免疫检查点抑制剂在肺癌肝转移患者中的临床疗效远远不能令人满意[1]。既往研究显示溶瘤病毒可增强抗PD-1/PD-L1单抗体内外的疗效[2, 3]。本研究旨在评估溶瘤病毒重组人5型腺病毒注射液(H101)联合特瑞普利单抗对表皮生长因子受体-酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor, EGFR-TKI)、化疗或免疫检查点抑制剂治疗后进展的晚期肺癌肝转移患者的安全性和有效性。本研究已在2022年12月7—9日瑞士日内瓦举行的欧洲肿瘤内科学会免疫肿瘤大会上进行壁报交流。上海市科学技术委员会"产学研医项目"(18DZ1910102)。肺癌是目前发病率和死亡最高的恶性肿瘤之一, 晚期患者治疗存在挑战, 尤其是肺癌肝转移患者, 预后差, 治疗手段有限, 病死率高[1]。PD-1抑制剂现已成为包括晚期肺癌在内的多种恶性肿瘤的标准治疗方法, 但是仍有相当部分患者对于PD-1抑制剂治疗反应不佳[2], 寻求新的治疗途径以提高疗效成为必然。而溶瘤病毒治疗是众多有极具治疗前景的有希望的免疫调节疗法之一。就溶瘤病毒而言, 其是一类趋向于感染肿瘤细胞, 通过自身在肿瘤细胞中的复制从而杀死并裂解肿瘤细胞的病毒, 同时进一步诱导机体抗肿瘤免疫反应。溶瘤病毒瘤内注射可以重塑肿瘤局部免疫微环境, 使"冷肿瘤"转变为"热肿瘤", 提高免疫治疗疗效[3-4], 其与抗PD-1抗体联合应用已经在国内外的一些临床研究中取得了很好的临床研究结果[5-7]。

目的·建立表达程序性死亡配体1(programmed death-ligand 1,PD-L1)的人源化免疫肺癌动物模型,并研究该模型在评估程序性死亡受体1(programmed death-1,PD-1)抑制剂疗效中的作用.方法·取晚期非小细胞肺癌患者新鲜的活检组织样本,或恶性胸腔积液中的肿瘤细胞,接种至CB17-SCID小鼠(重症联合免疫缺陷小鼠)皮下,建立患者来源异种移植物模型(patient-derived xenograft model,PDX模型),通过免疫组织化学法检测PDX模型肿瘤PD-L1的表达情况.将成熟的人外周血单个核细胞与PDX模型肿瘤细胞混合后接种NCG小鼠(高度免疫缺陷小鼠),建立人源化免疫的肺癌PDX模型,并在该模型上验证PD-1抑制剂的疗效.结果·在16个临床来源样本建立的PDX模型中,有2个PD-L1表达为强阳性,4个表达为阳性,其余均为阴性.在PD-L1强阳性的人源化免疫肺癌PDX模型中,PD-1抑制剂信迪利单抗在初次给药后21 d的肿瘤生长抑制率为82.6％;在PD-L1阴性的人源化免疫肺癌PDX模型中,PD-1抑制剂未显示出抗肿瘤活性.结论·成功建立了表达PD-L1的人源化免疫肺癌小鼠模型,且能在该模型上评估PD-1抑制剂的疗效.

Objective: Recently, a low frequency of de novo T790M mutations existing in tumor tissues before TKIs therapy has been reported. However, the origin of T790M and its impact on clinical outcomes is still being debated. This study aimed to use highly sensitive methods to detect T790M before and after TKIs therapy and investigated the correlation of T790M with clinical prognosis. Patients and methods: Matched tumor samples before and after treatment were collected from 61 lung adenocarcinoma (LAC) patients in Beijing Chest Hospital between June 2014 to October 2017. Presence of the T790M mutation was simultaneously detected using amplification refractory mutation system-PCR (ARMS-PCR) assay and droplet digital PCR (ddPCR) assay. Results: Of the 61 enrolled patients, 46 were candidates for and received TKIs treatment based on their EGFR mutation status. When these samples were assayed, ddPCR identified significantly more T790M mutations than ARMS-PCR (before TKIs treatment: 19.6% (9/46) vs. 2.2% (1/46), P = 0.040; after TKIs treatment: 78.3% (36/46) vs. 50% (23/46), P < 0.001, respectively). Patients with first-line TKIs treatment harboring de novo T790M mutations showed a shorter PFS compared to those without de novo T790M mutations (median, 7.0 months vs. 11.7 months, p = 0.013). In multivariate analyses, de novo T790M mutation was an independent predictor of PFS in EGFR-mutant patients who received TKIs treatment (p = 0.031, HR 0.310, 95% CI: 0.107-0.900). Conclusion: The ddPCR assay is an ultra-sensitive method to detect a minor amount of de novo T790M mutations in tumor samples. The de novo T790M mutation is a relatively unfavorable prognosis factor for patients receiving first-line TKIs treatment.

Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often develops resistance to early sensitive drug treatment, thus, the patient-derived xenograft (PDX) models are critical to evaluate drug sensitivity and resistance. We established PDX models from routine surgery tissues, as well as from tumor cells in pleural effusion specimens and from biopsies of advanced cancer patients who are refractory to treatments. Genetic profiling of the PDX lung models revealed a group of them with TKI drug-associated EGFR mutations (L858R, T790M, Exon19del, C797S). Among them, are an AZD9291-resistant sub-group with EGFR double mutations (Exon19Δ, T790M) in the clinic before AZD9291 treatment, and yet, acquired resistance to AZD9291 either through emergence C797S mutation or T790M loss in EGFR or through mutations in other pathways, providing insights into potential combo therapies. Indeed, combinations of AZD9291 with Cetuximab as well as with inhibitors targeting other signaling pathways such as MEK, are efficacious against an AZD9291-resistant lung PDX model with EGFR triple mutations (Exon19Δ, T790M, C797S). We also establish valuable lung models resistant to ALK inhibitors, Avastin, PD-1 antibody drugs, and resistant hematopoietic models. In summary, functional drug sensitivity profiling and genetic profiling with drug resistant PDX models provide insights into resistance mechanisms as well as precise therapeutic options against resistance emergence.Citation Format: Jijun Cheng, Feifei Zhang, Zhen Zhou, Yuan Long, Wenhua Xu, Shizhu Zhao, Hongkui Chen, Shun Lu, Danyi Wen. Drug resistant PDX models for testing targeted drug sensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1066.

目的·评估首诊至调查时间病程≥12个月的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的生活质量,探讨相关影响因素.方法·采用FACT-L(Functional Assessment of Cancer Therapy-Lung)量表对111名纳入研究的患者的生活质量进行评价,自制问卷收集患者人口学特征、医疗信息和情绪感受.结果·研究从治疗及患者主观感受2个路径探讨NSCLC患者生活质量的影响因素.单因素Logistic回归分析显示低生活质量的风险因素为:自卑孤独感、骨转移、病理类型、化学治疗周期、年龄、共住家庭成员结构和经济困难.结论·肺癌患者生活质量影响因素多元而广泛,情绪及症状管理亟待重视.

Abstract Advanced lung cancer of late stage patients is selectively sensitive to available targeted therapeutics and often develops resistance to early sensitive drug treatment. Surgery tumor tissues are usually not available to establish patient-derived xenograft (PDX) models which is critical to evaluate drug sensitivity and resistance. We applied CD45 magnet beads to enrich the tumor cell population from pleural effusion specimens of advanced lung cancer. Valuable drug-resistant PDX models were successfully established both from pleural effusion and from routine surgery tissues. Genetic profiling of the PDX models revealed TKI drug-associated EGFR mutations (L858R, T790M, Exon19del, C797S). In particular we successfully established a clinically AZD9291-resistant EGFR triple mutant (Ex19del, T790M, C797S) PDX model. In vivo efficacy results with gefitinib, erlotinib and AZD9291 well matched corresponding gene mutations among the models. Interestingly, we successfully induced AZD9291-resistant clones in vivo using an EGFR double mutant (L858R, T790M) PDX model, and NGS revealed mutations in kinases involved in other signaling pathways, indicating potential therapeutic options against resistance emergence. In conclusion, these precious PDX models provide insight into resistance mechanisms as well as serve as models to test potency of many drugs including current investigational TKIs. Citation Format: Feifei Zhang, Zhen Zhou, Yuan Long, Wenhua Xu, Shizhu Zhao, Yang Yang, Hui Liu, Jijun Cheng, Shun Lu, Danyi Wen. Pdx model of pleural effusion of lung cancer patient for testing on targeted drug sensitivity and resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1164.

