PD⁃1/PD⁃L1抑制剂治疗复发小细胞肺癌的真实世界研究

目的 探讨真实世界中,程序性死亡受体?1(PD?1)和程序性死亡受体?配体1(PD?L1)抑制剂治疗复发小细胞肺癌(SCLC)的有效性和安全性,并分析潜在的预后相关因素.方法 回顾性分析2015年6月至2019年6月在解放军总医院接受PD?1/PD?L1抑制剂治疗的复发SCLC患者.通过收集患者的基本临床特征、客观缓解...     

PD-L1在非小细胞肺癌中的表达及相关性

目的 探讨程序性死亡配体-1(PD-L1)在非小细胞肺癌(NSCLC)中的表达与其临床病理参数的关系.方法 采用免疫组织化学两步法检测80例NSCLC组织中PD-L1的表达与其临床病理参数的关系.结果 NSCLC腺癌中PD-L1高表达28例(73.7％,28/38),鳞癌9例(34.6％,9/26),混合癌7例(43....     

晚期非鳞非小细胞肺癌患者化疗疗效、缓解深度与无进展生存期的相关性

摘 要：［目的］ 探讨晚期非鳞非小细胞肺癌（NS-NSCLC)患者紫杉醇卡铂联合贝伐珠单抗（TCBev）方案化疗后治疗疗效、缓解深度（DpR）、肿瘤缩小速度分别与生存获益的关系。［方法］ 回顾性分析80例一线接受TCBev方案化疗的晚期NS-NSCLC患者的临床资料。治疗疗效按实体肿瘤疗效评价标准（RECIST）进行分类;按30%和60%的DpR将患者分为3个亚组;按中位DpR达到最大值时间（TTMD）将患者分为2个亚组。 ［结果］ 38例（47.5%）患者达PR,37例（46.2%）SD,5例（6.3%）治疗后病灶增大。PR比SD患者的无进展生存期（PFS）时间长（9.6个月vs 6.9个月,P＜0.001）;DpR越大,PFS时间越长（10.6个月vs 8.2 vs 6.4个月,P＜0.001）;快速缩小（TTMD≤4.07个月）和缓慢缩小的PFS无统计学差异（6.9个月vs 8.2个月,P=0.524）。［结论］ 晚期NS-NSCLC患者接受TCBev方案化疗后,出现PR或者肿瘤缩小越明显时,其PFS时间相对越长,然而,肿瘤缩小的速度与PFS无明显相关性。     

非小细胞肺癌治疗进展

肺癌是发病率及病死率增长最为迅速的恶性肿瘤,随着肺癌研究的进展及治疗方法的不断改进,使肺癌的疗效有了明显提高,现就非小细胞肺癌的治疗进展作一综述。1外科手术治疗在总的肺癌病例中,非小细胞肺癌(NSCLC)约占80%,其首选手术治疗,手术治疗的目的是切除肺部原发癌肿病灶和局     

非小细胞肺癌术后辅助化疗的临床研究

背景与目的 非小细胞肺癌术后辅助化疗一直是国内外的研究热点。本研究的目的是对比观察术后辅助化疗对非小细胞肺癌患者生存期的作用。方法 2000年6月～2003年12月，观察64例ⅠB～ⅢA期行完全性切除的非小细胞肺癌患者，包括接受术后长春瑞滨＋顺铂（NP）方案或紫杉醇＋卡铂（TP）方案化疗的化疗组和仅行术后观察的观察组，然后以Kaplan-Meier法对两组病例的1、2、3、4年生存率和中位生存时间进行分析。结果 化疗组的1、2、3、4年生存率分别为93．9％、84．6％、71．4％、58．4％，观察组分别为93．6％、83．1％、63．5％、43．1％，两组间3年和4年生存率差异均有统计学意义（P〈0．05）。化疗组与观察组中位生存时间分别为52个月和47个月（P〈0．05），无病生存时间分别为19个月和16个月（P〈0．05）。结论 术后含铂辅助化疗可以延长完全切除病灶的ⅠB～ⅢA期非小细胞肺癌患者的术后生存期。     

PD-1和PD-L1治疗非小细胞肺癌的临床研究现状

程序性死亡受体1(PD-1)与其配体PD-L1属于CD28/B7家族,两者相互结合后能够调节肿瘤的微环境,使突变的细胞在变成无限增殖的肿瘤细胞之前被特异性清除,对免疫应答发挥负性调节的作用.目前研究表明,PD-1/PD-L1抑制剂在非小细胞肺癌(NSCLC)的临床应用中显示出巨大的潜力,成为继化疗、放疗、手术治疗和分子靶向治疗之后的又一大焦点.因此,本文对PD-1/PD-L1治疗NSCLC的临床研究现状及展望进行综述.     

