Lysyl Oxidase 3 Is a Dual-Specificity Enzyme Involved in STAT3 Deacetylation and Deacetylimination Modulation.

In mammalian cells, histone deacetylase (HDAC) and Sirtuin (SIRT) are two families responsible for removing acetyl groups from acetylated proteins. Here, we describe protein deacetylation coupled with deacetylimination as a function of lysyl oxidase (LOX) family members. LOX-like 3 (Loxl3) associates with Stat3 in the nucleus to deacetylate and deacetyliminate Stat3 on multiple acetyl-lysine sites. Surprisingly, Loxl3 N-terminal scavenger receptor cysteine-rich (SRCR) repeats, rather than the C-terminal oxidase catalytic domain, represent the major deacetylase/deacetyliminase activity. Loxl3-mediated deacetylation/deacetylimination disrupts Stat3 dimerization, abolishes Stat3 transcription activity, and restricts cell proliferation. In Loxl3-/- mice, Stat3 is constitutively acetylated and naive CD4+ T cells are potentiated in Th17/Treg cell differentiation. When overexpressed, the SRCR repeats from other LOX family members can catalyze protein deacetylation/deacetylimination. Thus, our findings delineate a hitherto-unknown mechanism of protein deacetylation and deacetylimination catalyzed by lysyl oxidases.

Obesity and survival in advanced non-small cell lung cancer patients treated with chemotherapy, immunotherapy, or chemoimmunotherapy: a multicenter cohort study.

BACKGROUND: The association of body mass index (BMI) with survival outcomes in patients with advanced non-small cell lung cancer (NSCLC) treated with first-line chemotherapy, immunotherapy, or chemoimmunotherapy is controversial. We aimed to investigate these associations, including associations in male and female patients specifically, in a multicenter cohort study. METHODS: We retrospectively analyzed data from seven cohorts comprising 7021 advanced non-small cell lung cancer patients who received chemotherapy (three cohorts), immunotherapy (two cohorts), and chemoimmunotherapy (two cohorts) from five data sources, including a de-identified nationwide (US-based) NSCLC clinico-genomic database and two randomized, double-blind, phase 3 clinical trials. BMI was categorized as underweight, normal weight, overweight, or obese. Underweight patients were excluded because of their small proportion. The primary endpoints were the associations between BMI and progression-free survival (PFS) and overall survival (OS) stratified by treatment type and sex, which were assessed using Kaplan-Meier methods and adjusted Cox modeling. Meta-analyses were performed to combine the adjusted hazard ratios. RESULTS: In the pooled analysis, obesity was significantly associated with improved OS in patients receiving chemotherapy (hazard ratios [HR] = 0.84, 95% confidence interval (CI) 0.76-0.93), but there was no association with PFS (HR = 0.91, 95% CI 0.82-1.02). The association of BMI with OS for patients receiving chemotherapy differed by sex, with an inverse association in men (HR = 0.74, 95% CI 0.64-0.84), but no association observed in women (HR = 0.96, 95% CI 0.81-1.13, Pinteraction = 0.018). No impact of BMI on OS or PFS was detected in patients receiving immunotherapy or chemoimmunotherapy. Obese patients had the lowest level of tumor mutational burden, similar level of programmed death-ligand 1 expression and ESTIMATE scores. CONCLUSIONS: Obesity may be associated with an increased overall survival among male patients treated with chemotherapy, whereas not associated with the outcomes in patients treated with immunotherapy or chemoimmunotherapy.

ctDNA-adjusted bTMB as a predictive biomarker for patients with NSCLC treated with PD-(L)1 inhibitors.

