, the results of WIF-1 promoter region MSP were negative in all 35 patients with pleural effusion of benign origin. The age, gender, and smoking status of patients were not correlated with the methylation status of WIF-1 promoter region in NSCLC-related malignant pleural effusion., Conclusions: WIF-1 promoter region MSP might be used as an adjuvant tool to complement cytologic examination for the diagnosis of NSCLC-related malignant pleural effusion.

Background: Aberrant promoter methylation of Wnt inhibitory factor-1 (WIF-1) is a fundamental mechanism of epigenetic silencing in human cancers. Epigallocatechin-3-gallate (EGCG) has been reported to directly reactivate several methylation-silenced genes. The promoter demethylation and reactivation of WIF-1 has not previously been reported., Materials and Methods: Methylation-specific PCR, sequencing analysis and RT-PCR analysis were performed to evaluate promoter demethylation of WIF-1 and WIF-1 expression, Western blot analysis and luciferase reporter assay were performed to evaluate expression of cytosolic beta-catenin protein and Tcf/Lef reporter activity., Results: Promoter demethylation of WIF-1 and restoration of WIF-1 expression after EGCG treatment are demonstrated in H460 and A549 cell lines. EGCG also decreased cytosolic beta-catenin protein level and inhibited Tcf/Lef reporter activity., Conclusion: These results suggest the potential therapeutic use of EGCG for the reversal of WIF-1 promoter methylation.

Background: The prevalence of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients is about 40-50% in Taiwan, and there are significant correlations between EGFR mutations and clinical responses after gefitinib treatment. For most patients with advanced disease, surgical intervention for tissue sampling is not feasible. We therefore conducted this study to survey EGFR mutations in cells from NSCLC malignant pleural effusions and to evaluate the clinical significance., Methods: In the present study, malignant pleural effusion cells from 29 NSCLC patients were studied for EGFR mutations. Exons 18, 19, 20, 21 of the EGFR gene were analyzed by polymerase chain reaction (PCR) and automated sequencing. For 11 patients who had received gefitinib therapy, correlations between gefitinib effect and EGFR mutations were also evaluated., Results: EGFR mutations were detected in 12 of 29 specimens (41%). In-frame deletion mutations in exon 19 (8 of 12 specimens, 67%) and missense mutations in exon 21 (3 of 12 specimens, 25%) were the most frequent mutations detected. The frequency of EGFR mutations was significantly higher in gefitinib responders (4/4) than non-responders (1/7) (p = 0.015)., Conclusion: Our results suggest that detecting EGFR mutations in cells from malignant pleural effusions is a feasible adjunct method to finding the subgroup with favorable response to gefitinib therapy among patients with advanced NSCLC.

Aims: Proton pump inhibitors (PPIs) are often prescribed to prevent or treat gastrointestinal disease. Whether the combination of systemic anti-tumour therapy and PPIs leads to poor outcomes in patients with advanced non-small cell lung cancer (NSCLC) is unclear. This systematic review explored the relationship between PPIs and survival outcomes of patients with advanced NSCLC who are receiving systemic anti-tumour therapy., Methods: We searched studies reporting the overall survival (OS) and/or progression-free survival (PFS) of advanced NSCLC patients who are receiving systemic anti-tumour therapy with or without PPIs on PubMed, EMBASE and the Cochrane Library for literature published prior to 31 August 2021. The meta-analysis used a random effects model to estimate the hazard ratio (HR) with 95% confidence intervals (CI) and I 2 to assess statistical heterogeneity. Publication bias and sensitivity analysis were performed., Results: Fourteen retrospective studies comprising 13 709 advanced NSCLC patients were identified. Subgroup analyses showed that the use of PPI was correlated with the OS or PFS of patients receiving chemotherapy, targeted therapy, and immunotherapy (PPI users' group vs non-users' group: HR for OS = 1.35, 95% CI = 1.21-1.51, P < .00001; HR for PFS = 1.50, 95% CI = 1.25-1.80, P < .0001). Publication bias and sensitivity analyses confirmed that the results were robust., Conclusion: Meta-analysis demonstrated that PPI use in advanced NSCLC patients who were undergoing systemic anti-tumour therapy was correlated with increased mortality risk. Until results are further confirmed, caution should be applied when administering PPIs and systemic anti-tumour therapy to advanced NSCLC patients., (© 2022 British Pharmacological Society.)

