Afatinib in the treatment of brain metastases of lung cancer with one rare EGFR mutation: a two-case report.

Brain metastasis is one of the common distant metastases of lung cancer. The prognosis of patients with brain metastasis is worse and the survival time is shorter. In this report, we described a rare mutation of EGFR G2607A (rs1050171) in two patients over 50 years of age with brain metastasis of lung cancer. These two patients were both treated with afatinib, followed up for 13 months and 45 months respectively. Both patients showed that the tumor subsided, the curative effect was identified as partial response (PR), no recurrence and progress occurred and still being under follow-up. Our study provides a support that afatinib may be a reasonable therapeutic option for patients with brain metastasis of lung cancer.

Resveratrol inhibits lung cancer growth by suppressing M2-like polarization of tumor associated macrophages.

In cancer, tumor associated macrophages (TAMs) play an important role in the cancer progression, evasion of immunity and dissemination of cancer cells. Inhibition of the activation or the M2 polarization of TAMs is an effective therapy for cancer. In the present study, we investigated the ability of resveratrol (RES) to inhibit lung cancer growth using in vitro and in vivo studies, and examined the underlying mechanisms. We demonstrated that M2 polarization of human monocyte derived macrophage (HMDMs) induced by the lung cancer cells conditioned medium was inhibited by RES. Additionally, RES exhibited inhibitory function in lung cancer cells co-cultured with human macrophages. The activity of signal transducer and activator of transcription 3 (STAT3) was significantly decreased by RES. Moreover, in a mouse lung cancer xenograft model, RES significantly inhibited the tumor growth, which was associated with inhibition of cell proliferation and decreased expression of p-STAT3 in tumor tissues. Further, RES inhibits F4/80 positive expressing cells and M2 polarization in the tumors. These results suggest that RES can effectively inhibit lung cancer progression by suppressing the protumor activation of TAMs.

Construction of a Risk Model to Predict the Prognosis and Immunotherapy of Low-Grade Glioma Ground on 7 Ferroptosis-Related Genes.

Purpose: Ferroptosis is closely associated with tumors. The purpose of this study was to investigate the correlation between ferroptosis and prognosis of low grade glioma (LGG) via construction and verification of a risk model. Patients and Methods: The data of LGG were downloaded from public databases. Through LASSO analysis of characteristic genes, a gene signature was constructed. Patients into were divided two groups based on risk score. Subsequently, survival, clinical phenotype, functional enrichment, immune cell infiltration and somatic mutation analysis were performed. In addition, whether ferroptosis-related genes (FRGs) signature can predict the patient's response to anti-PD-1/PD-L1 immunotherapy was also investigated. Results: FRGs signature had strong prognostic assessment ability, and high risk score was associated with poor overall survival (OS) of LGG. The high risk score group had higher degree of immune cell infiltration, stronger stromal activity, higher immune score, and high expression of immune checkpoint. In low risk score group anti-PD-1/PD-L1 immunotherapy has significant therapeutic advantages and clinical response. Genes and frequency of somatic mutations and clinical phenotypes in the high and low risk score groups were significantly different. Conclusion: A prognostic model based on 7 FRGs can be used to predict the prognosis and immunotherapeutic response of LGG.

Experimental Investigation on Mechanical and Acoustic Emission Characteristics of Gassy Coal under Different Stress Paths.

Coal mining leads to stress loading-unloading variation in front of the working face, which influences the occurrence of disasters. In order to study the influence mechanism of stress loading-unloading to the coal failure, a series of experiments of gas-bearing coal deformation and failure under triaxial stress were conducted and acoustic emission (AE) was monitored. In this study, the effect of gas pressure on the mechanical behavior of gas-bearing coal in conventional triaxial stress (CTS) experiments and fixed axial stress and unloading confining stress (FASUCS) experiments was analyzed, and the damage evolution rules of gas-bearing coal in the CTS experiments and FASUCS experiments were determined using AE. The results show that with the increasing of gas pressure, the peak strength and peak strain of gas-bearing coal in the CTS experiments and FASUCS experiments gradually decrease, and the peak of AE ring-down counts lags behind the peak strength. Compared with the CTS experiments, the strength of gas-bearing coal in the FASUCS experiments is lower and the precursor information appears later. The trends in calculated stress and damage coefficient D are consistent with the stress path during unloading, and both begin to rise sharply after the sample enters the plastic stage. Therefore, AE ring-down counts, damage coefficient D, and calculated stress can be used as precursor information for failure of coal and rock, which has great significance for the further study of coal-rock material and for early hazard warning.

