IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

A novel small-animal locomotor activity recording device for biological clock research

The rodent running-wheel recording apparatus is a reliable approach for studying cir-cadian rhythm.This study demonstrated how to construct a simple and intelligent running-wheel recording system.The running wheel was attached to the cage's base,whereas the Hall sensor was attached to the cage's cover.Then,the RJ25 adaptor relayed the running signal to the main control board.Finally,the main control board was connected to the USB port of the computer with the USB connection.Data were collected using the online-accessible,self-created software Magturning.Through Magturning,generated data were saved and exported in real time.Afterward,the device was validated by collecting data on the locomotor activities of mice under dif-ferent light conditions.In conclusion,this new device can record circadian activity of rodents.Our device is appropriate for interdisciplinary investigations related to biological clock research.

洛拉替尼特殊不良反应管理中国专家共识

间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)融合基因是非小细胞肺癌(non-small cell lung cancer,NSCLC)中第二常见的肿瘤驱动基因。作为新型的第三代ALK酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI),洛拉替尼对多种ALK激酶域突变具有广谱且高效的临床活性,并具有强大的穿透血脑屏障效力。洛拉替尼的总体耐受性良好,其独特的不良反应或不良事件包括高脂血症与中枢神经系统反应等,多为轻至中度,通常经剂量调整和/或标准医疗干预即可管理。对于ALK阳性晚期NSCLC,开始洛拉替尼治疗前应充分评估患者基线特征与既往用药状况,预先告知患者可能经历的用药相关不良反应,并定期监测以实现药物临床获益的最大化。同时,多学科专家团队对于建立全面的诊断和治疗策略是至关重要的。

腹腔镜膀胱肌瓣代输尿管术治疗长段输尿管狭窄的初步体会

目的探讨腹腔镜膀胱肌瓣代输尿管术治疗中、下段输尿管长段狭窄的可行性与重建方法。方法回顾性分析2014年5月-2016年4月该科在腹腔镜下应用膀胱肌瓣代输尿管术治疗中、下段长段输尿管狭窄患者3例临床资料。男1例,女2例,2例有输尿管中、下段结石输尿管镜手术史,1例有输尿管结石反复体外冲击波碎石(ESWL)史。术前泌尿系B超、CT、静脉肾盂造影显示患侧肾脏重度积水,输尿管中、上段重度扩张,中、下段严重狭窄。结果 3例患者手术顺利,成形后的膀胱肌瓣管平均长度约9.6 cm,平均手术时间180 min,平均住院时间10 d,术后8周顺利拔除双J管,拔管时输尿管镜检查吻合口通畅,能顺利通过8.5 F输尿管镜,无感染及尿漏发生。术后随访3~18个月,泌尿系彩超提示3例患者上尿路积水显著减轻,静脉肾盂造影显示输尿管通畅,输尿管与肌瓣管连接处无狭窄,血肌酐值均在正常范围。结论腹腔镜膀胱肌瓣代输尿管术是治疗中、下段输尿管长段狭窄的有效方法,但术者需具备丰富的腹腔镜手术经验。

Nedaplatin/Gemcitabine Versus Carboplatin/Gemcitabine in Treatment of Advanced Non-small Cell Lung Cancer: A Randomized Clinical Trial

Objective： To evaluate the efficacy and safety of nedaplatin/gemcitabine （NG） and carboplatin/gemcitabine （CG） in the management of untreated advanced non-small cell lung cancer （NSCLC）. Methods： Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm （n=30） and the CG arm （n=32）. Only patients （24 and 25 in the NG and CG arms, respectively） who completed 〉2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate （ORR）. The secondary outcome measures included progression-free survival （PFS）, overall survival （OS） and adverse events. Results： There were no statistically significant differences in the efficacy measures （ORR, P=0.305; median PFS, P=0.298, median OS, P=0.961） or in the major adverse events （grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.222） between the two treatment arms. However, there was a trend towards higher ORR （37.5% vs. 24.0%）, longer PFS （6.0 vs. 5.0 months）, and less adverse events in the NG arm. Conclusion： NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.

