Apatinib, a novel VEGFR inhibitor plus docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR: a phase I trial.

Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m2 doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.

[Efficacy analysis of third-generation plus platinum doublets in the first-line chemotherapy of advanced non-small cell lung cancer].

OBJECTIVE: To compare the chemotherapeutic efficacies of third-generation plus platinum doublets in advanced non-small cell lung cancer (NSCLC) patients. METHODS: A total of 1112 patients were diagnosed as advanced NSCLC at Chinese Academy of Medical Science and Cancer Hospital from January 2005 to August 2009. Their clinical efficacies and regimen compositions were retrospectively analyzed. All calculations were performed by SPSS 17.0. RESULTS: Differences in objective response rate (ORR) existed among four third-generation agents (paclitaxel, gemcitabine, vinorelbine and docetaxel) plus platinum doublets. Their ORRs were 35.6%, 35.4%, 25.9% and 37.4% respectively (χ(2) = 16.331, P = 0.001). And vinorelbine doublets had the lowest ORR (all P < 0.01). The ORRs of cisplatin and carboplatin doublets were 35.2% and 33.5% respectively. There was no difference in ORR among them (χ(2) = 0.352, P = 0.569). Subgroup analysis showed that the ORRs of four third generation plus platinum doublets were 34.8%, 35.3%, 23.2% and 37.1% in non-agers. And the vinorelbine doublets performed the worst. In the patients with squamous-cell lung cancer, the ORRs of paclitaxel and gemcitabine doublets were 45.5% and 28.4% respectively. And the paclitaxel doublets had the better performance (χ(2) = 5.250, P = 0.026). When combined with carboplatin, the ORRs of four doublets were 36.2%, 16.7%, 15.4% and 32.0% respectively. And the paclitaxel regimen was more effective than the gemcitabine and vinorelbine regimens (P = 0.018 and P = 0.034). The influences of subsequent therapy were nullified when the progression-free survival (PFS) was analyzed. The PFSs of these doublets were (3.67 ± 0.19), (2.95 ± 0.18), (3.05 ± 0.36) and (3.40 ± 0.37) months respectively. There was no difference among them. Pairwise comparisons showed that the mean PFS of patients on paclitaxel doublets was longer than those on gemcitabine doublets. And their PFSs were (3.67 ± 0.19) and (2.95 ± 0.18) months respectively (χ(2) = 7.037, P = 0.008). The PFSs of cisplatin and carboplatin doublets were (3.05 ± 0.14) and (3.65 ± 0.20) months respectively. The patients on carboplatin doublets had a longer PFS than that of those on cisplatin doublets (χ(2) = 6.012, P = 0.014). CONCLUSIONS: No difference exist in ORRs among different third-generation plus platinum doublets. But as the first-line treatment of advanced NSCLC, carboplatin doublets is superior to cisplatin doublets in terms of PFS.

[Detection of epidermal growth factor receptor gene mutations in advanced non-small cell lung cancer].

OBJECTIVE: To investigate the mutations of epidermal growth factor receptor (EGFR) in tumor tissue and pleural effusion in advanced non-small cell lung cancer (NSCLC) patients, and to analyze the relationship between EGFR mutations and the clinicopathologic characteristics. METHODS: Two-hundred and forty-one cases of formalin-fixed, paraffin-embedded tumor tissues and 14 paired pleural effusions from advanced NSCLC patients were collected. Twenty-nine different EGFR mutations in exons 18-21 were assessed by scorpions and amplification refractory mutation system (scorpions ARMS) using real time PCR. The relationship between the EGFR mutations and clinical parameters was analyzed using statistical methods. EGFR mutation of 37 cases were detected with direct sequencing, and assessed the sensitivity, the specificity and the accuracy of scorpions ARMS. RESULTS: EGFR somatic mutations were detected in 114 of 234 advanced NSCLC patients, with the mutation rate of 48.7%, including deletions in exon 19 in 65 patients and point mutation of L858R in exon 21 in 39 patients; both accounting for 91.2% (104/114) of all types of EGFR mutations. The test results of 14 paired pleural effusion specimens were entirely the same to the tissues. The concordance rate of 2 different detection methods was 94.6%. Mutation rate was higher in women (55.9%) than in men (42.2%), and there was no difference in mutation rates between smokers and non-smokers; patients in stage IIIB and stage IV; adenocarcinoma and non-adenocarcinoma. CONCLUSIONS: EGFR somatic mutations appear to occur frequently in Chinese. Scorpions ARMS technology is a sensitive method to detect EGFR mutations and is suitable for screening patients who would likely respond to EGFR inhibitors therapy.

Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a real-world study.

Background: Dacomitinib is a first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on NSCLC with complex EGFR mutations is limited. Methods: Patients harboring complex (common mutations co-existing with uncommon mutations), or common (comparison cohort) EGFR mutations, who were treated with dacomitinib, were retrospectively evaluated in the Chinese National Cancer Center and the China PLA hospital between August 2019 and August 2021. Results: In total, 72 patients with NSCLC harboring complex (C+U group, n=18) or common (C group, n=54) EGFR mutations and being treated with dacomitinib were enrolled. In the C+U group, 16 cases (88.9%) harbored L858R mutations co-existing with uncommon mutations located from exon 18 to exon 25 of EGFR (mostly E709X), and two cases harbored exon 19 deletion co-existing with G724S or K754E. Among the 15 evaluable patients, the objective response rate (ORR) was 40% (6/15), and the disease control rate (DCR) was 73.3% (11/15). The median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI), 4.4-10.6 months]. Except for the application line of dacomitinib (P=0.039), no significant statistical differences were found in other characteristics and adverse events between the two groups. The Kaplan-Meier method revealed no significant differences in PFS (P=0.889) and overall survival (OS) (P=0.703). However, the stratified analysis found worse PFS in the C+U group than that observed in the C group when receiving 1st and ≥3rd line dacomitinib treatment, while its OS was worse than that of group C when receiving ≥3rd line treatment. Furthermore, in a multivariate analysis, complex mutation status was an independent prognostic factor for OS (P=0.038) in the entire cohort. Conclusions: This study indicated a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Further studies and data are needed to confirm this conclusion.

Dacomitinib for Advanced Non-small Cell Lung Cancer Patients Harboring Major Uncommon EGFR Alterations: A Dual-Center, Single-Arm, Ambispective Cohort Study in China.

Objective: Dacomitinib has been approved for non-small-cell lung cancer (NSCLC) patients harboring classical epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on major uncommon EGFR mutations is currently limited. Materials and methods: This was a dual-center, single-arm, ambispective cohort study in China. Patients with histologically confirmed metastatic or recurrent NSCLC harboring major uncommon EGFR mutations were eligible for the study. The objective response rate and disease control rate were determined by RECIST 1.1 every 1-2 months. Adverse events were assessed by CTCAE 5.0. Results: In total, 32 NSCLC patients were enrolled between July 2020 and January 2022, and 18 (56.3%) patients received dacomitinib as first-line therapy. Median age was 64 years, and 20 (62.5%) were female. The mutations identified were G719X (n = 24; 75%), followed by L861X (n = 10; 31.3%), and S768I (n = 8; 25%). In the first-line setting, 72.2% of patients (13/18) had a confirmed partial response and 100% (18/18) had disease control, and the median progression-free survival (PFS) and overall survival (OS) were unreached. In the whole cohort, 56.3% of patients (18/32) had a confirmed partial response and 90.6% (29/32) had disease control, and the median PFS was 10.3 months (95% confidence interval, 6.1-14.5) and the median OS was 36.5 months. Except for one case not available for brain re-evaluation, control of the intracranial metastases was observed in 13 patients (13/14, 92.9%). No grade 4-5 adverse events (AEs) occurred, but all patients had grade 1-2 AEs, and 12.5% (4/32) patients required a dosage reduction due to intolerable AEs. Conclusions: Dacomitinib demonstrated favorable activity with manageable toxicity in patients with NSCLC harboring major uncommon EGFR mutations.

Afatinib and Dacomitinib Efficacy, Safety, Progression Patterns, and Resistance Mechanisms in Patients with Non-Small Cell Lung Cancer Carrying Uncommon EGFR Mutations: A Comparative Cohort Study in China (AFANDA Study).