BACKGROUND: In non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs), higher blood tumor mutational burden (bTMB) was usually associated with better progression-free survival (PFS) and objective response rate (ORR). However, the association between bTMB and overall survival (OS) benefit remains undefined. It has been reported that patients harboring a high level of circulating tumor DNA (ctDNA) had poor survival. We hypothesized that ctDNA-adjusted bTMB might predict OS benefit in NSCLC patients receiving ICIs. METHODS: Our study was retrospectively performed in three cohorts, including OAK and POPLAR cohort (n = 853), Shanghai and Wuhan (SH&WH) cohort (n = 44), and National Cancer Center (NCC) cohort (n = 47). Durable clinical benefit (DCB) was defined as PFS lasting ≥ 6 months. The cutoff value of ctDNA-adjusted bTMB for DCB prediction was calculated based on a receiver operating characteristic curve. Interaction between treatments and ctDNA-adjusted bTMB was assessed. RESULTS: The bTMB score was significantly associated with tumor burden, while no association was observed between ctDNA-adjusted bTMB with tumor burden. In the OAK and POPLAR cohort, significantly higher ORR (P = 0.020) and DCB (P < 0.001) were observed in patients with high ctDNA-adjusted bTMB than those with low ctDNA-adjusted bTMB. Importantly, the interactions between ctDNA-adjusted bTMB and treatments were significant for OS (interaction P = 0.019) and PFS (interaction P = 0.002). In the SH&WH cohort, the interactions between ctDNA-adjusted bTMB and treatment were marginally significant for OS (interaction P = 0.081) and PFS (interaction P = 0.062). Similar result was demonstrated in the NCC cohort. CONCLUSIONS: Our study indicated that ctDNA-adjusted bTMB might predict OS benefit in NSCLC patients receiving ICIs. The potential of ctDNA-adjusted bTMB as a noninvasive predictor for immunotherapy should be confirmed in future studies.

DUBR suppresses migration and invasion of human lung adenocarcinoma cells via ZBTB11-mediated inhibition of oxidative phosphorylation.

Long noncoding RNAs (lncRNAs) are involved in a variety of cancers, but the role of LncRNA DUBR in lung adenocarcinoma (LUAD), the most prevalent form of lung cancer, remains unclear. In this study we investigated the expression of DUBR in LUAD to ascertain its association with the clinical pathology and prognosis of LUAD. Analysis of mRNA expression in The Cancer Genome Atlas (TCGA) LUAD database and in-house LUAD cohort (n = 94) showed that DUBR was significantly downregulated in LUAD, and was associated with poor prognosis. In LUAD cell lines (H1975, A549), overexpression of DUBR significantly suppressed the migration and invasion of the LUAD cells. We demonstrated that c-Myc could bind to the promoter of DUBR, and transcriptionally suppressed its expression. Knockdown of c-Myc almost completely blocked the invasion and migration of LUAD cells, whereas knockdown of DUBR partially rescued c-Myc-knockdown suppressed cell migration and invasion. Furthermore, DUBR overexpression significantly increased the expression of a downstream protein of DUBR, zinc finger, and BTB domain containing 11 (ZBTB11), in H1975 and A549 cells; knockdown of ZBTB11 partially rescued the DUBR-overexpression suppressed cell migration and invasion; knockdown of c-Myc significantly upregulated the expression of ZBTB11 in LUAD cells. Finally, we revealed that DUBR/ZBTB11 axis suppressed oxidative phosphorylation in LUAD cells. In short, we demonstrate that c-Myc/DUBR/ZBTB11 axis suppresses migration and invasion of LUAD by attenuating cell oxidative phosphorylation, which provides new insights into the regulatory mechanism of DUBR.

Prognostic and Predictive Value of Blood Tumor Mutational Burden in Patients With Lung Cancer Treated With Docetaxel.