PD-L1及TGF-β在非小细胞肺癌中的表达及其临床意义

目的 探讨在非小细胞肺癌(NSCLC)中PD-L1及TGF-β表达水平,及其与NSCLC临床病理参数和术后无病生存期(DFS)的关系.方法 收集81例NSCLC标本,采用免疫组化方法检测术后肿瘤组织中PD-L1、PD-1、Foxp3+和TGF-β蛋白的表达水平.结果 81例患者中PD-L1阳性表达为46例(56.8%),阴性表达35例(43.2%).TGF-β阳性36例(44.4%),阴性45例(55.6%).PD-1阳性33例(40.7%),阴性48例(59.3%);Foxp3+阳性44例(54.3%),阴性37例(45.7%).NSCLC中PD-L1蛋白表达与各临床病理参数无明显相关性.单因素分析发现T分期、TGF-β表达、PD-L1表达影响.SCLC术后DFS,具有统计学差异(P<0.05),多因素分析发现T分期、TGF-β表达、PD-L1表达是影响NSCLC术后DFS的独立因素(P<0.05).PD-L1阳性表达组术后DFS为(21.000±1.429)个月,阴性表达组为(14.500±1.615)个月,两组有统计学差异(χ2=6.930,P=0.008).TGF-β阳性组PFS为(14.500±0.813)个月,阴性组为(21.000±1.639)个月,两组有统计学差异(χ2=8.71,P=0.003).结论 非小细胞肺癌中PD-L1及TGF-β蛋白是预测NSCLC术后DFS的重要指标,且PD-L1表达越高预示术后DFS越长,而TGF-β则表达越高,预示术后DFS越短.     

早期非小细胞肺癌患者术前炎性指标的临床意义

目的:探讨术前炎性指标与早期非小细胞肺癌术后患者预后的相关性及系统性免疫炎性指标指导早期非小细胞肺癌术后患者后续治疗方案的可行性。方法:我们收集了30例2014年至2015年于徐州医科大学附属医院行肺癌根治术的早期非小细胞肺癌（I期-Ⅱ期）患者（实验组）的术前血液学指标（同期30例体检合格者为对照组）,并计算嗜中性粒细胞计数/淋巴细胞计数（NLR）、血小板计数/淋巴细胞计数（PLR）、血小板计数和嗜中性粒细胞计数/淋巴细胞计数（SII）、预后营养指数（PNI）、血浆血清乳酸脱氢酶（LDH）、平均血细胞容积（MCV）。比较亚组间各炎性指标的差异。结果:实验组患者的白蛋白水平、MCV、PNI低于对照组患者;SII高于对照组患者。I期患者的中性粒细胞计数、SII低于Ⅱ期患者;白蛋白水平、PNI高于Ⅱ期患者。SD组患者的中性粒细胞计数、NLR、PLR、SII低于PD组患者;MCV高于PD组患者。SII≥400的高水平组患者无进展生存率、无进展生存时间均显著低于SII＜400的低水平组患者。结论:术前炎性指标SII有助于预测早期非小细胞肺癌术后患者的预后,对于术前SII≥400的早期非小细胞肺癌患者术后应当采取更加积极的治疗措施。     

High expression of PD-L1 mainly occurs in non-small cell lung cancer patients with squamous cell carcinoma or poor differentiation

Background: Lung cancer is one of the most lethal cancers worldwide, but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), the more likely it will benefit from anti-PD-L1 immunotherapy. The purpose of our study was to collect and analyze abundant clinical samples in order to provide evidence for clinicians and patients who might consider anti-PD-L1 immunotherapy while jointly formulating treatment plans. Methods: On the one hand, we obtained cases from The Cancer Genome Atlas (TCGA) database, including 498 lung squamous cell cancer (LUSC) patients and 515 lung adenocarcinoma (LUAD) patients. We studied the lung caner driver gene in LUSC and LUAD. On the other hand, PD-L1 expression was detected in lung cancer tissues of 1,008 NSCLC patients with immunohistochemistry staining (IHC), and we studied the correlation between PD-L1 protein expression and clinicopathological characteristics. Results: PD-L1 expression was higher in LUSC than in LUAD at the mRNA level. In univariate analysis, PD-L1 expression at the protein level was higher in patients who were males, were LUSC, were smokers, had a tumor diameter >3 cm, had poor differentiation, or had stages III~IV disease. In multivariate analysis, PD-L1 expression was higher in patients who were LUSC or in poor differentiation. Conclusion: In term of protein level, PD-L1 expression was higher in NSCLC patients who were LUSC or in poor differentiation. We recommend that PD-L1 IHC detection can be routinely performed in such populations that are likely to benefit most from PD-L1 immunotherapy.     

