Bronchoalveolar lavage fluid assessment facilitates precision medicine for lung cancer

Lung cancer is the most common and fatal malignant disease worldwide and has the highest mortality rate among tumor-related causes of death.Early diagnosis and precision medicine can significantly improve the survival rate and prognosis of lung cancer patients.At present,the clinical diagnosis of lung cancer is challenging due to a lack of effective non-invasive detection methods and biomarkers,and treatment is primarily hindered by drug resistance and high tumor heterogeneity.Liquid biopsy is a method for detecting circulating biomarkers in the blood and other body fluids containing genetic information from primary tumor tissues.Bronchoalveolar lavage fluid(BALF)is a potential liquid biopsy medium that is rich in a variety of bioactive substances and cell components.BALF contains information on the key characteristics of tumors,including the tumor subtype,gene mutation type,and tumor environment,thus BALF may be used as a diagnostic supplement to lung biopsy.In this review,the current research on BALF in the diagnosis,treatment,and prognosis of lung cancer is summarized.The advantages and disadvantages of different components of BALF,including cells,cell-free DNA,extracellular vesicles,and micro RNA are introduced.In particular,the great potential of extracellular vesicles in precision diagnosis and detection of drug-resistant for lung cancer is highlighted.In addition,the performance of liquid biopsies with different body fluid sources in lung cancer detection are compared to facilitate more selective studies involving BALF,thereby promoting the application of BALF for precision medicine in lung cancer patients in the future.

Concordance between four PD-L1 immunohistochemical assays and 22C3 pharmDx assay in esophageal squamous cell carcinoma in a multicenter study

Background:The prediction of response to immunotherapy mostly depends on the programmed death-ligand 1(PD-L1)immunohistochemistry(IHC)status,and the 22C3 pharmDx assay has been approved in esophageal squamous cell carcinoma(ESCC).However,the widespread use of the 22C3 pharmDx assay is limited due to its availability.Thus,alternative PD-L1 assays are needed.We aimed to investigate the analytical and clinical diagnostic performances of four PD-L1 assays and to compare their concordances with the 22C3 pharmDx assay.Methods:The PD-L122C3 pharmDx assay was performed on the Dako Autostainer Link 48 platform,three testing assays(PD-L1 E1L3N XP antibody[Ab],PD-L1 BP6099 Ab and PD-L1 CST E1L3N Ab)on the Leica BOND-MAX/III platform,and one testing assay(PD-L1 MXR006 Ab)on the Roche VENTANA Benchmark Ultra platform.A total of 218 ESCC cases from four centers were included in this retrospective study.Professionals from each center stained and read the IHC slides independently and determined the combined positive score(CPS)and the tumor proportion score(TPS).Results:Regarding analytical performance,the four testing assays demonstrated good correlations with the 22C3 pharmDx assay when evaluated by the TPS or CPS(𝜌>0.8 for all four assays).Regarding diagnostic performance(CPS≥10 was used as the cutoff),the four testing assays showed moderate concordances with the 22C3 pharmDx assay(kappa>0.7 for all four assays).The overall percent agreements between each testing assay and the 22C3 pharmDx assay was at least 87.2%.Conclusion:This study provides insight into the potential interchangeability of the four PD-L1 assays with the 22C3 pharmDx assay.

不同治疗对肺癌患者血液循环游离DNA检测EGFR基因突变的影响及预后分析

背景与目的表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变与肺腺癌患者TKI靶向治疗疗效和预后密切相关,常规组织分析其突变状态有诸多局限。本研究旨在探讨非小细胞肺癌(non-small cell lung cancer,NSCLC)患者血液循环游离DNA(cell-free DNA,cfDNA)检测EGFR基因突变在治疗前、传统化疗以及靶向治疗后的表达差异。分析血液cfDNA是否能准确检测EGFR基因突变并监测耐药基因T790M的变化,以及TKI在靶向治疗患者中的预后价值。方法应用ARMS(amplification refractory mutation system)法检测107例(50例治疗前、29例传统化疗和28例靶向治疗)肺癌患者配对血液和肿瘤组织样本的EGFR基因突变并比较其表达差异;计算检测的一致性、敏感性和特异性;分析血检对靶向治疗患者的预后价值。结果血浆cfDNA检测EGFR总突变率在107例肺癌患者中为56%(60例),而配对肿瘤组织样本检出率为77.6%(83例)。一一配对比较发现两者总体一致率为68.2%。血检的敏感性是72.3%,特异性为100%。依据治疗状态分组后发现治疗前组患者血液和肿瘤组织样本的检测一致率最高(74%,37/50),而靶向组一致率最低(57.1%,16/28),提示靶向治疗改变血浆cfDNA中EGFR基因状态。具体分析靶向组不一致病例发现50%新检出含T790M的双突变,提示靶向治疗后耐药基因出现。生存分析证实血检含T790M双突变组的无进展生存期(progression-free survival,PFS)和总生存期(overall survival,OS)均显著低于无T790M突变组。结论应用ARMS法检测血液循环游离DNA(circulating cell-free DNA,cfDNA)的EGFR基因突变是一种特异性高、敏感性好的检测方法。适用于治疗前晚期肺癌患者的EGFR基因突变状态检测。同时,适用于靶向治疗后监测T790M耐药突变状态及预测患者预后。

