Histological Subtype Classification of Non-Small Cell Lung Cancer with Radiomics and 3D Convolutional Neural Networks.

Non-small cell lung carcinoma (NSCLC) is the most common type of pulmonary cancer, one of the deadliest malignant tumors worldwide. Given the increased emphasis on the precise management of lung cancer, identifying various subtypes of NSCLC has become pivotal for enhancing diagnostic standards and patient prognosis. In response to the challenges presented by traditional clinical diagnostic methods for NSCLC pathology subtypes, which are invasive, rely on physician experience, and consume medical resources, we explore the potential of radiomics and deep learning to automatically and non-invasively identify NSCLC subtypes from computed tomography (CT) images. An integrated model is proposed that investigates both radiomic features and deep learning features and makes comprehensive decisions based on the combination of these two features. To extract deep features, a three-dimensional convolutional neural network (3D CNN) is proposed to fully utilize the 3D nature of CT images while radiomic features are extracted by radiomics. These two types of features are combined and classified with multi-head attention (MHA) in our proposed model. To our knowledge, this is the first work that integrates different learning methods and features from varied sources in histological subtype classification of lung cancer. Experiments are organized on a mixed dataset comprising NSCLC Radiomics and Radiogenomics. The results show that our proposed model achieves 0.88 in accuracy and 0.89 in the area under the receiver operating characteristic curve (AUC) when distinguishing lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC), indicating the potential of being a non-invasive way for predicting histological subtypes of lung cancer.

Associations of sleep disorders with all-cause and cause-specific mortality in cancer survivors: a cross-sectional analysis of the NHANES 2005-2016.

BACKGROUND: The circadian clock and endoplasmic reticulum stress signaling play important roles in oncogenesis and development of cancer. Sleep disorders have been linked to an elevated risk of mortality in general populations. Nonetheless, the evidence for the sleep disorders-mortality association among cancer patients is limited. We aimed to prospectively investigate the association of sleep disorders with all-cause, cancer, and cardiovascular disease (CVD) mortality among cancer individuals. METHODS: We assessed 3187 participants with cancer from the National Health and Nutrition Examination Survey 2005-2016 cohorts with a median follow-up time of 83.0 months. Multivariable Cox proportional hazards models estimated the adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Multivariable Cox proportional hazards models showed that sleep disorders were associated with a higher risk of all-cause mortality (HR 1.23, 95%CI: 1.06,1.42), cancer mortality (HR 1.30, 95%CI: 1.02, 1.66), and cardiovascular disease mortality (HR 1.35, 95%CI: 1.02, 1.80). After the total group was stratified by gender, the high HRs were observed in men (P < 0.05), not in women. The correlation between sleep disorders and higher long-term mortality was also significant after individuals who died within 2 years of follow-up were excluded, with HR 1.24 (95%CI: 1.07, 1.45) in model I, HR 1.20 (95%CI: 1.02, 1.42) in model II for long-term all-cause mortality, HR (95%CI: 1.00, 1.74) in model I for long-term cancer mortality, and HR 1.5 (95%CI:1.12, 2.02) in model I, HR 1.45 (95%CI: 1.06, 1.99) in model II for long-term CVD mortality. CONCLUSIONS: Sleep disorders were associated with a higher risk of all-cause mortality, cancer mortality, and CVD mortality, as well as long-term mortality in cancer patients. Our finding underlies the importance of screening for sleep disorders for all cancer survivors and the urge to integrate sleep health as an important part of cancer care more effectively. Male individuals may be particularly vulnerable and could benefit from more frequent screening.

[Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell 
Lung Cancer Patients with Acquired EGFR T790M Mutation].

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. METHODS: A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. RESULTS: The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). CONCLUSIONS: Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

Durable response to immunotherapy plus chemotherapy in a patient with untreated, brain-metastatic, EGFR exon 20 insertion mutation lung adenocarcinoma: A case report.

