Chemoradiotherapy versus radiotherapy in high risk salivary gland cancer.

OBJECTIVE: The aim of this study was to investigate the potential survival benefits associated with chemoradiotherapy (CRT) as opposed to radiotherapy (RT) in patients with resected high-risk salivary gland cancer (SGC), with a specific focus on determining whether these benefits are influenced by the number of high-risk variables. METHODS: Patients who underwent surgical treatment for high-risk SGC were retrospectively enrolled and categorized into either CRT or RT groups. The impact of adjuvant therapy on locoregional control (LRC) and overall survival (OS) was assessed using a multivariable Cox model. RESULTS: A total of 152 patients were included following propensity score-matching. In comparison to RT, CRT did not demonstrate a significant survival advantage in terms of LRC (p = 0.485, HR: 1.14, 95%CI: 0.36-4.22) and OS (p = 0.367, HR: 0.99, 95%CI: 0.17-3.87) in entire population. But among patients with T3/4 stage, high-grade tumors, and 5 or more positive lymph nodes, the addition of chemotherapy to RT significantly (p = 0.042) correlated with a 15% reduction in the risk of cancer recurrence (95%CI: 4-54%). Conversely, in other subgroups with varying combinations of high-risk variables, CRT did not provide additional survival benefits for LRC and OS compared to RT. CONCLUSION: Adjuvant chemotherapy may be considered in conjunction with RT specifically in cases where there is a presence of T3/4 stage, high-grade tumors, and 5 or more metastatic lymph nodes in high-risk SGC.

Laboratory and field evaluation of a low-cost optical particle sizer.

Low-cost sensors are widely used to collect high-spatial-resolution particulate matter data that traditional reference monitoring devices cannot. In addition to the mass concentration, the number concentration and size distribution are also fundamental in determining the origin and hazard level of particulate pollution. Therefore, low-cost optical sensors have been improved to establish optical particle sizers (OPSs). In this study, a low-cost OPS, the Nova SDS029, is introduced, and it is evaluated in comparison to two reference instruments-the GRIMM 11-D and the TSI 3330. We first tested the sizing accuracy using polystyrene latex spheres. Then, we assessed the mass and number size distribution accuracy in three application scenarios: indoor smoking, ambient air quality, and mobile monitoring. The evaluations suggest that the low-cost SDS029 rivals research-grade optical sizers in many aspects. For example, (1) the particle diameters obtained with the SDS029 are close to the reference instruments (usually < 10%) in the 0.3-5 µm range; (2) the number of particles and mass concentration are highly correlated (r ≥ 0.99) with the values obtained with the reference instruments; and (3) the SDS029 slightly underestimates the number concentration, but the derived PM2.5 values are closer to monitoring station than the reference instruments. The successful application of the SDS029 in multiple scenarios suggests that a plausible particle size distribution can be obtained in an easy and cost-efficient way. We believe that low-cost OPSs will increasingly be used to map the sources and risk levels of particles at the city scale.

The Contribution of Double-strand Break Repair Radiation Sensitive Protein 51 Genotypes to Lung Cancer in Taiwan.

BACKGROUND/AIM: Numerous studies have reported the over-expression of the radiation-sensitive protein 51 (RAD51) in various types of cancer. However, the role of RAD51 genotypes in lung cancer remains largely unknown. This study aimed to assess the impact of the common variant RAD51 rs1801320 (G-135C) genotypes on the risk of lung cancer in Taiwan. MATERIALS AND METHODS: The contribution of RAD51 rs1801320 genotypes to lung cancer risk was investigated in a cohort comprising 358 lung cancer patients and 716 age- and sex-matched healthy controls, utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: The analysis revealed that among the control subjects, the percentages of GG, CG, and CC genotypes of RAD51 rs1801320 were 73.2%, 24.3%, and 2.5%, respectively. Among the lung cancer patients, these percentages were 71.0%, 25.1%, and 3.9%, respectively (p for trend=0.4075). Allelic frequency distributions showed no significant association between the C allele of RAD51 rs1801320 and lung cancer risk determination (p=0.2987). Specifically, the RAD51 rs1801320 CC genotypes were associated with an elevated risk of lung cancer among males [adjusted odds ratio (aOR)=2.28, 95% confidence interval (95%CI)=1.03-4.87] and smokers (aOR=2.93, 95%CI=1.23-5.87), but not among females and non-smokers. CONCLUSION: The RAD51 rs1801320 CC genotype was identified as a risk factor for elevated lung cancer risk in males and smokers. This genotype may serve as a molecular biomarker at the DNA level for early detection and prediction of lung cancer in Taiwan.