(1) Background: Afatinib has been approved for patients with non-small cell lung cancer (NSCLC) carrying major uncommon epidermal growth factor receptor gene (EGFR) mutations. Dacomitinib, another second-generation tyrosine kinase inhibitor, has also shown promising potential for uncommon EGFR mutations. However, no comparative study has been conducted. (2) Methods: Two cohorts were employed: the AFANDA cohort, an ambispective cohort including 121 patients with uncommon EGFR mutations admitted to two tertiary hospitals in China, and an external validation afatinib cohort (ex-AC), extracted from the Afatinib Uncommon EGFR Mutations Database (N = 1140). The AFANDA cohort was divided into an afatinib cohort (AC) and a dacomitinib cohort (DC) for internal exploration. Objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs) were assessed for comparison. Progression patterns and resistance mechanisms were explored. (3) Results: In total, 286 patients with advanced NSCLC carrying uncommon EGFR mutations treated with afatinib or dacomitinib were enrolled, including 79 in the AFANDA cohort (44 in the DC, 35 in the AC) and 207 in the ex-AC. In internal exploration, the ORR of the DC was significantly higher than that of the AC (60.5 vs. 26.7%, p = 0.008), but there was no significant difference in median PFS between the DC and the AC (12.0 months vs. 10.0 months, p = 0.305). Multivariate analysis confirmed an independent favorable effect of dacomitinib on PFS (hazard ratio (HR), 1.909; p = 0.047). In external validation, multivariate analysis confirmed the independent prognostic role of dacomitinib in PFS (HR, 1.953; p = 0.029). Propensity score matching analysis confirmed the superiority of dacomitinib over afatinib in terms of PFS in both univariate and multivariate analyses. Toxicity profiling analysis suggested more G1 (p = 0.006), but fewer G3 (p = 0.036) AEs in the DC than in the AC. Progression patterns revealed that the incidence of intracranial progression in the AC was significantly higher than that in the DC (50 vs. 21.1%, p = 0.002). Drug resistance analysis indicated no significant difference in the occurrence of T790M between the AC and the DC (11.8 vs. 15.4%, p = 0.772). (4) Conclusions: Compared with afatinib, dacomitinib demonstrated a more favorable activity with manageable toxicity and different progression patterns in patients with NSCLC carrying uncommon EGFR mutations.

[Association of serum EGFR protein concentration with the efficacy of Gefitinib in the treatment of advanced non-small cell lung cancer].

OBJECTIVE: To analyze the association between the EGFR protein level and the EGFR gene mutation status in advanced non-small cell lung cancer (NSCLC), and to explore whether the EGFR protein level is related to the efficacy and survival of the EGFR-TKI drug Gifitinib-treated patients with advanced NSCLC. METHODS: Ninety-nine cases were enrolled in this study. Pathological tissue specimens and paired peripheral blood samples were collected. Exons 19 and 21 of the EGFR gene mutation were detected by direct sequencing. The concentration of plasma EGFR protein was detected by ELISA. Univariate and multivariate statistical analyses of the efficacy and survival were performed using SPSS 13.0 software. RESULTS: The response rate (RR) and clinical benefit rate (CBR) of Gefitinib-treated patients were 51.5% and 79.8%, respectively. There were 35 (35.4%) with positive EGFR gene mutation of the 99 samples. The concentration limit of EGFR protein was 55.42 µg/L. The RR and CBR of patients with EGFR gene mutation was significantly higher than those without mutation (65.7% vs. 43.8%, P = 0.037; 94.3% vs. 71.9%, P = 0.008). The median PFS was prolonged (23 months vs. 10 months, P = 0.014). The CBR of patients with high EGFR protein expression (concentration ≥ 55.42 µg/L) was significantly higher than those with low expression (90.0% vs 64.1%, P = 0.004), and the median PFS was prolonged (21 months vs. 8 months, P = 0.016). EGFR protein level was an independent factor affecting the EGFR gene mutation status. The Correlation between EGFR gene mutation status and EGFR protein level was positive. CONCLUSIONS: Gefitinib is effective in the treatment of advanced NSCLC patients with EGFR gene mutation and high EGFR protein expression. EGFR protein level in peripheral blood may be a molecular biomarker in prediction of efficacy and survival of the Gefitinib treatment in patients with advanced NSCLC.