Lung cancer is the leading cause of global cancer-associated mortality. Genomic alterations in lung cancers have not been widely characterized, however, the molecular mechanism of tumor initiation and progression remain unknown, and no molecularly targeted have been specifically developed for its treatment and diagnosis. The present study observed the upregulation of Aldo-keto reductase family 1 member Bio10 (AKR1B10) lung cancer tissues by analyzing two public lung cancer gene expression datasets. Further experiments in silencing AKR1B10 demonstrated that the expression of AKR1B10 was associated with cell proliferation, cell cycle, adhesion and invasion, as well as extracellular-signal-regulated kinase/mitogen activated protein kinase signal pathway. The overexpression of AKR1B10 in lung cancer indicates the important role of AKR1B10 in tumorigenesis. These findings suggest that AKR1B10 could be a potential diagnosis and treatment mark of lung cancer.

Context. Maintenance of quality of life and symptom management are important in lung cancer therapy. To the author's knowledge, the interplay of respiratory symptoms and sleep disturbance in affecting quality of life in advanced lung cancer remains unexamined.Objectives. The study was designed to examine the relationships among respiratory symptoms, sleep disturbance, and quality of life in patients with advanced lung cancer.Methods. A total of 128 patients with advanced lung cancer (from chest oncology inpatient-units in Shanghai, China) participated in the study. They completed two questionnaires: the Functional Assessment of Cancer TherapyeLung and the Pittsburgh Sleep Quality Index.Results. Symptomatic breathing difficulty, coughing, shortness of breath, and tightness in the chest were reported in 78.1%, 70.3%, 60.9%, and 60.2% of the patients, respectively. Sleep disturbance affected 62.5% of the patients. The patients with severe respiratory symptoms were more likely to be poor sleepers and to have a lower quality of life. After the covariates were controlled for, regression analysis showed that respiratory symptoms and sleep disturbance were significant indicators of quality of life. In addition, some of the effect of the respiratory symptoms on quality of life was mediated by sleep disturbance.Conclusion. Respiratory symptoms and sleep disturbance were common in the advanced lung cancer patients and had a negative impact on their quality of life; sleep disturbance may mediate the relationship between respiratory symptoms and quality of life. (C) 2016 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

The purpose of this study is to examine the effect of financial burden, using objective and subjective indicators, on the health-related quality of life (HRQOL) in lung cancer patients.

目的 研究肺癌患者症状体验对生活质量评分的影响.方法 采用肺癌患者生活质量量表(FACT-L)对178例肺癌住院患者的症状感受与生活质量的相关性进行调查分析.结果 呼吸急促、体质量下降、思维不清、食欲下降、咳嗽、胸闷、呼吸困难的评分差异对生理状况的影响有显著统计学意义(P＜0.01);思维不清的评分差异对家庭/社会状况的影响有显著统计学意义(P＜0.01);呼吸急促、思维不清、食欲下降、胸闷的评分差异对情感状况的影响有显著统计学意义(P＜0.01);呼吸急促、体质量下降、思维不清、食欲下降、脱发、胸闷的评分差异对功能状况的影响有显著统计学意义(P＜0.01);呼吸急促、体质量下降、思维不清、食欲下降、胸闷和呼吸困难的评分差异对FACT-L量表总分的影响有显著统计学意义(P＜0.01).结论 症状体验是患者自评生活质量的主要依据,医疗方案选择应充分考虑患者主观感受.