BACKGROUND: Biomarkers for chemotherapy efficacy in non-small cell lung cancer (NSCLC) are lacking. This retrospective study assesses the association between blood-based tumor mutational burden (bTMB) and clinical benefit of chemotherapy. METHODS: Clinical and targeted next-generation sequencing data from the OAK trial (training set; n=318) and POPLAR trial (validation set; n=106) in the docetaxel arm were analyzed. The cutoff value of bTMB for outcome prediction was determined based on a time-dependent receiver operating characteristic curve in the training set, and propensity score matching (PSM) was conducted. The primary outcome was overall survival (OS). Durable clinical benefit (DCB) was defined as OS lasting >12 months. Interaction between treatment and bTMB was assessed in the combined set. RESULTS: A lower bTMB was observed in patients with DCB compared with no durable benefit, and in those with a partial response and stable disease compared with progressive disease. The optimized cutoff value of bTMB for predicting OS was 7 single-nucleotide variants per megabase. In the training set, a low bTMB was significantly associated with longer OS and progression-free survival (PFS). The prognostic value of bTMB was confirmed in the validation set and PSM set. The interaction between bTMB and treatment was significant for PFS (interaction P=.043) in the combined set. Mutations in KEAP1 were associated with high bTMB and a lack of benefit from chemotherapy. CONCLUSIONS: Low bTMB is associated with a survival advantage in patients with NSCLC treated with docetaxel, suggesting the prognostic and predictive potential of bTMB for determining chemotherapy efficacy.

Chromatin accessibility analysis reveals that TFAP2A promotes angiogenesis in acquired resistance to anlotinib in lung cancer cells.

Anlotinib, a multitarget tyrosine kinase inhibitor, is effective as a third-line treatment against non-small cell lung cancer (NSCLC). However, acquired resistance occurs during its administration. To understand the molecular mechanisms of anlotinib resistance, we characterized chromatin accessibility in both the parental and anlotinib-resistant lung cancer cell line NCI-H1975 through ATAC-seq. Compared with the parental cells, we identified 2666 genomic regions with greater accessibility in anlotinib-resistant cells, in which angiogenesis-related processes and the motifs of 21 transcription factors were enriched. Among these transcription factors, TFAP2A was upregulated. TFAP2A knockdown robustly diminished tumor-induced angiogenesis and partially rescued the anti-angiogenic activity of anlotinib. Furthermore, transcriptome analysis indicated that 2280 genes were downregulated in anlotinib-resistant cells with TFAP2A knocked down, among which the PDGFR, TGF-ß, and VEGFR signaling pathways were enriched. Meanwhile, we demonstrated that TFAP2A binds to accessible sites within BMP4 and HSPG2. Collectively, this study suggests that TFAP2A accelerates anlotinib resistance by promoting tumor-induced angiogenesis.

Association between polymorphisms of autophagy pathway and responses in non-small cell lung cancer patients treated with platinum-based chemotherapy.

Platinum-based chemotherapy is an important treatment for non-small cell lung cancer. However, the effectiveness of the treatment varies among the patients. We investigated the association between DNA polymorphisms of the autophagy pathway and responses of such treatment among 1004 Chinese patients. Ninety-nine SNPs located on 13 genes of the autophagy pathway were genotyped and assessed for their association with clinical benefit, progression-free survival (PFS) and overall survival (OS). The results showed that rs7953348 (G>A) (P=0.017, OR: 0.67, 95%CI: 0.49-0.93) and rs12303764 (A>C) (P=0.009, OR: 0.63, 95%CI: 0.45-0.89) at the ULK1 gene, and rs17742719 (C>A) (P=0.002, OR: 1.83, 95%CI: 1.26-2.66), rs8003279 (A>G) (P=0.006, OR: 1.65, 95%CI: 1.16~2.35) and rs1009647 (G>A) (P=0.002, OR: 1.70, 95%CI: 1.22-2.37) at the ATG14 gene were associated with clinical benefit. Polymorphisms at rs7955890 (G>A) (P=0.004, HR: 0.63; 95%CI: 0.46-0.86) and rs17032060 (G>A) (P=0.006, HR: 0.65, 95%CI: 0.48-0.88) at the DRAM gene, and rs13082005 (G>A) (P=0.012, HR: 1.27, 95%CI: 1.05-1.53) at the ATG3 gene were significantly associated with PFS. We also found that rs7953348 (G>A) (P=0.011, HR: 0.74, 95%CI: 0.58-0.93) at the ULK1 gene and rs1864183 (G>A) (P=0.016, HR: 0.42, 95%CI: 0.21-0.85) at the ATG10 gene were associated with OS. Thus, the study demonstrated that the autophagy pathway might play important role(s) in platinum-based chemotherapy. DNA polymorphisms in its component genes can potentially be predictors for clinical responses of platinum-based chemotherapy among the patients with non-small lung cancer.