Risk factors associated with acute respiratory distress syndrome in COVID-19 patients outside Wuhan: A double-center retrospective cohort study of 197 cases in Hunan, China.

BACKGROUND: There have been few reports on the risk factors for acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19), and there were obvious differences regarding the incidence of ADRS between Wuhan and outside Wuhan in China. AIM: To investigate the risk factors associated with ARDS in COVID-19, and compare the characteristics of ARDS between Wuhan and outside Wuhan in China. METHODS: Patients were enrolled from two medical centers in Hunan Province. A total of 197 patients with confirmed COVID-19, who had either been discharged or had died by March 15, 2020, were included in this study. We retrospectively collected the patients' clinical data, and the factors associated with ARDS were compared by the χ² test, Fisher's exact test, and Mann-Whitney U test. Significant variables were chosen for the univariate and multivariate logistic regression analyses. In addition, literature in the PubMed database was reviewed, and the characteristics of ARDS, mortality, and biomarkers of COVID-19 severity were compared between Wuhan and outside Wuhan in China. RESULTS: Compared with the non-ARDS group, patients in the ARDS group were significantly older, had more coexisting diseases, dyspnea, higher D-dimer, lactate dehydrogenase (LDH), and C-reactive protein. In univariate logistic analysis, risk factors associated with the development of ARDS included older age [odds ratio (OR) = 1.04), coexisting diseases (OR = 3.94), dyspnea (OR = 17.82), dry/moist rales (OR = 9.06), consolidative/mixed opacities (OR = 2.93), lymphocytes (OR = 0.68 for high lymphocytes compared to low lymphocytes), D-dimer (OR = 1.41), albumin (OR = 0.69 for high albumin compared to low albumin), alanine aminotransferase (OR = 1.03), aspartate aminotransferase (OR = 1.02), LDH (OR = 1.02), C-reactive protein (OR = 1.04) and procalcitonin (OR = 17.01). In logistic multivariate analysis, dyspnea (adjusted OR = 27.10), dry/moist rales (adjusted OR = 9.46), and higher LDH (adjusted OR = 1.02) were independent risk factors. The literature review showed that patients in Wuhan had a higher incidence of ARDS, higher mortality rate, and higher levels of biomarkers associated with COVID-19 severity than those outside Wuhan in China. CONCLUSION: Dyspnea, dry/moist rales and higher LDH are independent risk factors for ARDS in COVID-19. The incidence of ARDS in Wuhan seems to be overestimated compared with outside Wuhan in China.

Circulating tumor cells (CTCs)/circulating tumor endothelial cells (CTECs) and their subtypes in small cell lung cancer: Predictors for response and prognosis.

BACKGROUND: The aim of the study was to define the clinical significance of circulating tumor cells (CTCs)/circulating tumor endothelial cells (CTECs) and their subtypes in small cell lung cancer (SCLC) patients. METHODS: CTCs/CTECs and their subtypes were determined using SE-iFISH technology in 33 SCLC patients before initial treatment (B1), after two cycles of chemotherapy (B2), at the completion of chemotherapy (B3), and disease progression (B4). The correlations with clinical characteristics, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: CTCs and CTECs were detected in 96.6% and 65.5% of patients, respectively. Patients had higher levels of CTCs compared with CTECs in circulation (p < 0.05). Extensive-stage SCLC patients tended to have higher CTEC counts (p = 0.035), and the detection of CTC-white blood cell (CTC-WBC) clusters was associated with a worse response to treatment (p = 0.030). Patients with CTC-WBC clusters at B1 (17.3 vs. 22.6 months, p = 0.041) and B2 (19.9 vs. 25.2 months, p = 0.018) had significantly shorter OS than those with no detection. Additionally, their presence was revealed as independent predictors for a worse OS in multivariable analyses (B1: HR 9.3, 95% CI: 1.4-48, p = 0.0079; B2: HR 4.4, 95% CI: 1.1-18, p = 0.041). A high CTC level at B4 was an adverse prognostic factor for SCLC patients (PFS: 8.7 vs. 22.5 months, p = 0.0026; OS: 19 months vs. not reached, p = 0.0086). CTC clusters and CTECs also showed prognostic values. CONCLUSIONS: The presence of CTC-WBC clusters at baseline and after two-cycle chemotherapy and the total CTC counts at the completion of chemotherapy are strong predictors for the prognostic survival of SCLC patients receiving first-line treatment.