Detecting the spectrum of multigene mutations in non-small cell lung cancer by Snapshot assay

As molecular targets continue to be identified and more targeted inhibitors are developed for personalized treatment of non-small cell lung cancer(NSCLC), multigene mutation determination will be needed for routine oncology practice and for clinical trials. In this study, we evaluated the sensitivity and specificity of multigene mutation testing by using the Snapshot assay in NSCLC. We retrospectively reviewed a cohort of 110 consecutive NSCLC specimens for which epidermal growth factor receptor(EGFR) mutation testing was performed between November 2011 and December 2011 using Sanger sequencing. Using the Snapshot assay, mutation statuses were detected for EGFR, Kirsten rate sarcoma viral oncogene homolog(KRAS), phosphoinositide-3-kinase catalytic alpha polypeptide(PIK3CA), v-Raf murine sarcoma viral oncogene homolog B1(BRAF), v-ras neuroblastoma viral oncogene homolog(NRAS), dual specificity mitogen activated protein kinase kinase 1(MEK1), phosphatase and tensin homolog(PTEN), and human epidermal growth factor receptor 2(HER2) in patient specimens and cell line DNA. Snapshot data were compared to Sanger sequencing data. Of the 110 samples, 51(46.4%) harbored at least one mutation. The mutation frequency in adenocarcinoma specimens was 55.6%, and the frequencies of EGFR, KRAS, PIK3 CA, PTEN, and MEK1 mutations were 35.5%, 9.1%, 3.6%, 0.9%, and 0.9%, respectively. No mutation was found in the HER2, NRAS, or BRAF genes. Three of the 51 mutant samples harbored double mutations: two PIK3 CA mutations coexisted with KRAS or EGFR mutations, and another KRAS mutation coexisted with a PTEN mutation. Among the 110 samples, 47 were surgical specimens, 60 were biopsy specimens, and 3 were cytological specimens; the corresponding mutation frequencies were 51.1%, 41.7%, and 66.7%, respectively(P = 0.532). Compared to Sanger sequencing, Snapshot specificity was 98.4% and sensitivity was 100%(positive predictive value, 97.9%; negative predictive value, 100%). The Snapshot assay is a sensitive and easily customized assay for multigene mutation testing in clinical practice.

Different dissecting orders of the pulmonary bronchus and vessels during right upper lobectomy are associated with surgical feasibility and postoperative recovery for lung cancer patients

Background: Right upper lobectomy(RUL) for lung cancer with di erent dissecting orders involves the most vari?able anatomical structures, but no studies have analyzed its e ects on postoperative recovery. This study compared the conventional surgical approach, VAB(dissecting pulmonary vessels first, followed by the bronchus), and the alter?native surgical approach, a BVA(dissecting the posterior ascending arterial branch first, followed by the bronchus and vessels) on improving surgical feasibility and postoperative recovery for lung cancer patients.Methods: According to the surgical approach, consecutive lung cancer patients undergoing RUL were grouped into a BVA and VAB cohorts. Their clinical, pathologic, and perioperative characteristics were collected to compare periop?erative outcomes.Results: Three hundred one patients were selected(109 in the a BVA cohort and 192 in the VAB cohort). The mean operation time was shorter in the a BVA cohort than in the VAB cohort(164 vs. 221 min, P < 0.001), and less blood loss occurred in the a BVA cohort(92 vs. 141 m L, P < 0.001). The rate of conversion to thoracotomy was lower in the a BVA cohort than in the VAB cohort(0% vs. 11.5%, P < 0.001). The mean duration of postoperative chest drainage was shorter in the a BVA cohort than in the VAB cohort(3.6 vs. 4.5 days, P rvival was n= 0.001). The rates of postoperative complica?tions were comparable(P = 0.629). The median overall suot arrived in both cohorts(P > 0.05). The median disease?free survival was comparable for all patients in the two cohorts(not arrived vs. 41.97 months) and for patients with disease recurrences(13.25 vs. 9.44 months)(both P > 0.05). The recurrence models in two cohorts were also comparable for patients with local recurrences(6.4% vs. 7.8%), distant metastases(10.1% vs. 8.3%), and both(1.8% vs. 1.6%)(all P > 0.05).Conclusions: Dissecting the right upper bronchus before turning over the lobe repeatedly and dissecting veins via the a BVA approach during RUL would promote surgical feasibility and achieve comparable postoperative recovery for lung cancer patients.