RATIONAL: Epidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion. PATIENT CONCERNS: A 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis. DIAGNOSIS: Next-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y). INTERVENTIONS: The patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019. OUTCOMES: The patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18 months since initiation of 1st-line treatment. LESSONS: This is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.

[Immune Checkpoint Inhibitors-induced Myasthenia Gravis: From Diagnosis to Treatment].

Immune checkpoint inhibitor (ICI) has been proven to be a major breakthrough in the treatment of various tumor types. Despite the favorable results in terms of oncological outcomes, these treatments have been associated with a variety of immune-related adverse events (irAEs). Myasthenia gravis (MG) is one of rare but life-threatening irAEs, with acute onset and rapid progression after ICI initiation. Early diagnosis and active treatment are crucial. Herein, we review recent literatures to provide guidance to frequently asked questions concerning the diagnosis and management of ICI-MG.

HER2 Exon 20 Insertion Mutations in Lung Adenocarcinoma: Case Series and Response to Pyrotinib.

HER2 mutations have emerged as oncogenic driver gene mutations in non-small cell lung cancer (NSCLC), which have not been described in detail like other driver gene mutations. Here, 295 patients with advanced lung adenocarcinoma were retrospectively screened for HER2 mutations using next-generation sequencing (NGS), and the positive cases were validated by Sanger sequencing. We identified five cases with HER2 exon 20 insertions, representing 1.7% of 295 lung adenocarcinomas. Among them, four different subtypes of HER2 exon 20 insertions were identified, including a rare subtype G778_S779insCPG never reported before with a partial response (PR) to pyrotinib and progression-free survival (PFS) of 12.8 months. Our findings reveal that HER2 exon 20 insertion mutations were detected in a small subset of lung adenocarcinomas. Given the different drug sensitivities, determining the mutation subtype by next-generation sequencing at the time of diagnosis might make sense.

Nivolumab-induced Thyroid Dysfunctions in Patients with Previously Treated Non-small Cell Lung Cancer.

BACKGROUND: Nivolumab, a fully human IgG4 programmed cell death-1 checkpoint inhibitor, demonstrated its benefit of prolonged survival in advanced non-small cell lung cancer (NSCLC). However, nivolumab generated unique immune-related adverse events such as thyroid dysfunctions. Herein we assessed nivolumab-induced thyroid dysfunctions in patients with previously treated advanced NSCLC in our hospital. METHODS: The medical records of 11 patients with advanced NSCLC who were initiated with nivolumab treatment between June 28, 2018, and January 15, 2019, in our hospital were reviewed. Serological tests of thyroid-stimulating hormone and free tetraiodothyronine were measured at baseline and every 8 weeks. RESULTS: Three out of 11 patients developed new-onset hypothyroidism during the treatment, and two of three patients had transient hyperthyroidism first. Two patients were diagnosed with Grade 2 hypothyroidism and received levothyroxine therapy. The other one was Grade 1 hypothyroidism and asymptomatic. All these three patients continued nivolumab therapy. CONCLUSION: Nivolumab-induced thyroid dysfunctions in advanced NSCLC were mostly mild and controlled. Thyroid function needs to be monitored for early prediction and appropriate managements of thyroid dysfunctions.

PD-L1 Expression and Its Regulation in Lung Adenocarcinoma with ALK Translocation.