Survival and pretreatment prognostic factors for extensive-stage small cell lung cancer: A comprehensive analysis of 358 patients.

BACKGROUND: Extensive-stage small cell lung cancer (ES-SCLC) is deemed as a fatal malignancy with a poor prognosis. Although immunotherapy has gradually played an important role in the treatment of ES-SCLC since 2018, ES-SCLC treatment data and patient outcome before 2018, when chemotherapy served as a fundamental therapeutic strategy, is still meaningful as a summary of the situation regarding previous medical treatment and is a baseline for comparative data. In addition, the prognostic factors of ES-SCLC have failed to reach a consensus until now. Therefore, this study aimed to evaluate survival and identify the prognostic factors in an ES-SCLC population. METHODS: We retrospectively collected the detailed medical records of 358 patients with ES-SCLC from January 1, 2011 to December 31, 2018 in a Chinese top-level cancer hospital. The prognostic factors were evaluated by Cox univariate and multivariate analysis. RESULTS: The median overall survival (OS) of ES-SCLC patients (N = 358) was 14.0 months, the one- and two-year OS rates were 56.2% and 21.7%, respectively. Moreover, we identified two demographic characters (age ≥ 70, smoking index ≥ 400), one tumor burden factor (bone multimetastasis), two tumor biomarkers (cyfra211, CA125) and two laboratory indexes (decreased Na, PLR < 76) as independent prognostic factors for OS in this patient population. Progression-free survival (PFS) data of 238 patients was obtained for further analysis, and the median PFS was 6.2 months, and six-month and one-year PFS rates were 51.7% and 14.3%, respectively. Elevated cyfra211, decreased Hb and Na were identified as independent prognostic factors for PFS. CONCLUSIONS: This study provides real-world evidence of the survival and prognosis of ES-SCLC patients which will enable better evaluation and clinical decision-making in the future.

Emerging immunotherapy targets in lung cancer.

Immunotherapy has become the mainstay for lung cancer treatment, providing sustained therapeutic responses and improved prognosis compared with those obtained with surgery, chemotherapy, radiotherapy, and targeted therapy. It has the potential for anti-tumor treatment and killing tumor cells by activating human immunity and has moved the targets of anti-cancer therapy from malignant tumor cells to immune cell subsets. Two kinds of immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1), are the main targets of current immunotherapy in lung cancer. Despite the successful outcomes achieved by immune checkpoint inhibitors, a small portion of lung cancer patients remain unresponsive to checkpoint immunotherapy or may ultimately become resistant to these agents as a result of the complex immune modulatory network in the tumor microenvironment. Therefore, it is imperative to exploit novel immunotherapy targets to further expand the proportion of patients benefiting from immunotherapy. This review summarizes the molecular features, biological function, and clinical significance of several novel checkpoints that have important roles in lung cancer immune responses beyond the CTLA-4 and PD-1/PD-L1 axes, including the markers of co-inhibitory and co-stimulatory T lymphocyte pathways and inhibitory markers of macrophages and natural killer cells.

CD56+ lymphoepithelioma-like carcinoma of the lung: A case report and literature review.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is a non-keratinizing carcinoma with rich lymphocytic infiltration, which primarily originates from the nasopharynx. Primary lung LELC is a type of lung cancer with a relatively low incidence. Herein, we report a rare case of lung LELC with expression of CD56. We also performed a literature review to summarize the epidemiological, clinical, and prognostic features of this disease. CASE SUMMARY: A 51-year-old man was admitted to Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College due to cough and chest pain lasting > 2 mo and 1 wk, respectively. Positron emission tomography-computed tomography and magnetic resonance imaging examinations revealed the presence of a mass in the right upper lobe with enlargement of lymph nodes and multiple bone metastases. According to the results of bronchoscopy and cervical lymph node biopsy, a diagnosis of lung LELC with CD56-positive staining (CD56+ lung LELC) was made. In the literature, 458 cases of lung LELC have been reported. However, only one other case of CD56+ lung LELC has been reported thus far. CONCLUSION: The mechanism and potential role of CD56 expression in CD56+ lung LELC require further investigation.