Effective Treatment With Afatinib of Lung Adenocarcinoma With Leptomeningeal Metastasis Harboring the Exon 18 p.G719A Mutation in the EGFR Gene Was Detected in Cerebrospinal Fluid: A Case Report.

Background: In patients with lung adenocarcinoma and leptomeningeal metastases, it remains unknown whether non-classical mutations in the epidermal growth factor receptor (EGFR) gene can be detected in the cerebrospinal fluid (CSF) and how it may be used to design directed therapy. Methods: On April 18, 2018, the Interventional Department of Tianjin Huanhu Hospital admitted a 34-years-old male patient with lung adenocarcinoma and leptomeningeal metastasis. An emergency lateral ventriculoperitoneal shunt was performed to relieve the clinical symptoms of intracranial hypertension. Next-generation sequencing (NGS) of the CFS specimens revealed a mutation in EGFR exon 18 p.G719A, and afatinib was administered. Follow-up showed significantly relieved headache, with significantly reduced soft leptomeningeal abnormal enhancement as revealed by enhanced magnetic resonance imaging and significantly smaller tumors in the left lung by chest computed tomography. Carcinoembryonic antigens (CEAs) in cerebrospinal fluid and peripheral blood were significantly reduced. The patient responded well to afatinib, with mild adverse complications. The patient died on October 27, 2019 from respiratory failure as a result of lung infection unrelated to cancer progression. The overall survival (OS) using afatinib was 530 days. Conclusion: CSF can be used as a liquid biopsy for NGS gene detection in patients with lung adenocarcinoma and leptomeningeal metastases. Afatinib exhibits a beneficial effect in patients with lung adenocarcinoma and leptomeningeal metastases harboring the EGFR exon 18 p.G719A mutation.

Efficacy of afatinib for pulmonary adenocarcinoma with leptomeningeal metastases harboring an epidermal growth factor receptor complex mutation (exon 19del+K754E): A case report.

RATIONALE: Liquid biopsy of cerebrospinal fluid (CSF) and sequencing of cell-free DNA has rarely been used to identify epidermal growth factor receptor (EGFR) mutations, which can guide the design of precise, personalized treatment for patients with leptomeningeal metastasis from lung adenocarcinoma. PATIENT CONCERNS: A 42-year-old woman with lung adenocarcinoma and leptomeningeal metastasis was admitted to our hospital on March 31, 2019. She exhibited no response to treatment with gefitinib, osimertinib, or chemoradiotherapy and was in critical condition, with an expected survival of <4 weeks. DIAGNOSIS: Next-generation sequencing of CSF and peripheral blood samples identified an EGFR complex mutation (exon19del+K754E). INTERVENTIONS: On April 10, 2019, the patient started oral afatinib (40 mg po qd), but she developed a grade III oral mucosal reaction 1 week later. The afatinib dose was reduced to 30 mg po qd. OUTCOMES: At the follow-up examination on May 15, 2019, the patient reported relief from headaches. Enhanced magnetic resonance imaging revealed a reduction in abnormal leptomeningeal enhancement, and the CSF pressure and carcinoembryonic antigen levels were also reduced. The patient continued to respond to afatinib treatment (30 mg once daily) with minimal adverse effects. LESSONS: This is the first case report of clinical improvement after afatinib treatment in a patient with lung adenocarcinoma and leptomeningeal metastasis harboring an EGFR complex mutation (exon19del+K754E), and thus provides a clinical reference for treatment with afatinib of cancers harboring EGFR compound mutations.

miR-577 suppresses cell proliferation and epithelial-mesenchymal transition by regulating the WNT2B mediated Wnt/ß-catenin pathway in non-small cell lung cancer.

MicroRNAs (miRNAs/miRs) serve important roles in regulating malignant phenotype in numerous cancers, such as non-small cell lung cancer (NSCLC); however, the role and function of miR-577 in NSCLC remains unknown. In the present study, miR-577 expression levels were observed to be downregulated in NSCLC via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assay, and inhibited cell proliferation, cell migration and invasion and epithelial-mesenchymal transition progress in NSCLC cells. The predicted target genes of miR-577 were determined by enhanced green fluorescent protein reporter assay, RT-qPCR and western blot analyses. miR-577 was demonstrated to suppress the expression of WNT2B by targeting the 3'-untranslated region of WNT2B mRNA in H522 and A549 cells. WNT2B was upregulated in NSCLC cells as observed via RT-qPCR analysis, and the malignant phenotype of H522 and A549 cells were promoted by WNT2B overexpression. In addition, miR-577 inactivated the Wnt/ß-catenin pathway by targeting WNT2B in NSCLC cells. Collectively, miR-577 may function as a suppressor gene by directly downregulatingWNT2B mRNA and protein expression levels in H522 and A549 cells, and may serve important roles in the malignancy of NSCLC.