BACKGROUND: The mechanism of regulation of PD-L1 expression by ALK translocation remains unclear. We detected PD-L1 protein expression and its regulation in lung adenocarcinoma patients with EML4-ALK fusion gene. METHODS: PD-L1 and ALK expression at protein level in human lung adenocarcinoma cell lines and tumor tissue specimens was evaluated by immunohistochemistry analysis and Western blotting. The expression at DNA level and RNA level was indicated by quantitative real-time PCR analysis. The signal pathway was indicated at protein level by western blotting. RESULTS: The PD-L1 protein expression was higher in human lung adenocarcinoma cell lines with EML4-ALK fusion gene than that without this fusion gene. Induced expression of EML4-ALK in A549 cells significantly increased PD-L1 protein expression, whereas PD-L1 protein expression was downregulated after crizotinib and pembrolizumab successively. Significant positive correlations between PD-L1 and p-ERK, p-STAT3 or p-AKT expression were observed in ALK-translocated tumors. PD-L1 overexpression was significantly associated with shorter progressive survival and overall survival after crizotinib in ALK-translocated patients. CONCLUSIONS: We demonstrate that ALK translocation can upregulate PD-L1 expression by activating ERK, STAT3 and AKT pathways. ALK inhibitor combined with a PD-L1-targeted therapy may be a potential strategy in ALK-translocated lung adenocarcinoma patients.

Circulating CD137+ CD8+ T cells accumulate along with increased functional regulatory T cells and thoracic tumour burden in lung cancer patients.

CD137 is a promising target for immunostimulation strategies against cancer. Previous studies showed that CD137+ CD8+ T cells are enriched in antitumour effector T cells in both preclinical tumour models and cancer patients, but to date, such T cells in the blood of lung cancer patients have not been sufficiently investigated. In this study, circulating antigen-activated CD8+ T cell subsets, identified as CD137+ CD8+ or PD-1+ (programmed cell death protein 1) CD8+ , and regulatory T cells (Treg), identified as CD4+ CD25+ CD127low/- , in 40 untreated lung cancer patients and in 49 age- and sex-matched healthy controls (HCs) were assessed by flow cytometry. Results were evaluated for associations with lung cancer patient clinical characteristics. Correlations between antigen-activated CD8+ T cells and effector Treg (CTLA-4+ [cytotoxic T-lymphocyte antigen 4] CD4+ CD25+ CD127low/- ) were also investigated. Higher percentages of PD-1+ , CD137+ and PD-1+ CD137+ amongst CD8+ T cells were observed in lung cancer patients compared with HCs. The percentages of CD137+ CD8+ and PD-1+ CD137+ CD8+ T cell subsets amongst CD8+ T cells were positively correlated with thoracic tumour burden and were strongly positively correlated with the percentage of effector Treg subset. Smoking patients harboured higher percentages of the PD-1+ CD8+ T cell subset compared with non-smoking patients. This study demonstrated that circulating antigen-activated CD8+ T cells accumulated in lung cancer patients along with increased effector Treg and thoracic tumour burden. These findings aid a better understanding of immune-host interactions in lung cancer patients using peripheral blood, and further support immunotherapeutic intervention strategies using combination therapy for differential control of Treg and activation of tumour-specific effector T cells.

Isolation of circulating tumor cells and detection of EGFR mutations in patients with non-small-cell lung cancer.

The aim of the present study was to develop a procedure for the isolation of circulating tumor cells (CTCs), and to evaluate its application in the detection of epidermal growth factor receptor (EGFR) mutations, and potential heterogeneity in patients with non-small-cell lung cancer (NSCLC). Peripheral blood samples were collected from 91 patients with lung cancer, 10 patients with benign disease and 10 healthy volunteers. CTCs were enriched by positive immunomagnetic separation, detected by immunocytochemistry, and processed for single-cell capture. Pure CTC DNA was amplified, and the EGFR gene was analyzed using the amplification refractory mutation system (ARMS) and digital polymerase chain reaction (dPCR). The CTC capture rate in patients with lung cancer was 61.5% (56/91), whereas no CTCs were detected in patients with benign lung disease or in healthy volunteers. The CTC-positive detection rates were 69.3% (52/75) and 25.0% (4/16) in patients with TNM stage III and IV disease, respectively. Markedly more CTCs were captured from patients with small-cell lung cancer compared with patients with other types of cancer. In patients who were positive for EGFR mutations, the detection rate of these mutations was low (16.67%, 2/12), at the single CTC level. The sensitivity increased as the number of CTCs per sample increased. A total of four patients displayed consistent detection of EGFR mutations at the 10-cell level, and one patient exhibited a clear, inconsistent and rare mutation (G719×) between CTCs. A simplified technique for isolating CTCs from blood was established, though multiple CTCs were required to sensitively detect mutations in these cells. The detection of EGFR mutations in CTCs and tissue specimens was generally homogeneous, and therefore, the CTC-level mutation analysis may potentially contribute to the discovery of heterogeneous mutations.