RAD18 polymorphisms are associated with platinum-based chemotherapy toxicity in Chinese patients with non-small cell lung cancer.

AIM: Although targeted therapy is very efficient for lung cancer, traditional platinum-based chemotherapies are still the principal strategy in the absence of positive biomarkers. The aim of the present study is to evaluate the contribution of RAD18 polymorphisms to platinum-chemotherapy response and its potential side effects in Chinese patients with non-small cell lung cancer (NSCLC). METHODS: A total of 1021 Chinese patients with histological diagnosis of advanced NSCLC were enrolled. Treatment responses were classified into 4 categories (complete response, partial response, stable disease and progressive disease). Gastrointestinal and hematological toxicity incidences were assessed twice a week during the first-line treatment. Ten RAD18 SNPs were genotyped. A logistic regression model was utilized to analyze the associations between RAD18 SNPs and treatment response or toxicity. RESULTS: Among the 10 SNPs tested, none was significantly correlated with the treatment response in a combined cohort. For gastrointestinal toxicity incidences, rs586014 was significantly associated with an increased risk of grade 3 or 4 gastrointestinal toxicity in non-smokers and in the combined cohort; rs654448 and rs618784 were significantly associated with gastrointestinal toxicity in non-smokers; rs6763823 was significantly associated with gastrointestinal toxicity in smokers. For hematological toxicity incidences, rs586014, rs654448 and rs618784 were significantly associated with hematologic toxicity in non-smokers; rs6763823 and rs9880051 were significantly associated with leukocytopenia in smokers. CONCLUSION: RAD18 polymorphisms are correlated with the side effects of platinum-chemotherapy in Chinese patients with advanced NSCLC.

Correlation between serum CEA levels and EGFR mutations in Chinese nonsmokers with lung adenocarcinoma.

AIM: To evaluate the relationship between epidermal growth factor receptor (EGFR) mutations and serum carcinoembryonic antigen (CEA) levels in Chinese nonsmokers with pulmonary adenocarcinoma. METHODS: We sequenced exons 18-21 of the EGFR gene in 98 cases. The patients were divided into two groups based on their pre-treatment serum CEA levels (below or above 5 ng/mL) for analyzing the correlations with EGFR mutations. RESULTS: Sixty-seven cases harbored EGFR mutations. The rates of EGFR mutations and exon 19 mutations in the high-CEA group (78.2% and 49.1%, respectively) were significantly higher those in the low-CEA group (55.8% and 20.9%, respectively). Serum CEA levels were found to be the only independent predictor of EGFR mutation (OR 2.837; 95% CI: 1.178-6.829) and exon 19 mutation (OR 3.618; 95% CI: 1.319-9.918). Furthermore, a higher serum CEA level was associated with a higher EGFR mutation rate and a higher exon 19 mutation rate: patients with serum CEA levels <5 ng/mL, ≥5 and <20 ng/mL, ≥20 ng/mL showed the EGFR mutation rate of 55.8%, 74.1%, 82.1%, respectively, and the exon 19 mutation rate of 20.9%, 40.7%, 57.1%, respectively. Patients with EGFR mutations displayed a significantly higher incidence of abnormal serum CEA levels (>5 ng/mL) than patients without EGFR mutations (64.2% vs 38.7%). CONCLUSION: Elevated serum CEA levels predict the presence of EGFR gene mutations in Chinese nonsmokers with pulmonary adenocarcinoma.

First-line treatment with camrelizumab plus famitinib in advanced or metastatic NSCLC patients with PD-L1 TPS ≥1%: results from a multicenter, open-label, phase 2 trial.

BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.

Lack of association between XRCC3 rs861539 (C > T) polymorphism and lung cancer risks: an update meta-analysis.