MicoRNA-425-5p is a potential prognostic biomarker for cervical cancer.

Background MicroRNAs have been implicated in many biological pathways involved in tumourigenesis and can serve as prognostic biomarkers in many cancer types. The present study aims at evaluating the prognostic significance of miR-425-5p in cervical cancer. Methods Real-time polymerase chain reaction was performed to assess the expression levels of miR-425-5p in 35 pairs of cervical cancer tissues and their matched normal tissues as well as serum samples from 40 cervical cancer patients, 13 benign cervical disease patients and 32 healthy controls. The association between miR-425-5p expression levels in tissue and serum, and clinicopathological factors was examined. The correlation between serum miR-425-5p expression levels and overall survival of cervical cancer patients was assessed by Kaplan-Meier analysis and Cox proportional hazards model. Results MiR-425-5p expression levels were significantly increased in cervical cancer tissues compared with matched non-cancerous tissues. Higher expression of miR-425-5p was positively associated with high tumour stage ( P = 0.0003) and positive lymph node metastasis ( P = 0.0107). Serum concentrations of miR-425-5p in cervical cancer patients were significantly higher compared with benign cervical disease and healthy controls. Moreover, the up-regulation of serum miR-425-5p occurred more frequently in cervical cancer patients with high TNM stage ( P = 0.0003) and positive lymph node metastasis ( P = 0.0037). Kaplan-Meier analysis showed that high serum miR-425-5p expression levels predicted poor survival ( P = 0.0571). Cox proportional hazards risk analysis demonstrated that miR-425-5p was an independent prognostic factor for cervical cancer. Conclusion Our study suggests that miR-425-5p is up-regulated in cervical cancer and serum miR-425-5p may serve as a potential prognostic biomarker for cervical cancer.

Novel method for the detection and quantification of malignant cells in the CSF of patients with leptomeningeal metastasis of lung cancer.

The aim of the present study was to discuss a novel method for the detection of malignant tumor cells in cerebrospinal fluid (CSF), by observing tumor marker-immunostaining fluorescence in situ hybridization (TM-iFISH) enrichment and by counting CSF malignant tumor cells in patients with lung cancer leptomeningeal metastasis (LM). A total of 10 CSF samples were collected from 6 patients that presented with lung cancer LM. For each patient, 20 ml CSF was obtained through a lumbar puncture, of which 7.5 ml was used to count the number of malignant tumor cells in the CSF using TM-iFISH enrichment. Cytological and biochemical examinations were conducted on the remaining 10 ml and 2.5 ml CSF, respectively. The 10 CSF samples were successfully analyzed by TM-iFISH, and the tumor cell count range was 3-1,823 cells/7.5 ml CSF in 7 of the samples detected. There were no tumor cells detected in the remaining 3 samples. Tumor cells were revealed in 3 of the samples through the CSF cytological examinations, and albumin protein levels were indicated to be greater than the normal range (normal range, 0.15-0.45 g/l), in 9 of the samples using CSF biochemical examinations. Additionally, TM-iFISH was performed again to count the CSF malignant tumor cells in 3 of the patients following intrathecal injection of chemotherapy (methotrexate 10 mg and dexamethasone 5 mg). The results indicated that the malignant tumor cell count of 2 of the patients had decreased in comparison to the pre-treatment cell count. As it is capable of enriching and counting CSF malignant tumor cells in patients with lung cancer LM, TM-iFISH may be an effective method to diagnose lung cancer LM and to evaluate its efficacy.

Detection value of tumor cells in cerebrospinal fluid in the diagnosis of meningeal metastasis from lung cancer by immuno-FISH technology.