Author Correction: Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer.

The original version of this Article contained an error in Fig. 2, in which the left y-axis labels 'tDNA' and 'ctDNA' were inadvertently inverted. This has been corrected in the PDF and HTML versions of the Article.

Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer.

Subclonal architecture and genomic evolution of small-cell lung cancer (SCLC) under treatment has not been well studied primarily due to lack of tumor specimens, particularly longitudinal samples acquired during treatment. SCLC is characterized by early hematogenous spread, which makes circulating cell-free tumor DNA (ctDNA) sequencing a promising modality for genomic profiling. Here, we perform targeted deep sequencing of 430 cancer genes on pre-treatment tumor biopsies, as well as on plasma samples collected prior to and during treatment from 22 SCLC patients. Similar subclonal architecture is observed between pre-treatment ctDNA and paired tumor DNA. Mean variant allele frequency of clonal mutations from pre-treatment ctDNA is associated with progression-free survival and overall survival. Pre- and post-treatment ctDNA mutational analysis demonstrate that mutations of DNA repair and NOTCH signaling pathways are enriched in post-treatment samples. These data suggest that ctDNA sequencing is promising to delineate genomic landscape, subclonal architecture, and genomic evolution of SCLC.

[Clinical Analysis of 107 NSCLC Patients Harboring KRAS Mutation].

BACKGROUND: Kirsten rat sarcoma viral oncogene (KRAS) mutation is one of the major driver genes of non-small cell lung cancer (NSCLC). KRAS is a resistant predictor of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), which raises controversy because of its role in chemotherapy sensitivity and prognosis. The aim of this study is to accumulate clinical experience in treating NSCLC patients harboring KRAS mutation. METHODS: A total of 107 NSCLC patients harboring KRAS mutation were analyzed retrospectively. The efficacy was analyzed in terms of first-line chemotherapy or EGFR-TKIs therapy. RESULTS: The objective response rate (ORR) to first-line chemotherapy of 52 patients with advanced disease harboring KRAS mutation was 9.6%. The disease control rate (DCR) was 53.8%, and the median progression-free survival (PFS) was 3 months. The ORR to EGFR-TKIs therapy in 21 patients harboring KRAS mutation and EGFR/KRAS co-mutation was 9.5%; the DCR was 23.8%, and the median PFS was 1 month. The ORR and DCR to EGFR-TKIs therapy of patients with EGFR/KRAS co-mutation were significantly higher than those of patients with KRAS mutation (50% vs 0, P=0.029; 75% vs 11.8%, P=0.043); the median PFS was also significantly longer (3 months vs 1 month, P=0.004). CONCLUSIONS: The efficacy to first-line chemotherapy and EGFR-TKIs therapy in NSCLC patients harboring KRAS mutation was poor; thus, new drugs should be developed. Furthermore, the existence of EGFR/KRAS co-mutation was confirmed. Hence, EGFR-TKIs therapy should be administered to patients with EGFR/KRAS co-mutation.

Crizotinib versus platinum-based double-agent chemotherapy as the first line treatment in advanced anaplastic lymphoma kinase-positive lung adenocarcinoma.