The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs

Backgrounds

Recent clinical trials have shown that immune-checkpoint blockade yields remarkable response in a subset of non–small cell lung cancer (NSCLC) patients. However, few studies directly focus on the association between epidermal growth factor receptor (EGFR) mutational status and programmed cell death-ligand 1 (PD-L1) expression. We examined whether PD-L1 is related to clinicopathologic factors and prognosis in patients with advanced NSCLC treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs).

Methods

One-hundred and seventy patients with advanced NSCLC were explored. Paraffin-embedded tumour sections were stained with PD-L1 antibody. EGFR mutation was examined by fluorescent quantitative polymerase chain reaction (PCR). The correlations between PD-L1 expression and EGFR status and survival parameters were analyzed.

Results

The overall frequency of PD-L1 over-expression was 65.9% (112/170). In lung adenocarcinoma, PD-L1 tended to be associated with mutant EGFR (PD-L1 overexpression in mutant and wild-type EGFR, 64/89 (71.9%) vs. 32/56 (57.1%), respectively; p=0.067). Subgroup analyses showed that high PD-L1 expression was associated with significantly shorter overall survival (OS) in EGFR wild-type patients (p=0.029) but not in EGFR mutant patients (p=0.932) treated with EGFR-TKIs. Even more, for EGFR mutant patients, higher expression of PD-L1 might only signal better outcome with TKIs.

Conclusions

High PD-L1 expression was likely to be associated with the presence of EGFR mutation in advanced lung adenocarcinoma. For EGFR wild-type patients, the PD-L1 over expression can be considered as a poor prognostic indicator of OS.     

Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer

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MicroRNA-20a promotes non-small cell lung cancer proliferation by upregulating PD-L1 by targeting PTEN

Non-small cell lung cancer (NSCLC) remains one of the most common malignant tumors worldwide. The aim of the present study was to investigate the possibility of microRNA-20a (miR-20a) as a biomarker and therapeutic target for the diagnosis and treatment of NSCLC. Bioinformatics prediction, together with functional validation, confirmed miR-20a bound to programmed death ligand-1 (PD-L1) 3′-untranslated region to upregulate PD-L1 expression. Both miR-20a and PD-L1 could promote the proliferation of NSCLC cells. The expression level of PD-L1 was controlled by PTEN; however, further upstream regulation of PD-L1 expression was largely unknown. The present study showed that miR-20a could not restore the inhibition of PD-L1 expression levels by PTEN. Knockdown of PTEN expression upregulated the expression level of PD-L1 and promoted the proliferation of NSCLC cells. PTEN negatively regulated the Wnt/β-catenin signaling pathway by inhibiting β-catenin and Cyclin D1. Interestingly, PTEN could reverse miR-20a-mediated proliferation of NSCLC cells and the inhibitory effect was similar to that of XAV-939. miR-20a promotes the proliferation of NSCLC cells by inhibiting the expression level of PTEN and upregulating the expression level of PD-L1. It is suggested that miR-20a could be used as a biomarker and therapeutic target for the treatment of NSCLC.     

卵巢上皮性癌BRCA1、p53及Ki67蛋白表达与生存时间相关性研究

目的本研究旨在通过检测卵巢癌组织中BRCA1、p53及Ki67蛋白表达情况及其相关性;了解BRCA1、p53及Ki67的表达与患者生存时间之间的关系。方法 选取50例2003年卵巢上皮性癌根治术标本, 对照组为10例正常卵巢组织标本;运用PV-9000二步免疫组化法检测BRCA1、p53及Ki67蛋白的表达, 以及检测其与患者生存率的关系。结果 BRCA1蛋白在卵巢癌组织中表达明显增多(阳性率为88.0%, P＜0.05);BRCA1、p53及Ki67蛋白表达与患者年龄无关(P＞0.05);BRCA1、p53及Ki67蛋白之间没有明显相关性(P＞0.05);BRCA1、p53及Ki67蛋白表达与患者预后没有明显相关性(P＞0.05)。结论 BRCA1蛋白在卵巢癌组织的表达量明显高于在正常卵巢组织中;BRCA1、p53、Ki67蛋白是否与患者的预后有关尚有待进一步深入研究。     