Background Because cell signaling and cell metabolic pathways are executed through proteins, protein signatures in primary tumors are useful for identifying key nodes in signaling networks whose alteration is associated with malignancy and/or clinical outcomes. This study aimed to determine protein signatures in primary lung cancer tissues. Methodology/ Principal Findings We analyzed 126 proteins and/or protein phosphorylation sites in case-matched normal and tumor samples from 101 lung cancer patients with reverse-phase protein array (RPPA) assay. The results showed that 18 molecules were significantly different (p<0.05) by at least 30% between normal and tumor tissues. Most of those molecules play roles in cell proliferation, DNA repair, signal transduction and lipid metabolism, or function as cell surface/matrix proteins. We also validated RPPA results by Western blot and/or immunohistochemical analyses for some of those molecules. Statistical analyses showed that Ku80 levels were significantly higher in tumors of nonsmokers than in those of smokers. Cyclin B1 levels were significantly overexpressed in poorly differentiated tumors while Cox2 levels were significantly overexpressed in neuroendocrinal tumors. A high level of Stat5 is associated with favorable survival outcome for patients treated with surgery. Conclusions/ Significance Our results revealed that some molecules involved in DNA damage/repair, signal transductions, lipid metabolism, and cell proliferation were drastically aberrant in lung cancer tissues, and Stat5 may serve a molecular marker for prognosis of lung cancers.

目的:分析肺癌术后发生静脉血栓栓塞（venous thromboembolism,VTE）的高危因素及其预后。方法:对1001例有完整临床随访资料的肺癌手术患者进行回顾性分析。应用螺旋CT、肺动脉造影和彩色多普勒超声诊断VTE。寿命表法绘制血栓发生曲线,COX多因素分析VTE高危因素。Kaplan-Meier法及log-rank检验绘制并比较高危因素血栓发生曲线及生存曲线。结果:术后1、3、5、11和30个月的VTE累积发生率分别为2.0%、3.0%、4.0%、5.0%和5.3%。COX多因素回归分析显示,接受不完全切除术患者发生VTE的风险比（hazard ratio,HR）为9.867（95%可信区间为5.275～18.459）,P=0.000;术后接受化疗联合重组人血管内皮抑制素治疗患者的HR为3.472（95%可信区间为1.761～6.845）,P=0.000;术后接受表皮生长因子受体酪氨酸激酶抑制剂治疗患者的HR为2.808（95%可信区间为1.439～5.479）,P=0.002;术前基线血浆D-二聚体水平升高者的HR为7.520（95%可信区间为3.968～14.250）,P=0.000。肺癌术后伴VTE患者的生存时间明显短于无VTE的患者（P=0.000）。结论:不完全切除术、术后化疗联合重组人血管内皮抑制素治疗、表皮生长因子受体酪氨酸激酶抑制剂治疗和术前基线血浆D-二聚体水平升高是肺癌手术患者术后并发VTE的高危因素。肺癌术后伴VTE患者的生存时间明显短于无VTE的患者。

目的:了解含铂方案术后辅助化疗对老年非小细胞肺癌患者生存期的影响。方法:回顾性分析2001-01-2004-12上海户籍≥65岁的老年非小细胞肺癌手术患者314例。分为年轻老年人（65～＜70岁）、中等老年人（70～＜75岁）、高龄老年人（≥75岁）3组。结果:术后愿意接受辅助化疗的患者仅29.9%。接受辅助化疗与未接受化疗者相比,未明显延长生存期（P=0.6365）,中位生存期分别为（39.4±8.39）和（25.70±6.83）个月。其中61.7%患者能完成3/4个周期,完成≥3个周期者比未能完成者有显著的生存获益（P=0.0336）,中位生存期分别为（86.60±26.99）和（23.40±6.01）个月,降低死亡风险（P=0.002,HR=0.806）。经Cox多因素分析,年龄不是影响生存的主要因素,而病理分期及含铂方案术后辅助化疗（≥3个周期）是影响生存的主要因素。结论:老年非小细胞肺癌患者术后能接受≥3个周期化疗者可明显延长生存期,降低死亡风险。高龄患者对含铂方案辅助化疗耐受性较差。