BACKGROUND: To explore the efficacy and safety of crizotinib versus platinum-based double agent chemotherapy as the first-line treatment in patients with advanced anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma. METHOD: We retrospectively analyzed data from 19 patients with advanced ALK-positive lung adenocarcinoma who had received no previous systemic treatment for advanced disease. Seven patients received oral crizotinib at a dose of 250 mg twice daily; 12 patients were administered standard chemotherapy (pemetrexed, paclitaxel, vinorelbine or gemcitabine plus either cisplatin or carboplatin) every three weeks for up to six cycles. The primary endpoint was overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: The ORR was significantly higher with crizotinib than with chemotherapy (83.3% in the crizotinib vs. 25.0% in the chemotherapy group, P < 0.05); the DCRs were 100% and 75%, respectively (P < 0.05). The common adverse events associated with crizotinib were visual abnormality and diarrhea, whereas those associated with chemotherapy were neutropenia and nausea. In the crizotinib group, liver aminotransferase elevation (adverse events grade 3 or 4) occurred in one patient (14.3%). In the chemotherapy group, the same grade neutropenia adverse event occurred in two patients (16.6%). The incidence of treatment-related grade 3 or 4 adverse events was similar in both groups. Compared with chemotherapy, crizotinib was associated with a greater reduction in lung cancer symptoms and a greater improvement in quality of life. CONCLUSION: As a first-line treatment, crizotinib was superior to platinum-based double chemotherapy in patients with previously untreated advanced ALK-positive lung adenocarcinoma. Therefore, crizotinib is an optimal therapy as a first-line treatment in these patients.

[Clinical Observation of Icotinib Hydrochloride for Advanced Non-small Cell Lung Cancer Patients with EGFR Status Identified].

BACKGROUND: Icotinib is the first self-developed small molecular drug in China for targeted therapy of lung cancer. Compared to the other two commercially available epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib, icotinib is similar to them in chemical structure, mechanism of activity and therapeutic effects. To explore the efficacy and side effects of icotinib hydrochloride in the treatment of the advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation and wild-type. METHODS: Patients with advanced NSCLC who were treated with icotinib hydrochloride in Beijing Chest Hospital were retrospective analyzed from March 2009 to December 2014. RESULTS: The clinical data of 124 patients (99 with EGFR mutation and 25 with wild type) with advanced NSCLC were enrolled in this study. The patients' overall objective response rate (ORR) was 51.6 % and the disease control rate (DCR) was 79.8%; The patients with EGFR mutation, ORR was 63.6%, DCR was 93.9%. The ORR was 4.0% and the DCR was 24.0% in the wild-type patients. Median progression-free survival (PFS) with icotinib treatment in EGFR mutation patients was 10.5 months and 1.0 month in wild-type patients. The major adverse events were mild skin rash (30.6%) and diarrhea (16.1%). CONCLUSIONS: Monotherapy with icotinib hydrochloride is effective and tolerable for the advanced NSCLC EGFR mutation patients.


Subsequent treatment of epidermal growth factor receptor-tyrosine kinase inhibitor failure in patients with advanced lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) effectively treat advanced non-small cell lung cancer with EGFR-mutation. However, most patients develop acquired resistance without effective therapy subsequent to EGFR-TKI failure. We evaluated the efficacy of subsequent treatment strategies for EGFR-TKI resistance. METHODS: We retrospectively analyzed 240 patients with advanced lung adenocarcinoma with EGFR-TKI failure and following subsequent treatment. According to the first subsequent strategies after EGFR-TKI failure, patients were divided into groups of EGFR-TKI continuation (21 cases), EGFR-TKI continuation with chemotherapy (23 cases), chemotherapy alone (143 cases), and best supportive care (BSC) (53 cases). RESULTS: Except for 53 cases of BSC, the disease control rates (DCR) of the remaining 187 patients in the EGFR-TKI continuation, EGFR-TKI continuation with chemotherapy, and chemotherapy alone groups were 66.7%, 73.9%, and 44.8%, respectively. The median post-progression progression-free survival (PFS) for the three groups was 3.0, 3.3, and 2.0 months, respectively. The DCR for the EGFR-TKI continuation with chemotherapy group was significantly higher than the chemotherapy alone group (P = 0.006). The post-progression PFS of the EGFR-TKI continuation with chemotherapy group was significantly longer than the chemotherapy alone group (P = 0.037). The median overall survival in the EGFR-TKI continuation, EGFR-TKI continuation with chemotherapy, chemotherapy alone, and BSC groups were 6.9, 11.6, 8.8, and 0.9 months, respectively. Compared to the BSC group, all groups achieved a survival benefit (P < 0.001). CONCLUSIONS: EGFR-TKI continuation with chemotherapy could provide benefits for patients with acquired resistance to EGFR-TKI.