X-ray repair cross-complementing protein 3 (XRCC3) belongs to DNA double-strand break repair pathway and XRCC3 rs861539 (C > T) polymorphism has been suspected with lung cancer risk. However, results from previous studies are inconclusive and affected by bias. Electronic databases of PubMed, EMBASE, China National Knowledge Infrastructure, and SinoMed were searched. References of relative reviews were also screened. Pooled odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated to estimate the association strength. A number of 18 eligible studies with 6 studies of Asians, 11 of Caucasians, and 1 of African were extracted and analyzed, including 4,896 lung cancer cases and 6,360 controls. No significant correlation between XRCC3 polymorphism and lung cancer risk was observed in homozygote comparison (CC vs. TT; OR=0.877; 95 % CI, 0.659, 1.168), heterozygote comparison (CT vs. TT; OR=0.857; 95 % CI, 0.675, 1.089), dominant model (CC/CT vs. TT; OR=0.862; 95 % CI, 0.663, 1.123), or recessive model (CC vs. CT/TT; OR=1.047; 95 % CI, 0.956, 1.145). Subgroup analyses of ethnicity and controls did not reveal any significant association with lung cancer risk. No publication bias was detected. In this update meta-analysis of 18 studies and 11,256 participants, we find that XRCC3 rs861539 polymorphism does not contribute to lung cancer risk and there is no difference between Asians and Caucasians.

[Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of intrapulmonary lesions].

OBJECTIVE: To evaluate real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of intrapulmonary lesions. METHODS: From October 2009 to November 2011, EBUS-TBNA was performed in 78 patients with parabrachial or parabronchial intrapulmonary lesions proved by CT scan. On-site cytological evaluation was not performed. Immunohistochemistry was applied to distinguish the type of malignant tumor when necessary. RESULTS: Sixty-five malignancies and 13 benign diseases were finally diagnosed in 78 intrapulmonary lesions, of which 62 malignancies and 13 benign diseases were distinguished by EBUS-TBNA, including 61 primary lung cancer (adenocarcinoma 36, squamous carcinoma 8, poorly-differentiated carcinoma 5, unknown type carcinoma 3, small cell carcinoma 9), one metastatic lung cancer, 7 pulmonary inflammation, 5 pulmonary tuberculosis and one fibrosis. There were 3 false negative cases which were diagnosed as pulmonary poorly-differentiated carcinoma, pulmonary sarcomatoid carcinoma and pulmonary lymphoma, respectively. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of EBUS-TBNA in distinguishing malignant from benign thoracic lesions was 95%, 100%, 81%, 100%, 96%, respectively. Immunohistochemistry was performed in 8 malignant tumors without definite type or origin, 5 primary lung cancer and one metastatic lung adenocarcinoma were further confirmed. Moderate bleeding from the puncture site during needle aspiration forming blood clot and obstructing the central airway was noted in 1 hypercoagulable subject. CONCLUSIONS: EBUS-TBNA is a minimally invasive, safe procedure with high sensitivity for distinguishing malignant from benign lesions. Immunohistochemistry can provide evidence for the definitive diagnosis of malignant lesions.

The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib.

AIM: To elucidate the roles of receptor tyrosine kinases RET and VEGFR2 and the RAF/MEK/ERK signaling cascade in cancer treatment with sorafenib. METHODS: The cell lines A549, HeLa, and HepG2 were tested. The enzyme activity was examined under cell-free conditions using 384-well microplate assays. Cell proliferation was evaluated using the Invitrogen Alarmar Blue assay. Gene expression was analyzed using the Invitrogen SYBR Green expression assays with a sequence detection system. Protein expression analysis was performed using Western blotting. RESULTS: Sorafenib potently suppressed the activities of cRAF, VEGFR2, and RET with IC(50) values of 20.9, 4 and 0.4 nmol/L, respectively. Sorafenib inhibited cRAF, VEGFR2, and RET via non-ATP-competitive, ATP-competitive and mixed-type modes, respectively. In contrast, sorafenib exerted only moderate cytotoxic effects on the proliferation of the 3 cell lines. The IC(50) values for inhibition of A549, HeLa, and HepG2 cells were 8572, 4163, and 8338 nmol/L, respectively. In the 3 cell lines, sorafenib suppressed the cell proliferation mainly by blocking the MEK/ERK downstream pathway at the posttranscriptional level, which in turn regulated related gene expression via a feed-back mechanism. CONCLUSION: This study provides novel evidence that protein kinases RET and VEGFR2 play crucial roles in cancer treatment with sorafenib.