To investigate the detection value of tumor cells in cerebrospinal fluid (CSF) in the adjuvant diagnosis of meningeal metastasis from lung cancer by immunofluorescence in situ hybridization (immuno-FISH) technology. The circulating tumor cells (CTCs) in the CSF of 16 patients with meningeal metastasis from lung cancer and 8 with non-tumor diseases in the brain were detected using immuno-FISH technology. The diagnosis of meningeal metastasis from lung cancer was based on neurological symptoms, enhanced magnetic resonance imaging (MRI) scans and CSF cytological examination. The number of CTCs in the patients with meningeal metastasis from lung cancer was significantly higher than those with non-tumor diseases in the brain (P<0.01). The critical point of the maximum correct diagnostic index (Youden index) was regarded as the judging criterion for positive tumor cells in CSF according to the receiver operating characteristic curve. When there was one tumor cell in 7.5 ml CSF, the area under curve was 0.875 (95% confidence interval, 0.705~1.000). The diagnostic sensitivity, specificity, effectiveness, positive and negative predictive values were 75.0, 100.0, 83.3, 100.0 and 66.7%, respectively. There may be great clinical value in the detection of CTCs in CSF for the diagnosis of meningeal metastasis from lung cancer by immuno-FISH technology.

[Clinical Observation of Recombinant Human Vascular Endostatin Durative Transfusion Combined with Window Period Arterial Infusion Chemotherapy in the Treatment of 
Advanced Lung Squamous Carcinoma].

BACKGROUND AND OBJECTIVE: Lung cancer is one of the most common malignant tumors in China. The aim of this study is to observe the efficacy and safety of recombinant human vascular endostatin (endostar) durative transfusion combined with window period arterial infusion chemotherapy in the treatment of advanced lung squamous carcinoma. METHODS: From February 2014 to January 2015, 10 cases of the cytological or histological pathology diagnosed stage IIIb - stage IV lung squamous carcinoma were treated with recombinant human vascular endostatin (30 mg/d) durative transfusion combined with window period arterial infusion chemotherapy. Over the same period of 10 cases stage IIIb - stage IV lung squamous carcinoma patients for pure arterial perfusion chemotherapy were compared. Recombinant human vascular endostatin was durative transfused every 24 hours for 7 days in combination group, and in the 4th day of window period, the 10 patients were received artery infusion chemotherapy, using docetaxel combined with cisplatin. Pure treatment group received the same arterial perfusion chemotherapy regimen. 4 weeks was a cycle. 4 weeks after 2 cycles, to evaluate the short-term effects and the adverse drug reactions. RESULTS: 2 groups of patients were received 2 cycles treatments. The response rate (RR) was 70.0%, and the disease control rate (DCR) was 90.0% in the combination group; In the pure treatment group were 50.0%, 70.0% respectively, there were no statistically significant difference (P=0.650, 0.582). The adverse reactions of the treatment were mild, including level 1-2 of gastrointestinal reaction and blood toxicity, there were no statistically significant difference (P=0.999, P=0.628). In the combination group, 1 patient occurred level 1 of cardiac toxicity. CONCLUSIONS: Recombinant human vascular endostatin durative transfusion combined with window period arterial infusion chemotherapy in the treatment of advanced lung squamous carcinoma could take a significant curative effect, and the patients were well tolerated by the mild adverse reactions.

[Research progress of lung cancer with leptomeningeal metastasis].

Leptomeningeal metastases is one of the most serious complications of lung cancer, the patients with poor prognosis. Leptomeningeal metastasis in patients with lack specificity of clinical manifestations. The main clinical performance are the damage of cerebral symptoms, cranial nerve and spinal nerve. The diagnosis primarily based on the history of tumor, clinical symptoms, enhance magnetic resnance image (MRI) scan and cerebrospinal fluid cytology. In recent years, new ways of detecting clinically, significantly increase the rate of early detection of leptomeningeal metastases. The effect of comprehensive treatments are still sad. The paper make a review of research progress in pathologic physiology, clinical manifestations, diagnosis methods and treatments of lung cancer with leptomeningeal metastases.

Experimental study on residual tumor angiogenesis after cryoablation.

OBJECTIVE: To explore the mechanism and significance of tumor angiogenesis by observing changes of micro-vessel density (MVD) and expression of vascular endothelial growth factor (VEGF) in residual tumor tissues after cryoablation. MATERIALS AND METHODS: A total of 18 nude mice xenograft models with transplanted lung adenocarcinoma cell line A549 were established and randomly divided into 3 groups when the maximum diameter of tumor reached 1 cm: control, cisplatin (DDP) and cryoablation. The nude mice were sacrificed after 21-d cryoablation to obtain the tumor tissues. Then immunohistochemistry was applied to determine MVD and the expression of VEGF in tumor tissues. RESULTS: The tumor volumes of control group, DDP group and cryoablation group were 1.48 ± 0.14 cm3, 1.03 ± 0.12 cm3 and 0.99 ± 0.06 cm3 respectively and the differences were significant (P < 0.01), whereas MVD values were 21.1 ± 0.86, 24.7 ± 0.72 and 29.2 ± 0.96 (P < 0.01) and the positive expression rates of VEGF were 36.2 ± 1.72%, 39.0 ± 1.79% and 50.8 ± 2.14% (P < 0.01), respectively, showing that MVD was proportional to the positive expression of VEGF (r = 0.928, P < 0.01). CONCLUSIONS: Cryoablation can effectively inhibit tumor growth, but tumor angiogenesis significantly increases in residual tumors, with high expression of VEGF playing an important role in the residual tumor angiogenesis.