Safety, tolerability, and pharmacokinetics of simotinib, a novel specific EGFR tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer: results of a phase Ib trial.

Purpose: The aim of this phase Ib study (clinicaltrials.gov: NCT01772732) was to assess safety, tolerability, and pharmacokinetics (PKs) of simotinib (a novel EGFR tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer (NSCLC) and EGFR gene mutation. Patients and methods: 41 patients with EGFR gene mutations were enrolled and received simotinib orally administered twice daily with dose escalating from 100 to 650 mg in 28 days cycle. Safety and tolerability were assessed through the study. Blood samples were collected for PK analysis on Days 1, 8, 9, 10, 15, 22 and 29. Tumor response was assessed at baseline, on Day 29 and every 8 weeks thereafter. Results: Simotinib was well tolerated, with no dose-limiting toxicities. Maximum tolerated dose (MTD) was not found. 95.1% of patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequently reported AEs. Simotinib was rapidly absorbed and eliminated with average T max ranging from 1 to 4 hrs and T 1/2 ranging between 6.2 and 13.0 hrs after multiple-dose administration. No dose-response relationship between dose and exposure was observed after multiple-dose administration. 39.3% of the enrolled patients achieved a partial response and 46.3% had stable disease. Median progression-free survival and overall survival were 9.9 (CI% 4.7; 12.1) months and 14.6 (95%CI 12.3; 22.5) months, respectively. Conclusion: Simotinib was well tolerated, with manageable AEs at doses of up to 650 mg and MTD was not reached. Further studies to explore higher doses are ongoing.

Circular RNA profiling identified as a biomarker for predicting the efficacy of Gefitinib therapy for non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become important treatment options for non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutation. However, the detection of EGFR driver mutation is impeded by the lack of adequate tumor tissues, histopathological type, long detection period, and the heterogeneity of a tumor. Therefore, it is necessary to develop a more convenient method to guide the clinical use of EGFR-TKI. Circular RNAs (circRNAs) are characterized as a closed structure with covalently joined ends resistant to exonucleases may be a potential biomarker. In the present study, we aimed to screen circRNAs that may be associated with the efficacy of EGFR-TKI. METHODS: The expression of circRNAs sequenced by circular microarray in plasma samples between gefitinib effective and ineffective groups were compared. RT-qPCR further validated the results in an independent cohort. Kaplan-Meier curves were used to analyze the association between circRNA and progression-free survival (PFS) of NSCLC patients treated with gefitinib. RESULTS: In total, 52 NSCLC patients treated with gefitinib were included for analysis. 1,377 circRNAs were differentially expressed in gefitinib effective and ineffective groups, among which 989 circRNAs were up-regulated, and 388 circRNAs were down-regulated in the effective group. Furthermore, two differentially expressed circRNAs, hsa_circ_0109320 and hsa_circ_0134501, were validated by RT-qPCR in an independent cohort of 38 gefitinib-treated NSCLC patients. Elevated hsa_circ_0109320 was associated with longer PFS in gefitinib-treated NSCLC patients. CONCLUSIONS: Taken together, hsa_circ_0109320 may be a potential biomarker for the efficacy of EGFR-TKI in NSCLC patients. This provides a new molecular typing method for individualized precision treatment.

Depth of Response was Associated with Progression-Free Survival in Patients with Advanced Non-small Cell Lung Cancer treated with EGFR-TKI.

Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate new therapeutic strategies in cancer. However, RECIST fails to assess the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as the maximum percentage change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or exon 19 deletion) treated with EGFR-TKI from August 2014 to July 2017 from two sites were retrospetively collected for analysis. Patients were divided into four groups by DepOR (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS against DepOR and the hazard ratio (HR) was determined through univariable and multivariable cox regression models. Results: In total, 265 patients were included for analysis. The number of patients in Group Q1-Q4 were 91 (34.3%), 73 (27.5%), 65 (24.5%) and 36 (13.6%), respectively. A greater DepOR was significantly associated with a longer PFS (Log-rank P<0.0001). The HRs (95% CI) for PFS comparing patients with different DepOR status were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3, and 0.33 (0.22-0.50) for Q4, all compared with patients in Q1. DepOR as a continuous variable was also associated with prolonged PFS (HR, 0.20; 95% CI, 0.13-0.33; P<0.001). Additionally, in the multivariable cox regression model, abnormal LDH, brain metastasis and male were found to be associated with worse PFS outcomes (P<0.05). Conclusion: A greater DepOR is significantly associated with PFS benefit in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to evaluate the response of targeted therapy.