Establishment and application of a multiplex genetic mutation-detection method of lung cancer based on MassARRAY platform

Objective: This study aims to establish a method for highly parallel multiplexed detection of genetic mutations in Chinese lung cancer samples through Agena i PLEX chemistry and matrix-assisted laser desorption ionization time-of-flight analysis on Mass ARRAY mass spectrometry platform.Methods: We reviewed the related literature and data on lung cancer treatments. We also identified 99 mutation hot spots in 13 target genes closely related to the pathogenesis, drug resistance, and metastasis of lung cancer. A total of 297 primers, composed of99 paired forward and reverse amplification primers and 99 matched extension primers, were designed using Assay Design software. The detection method was established by analyzing eight cell lines and six lung cancer specimens. The proposed method was then validated through comparisons by using a Lung Carta^(TM) kit. The sensitivity and specificity of the proposed method were evaluated by directly sequencing EGFR and KRAS genes in 100 lung cancer cases.Results: The proposed method was able to detect multiplex genetic mutations in lung cancer cell lines. This finding was consistent with the observations on previously reported mutations. The proposed method can also detect such mutations in clinical lung cancer specimens. This result was consistent with the observations with Lung Carta^(TM) kit. However, an FGFR2 mutation was detected only through the proposed method. The measured sensitivity and specificity were 100% and 96.3%, respectively.Conclusions: The proposed Mass ARRAY technology-based multiplex method can detect genetic mutations in Chinese lung cancer patients. Therefore, the proposed method can be applied to detect mutations in other cancer tissues.

Polycystic kidney and hepatic disease 1 gene mutations in von Meyenburg complexes: Case report

Von Meyenburg complexes(VMCs) are a rare type of ductal plate malformation. We herein report two Chinese families with VMCs, and the suspicious gene mutation of this disease. Proband A was a 62-year-old woman with abnormal echographic presentation of the liver. She received magnetic resonance imaging(MRI) examination and liver biopsy, and the results showed she had VMCs. Histologically proved hepatocellular carcinoma was found 1 year after the diagnosis of VMCs. Proband B was a 57-year-old woman with intrahepatic diffuselesions displayed by abdominal ultrasonography. Her final diagnoses were VMCs, congenital hepatic fibrosis, and hepatitis B surface e antigen-negative chronic hepatitis B after a series of examinations. Then, all the family members of both proband A and proband B were screened for VMCs by MRI or ultrasonography. The results showed that four of the 11 family members from two families, including two males and two females, were diagnosed with VMCs. DNA samples were extracted from the peripheral blood of those 11 individuals of two VMCs pedigrees and subjected to polymerase chain reaction amplification of the polycystic kidney and hepatic disease 1(PKHD1) gene. Two different mutation loci were identified. Heterozygous mutations located in exon 32(c.4280 delG, p.Gly1427 ValfsX 6) in family A and exon 28(c.3118 C>T, p.Arg1040 Ter) in family B were detected. We speculate that PKHD1 gene mutations may be responsible for the development of VMCs.