Although anti-angiogenic agents have been of limited use in the treatment of non-small cell lung cancer (NSCLC) until recently, further roles for the use of angiogenesis inhibition have emerged in the era of targeted therapy and immune checkpoint blockade. Given the shared common downstream signals of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) with their complementary roles in tumorigenesis and tumor angiogenesis, the dual inhibition of EGFR and VEGF pathways represents a rational strategy to maximize clinical efficacy and overcome resistance in the treatment of EGFR-mutant NSCLC. VEGF-driven angiogenesis is a potent driver of immunosuppressive tumor microenvironment (TME), with the recruited immunosuppressive cells driving angiogenesis, highlighting the interplay between the tumor vasculature and the anticancer immunity. Anti-angiogenic therapy can normalize the tumor vasculature and reprogram the TME from immunosuppressive into immunosupportive. Intensive research is under way to utilize the anti-angiogenic combination therapy to its full potential in diverse clinical settings in urgent unmet needs for the treatment of NSCLC. In this review, we present an overview of tumor angiogenesis and summarize the scientific background and preclinical and clinical evidence of anti-angiogenic therapy in combination with target therapy and immunotherapy for the treatment of NSCLC., (© 2022. The Pharmaceutical Society of Korea.)

Objective: The objective of this study was to compare the cost effectiveness of first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer., Methods: This study used Ontario Cancer Registry-linked administrative data to identify patients with a primary diagnosis of lung cancer who received EGFR-TKIs as first-line treatment between 1 January, 2014 and 31 August, 2019. A net benefit regression approach accounting for baseline covariates and propensity scores was used to estimate incremental net benefits and incremental cost-effectiveness ratios. Outcome measures were calculated over a 68-month period and were discounted with an annual rate of 1.5%. Sensitivity analyses were conducted to assess and characterize the uncertainties., Results: A total of 547 patients were included in the study, of whom 20.1%, 23.6%, and 56.3% received afatinib, erlotinib, and gefitinib, respectively. Erlotinib was dominated by afatinib and gefitinib. Compared to gefitinib, afatinib was associated with higher effectiveness (adjusted incremental quality-adjusted life-year: 0.21), higher total costs (adjusted incremental costs: $9745), and an incremental cost-effectiveness ratio of $46,506 per quality-adjusted life-year gained. Results from the sensitivity analyses indicated the findings of the base-case analysis were robust., Conclusions: Contrary to previously published studies, our study established head-to-head comparisons of effectiveness and treatment-related costs of first-line EGFR-TKIs. Our findings suggest afatinib was the most cost-effective option among the three EGFR-TKIs.

Purpose: Inconsistent results of lipid-lowering medications (LLMs) on improved cancer survival need more investigations. We tested the hypothesis that adherence to the drug would be associated with a lower cancer-specific mortality in a homogeneous population who has ever used the drug., Methods: Utilising data from the Australian Cancer database, linked to the Pharmaceutical Benefits Scheme data and the National Death Index, we identified two separate cohorts of 4519 and 3083 women patients with newly diagnosed endometrial and lung cancer respectively between 2003 and 2013. Adherence to this drug was calculated by proportion of days covered. Cox regression models with time-varying covariates were used to estimate the multivariable-adjusted cause-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of adherence to LLMs, statins, lipophilic and hydrophilic statins, and cancer-specific mortality., Results: Each 10% increase in 1-year adherence to LLMs reduced cancer-specific mortality among women with endometrial cancer (adjusted HR=0.93, 95% CI 0.90-0.96) or lung cancer (adjusted HR=0.95, 95% CI 0.93-0.97). The inverse associations remained unchanged in different subgroup analyses. The reductions in lung cancer mortality were not apparent for women who adhered to lipophilic statins albeit better endometrial cancer survival appeared in the lipophilic statin group and borderline statistical improvement in the hydrophilic statin group., Conclusions: Among LLM users, adherence to this drug is inversely associated with reduced cancer-specific mortality. Together with previous evidence, randomised controlled trials are called for to confirm whether LLMs could be considered as an adjuvant treatment to improve prognosis.