自然杀伤细胞治疗急性髓系白血病的研究进展

自然杀伤细胞(natural killer cell,NK)为一种存在于天然免疫系统中的淋巴细胞,具有杀伤肿瘤细胞和抗病毒感染的能力,在天然免疫和过继免疫治疗中发挥重要作用。随着NK细胞的特征和功能越来越被熟知,其已被广泛应用于临床抗肿瘤治疗,特别是血液系统恶性肿瘤如急性髓系白血病(acute myeloid leukemia,AML)、淋巴瘤等治疗。目前,基于NK细胞的免疫治疗主要包括自体NK细胞输注、异体NK细胞输注、嵌合抗原修饰NK(chimeric antigen receptor,CAR)细胞输注以及基于NK细胞的其他免疫治疗等。以NK细胞为基础的免疫治疗旨在增强NK细胞的抗肿瘤能力以及克服肿瘤免疫逃逸。随着研究进展,NK细胞将成为治疗AML的有效方法。

Dynamization of retrograde interlocking intramedullary nail for nonunion of distal femoral intercalary allograft reconstruction:a case report and literatures review

Intercalary allograft reconstruction offers a joint-sparing reconstructive option, but nonunion is a devastating complication. In this article, we want to share our experience of proper dynamization of interlocking intramedullary nail for nonunion after proximal femoral intercalary allograft reconstruction. In this report, a 19-year-old girl was diagnosed proximal femoral fibroblast osteosarcoma （Enneking lib）. After neoadjuvant chemotherapy, she underwent proximal femoral intercalary allograft reconstruction fixed by retrograde interlocking intramedullary nail. At her follow-up point of one year postoperatively, nonunion was observed in the proximal host-allograft junction. Therefore she underwent the second surgery of dynamization of the interlocking intramedullary nail. After 12 months＇ partial and full weight bearing exercise, bone union occurred. Our early observations show that dynamization of interlocking intramedullary nail can still be a useful means to treat nonunion of host- allograft junction if the local condition of the host and allograft bone are good enough.

A case of large-cell neuroendocrine carcinoma harboring rare ALK fusion with initial response to the ALK inhibitor crizotinib and acquired F1174L mutation after resistance

A 51-year-old,male,non-smoker with a 3.4 cm mass in the right middle lobe was diagnosed with large cell neuroendocrine carcinoma(LCNEC).Fluorescence in situ hybridization revealed anaplastic lymphoma kinase(ALK)gene translocation,in agreement with the immunohistochemistry result obtained with use of ALK-Ventana.Radiographic examinations showed both bone and brain metastasis.After two cycles of chemotherapy consisting of etoposide and cisplatin,the patient achieved stable disease,and was subsequently switched to crizotinib.Both computed tomography and magnetic resonance imaging revealed partial response after 4 months of crizotinib,but progressed after treatment for 10 months,when several hard lymph nodes were palpable in the left supraclavicular fossa.Lymph node biopsy showed similar histology of tumor cells and targeted next-generation sequencing revealed ALK F1174L on exon 23 with two rare forms of ALK rearrangements.This case provides evidence of responsiveness of ALK inhibitors for a rare pattern of ALK-rearranged LCNEC,and suggests that F1174L,a common resistant mutation found in non-small-cell lung cancer,also causes crizotinib resistance in LCNEC.

Partial treatment response to alectinib in metastatic non-small cell lung cancer with KIDINS220-ALK fusion

Dear Editor,Anaplastic lymphoma kinase(ALK)rearrangement is a key driver gene in non-small cell lung cancer(NSCLC),and the effectiveness of targeted therapies directed at ALK fusion has been confirmed.1 However,the activity of ALK-tyrosine kinase inhibitors(ALK-TKIs)against rare ALK rearrangements is variable,with limited clinical evidence.Here,we reported the case of a novel kinase D interacting substrate 220(KIDINS220)-ALK fusion that showed favorable response to alectinib.