[A multicenter, randomized, double-blind, placebo-controlled safety study to evaluate the clinical effects and quality of life of paclitaxel-carboplatin (PC) alone or combined with endostar for advanced non-small cell lung cancer (NSCLC)].

OBJECTIVE: To analyze the efficacy and quality of life and safety for paclitaxel and carboplatin (TC) and TC combined with endostar in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: This is a prospective, multicenter, randomized, double-blind, placebo-controlled clinical study. A total of 126 cases of untreated advanced NSCLC were enrolled in this study. There were 63 patients in the TC control arm and TC combined endostar arm, respectively. All enrolled patients were continuously followed-up for disease progression and death. RESULTS: The objective response rate (ORR) of TC combined with endostar arm was 39.3%, and that of TC control arm was 23.0%, P = 0.078. The progression-free survival rates for TC combined with endostar arm and TC control arm were 78.3% and 58.8%, respectively, in 24 weeks (P = 0.017). The hazard ratio for the risk of disease progression was 0.35 (95%CI 0.13 to 0.90, P = 0.030). The median time to progression (TTP) of the TC combined with endostar arm was 7.1 months and TC arm 6.3 months (P > 0.05). The follow-up results showed that the median survival time (mOS) of the TC + Endostar arm was 17.6 months; (95%CI 13.4 to 21.7 months), and the TC + placebo arm 15.8 months (95%CI 9.4 to 22.9 months) (P > 0.05). The quality of life scores (LCSS patient scale) after treatment of the TC combined with endostar arm was improved, and that of the TC group was improved after completion of two cycles and three cycles of treatment. The quality of life scores compared with baseline after the completion of one cycle treatment was significantly improved for both the TC combined with endostar arm (P = 0.028 and), and TC arm (P = 0.036). It Indicated that TC combined with endostar treatment improved the patient's quality of life in the early treatment. The difference of adverse and serious adverse event rates between the two groups was not significant (P > 0.05). CONCLUSIONS: Compared with TC alone treatmrnt, TC combined with endostar treatment can reduce the risk of disease progression at early time (24 weeks), increase the ORR, and can be used as first-line treatment for advanced NSCLC. The TC combined with endostar treatment has good safety and tolerability, improves the quality of life, and not increases serious adverse effects and toxicity for patients with advanced NSCLC.

[Epidermal growth factor receptor gene mutations, amplification and clinicopathologic correlation in patients with lung cancer].

OBJECTIVE: To investigate the clinicopathological features of patients with lung cancers associated with epidermal growth factor receptor (EGFR) gene amplification and/or mutations. METHODS: Mutations and amplification status of EGFR gene were detected by PCR-DNA sequencing and FISH, respectively, followed by subsequent clinicopathological correlative studies. RESULTS: Among 454 patients, the overall mutation rate of EGFR was 48.2% (219/454). The EGFR mutation rate in females was significantly higher than that of males, 59.6% (118/198) vs. 39.5% (101/256), P<0.001. The mutation rate of EGFR gene of non-smokers was higher than that of smokers, 52.7% (147/279) vs. 41.4% (72/175), P=0.017. The mutation rate in patients with adenocarcinoma was higher than that in patients with other cancer types, 56.8% (193/340) vs. 22.8% (26/114), P<0.05. Moreover, a significant difference of mutation rates among different subtypes of adenocarcinomas was found (P=0.001). Among 134 patients with available FISH analysis, no statistical significance of EGFR gene amplification was found in age, gender, histopathological types and subtypes of adenocarcinomas (P>0.05). There was a significant correlation between EGFR mutation and its gene amplification (P=0.0005), although with poor consistency (P=0.275). CONCLUSIONS: EGFR gene mutations occur more frequently in females, non-smokers and patients with adenocarcinoma subtype. A significant variation of the mutation types exits among the subtypes of adenocarcinoma. The presence of EGFR amplification appears not related to age, gender, histopathological types of lung cancer and subtypes of adenocarcinoma. There is a significant correlation between EGFR mutations and its gene amplification (P=0.0005), although with poor consistency.