Programmed cell death ligand-1 (PD-L1) expression combined with CD8 tumor infiltrating lymphocytes density in non-small cell lung cancer patients

Cancer immunotherapy targeting programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway has shown promising results in treatment of non-small cell lung cancer (NSCLC) patients. T cells play a major role in tumor-associated immune response. This study aimed to investigate PD-L1 expression alone and combined with CD8 tumor infiltrating lymphocytes (TILs) density in relation to clinicopathologic parameters and survival in NSCLC patients. Immunohistochemical analysis was used to evaluate PD-L1 expression and CD8 TILs density in 55 NSCLC patients. PD-L1 immunopositivity was detected in 36 (65.5%) of NSCLC cases. PD-L1 expression was significantly related to high tumor grade (p value?=?0.038) and low CD8 TILs density (p value?=?0.004), whereas no significant relations were detected between PD-L1 expression and tumor stage (p value?=?0.121), overall survival (OS) (p value?=?0.428) and progression-free survival (PFS) (p value?=?0.439). Among PD-L1/CD8 TILs density groups, PD-L1⁺/CD8^Low group was significantly associated with high tumor grade compared to PD-L1^?/CD8^high group (pairwise p?=?0.016). PD-L1⁺/CD8^Low group was significantly related to advanced tumor stage compared to PD-L1⁺/CD8^high and PD-L1^?/CD8^Low groups (pairwise p?=?0.001 and 0.013 respectively). PD-L1^?/CD8^high group exhibited the best OS and PFS whereas PD-L1⁺/CD8^low group had the poorest OS and PFS (p value?=?0.032 and 0.001 respectively). Assessment of PD-L1 combined with CD8 TILs density, instead of PD-L1 alone, suggested important prognostic relevance in NSCLC patients.     

Pin1在宫颈癌中过表达及其与Ki67关系的研究

目的:探讨宫颈癌中肽基脯氨酰顺反异构酶Pin1表达、与Ki67的相关性及其临床意义。方法:应用RT-PCR和免疫组化技术检测宫颈癌组织中Pin1mRNA和蛋白表达水平及其与Ki67蛋白表达的相关性。结果:1)宫颈癌组织中Pin1mRNA表达明显高于正常宫颈组织(P<0.05);2)从正常宫颈到CIN再到浸润癌Pin1蛋白表达逐渐增强(P<0.05);3)Pin1蛋白过表达与临床分期、病理分级、淋巴结转移无明显相关(P>0.05);但宫颈腺癌Pin1表达明显高于宫颈鳞癌(P<0.05);4)Pin1过表达与Ki67表达呈显著正相关(P<0.05)。结论:1)Pin1过表达与宫颈癌细胞增殖有关,参与宫颈癌发生发展;2)Pin1过表达可作为宫颈癌诊断的辅助指标。     

TTI1 promotes non-small-cell lung cancer progression by regulating the mTOR signaling pathway

The role of TELO2-interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non-small-cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK-8, wound healing, and colony formation assays. In addition, quantitative real-time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan–Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease-free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients.     

RET、HBME-1和Ki67在甲状腺良、恶性肿瘤中的表达

目的 探讨甲状腺良、恶性肿瘤中RET、HBME-1和Ki67基因蛋白的表达.方法 利用组织芯片技术采用二步法(PV-9000)进行免疫组化染色,检测22例结节性甲状腺肿、7例甲状腺滤泡性腺瘤,47例甲状腺乳头状癌、7例未分化癌、5例髓样癌、4例滤泡性癌、1例低分化岛状癌及1例鳞状细胞癌中上述3种蛋白的表达情况.结果 良性病变与恶性病变中3种蛋白的表达差异均有显著意义(P＜0.01),而良性病变中的不同类型间的差异无显著性(P＞0.05).HBME-1在甲状腺乳头状癌的阳性率高于滤泡性癌、髓样癌及未分化癌的表达,之间均有显著性差异(P＜0.01).Ki67在未分化癌阳性率高于乳头状癌的表达,二者比较差异显著(P＜0.05).结论 RET、HBME-1和Ki67的同时检测可作为良恶性甲状腺肿瘤鉴别诊断的指标,其中以HBME-1的敏感性最佳,RET次之,Ki67高表达可能是去分化、浸润和转移的标志.在甲状腺良性肿瘤中RET、HBME-1和Ki67同时阳性应视为恶变的高危状态.