Evaluating the performance and influencing factors of three portable black carbon monitors for field measurement.

Black carbon (BC) is associated with adverse human health and climate change. Mapping BC spatial distribution imperatively requires low-cost and portable devices. Several portable BC monitors are commercially available, but their accuracy and reliability are not always satisfactory during continuous field observation. This study evaluated three models of portable black carbon monitors, C12, MA350 and DST, and investigates the factors that affect their performance. The monitors were tested in urban Beijing, where portable devices running for one month alongside a regular-size reference aethalometer AE33. The study considers several factors that could influence the monitors' performance, including ambient weather, aerosol composition, loading artifacts, and built-in algorithms. The results show that MA350 and DST present considerable discrepancies to the reference instrument, mainly occurring at lower concentrations (0-500 ng/m3) and higher concentrations (2500-8000 ng/m3), respectively. These discrepancies were likely caused by the anomalous noise of MA350 and the loading artifacts of DST. The study also suggests that the ambient environment has limited influence on the monitors' performance, but loading artifacts and accompanying compensation algorithms can result in unrealistic data. Based on the evaluation, the study suggests that C12 is the best choice for unsupervised field measurement, DST should be used in scenarios where frequent maintenance is available, and MA350 is suitable for research purposes with post-processing applicable. The study highlights the importance of assigning portable BC monitors to appropriate applications and the need for optimized real-time compensation algorithms.

Bevacizumab versus Ramucirumab in EGFR-Mutated Metastatic Non-Small-Cell Lung Cancer Patients: A Real-World Observational Study.

The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study's final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar.

Significant Contribution of Interleukin-18 Genotypes to Lung Cancer Risk in Taiwanese.

BACKGROUND/AIM: The elevated expression of interleukin-18 (IL-18) among lung cancer patients raised our curiosity to examine the role of IL-18 genotypes in lung cancer. MATERIALS AND METHODS: IL-18 -656 (rs1946519), -607 (rs1946518), and -137 (rs187238) genotypes of 358 lung cancer cases and 716 controls were determined via the PCR-RFLP methodology. RESULTS: The distributions of genotypic and allelic frequencies of IL-18 -607, but not those of -656 or -137, were differentially distributed between cases and controls. IL-18 -607 AC and CC genotypes were both lower (45.8% and 16.2%) in lung cancer patients compared to controls (51.4% and 24.7%). In addition, IL-18 -607 AC and CC genotypes were of significantly lower percentages both among non-smokers and smokers. Otherwise, no differential distribution was found regarding IL-18 -656 or -137. CONCLUSION: IL-18 -607 C allele can serve as a protective predictor for lung cancer risk in Taiwanese.

The Contribution of Interleukin-8 Rs4073 Genotypes to Triple Negative Breast Cancer Risk in Taiwan.

BACKGROUND/AIM: Triple negative breast cancer (TNBC) is one of the most challenging breast cancer types. Interleukin-8 (IL-8) is a pro-tumorigenic cytokine, promoting tumor proliferation and migration. This study aimed to examine the contribution of IL-8 rs4073 genotypes to breast cancer risk and provide a summary of related literature. MATERIALS AND METHODS: IL-8 genotypic profiles were determined among 1,232 breast cancer cases and 1,232 controls via polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The IL-8 rs4073 AT and AA genotypes had significantly lower prevalence in the case group compared to control group. Allelic frequency analysis showed that individuals carrying the A allele have relatively decreased risk for breast cancer. The stratification analysis showed that IL-8 rs4073 genotypes were protective markers for those with younger (≤55) age. CONCLUSION: IL-8 rs4073 A allele is a novel predictor for breast cancer, especially TNBC.

The optimal therapy strategy for epidermal growth factor receptor-mutated non-small cell lung cancer patients with brain metastasis: A real-world study from Taiwan.

BACKGROUND: The treatment options for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR-tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole-brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial. METHODS: A total of 150 EGFR-mutant NSCLC patients with BMs who received first- or second-generation EGFR-TKIs as first-line treatment between January 2012 and October 2019 were included in this analysis. RESULTS: After multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung-mol GPA) ≥3 (hazard ratio [HR]: 0.538, 95% confidence interval [CI]: 0.35-0.83), who received afatinib or erlotinib as first-line treatment (HR: 0.521, 95% CI: 0.33-0.82), underwent SRS therapy (HR: 0.531, 95% CI: 0.32-0.87), or were sequentially treated with osimertinib (HR: 0.400, 95% CI: 0.23-0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR-TKI provided more OS benefits in patients with Lung-mol GPA ≥3 compared with EGFR-TKI alone in our patient cohort (44.9 vs. 26.7 months, p = 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p < 0.001), regardless of T790 mutation status (positive vs. negative vs. unknown: 40.4 vs. 54.6 vs.43.4 months, p = 0.227). CONCLUSIONS: The study demonstrated that EGFR-mutant NSCLC patients with BMs could be precisely treated with SRS according to Lung-mol GPA ≥3. Sequential osimertinib was associated with prolonged survival, regardless of T790M status.