[Detection and Analysis of EGFR and KRAS Mutation with Lung Adenocarcinoma].

BACKGROUND AND OBJECTIVE: Mutations in epidermal growth factor receptor (EGFR) and KRAS are important markers in non-small cell lung cancer, which are closely related to the clinical therapeutic effect. To analysis the EGFR and KRAS gene mutation rate and its relationship with clinical features in patients with lung adenocarcinoma. METHODS: 395 patients with treatment naïve lung adenocarcinoma, tumor tissue samples were available for testing. Tumor sample EGFR and KRAS mutation status were detected using mutant enriched liquidchip. RESULTS: 395 cases of lung adenocarcinoma, EGFR mutations were detected in 192 cases (48.9%), KRAS mutations were detected in 29 cases (7.8%), and the presence of EGFR and KRAS mutation were detected in 1 case (0.3%). EGFR mutations were found to occur significantly more often in female than in male patients (62.0% vs 37.1%, P<0.001) and in never smokers than in smokers (61.9% vs 30.3%, P<0.001), no significant differences were observed in age, stage and different biopsy type. KRAS mutations were not found to have statistical significance (P>0.05) in each clinical factors, only occurred in the wild type EGFR gene in patients (13.5%, 27/200) was significantly higher than that of patients with EGFR mutation (1.0%, 2/192), the difference was statistically significant (P<0.001). CONCLUSIONS: In lung adenocarcinomas, EGFR mutation was higher in female and non-smoking patients, KRAS mutation only in patients with wild-type EGFR gene was higher. Before using TKI targeted therapy, EGFR and KRAS mutations should be detected.


[Detection and Analysis of EGFR and KRAS Mutations 
in the Patients with Lung Squamous Cell Carcinomas].

BACKGROUND: Activating mutations in epidermal growth factor receptor (EGFR) and KRAS are important markers in non-small cell lung cancer. However, EGFR and KRAS gene mutations in lung squamous cell carcinoma are rarely reported. The aim of this study was to analyze EGFR and KRAS gene mutation rate and their relationship with clinical features in patients with lung squamous cell carcinomas. METHODS: A total of 139 patients undergoing treatment for naïve lung squamous cell carcinomas with tumor tissue samples available for testing were recruited. EGFR and KRAS mutation statuses of the tumor samples were detected using a mutant enriched liquid chip. RESULTS: Of the 139 cases of lung squamous cell carcinoma, EGFR mutations were detected in 25 cases (18%), KRAS mutations were detected in 7 cases (5%), and the presence of both EGFR and KRAS mutations was detected in 1 case (0.7%). EGFR mutations occurred more often in females than in males (33.3% vs 16.5%) and in patients that never smoked than in those who smoke (29.6% vs 16.1%). However, the difference did not reach statistical significance (P>0.05). No significant differences were observed in age, stage, and different biopsy type. KRAS mutations occurred more often in males than in females (5.5% vs 0%), but the difference did not reach statistical significance (P>0.05). No significant differences were observed in age, stage, different biopsy type, and smoking status (P>0.05). CONCLUSIONS: EGFR and KRAS mutations were low in lung squamous cell carcinomas, and had no significant correlation with clinical features. Before using tyrosine kinase inhibitor targeted therapy, EGFR and KRAS mutations should be detected in patients with lung squamous cell carcinomas.

[Association between the epidermal growth receptor status and the efficacy of
 first-line chemotherapy in patients with advanced non-small cell lung cancer].