Background and purpose:Zoledronic acid has been proved to have anti-tumour effects.The purpose of this study was to establish a human lung adenocarcinoma cell line(SPC-A-1BM)with high metastatic potential in bone of immunodeficient(SCID)mouse model,and to evaluate the efficacy of zoledronate alone and combined with paclitaxel in reducing the tumor-induced bone disease.Methods:The human lung adenocarcinoma cancer cells SPC-A-1BM were inoculated into the cardiac ventricle of 40 SCID mice(NIH-BNX).They were randomized into 4 groups,and were treated with zoledronate alone,zoledronate combined with paclitaxel,or paclitaxel alone,or control group,respectively for 5 weeks after 7 days of tumor implantation.Bone metastases was assessed,measurement of total-body nuclei bone scan,X-rays,serum NTx were done,bone lesions for pathologic evaluation,the incidence of other organ metastasis,weight loss and survival time until 8 weeks were also analyzed.Results:The zoledronate combined with paclitaxel was very effective in reducing NSCLC bone metastases.Bone nuclei scan,radiographic and histological results revealed that there were more bone metastatic lesions in the control group than that in the treatment group.In the treatment groups,bone nuclei scan and radiographic imagine suggested that the combined group significantly reduced bone metastasis(P=0.013,P=0.036).Histological analysis showed that there was a marginal difference(P=0.058)between the combined group and the control.The numbers of bone metastases mice in combined group equaled to that in the paclitaxel group,there were less bone metastases than the control's.Moreover,the bone turnover biomarker NTx level was reduced by inhibiting osteoclast activity in the combined group,there was a significant difference between the control and paclitaxel group,respectively(P=0.017,P=0.022).The combined group inhibited lung metastases(P=0.036).Only the combined group significantly prolonged the survival time(log rank=0.022).Conclusions:The results indicated that zoledronate inhibited the osteoclast activity,zoledronate enhanced the effects of paclitaxel synergistically,reduced the incidence of NSCLC bone metastasis and prolonged survival time.

Objective: To investigate the association of nuclear DNA content and vascular endothelial growth factor (VEGF) and p53 expression with therapeutic response of malignant pleural effusion and their value in predicting the prognosis of wet lung cancer. Methods: The survival periods of 43 lung cancer patients with pleural effusions were followed up. The DNA content of 39 patients was measured by the image cytometry (ICM) and the expression of VEGF and p53 was determined by Envision immunohistochemical method. Twenty-nine patients were given bleomycin or interleukin-2 intrathoracically after drainage. Results: DNA aneuploid had a tendency to correlate with therapeutic efficacy of malignant pleural effusion (P=0.054). Cox multivariate analysis showed that only p53 expression was independent prognostic factor for lung patients with pleural effusion (P=0.05). The median survival time of patients was (10.4±3.5) months for p53-negative patients and (2.8±0.6) months for p53-positive patients (log rank=0.013 2). One-year survival rate was 17.7% for p53-negative patients and 0% for p53-positive patients. Conclusion: DNA content measured by ICM tended to correlate with the therapeutic efficacy of malignant pleural effusion; p53 expression is a unique independent prognostic factor for lung cancer patients with pleural effusions.

评估初诊非小细胞肺癌局部或远处淋巴结转移以及远道器官转移主要依靠TNM分期,肺癌分期的作用不仅能提供重要的生存预后信息,还能选择合适的治疗方式,明确原发肿瘤侵犯范围及有无肺内外转移,判断手术切除的可行性.通常临床分期Ⅰ、Ⅱ期及部分ⅢA期疾病可选择手术治疗,而广泛ⅢA期、ⅢB期及Ⅳ期可放射治疗、化疗及放化疗.并且,采用统一的UICC(1997年)国际肺癌TNM分期标准,使评估不同治疗方案的疗效具有可比性.

Objective To assess the safety and pracfibility of treatment with cisplatin-based regimens in old patients with non-small cell lung cancer(NSCLC). Methods A retrospective survey was conducted in 200 patients suffered from advanced NSCLC treated with cisplatin-based regimens. The patients were divided into three groups by aged: group A≥70,group B 60≤age70 and group C60 . The effects and toxicities among three groups were compared. Results RR and CCR in A, B and C group were 31.3% and 75. 0% ,34. 3% and 78. 6% ,34. 1% and 80. 5% .respectively,i, e. , no significant differences were found among three groups. Adverse drug reactions such as hematological, renal, hepatic, gastro-intestinal and other toxicities were similar in three groups. Conclusion It is safety and practicability to apply standard dosage of cisplatin-based combination regimens for old age patients with advanced NSCLC patients using Karnofsky performance status(score70).