Insight into early-phase trials for lung cancer in the United States

Introduction:Few data have been published comparing early-phase trials for lung cancer between China and the United States(US).This study was to investigate the differences of phase 1 trials for lung cancer between these two countries.Methods:In 2014,a cross-sectional survey was conducted to compare phase 1 trials for lung cancer between the Guangdong Lung Cancer Institute(GLCI),the University of Wisconsin Carbone Cancer Center(UWCCC),and the University of Texas MD Anderson Cancer Center(MDACC).Results:We found that the GLCI had a lower percentage of phase 1 lung cancer trials than the MDACC in December2014(23.8%[5/21]vs.59.8%[28/47],P = 0.006) and the UWCCC in September 2014(16.7%[3/18]vs.34.8%[8/23],P = 0.345).Descriptive analyses were performed for early-phase trials conducted by the CancerTherapy Evaluation Program at the National Cancer Institute(CTEP/NCI),the MDACC,and the Chinese Thoracic Oncology Group(CTONG).There were 149 ongoing early-phase trials in the Department of Investigational Cancer Therapeutics(Phase 1 program) at the MDACC in October 2014.In contrast,no phase 1 trials had been initiated by the CTONG since its establishment in 2007.Conclusions:These data suggest that a significantly higher percentage of phase 1 trials for lung cancer were conducted in the US than in China.Early-phase oncology trials with robust preclinical data had a higher chance of being approved by the Investigational Drug Branch at the CTEP/NCI.Given the importance of early-phase oncology trials in developing innovative cancer medicines,such studies should be highly encouraged and strategically funded in China.

右上肺叶切除术中肺支气管和血管不同的解剖顺序与肺癌患者的手术可行性和术后恢复相关

背景与目的不同解剖顺序的肺癌右上肺叶切除术(right upper lobectomy,RUL)涉及十分多变的解剖结构,但仍没有研究分析其对术后恢复的影响。本研究比较了常规手术入路VAB(首先解剖肺血管,然后是支气管)和另一种手术入路aBVA(先解剖后升动脉,然后是支气管和血管),在肺癌患者手术可行性和术后恢复方面的差异。方法根据手术方法,将接受RUL的肺癌患者分为aBVA和VAB两组。并收集他们的临床信息、病理资料和围手术期特征,用以比较围手术期结局。结果 301例患者纳入研究(aBVA组109例和VAB组192例)。aBVA组的平均手术时间短于VAB组(164 min vs. 221 min,P <0.001),aBVA组的出血量比VAB组更少(92 mL vs. 141 mL,P <0.001)。aBVA组行开胸手术的比率低于VAB组(0%vs. 11.5%,P <0.001)。术后胸腔引流的平均持续时间aBVA组比VAB组短(3.6 d vs. 4.5 d,P=0.001)。两组的术后并发症发生率相似(P=0.629)。两组均未达到中位总生存期(P> 0.05)。比较了两组中所有患者的中位无病生存期(未达到vs. 41.97个月)(P> 0.05)和疾病复发患者的中位无病生存期(13.25个月vs. 9.44个月)(P>0.05)。在两组中对复发类型也进行了比较:局部复发率(6.4%vs. 7.8%)、远处转移率(10.1%vs. 8.3%)、局部复发合并远处转移率(1.8%vs. 1.6%)(均P> 0.05)。结论在RUL中采用aBVA方法,在反复翻转肺叶和解剖静脉之前解剖右上支气管,将可提高肺癌患者的手术可行性和促进术后恢复。

Single nucleotide polymorphisms of MAGE-A3 gene and its clinical implications in Chinese patients with non-small cell lung cancer(NSCLC)

Background： Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism（SNP） loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors.Methods： Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR m RNA expression were detected by q RT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors.Results： Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC（0.681）/CT（0.319）, CC（0.660）/CG（0.340）, CC（0.681）/CA（0.319）, AA（0.984）/AT（0.016） and GG（1.000）/GA（0.000）, respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mR NA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients.Conclusions： Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR m RNA expression levels and helpful to the selection of patients for epidermal growth factor receptor（EGFR） targeted immunotherapy.

Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer

Background:Osimertinib is standard-of-care therapy for previously untreated epidermal growth factor receptor(EGFR)mutation-positive advanced non-small-cell lung cancer(NSCLC).The efficacy and safety of osimertinib as adjuvant therapy are unknown.Methods:In this double-blind,phase 3 trial,we randomly assigned patients with completely resected EGFR mutation-positive NSCLC in a 1:1 ratio to receive either osimertinib(80 mg once daily)or placebo for 3 years.The primary end point was disease-free survival among patients with stage Ⅱ to ⅢA disease(according to investigator assessment).