[Assessment of therapeutic efficacy on treating advanced non-small cell lung cancer in the aged by Chinese medicine adopting the international questionnaire of quality of life].

OBJECTIVE: To assess the therapeutic efficacy of treating advanced non-small cell lung cancer (NSCLC) in the aged by Chinese medicine (CM) adopting the international questionnaire of quality of life (QOL). METHODS: 91 aged patients with advanced NSCLC were randomly assigned to three groups. There were 31 in the CM group (Group I), 30 in the chemotherapy group (Group II), and 30 in the CM and chemotherapy combination group (Group III). Oral administration of CM decoction and intravenous dripping of Chinese patent medicine was given to those in Group I. Patients in Group II received chemotherapeutic protocol alone. Patients in Group III received chemotherapeutic protocol while orally taking CM decoction. Twenty-eight days were taken as one therapeutic course, and two courses in total. Assessment was performed using European Organization for Research and Treatment of Lung Cancer Quality of Life Questionnaire LC-43 (EORTC QLQ-LC43) before treatment, the 10th day of the second therapeutic course, and the 28th day of the second therapeutic course, respectively. RESULTS: After two therapeutic courses of treatment, compared with Group II, better effects were obtained in Group I and Group III in the aspects of the physical function, roles function, emotional functions, social functions, general health state, and short breath, cough, fatigue, insomnia, poor appetite, and constipation (P<0.05, P<0.01). CONCLUSIONS: CM therapy could relieve the clinical symptoms of aged patients with advanced NSCLC and improve their QOL.

Atezolizumab prolongs overall survival over docetaxel in advanced non-small-cell lung cancer patients harboring STK11 or KEAP1 mutation.

Somatic mutations of STK11 or KEAP1 are associated with poor clinical outcomes for advanced non-small-cell lung cancer (aNSCLC) patients receiving immune checkpoint inhibitors (ICIs), chemotherapy, or targeted therapy. Which treatment regimens work better for STK11 or KEAP1 mutated (SKmut) aNSCLC patients is unknown. In this study, the efficacy of atezolizumab versus docetaxel in SKmut aNSCLC was compared. A total of 157 SKmut aNSCLC patients were identified from POPLAR and OAK trials, who were tested by blood-based FoundationOne next-generation sequencing assay. Detailed clinical data and genetic alterations were collected. Two independent cohorts were used for biomarker validation (n = 30 and 20, respectively). Median overall survival was 7.3 months (95% confidence interval [CI], 4.8 to 9.9) in the atezolizumab group versus 5.8 months (95% CI, 4.4 to 7.2) in the docetaxel group (adjusted hazard ratio [HR] for death, 0.70; 95% CI, 0.49 to 0.99; P = .042). Among atezolizumab-treated patients, objective response rate, disease control rate, and durable clinical benefit were higher when blood tumor mutation burden (bTMB) and PD-L1 being higher (biomarker 1, n = 61) or with FAT3 mutation-positive tumors (biomarker 2, n = 83) than otherwise. The interactions for survival between these two biomarkers and treatments were significant, which were further validated in two independent cohorts. In SKmut patients with aNSCLC, atezolizumab was associated with significantly longer overall survival in comparison to docetaxel. Having FAT3 mutation or high TMB and PD-L1 expression potentially predict favorable response in SKmut patients receiving atezolizumab.

The expression of stem cell-related indicators as a prognostic factor in human lung adenocarcinoma.