Experimental study of Endostar injection concomitant with cryoablation on lung adenocarcinoma A549 xenografts.

OBJECTIVE: To explore the inhibiting effect and mechanism of Endostar injection concomitant with cryoablation on lung adenocarcinoma A549 xenografts in nude mice. MATERIALS AND METHODS: A total of 24 nude mice with subcutaneous xenografts of the A549 cell line were established and divided into 4 groups when the maximal diameters of tumors became 1 cm: control group, Endostar group, cryoablation group and combination group (Endostar concomitant with cryoablation). The nude mice were sacrificed after 21-days treatment, tumour tissues were removed to measure their volume, in situ test of TdT-mediated dUTP nick end labeling (TUNEL) was adopted to determine the cellular apoptosis around freezing injury zones, and immunohistochemical SP test was applied for the detection of micro-vessel density (MVD) and vascular endothelial growth factor (VEGF) expression levels. RESULTS: At 21-days after treatment, the growth velocities of control group, Endostar group, cryoablation group and combination group were 236.7 ± 51.2%, 220.0 ± 30.6%, 159.5 ± 29.3% and 103.3 ± 25.5% (P<0.01), while cellular apoptosis rates of tumors were 21.7 ± 2.34%, (22.17 ± 1.47)%, 38.3 ± 1.37% and 49.2 ± 1.72%, (P<0.01), respectively, according to the immunohistochemical test. MVD and VEGF expression levels in the combination group were both lower than in other groups (P<0.01), also being positively related (r=0.925, P<0.01). CONCLUSIONS: Endostar can significantly improve the inhibitory effects of cryoablation on xenografts of lung adenocarcinoma A549, and the mechanism is probably associated with its function as an inhibitor of tumour neo-angiogenesis through down-regulating VEGF expression.

[Selected arterial infusion chemotherapy combined with target drugs for non-small cell lung cancer with multiple brain metastase].

BACKGROUND AND OBJECTIVE: The aim of this study is to evaluate the efficacy of selected arterial infusion chemotherapy in treating non-small cell lung cancer (NSCLC) with multiple brain metastases and corresponding factors to influencing prognosis. METHODS: From September 2008 to October 2011, a total of 31 patients of NSCLC with multiple brain metastases (≥3) received selected incranial, bronchial and corresponding target arterial infusion chemotherapy combined with EGFR-TKIs. Interventional treatment was performed every four weeks, two-six cycles with synchronized or sequential targeted drugs (erlotinib, gefitinib or icotinib). Follow-up CT and MRI were regularly finished at interval of four weeks after two cycles of interventional treatment were finished or during taking targeted drugs in order to evaluate efficacy of the therapy. The procedure was stopped for the tumor disease was worse or the patient could not tolerate the toxity of drugs any longer. RESULTS: 31 patients was performed two to six cycles of interventional therapy, 3 cycles at average. Response assessment showed that 5 (16.1%) patients got a complete response (CR), 7 (22.6%) had a partial response (PR), 11 (35.5%) had a stable disease (SD) and 8 (25.8%) had a progressive disease (PD). The objective response rate (ORR) was 38.7%, and the disease control rate was 74.2%. The median progression free survival (PFS) and overall survival (OS) were 13.1 months and 15.1 months. The 6-month survival rate, one-year survival rate and two-year survival rate were 79%, 61.1%, and 31.1%, respectively. The patients' OS and PFS were influenced by smoking state, tumor pathology, extracranial metastases, period of targeted drug taking and performance status, not by sex, age, before therapy and the total of brain metastases. CONCLUSION: Selected arterial infusion chemotherapy with targeted drugs is one of the most effective and safe treatment to NSCLC with multiple brain metastases. Smoking status, tumor pathology, extracranial metastases, targeted drug taking and performance status are corresponding the patient's prognosis.