Association of Interleukin-8 Promoter Genotypes With Taiwan Lung Cancer Risk.

BACKGROUND/AIM: Chronic inflammation is believed to play a critical role in the pathogenesis of lung cancer. Interleukin-8 (IL-8) is an inflammatory cytokine and plays an important role in cancer development. Few studies have investigated the association between interleukin-8 - 251T/A (rs4073) genotype and lung cancer risk in various populations. MATERIALS AND METHODS: In the current study, genotypes of interleukin-8 rs4073 were analyzed in 358 lung cancer patients and 716 healthy controls in Taiwan, by the PCR-RFLP methodology. RESULTS: The distribution frequencies of interleukin-8 rs4073 genotypes between control and case groups were compared, and the homozygous variant AA genotypes showed a lower percentage in the case group compared to the control group (OR=0.57, 95%CI=0.39-0.85, p=0.0059). The distributions of alleles frequencies also exhibited statistical difference (p=0.0066). There was an interaction between interleukin-8 rs4073 and smoking habits (p=0.0051). CONCLUSION: Interleukin-8 rs4073 genotypes were associated with lung cancer susceptibility, especially for smokers.

l-lactic acidosis confers insensitivity to PKC inhibitors by competing for uptake via monocarboxylate transporters.

Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.

The Feasibility of Interventional Pulmonology Methods for Detecting the T790M Mutation after the First or Second-Generation EGFR-TKI Resistance of Non-Small Cell Lung Cancer.

The development of third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) targeting T790M-mutant non-small cell lung cancer (NSCLC) has raised the importance of re-biopsy after EGFR-TKI failure. This study aimed to investigate the feasibility of interventional pulmonology (IP) procedures as re-biopsy methods for identifying the T790M mutation in EGFR-TKI-resistant patients. One hundred and thirty-nine NSCLC patients who underwent IP procedures for re-biopsy as their initial investigation after EGFR-TKI treatment failure were enrolled in this study between January 2020 and August 2022. All patients underwent a first re-biopsy with IP methods, with a diagnostic yield of 81.2% and T790M mutation detection rate of 36%. Thirty patients underwent a second re-biopsy; IP methods were used for 17 (56.6%) patients and non-IP methods for 13 (43.4%) patients; the T790M mutation detection rate was 36.4%. Only six patients underwent a third re-biopsy; no T790M mutation was noted. The T790M mutation detection rate did not differ between IP and non-IP methods (33.6 % vs. 37.5%, p = 0.762). In 11 cases (7.5%), a re-biopsy revealed histologic transformation from lung adenocarcinoma. IP procedures, as first-line re-biopsy methods for NSCLC, are feasible and provide sufficient tissue for identification of the resistance mechanism and target gene T790M mutation.

Association of TIMP-2 Rs8179090 Genotypes With Lung Cancer Risk in Taiwan.

BACKGROUND/AIM: The tissue inhibitor of metalloproteinase-2 (TIMP-2) is a critical inhibitor of matrix metalloproteinases (MMPs). Along with MMPs, TIMP-2 regulates the breakdown and remodeling of the extracellular matrix (ECM) and basement membranes. This study investigated the role of genotypes of the TIMP-2 -418G/C (rs8179090) single nucleotide polymorphism on lung risk. MATERIALS AND METHODS: A total of 358 lung cancer patients and 716 healthy subjects were recruited in this study. Genotypes were identified via the polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The distribution of alleles and genotype frequencies of TIMP-2 -418G/C genotypes between the two groups were compared and no statistically significant difference (p>0.05) was found. The heterozygous and homozygous variant genotypes showed no differential distribution between the control and case groups (p>0.05). CONCLUSION: TIMP-2 -418G/C variants might not be associated with lung cancer susceptibility and could not serve as predictors.

Advances in Diagnostic Bronchoscopy.