The aim of this study was to explore the potential value of autoantibody to epidermal growth factor receptor (EGFR) in the diagnosis of lung cancer (LC) and its relation with EGFR mutations. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the level of autoantibody to EGFR in sera from 254 LC patients and 222 normal controls (NCs). Besides, the mRNA and protein levels of EGFR were investigated in Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) database, respectively. The level of autoantibody to EGFR (anti-EGFR) in LC even different types of LC was obviously higher than that in NC (P < 0.05). The area under the curve (AUC) of anti-EGFR was 0.695 (95% CI 0.645-0.742) when comparing LC patients with NC, while the AUC of carcinoembryonic antigen (CEA) was 0.681 (95% CI 0.629-0.730). Moreover, by integrating anti-EGFR with CEA to diagnose LC, the AUC was up to 0.784 (95% CI 0.737-0.826). However, the expression level of autoantibody to EGFR had no difference between LC patients with and without EGFR gene mutation (P > 0.05). EGFR mRNA expression level was obviously upregulated in squamous cell carcinoma (SCC) tissues compared with normal tissues (P < 0.05), but not in adenocarcinoma (ADC) (P > 0.05). The study confirmed that anti-EGFR could be a potential biomarker for LC diagnosis; additionally, it could improve the diagnostic value of CEA in clinical work.

Although proliferating cell nuclear antigen (PCNA) plays an important role in tumor proliferation and its expression level is closely related to the biological activity of tumor cells, PCNA expression in non-small cell lung cancer (NSCLC) has been seldom reported. In this study, we aimed to investigate the significance of PCNA expression in NSCLC tissues. PCNA expression in NSCLC and adjacent tissues were assessed by immunohistochemistry (IHC), western blotting, and reverse transcription polymerase chain reaction. Single factor analysis was used to study the relationship between the expression of PCNA and clinicopathological features of NSCLC. Multi-factor Cox survival analysis was used to evaluate the relationship between the expression of PCNA and overall survival of postoperative NSCLC patients. The areas under the receiver operating characteristics were calculated to evaluate the value of PCNA expression level in predicting the 3-year survival of NSCLC patients. IHC analysis showed that the positive expression rates of PCNA protein in NSCLC and adjacent tissues were 91.79% (257/280) and 25.83% (31/120), respectively. Western blotting confirmed that PCNA protein level was significantly higher in NSCLC tissues than in the adjacent tissues (P < .05). Reverse transcription polymerase chain reaction showed that the positive rate of PCNA mRNA in NSCLC was 88.93% (249/280), which was significantly higher than that in adjacent tissues 29.17% (35/120) (P < .05). Both PCNA mRNA and protein levels were correlated with tumor differentiation, size, metastasis, and stage in NSCLC. Patients exhibiting higher PCNA protein expression had a significantly shorter disease-specific survival rate than the other patients. PCNA protein level and tumor pathological type, metastasis, differentiation degree, and stage were independent factors affecting the overall survival of postoperative patients. The areas under the receiver operating characteristics of PCNA mRNA for predicting the 3-year survival of NSCLC patients was 0.89 (0.79-0.98), with a sensitivity and specificity of 0.84 and 0.76, respectively. In conclusion, high PCNA protein and mRNA levels may be associated with the occurrence, development, and prognosis of NSCLC.

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Copyright of Tianjin Medical Journal is the property of Tianjin Medical Journal and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)