BACKGROUND: Status of epidermal growth factor receptor (EGFR) gene is a predictor of response to EGFR tyrosine kinase inhibitor (TKI). However, little is know about the relationship between EGFR status and response to chemotherapy. We evaluated the prediction value of EGFR mutation status on response to first-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: The data of 181 patients with stage IIIb/IV NSCLC who diagnosed by histopathology from January 10, 2006 to December 20, 2013 in Beijing Chest Hospital, Capital Medical University were collected. The relationships between EGFR gene status, clinical characteristics and response and progression-free survival (PFS) were analyzed. RESULTS: All of the 181 patients' EGFR statuses were determined. 75 (41.4%) patients harbored EGFR-activating mutations and 106 (58.6%) patients were EGFR wild-type. All patients received first-line chemotherapy. The objective response rate (ORR) was 26.0% and disease control rate (DCR) was 70.2%. Patients with EGFR-activating mutations had a higher DCR than patients with EGFR wild-type (84.0% vs 60.4%, P=0.001) did. Subgroup analysis showed that the ORR and DCR in patients with EGFR exon 19 deletions were remarkably higher than those with EGFR wild-type (P = 0.049, 0.002, respectively). The DCR in patients with EGFR exon 21 L858R mutation was significantly higher than that in patients with EGFR wild-type (P=0.010). 168 patients were available for response evaluation in all of 181 patients and median PFS was 4.3 mo. The PFS of patients with adenocarcinoma was significantly higher than that patients with squamous cell carcinoma (4.7 mo vs 3.0 mo, P=0.036). The PFS in patients harbored EGFR-activating mutations was significantly higher than that in the patients with EGFR wild-type (6.3 mo vs 3.0 mo, P=0.002). The PFS of patients with a performance status (PS) of 0-1 was significantly higher than that in patients with a PS of 2 (4.4 months vs. 0.7 months, P= 0.016). Cox multivariate analysis indicates the EGFR-activating mutation is an independent factor affecting PFS (HR=0.654, 95%CI: 0.470-0.909, P=0.012). CONCLUSIONS: EGFR-activating mutation is a predictor for PFS of first-line chemotherapy in advanced NSCLC patients.
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Clinical characteristics and outcomes of patients with primary lung adenocarcinoma harboring ALK rearrangements detected by FISH, IHC, and RT-PCR.

EML4-ALK is a new driver gene of non-small cell lung cancer and a target of crizotinib. The objectives of this study were to determine the frequency of ALK rearrangements in a large cohort of patients with primary lung adenocarcinoma and to analyze the association of ALK rearrangements with clinicopathological characteristics and clinical outcomes. The roles of fluorescence in situ hybridization (FISH), Ventana immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR) in the detection of ALK rearrangements were evaluated. The ALK rearrangement was detected in 430 specimens from individual patients with primary lung adenocarcinoma using FISH and Ventana IHC based on tissue microarrays. The EGFR status was detected in all of the specimens through DNA sequencing. An RT-PCR was performed on 200 of the specimens and confirmed by sequencing. Of the 430 patients, 46 (10.7%) harbored ALK rearrangements. The ALK rearrangements were associated with a younger age and the EGFR wild type in comparison with ALK-negative patients. The sensitivity and specificity of the Ventana IHC were 100% and 98.2%, respectively, and the concordance rate between the FISH and the Ventana IHC was 98.4%. The sensitivity and specificity of RT-PCR were 95.5% and 87.0%, respectively, and the concordance rate between the FISH and the RT-PCR was 89.0%. The Cox analysis indicated that an early stage and EGFR-activating mutations were independently associated with a longer OS. This study demonstrated that ALK rearrangements are associated with a younger age and the EGFR wild type rather than with other clinicopathological factors. Although the FISH and Ventana IHC have better concordance, and RT-PCR is a more sensitive method and can identify different variants or partners, the IHC and RT-PCR need to be further evaluated in clinical trials to identify their roles in guiding patients' targeted therapy using crizotinib.