The increase in incidental discovery of pulmonary nodules has led to more urgent requirement of tissue diagnosis. The peripheral pulmonary nodules are especially challenging for clinicians. There are various modalities for diagnosis and tissue sampling of pulmonary lesions, but most of these modalities have their own limitations. This has led to the development of many advanced technical modalities, which have empowered pulmonologists to reach the periphery of the lung safely and effectively. These techniques include thin/ultrathin bronchoscopes, radial probe endobronchial ultrasound (RP-EBUS), and navigation bronchoscopy-including virtual navigation bronchoscopy (VNB) and electromagnetic navigation bronchoscopy (ENB). Recently, newer technologies-including robotic-assisted bronchoscopy (RAB), cone-beam CT (CBCT), and augmented fluoroscopy (AF)-have been introduced to aid in the navigation to peripheral pulmonary nodules. Technological advances will also enable more precise tissue sampling of smaller peripheral lung nodules for local ablative and other therapies of peripheral lung cancers in the future. However, we still need to overcome the CT-to-body divergence, among other limitations. In this review, our aim is to summarize the recent advances in diagnostic bronchoscopy technology.

Hesperidin Is a Potential Inhibitor against SARS-CoV-2 Infection.

Hesperidin (HD) is a common flavanone glycoside isolated from citrus fruits and possesses great potential for cardiovascular protection. Hesperetin (HT) is an aglycone metabolite of HD with high bioavailability. Through the docking simulation, HD and HT have shown their potential to bind to two cellular proteins: transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2), which are required for the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results further found that HT and HD suppressed the infection of VeroE6 cells using lentiviral-based pseudo-particles with wild types and variants of SARS-CoV-2 with spike (S) proteins, by blocking the interaction between the S protein and cellular receptor ACE2 and reducing ACE2 and TMPRSS2 expression. In summary, hesperidin is a potential TMPRSS2 inhibitor for the reduction of the SARS-CoV-2 infection.

Etiologies of delayed diagnosis and six-month outcome of patients with newly diagnosed advanced lung cancer with respiratory failure at initial presentation.

BACKGROUND: This study aimed to evaluate the characteristics of patients with newly diagnosed advanced lung cancer who initially presented with respiratory failure. METHODS: This was a retrospective study which analyzed patients in the intensive care unit (ICU) with newly diagnosed advanced lung cancer who were placed on mechanical ventilation (MV). We defined newly diagnosed lung cancer as pathological or molecular results for treatment decisions not yet determined when the patient was admitted to ICU. RESULTS: During the 14-year inclusion period, 845 lung cancer patients requiring MV were screened. A total of 56 newly diagnosed extensive lung cancer patients were analyzed. Cancer-related to central airway obstruction (n = 29, 51.8%) was the leading cause of respiratory failure. The significant etiologies of delay in the diagnosis of lung cancer were diagnostic error, mistaking cancer for tuberculosis, and missed hilar lesions. The six-month survival rate was only 7.1% (n = 4). The sequential organ failure assessment (SOFA) score was significantly associated with mortality (HR = 1.142, 95% CI = 1.012-1.288, P = 0.031). The six-month survival rate in patients receiving suitable targeted therapy and accepting chemotherapy and best supportive care was 40% (2/5), 0% (0/7), and 4.5% (2/44), respectively. CONCLUSIONS: Patients with newly diagnosed advanced lung cancer with acute life-threatening respiratory failure have poor outcomes. Cancer-related to central airway obstruction is a leading cause of respiratory failure. Diagnostic errors such as tuberculosis and missed hilar lesions are the two main etiologies of a delay in diagnosis. The SOFA score is correlated with mortality. Targeted therapy can raise the six-month survival rates in patients with oncogenic mutation adenocarcinoma, who survive after presentation in a critical condition.

ZIP7 (SLC39A7) expression in colorectal cancer and its correlation with clinical prognosis.