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC(CTONG1804):a multicenter open-label phase II study

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK alterations.Patients received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 expression.The primary endpoint was the major pathological response(MPR).Key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and EFS.Fifty-two patients were enrolled,with 46 undergoing surgeries.The MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,respectively.Thirteen(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment.Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–vs.ctDNA+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).

Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer:final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial

EMERGING-CTONG 1103 showed improved progression-free survival(PFS)with neoadjuvant erlotinib vs.chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer(NSCLC)(NCT01407822).Herein,we report the final results.Recruited patients were randomly allocated 1:1 to the erlotinib group(150 mg/day orally;neoadjuvant phase for 42 days and adjuvant phase to 12 months)or to the GC group(gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously;2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase).Objective response rate(ORR),complete pathologic response(pCR),PFS,and overall survival(OS)were assessed along with safety.Post hoc analysis was performed for subsequent treatments after disease recurrence.Among investigated 72 patients(erlotinib,n=37;GC,n=35),the median follow-up was 62.5 months.The median OS was 42.2 months(erlotinib)and 36.9 months(GC)(hazard ratio[HR],0.83;95%confidence interval[CI],0.47-1.47;p=0.513).The 3-and_(5-y)ear OS rates were 58.6%and 40.8%with erlotinib and 55.9%and 27.6%with GC(p_(3-y)=0.819,p_(5-y)=0.252).Subsequent treatment was administered in 71.9%and 81.8%of patients receiving erlotinib and GC,respectively;targeted therapy contributed mostly to OS(HR,0.35;95%CI,0.18-0.70).After disease progression,the ORR was 53.3%,and the median PFS was 10.9 months during the EGFR-TKI rechallenge.During postoperative therapy,grade 3 or 4 adverse events(AEs)were 13.5%in the erlotinib group and 29.4%in the GC group.No serious adverse events were observed.Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer

Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer(NSCLC)patients according to the predicted response to c-Met inhibitors(c-Metis),yet the overall clinical benefit of this strategy is quite limited.Notably,c-Met protein overexpression,which occurs in approximately 20–25%of NSCLC patients,has not yet been clearly defined as a clinically useful biomarker.An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking.Herein,we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status.Furthermore,TGF-β1 treatment resulted in SYK transcriptional downregulation,increased Sp1-mediated transcription of FRA1,and restored the mesenchymal state,which conferred resistance to c-Metis.Clinically,a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3%and longer progression-free survival with c-Meti treatment than other patients.SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance.In summary,SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state.Furthermore,our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.

Establishment of a Novel Method for Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Mutations in Lung Cancer

Background： Drug resistance to targeted therapies occurs in lung cancer, and resistance mechanisms related to epidermal growth factor receptor （EGFR） tyrosine kinase inhibitors （TKIs） are continuously being discovered. We aimed to establish a novel method for highly parallel multiplexed detection of genetic mutations related to EGFR TKl-resistant lung cancer using Agena iPLEX chemistry and niatrix-assisted laser desorption ionization time-of-flight analysis on the MassARRAY mass spectrometry platform. Methods： A review of the literature revealed 60 mutation hotspots in seven target genes （EGFR, KRAS, PIK3CA, BRAF, ERBB2, NRAS, and BIM） that are closely related to EGFR TKI resistance to lung cancer. A total of 183 primers comprised 61 paired forward and reverse amplification primers, and 61 matched extension primers were designed using Assay Design Software. The detection method was established by analyzing nine cell lines, and by comparison with LungCartaTM kit in ten lung cancer specimens. EGFR, KRAS. and BIM genes in all cell lines and clinical samples were subjected to Sanger sequencing for confirming reproducibility. Results： Our data showed that designed panel was a high-throughput and robust tool, allowing genotyping for sixty hotspots in the same run. Moreover, it made efficient use of patient diagnostic samples for a more accurate EGFR TKIs resistance analysis. The proposed method could accurately detect mutations in lung cancer cell lines and clinical specimens, consistent with those obtained by the LungCartaTM kit and Sanger sequencing. We also established a method for detection of large-fragment deletions based on single-base extension technology of MassARRAY platform. Conclusions： We established an effective method for high-throughput detection of genetic mutations related to EGFR TKI resistance based on the MassARRAY platform, which could provide more accurate information for overcoming cancers with de novo or acquired resistance to EGFR-targeted therapies.