Diagnostic accuracy of transient elastography (FibroScan) in detection of esophageal varices in patients with cirrhosis: A meta-analysis.

AIM: To investigate the diagnostic accuracy of FibroScan (FS) in detecting esophageal varices (EV) in cirrhotic patients. METHODS: Through a systemic literature search of multiple databases, we reviewed 15 studies using endoscopy as a reference standard, with the data necessary to calculate pooled sensitivity (SEN) and specificity (SPE), positive and negative LR, diagnostic odds ratio (DOR) and area under receiver operating characteristics (AUROC). The quality of the studies was rated by the Quality Assessment of Diagnostic Accuracy studies-2 tool. Clinical utility of FS for EV was evaluated by a Fagan plot. Heterogeneity was explored using meta-regression and subgroup analysis. All statistical analyses were conducted via Stata12.0, MetaDisc1.4 and RevMan5. RESULTS: In 15 studies (n = 2697), FS detected the presence of EV with the summary sensitivities of 84% (95%CI: 81.0%-86.0%), specificities of 62% (95%CI: 58.0%- 66.0%), a positive LR of 2.3 (95%CI: 1.81-2.94), a negative LR of 0.26 (95%CI: 0.19-0.35), a DOR of 9.33 (95%CI: 5.84-14.92) and an AUROC of 0.8262. FS diagnosed the presence of large EV with the pooled SEN of 0.78 (95%CI: 75.0%-81.0%), SPE of 0.76 (95%CI: 73.0%-78.0%), a positive and negative LR of 3.03 (95%CI: 2.38-3.86) and 0.30 (95%CI: 0.23-0.39) respectively, a summary diagnostic OR of 10.69 (95%CI: 6.81-16.78), and an AUROC of 0.8321. A meta-regression and subgroup analysis indicated different etiology could serve as a potential source of heterogeneity in the diagnosis of the presence of EV group. A Deek's funnel plot suggested a low probability for publication bias. CONCLUSION: Using FS to measure liver stiffness cannot provide high accuracy for the size of EV due to the various cutoff and different etiologies. These limitations preclude widespread use in clinical practice at this time; therefore, the results should be interpreted cautiously given its SEN and SPE.

Survival of patients with advanced lung adenocarcinoma before and after approved use of gefitinib in China.

BACKGROUND: To compare the overall survival (OS) of patients with advanced lung adenocarcinoma in China before and after the approved use of gefitinib, and analyze clinical factors that may affect OS. METHODS: Clinical data of 558 patients with advanced lung adenocarcinoma who received chemotherapy from January 2002 to December 2010 were retrospectively analyzed. According to the matched-pair case-control study design, 255 patients who only received chemotherapy and 255 patients who received gefitinib treatment after its approval were stringently matched by age, gender, and smoking history and enrolled in the study. Clinical factors including age, gender, smoking history, Eastern Cooperative Oncology Group (ECOG) performance status (PS), tumor stage, organ metastasis, and the number of prior chemotherapies were analyzed to determine their correlations with OS. RESULTS: The median survival time (MST) of the 510 enrolled patients with advanced lung adenocarcinoma was 22.8 months. The MST of the patients who received gefitinib treatment was significantly longer than that of patients who did not receive gefitinib treatment (33.5 vs. 14.1 months, P < 0.001). The OS in patients who received gefitinib treatment was significantly longer than in patients who did not receive gefitinib treatment in almost all clinical factor-based subgroups, including age, gender, smoking history, ECOG PS 0-1, tumor stage, the presence or absence of lung, pleural, bone, brain, adrenal gland and liver metastasis, and the number of prior chemotherapies (all P < 0.001), except in the ECOG PS ≥2 subgroup. CONCLUSIONS: Gefitinib treatment significantly improved the survival of patients with advanced lung adenocarcinoma in China.