BACKGROUND: Colorectal cancer (CRC) is a common gastrointestinal malignant tumor that occurs in the colon site and accounts for 9% of the total malignant tumors. Among malignant tumors, its morbidity and mortality respectively rank third and fourth, seriously threatening human health and causing a heavy economic burden on society. ZIP7 (SLC39A7), a kind of zinc transporter, plays a crucial role in the self-renewal of intestinal epithelial cells; however, its role in CRC has not been extensively examined. Therefore, our study aimed to analyze the biological function and expression of this zinc transporter in CRC, along with its correlation with disease activity. METHODS: In this study, 118 cases of colorectal carcinoma tissues, 30 normal tissue samples from adjacent cancer tissues, and 30 normal intestinal mucosa tissue samples from non-intestinal cancer patients were collected in our hospital between February 2014 and February 2015. The expressions of ZIP7 were examined immunohistochemically, and the relationship between ZIP7 expression and the clinical pathological features of CRC were analyzed. After appropriate surgical treatment, the patients accepted a 5-year follow-up for evaluation of their recurrence situation and 5-year survival rate. RESULTS: Immunohistochemically, out of 80 CRC tissue samples, 67.8% were found to be positive for ZIP7, 55% (44 cases) were strong positives, and 45% (36 cases) were weak positives. There was a striking coherence between the expression of ZIP7, the depth of lymph node metastasis, CRC invasion, and CRC Dukes stage (P<0.05). Subsequent studies indicated that the mortality rate was positively correlated with the staining intensity of ZIP7 (P<0.05), and the Cox proportional hazards model confirmed that ZIP7 is an independent element of prognostic in patients with CRC (RR =3.896; 95% CI: 1.526-9.951; P=0.004). CONCLUSIONS: The high expression of ZIP 7 in epithelial cells is related to the clinical stage and prognosis of CRC and can be utilized as a biomarker to predict the prognosis of CRC patients.

Reactive Oxygen Species-Mediated Tumor Microenvironment Transformation: The Mechanism of Radioresistant Gastric Cancer.

Radioresistance is one of the primary causes responsible for therapeutic failure and recurrence of cancer. It is well documented that reactive oxygen species (ROS) contribute to the initiation and development of gastric cancer (GC), and the levels of ROS are significantly increased in patients with GC accompanied with abnormal expressions of multiple inflammatory factors. It is also well documented that ROS can activate cancer cells and inflammatory cells, stimulating the release of a variety of inflammatory cytokines, which subsequently mediates the tumor microenvironment (TME) and promotes cancer stem cell (CSC) maintenance as well as renewal and epithelial-mesenchymal transition (EMT), ultimately resulting in radioresistance and recurrence of GC.

The role of STAT3 in leading the crosstalk between human cancers and the immune system.

The development and progression of human cancers are continuously and dynamically regulated by intrinsic and extrinsic factors. As a converging point of multiple oncogenic pathways, signal transducer and activator of transcription 3 (STAT3) is constitutively activated both in tumor cells and tumor-infiltrated immune cells. Activated STAT3 persistently triggers tumor progression through direct regulation of oncogenic gene expression. Apart from its oncogenic role in regulating gene expression in tumor cells, STAT3 also paves the way for human cancer growth through immunosuppression. Activated STAT3 in immune cells results in inhibition of immune mediators and promotion of immunosuppressive factors. Therefore, STAT3 modulates the interaction between tumor cells and host immunity. Accumulating evidence suggests that targeting STAT3 may enhance anti-cancer immune responses and rescue the suppressed immunologic microenvironment in tumors. Taken together, STAT3 has emerged as a promising target in cancer immunotherapy.

Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations.

OBJECTIVE: Approximately 10%-15% patients with epidermal growth factor receptor (EGFR) mutations harbor non-classical mutations. However, the effects of EGFR-tyrosine kinases (TKIs), particularly second-generation EGFR-TKI (afatinib) compared to first-generation EGFR-TKIs (gefitinib/erlotinib), in patients with non-classical EGFR mutations remain unknown. METHODS: We conducted this retrospective study at the China Medical University Hospital (Taichung, Taiwan) from June 2011 to July 2016. Specimens from 1632 patients were tested for EGFR mutations. We surveyed the effectiveness of afatinib and gefitinib/erlotinib in stage IIIb-IV lung adenocarcinoma patients with non-classical EGFR mutations. RESULTS: Fifty-six patients with advanced-stage (stage IIIB-IV) lung adenocarcinoma with non-classical mutations and receiving EGFR-TKI treatment had completed follow-up and were further analyzed. Afatinib versus gefitinib/erlotinib showed that the objective response rates were 62.5% versus 50.0% (p=0.35). Median progression-free survival (PFS) of 11.0 versus 3.6 months (p=0.03), respectively, was observed for the 51 non-classical EGFR mutated (excluding 5 patients with exon 20 insertions) lung adenocarcinomas. Subset analysis showed that PFS curves of afatinib were more easily distinguished in non-classical EGFR mutations lacking a combination with a classical mutation (non-classical with classical complex mutations group: median PFS, 11.0 versus 8.2 months, p=0.19; non-classical mutation alone or in combination with other non-classical mutations group: median PFS, 18.3 versus 2.8 months, p=0.07). CONCLUSIONS: Afatinib may be a first-choice EGFR-TKI for patients with advanced-stage lung adenocarcinomas harboring non-classical mutations.