INTRODUCTION: The purpose of the present study was to detect the presence of BASC-like stem cell-related indicators, such as clara cell secretory protein (CCSP), Octamer-4 (OCT4) and Bmi-1, and evaluate their implications in the prognosis of patients with lung adenocarcinoma. METHODS: Specimens of 134 cases of lung adenocarcinoma were collected after radical surgery from January 1999 to June 2004. RESULTS: One hundred and twenty-six cases showed cells that were positive for CCSP, 99 cases positive for OCT4, 91 cases simultaneous expression of CCSP and OCT4 and 74 cases positive for Bmi-1. Bmi-1 was significantly higher in patients at stage III compared to patients at stages I and II. The pattern of survival curves showed that Bmi-1 was a significant prognostic factor of poor overall survival in lung adenocarcinoma patients (P = 0.0000), and the patients with OCT4(+) expression showed a greater increase in mortality than OCT4(-) patients (P = 0.0103). The results of univariate and multivariate Cox analysis revealed that the pathological stages of tumor node metastases (P = 0.037), OCT4 (P = 0.046) and Bmi-1 expression (P = 0.001) were independent prognostic factors. CONCLUSIONS: OCT4 and Bmi-1 may be good biomarkers to predict the prognosis of patients with completely resected lung adenocarcinoma.

The value of tumor markers in evaluating chemotherapy response and prognosis in Chinese patients with advanced non-small cell lung cancer.

OBJECTIVE: The aim of this study was to assess the value of tumor markers in monitoring chemotherapy response and predicting prognosis in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We studied carcinoembryonic antigen (CEA), CYFRA21-1 and neuron-specific enolase (NSE) of 111 untreated patients with advanced NSCLC before and after 2 cycles of chemotherapy, meanwhile evaluating the response according to the image, and analyzed the relationship between tumor markers and response rate, time to progression (TTP) and overall survival (OS). RESULTS: The mean percentages of CEA decrease of the 111 patients with advanced NSCLC whose image response was partial response, no response and progressive disease were 22.8, -5.5 and -59.8% (p = 0.002), 28.1, 1.8 and -70.8% for CYFRA21-1 (p = 0.001), and 17.5, -3.1 and -16.9% for NSE, respectively (p = 0.03). The median TTP for all patients was 6.7 months, while the median TTP for CEA decrease and CEA elevated or stable patients was 9.2 and 4.3 months, respectively (p < 0.001). Radiologic and CYFRA21-1 responses were significant predictive factors for TTP on multivariate analysis (p < 0.001 and p = 0.003, respectively). The median OS was 19.2 months for all patients, with a 1-year survival rate of 69.4%. Baseline CEA, baseline CYFRA21-1 and CEA response were significant predictive factors for OS on multivariate analysis (P = 0.004, P = 0.004 AND P < 0.001, respectively). CONCLUSION: CEA, CYFRA21-1 and NSE can be used in evaluating chemotherapy response, and CYFRA21-1 response was a significant predictive factor for TTP, while baseline CEA, baseline CYFRA21-1 and CEA response were significant predictive factors for OS in Chinese patients with advanced NSCLC.

[Clinical observation of gefitinib for the treatment of 125 cases with advanced non-small cell lung cancer].

OBJECTIVE: To evaluate the efficacy and safety of gefitinib for the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: 125 patients with advanced NSCLC who had failed or not tolerated or refused chemotherapy received 250 mg oral doses of gefitinib once daily until the disease progression or intolerable toxicity. RESULTS: A total of 125 NSCLC patients were studied, the overall response rate (RR) and the disease control rate (DCR) after administration of gefitinib were 35.2% (44/125) and 77.6% (97/125), respectively. The median progression-free survival and the median survival time were 5.8 and 11.2 months, respectively. The one-year survival rate was 40.5%. The response rate was significantly higher in females, adenocarcinoma and nonsmokers than that in males, non-adenocarcinoma and smokers (P < 0.05). The response rate did not show significant differences regarding ECOG score or previous treatment. The median progression-free survival was significantly longer in ECOG PS 0-1 and gefitinib effective patients than that in ECOG PS >or= 2 and gefitinib ineffective patients (P < 0.01). The median survival time was significantly longer in adenocarcinoma, nonsmokers and gefitinib effective patients than that in non-adenocarcinoma, smokers and gefitinib ineffective patients (P < 0.05). The most common side effects were rash (51.2%) and diarrhea (34.4%), but usually were mild. CONCLUSION: Gefitinib is effective and safe in the treatment of advanced NSCLC patients.