An immunological storm for cancer therapy: 2018 Nobel Prize in Physiology or Medicine

Immunotherapy with checkpoint inhibitors (CPIs)is a new approach to cancer therapy that harnesses and enhances the innate abilities of the immune system to recognize and fight cancers.It has become a breakthrough in the history of cancer treatment and is of epoch-making significance [1 ]. In the past century,Nobel Prize has been awarded to the advances in immunology for 15 times.This year,it won for the 16th time.James P.Allison from the University of Texas MD Anderson Cancer Center and Japanese immunologist Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine,for their great contributions to the discovery of the CTLA-4 and PD-1 and the development of promising cancer therapy by inhibition of negative immune regulation.Their research shows how different strategies to inhibit the brakes on the immune system can be used in the treatment of cancer,which became a landmark in the history of cancer therapy.

Gasdermin D Inhibitor Necrosulfonamide Alleviates Lipopolysaccharide/D-galactosamine-induced Acute Liver Failure in Mice

Background and Aims:Acute liver failure(ALF)is as-sociated with high mortality.Gasdermin D(GSDMD)is the executioner of pyroptosis and is involved in the patho-physiology of immune dysregulation This study investi-gated the role of the GSDMD inhibitor necrosulfonamide(NSA)in ALF.Methods:An ALF model was established by lipopolysaccharide/D-galactosamine challenge in C57BL/6J mice.Mice were divided into four groups:normal controls(control group),ALF group(ALF group),dimethyl sulfoxide group(DMSO group),and NSA intervention group(NSA group).Survival was monitored,liver damage was de-termined by hematoxylin and eosin staining,and serum alanine aminotransferase(ALT).Underlying mechanisms were explored by quantitative real-time PCR,western blot-ting,and enzyme-linked immunosorbent assays.Results:Pyroptosis was activated in ALF model mice.Mice treat-ed with GSDMD inhibitor NSA developed less severe liver failure.NSA reduced the expression of GSDMD,NLRP3,cleaved caspase-1,cleaved caspase-11,and secretion of interleukin-1 beta in ALF mice model.Conclusions:Py-roptosis was activated in ALF.NSA alleviated ALF via the pyroptosis pathway.

Integrative Analyses of Lung Squamous Cell Carcinoma in Ten Chinese Patients with Transcriptome Sequencing

Few effective therapies have been developed for the treatment of lung squamous cell carcinoma （SQCC）, in part due to a lack of un- derstanding regarding the mechanisms underlying the initiation and development of this disease. Whole transcriptome sequencing not only provides insight into the expression of all transcribed genes, but offers an efficient approach for identifying genetic variations, including gene fusions, mutations and alternative splicing. In this study, we performed whole transcriptome sequencing of 10 patients with stage IIIA lung SQCC, and discovered a large number of single nucleotide variants （SNVs： mean of 12.2 SNVs/Mb）, with C〉T/G〉A and A〉G/T〉C transitions being the most frequently observed. Additionally, a total of 132 gene fusions were identified based upon TopHat alignments, 70.5% （93/132） of which occurred as a result of intra-chromosomal rearrangements. Based on the number of supporting reads for each fusion, we further validated 20 of the 26 top gene fusions by RT-PCR and Sanger sequencing. Taken together, these data provide an in-depth view of transcriptional alterations in lung SQCC patients, and may be useful for identification of new therapeutic targets.