Improved treatment outcome of pembrolizumab in patients with nonsmall cell lung cancer and chronic obstructive pulmonary disease

Emerging immune profiling data suggest a higher sensitivity to immune checkpoint inhibitors (ICIs) in nonsmall cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD), compared to those without COPD. This study aimed to investigate the clinical impact of COPD on the treatment response to ICIs in a large number of patients with NSCLC. In total, 133 patients with spirometry test results were retrospectively identified among those who received palliative pembrolizumab for NSCLC. COPD was defined as pre-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.7. Overall survival (OS), progression-free survival (PFS), and objective response rate were analyzed according to the presence of COPD. Spirometry-based COPD was present in 59 (44%) patients. Patients with COPD had better OS (hazard ratio [HR] for death, 0.45; 95% confidence interval [CI], 0.26–0.78) and PFS (HR for disease progression or death, 0.50; 95% CI, 0.31–0.79) than those without COPD. These associations persisted after adjusting for potential confounders including smoking history. The response rate was also higher in patients with COPD than in those without COPD (38.2% vs. 20.5%, p = 0.028). Spirometry-defined COPD was associated with a significantly longer OS and PFS in patients with NSCLC treated with palliative pembrolizumab. Identifying coexisting COPD could predict favorable treatment outcomes in patients with NSCLC treated with pembrolizumab.     

肺鳞癌的分子病理学研究进展

肺鳞癌是最具代表性的多发于吸烟人群的恶性肿瘤。目前研究多集中在肺腺癌和不吸烟患者,对鳞癌分子病理学改变的认知远远落后于腺癌。未来非小细胞肺癌的研究热点将集中在鉴定不同肺癌亚型的分子改变及研发相应靶点的靶向治疗药物。近来研究已发现多个具有潜在临床指导意义的抗肿瘤靶点并即将制成鳞癌基因图谱,有望为鳞癌的基因分型提供依据。本文将对肺鳞癌分子病理学的最新研究进展作一综述。     

Membrane proteomic analysis comparing squamous cell lung cancer tissue and tumour-adjacent normal tissue

Lung cancer is the leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is one of the predominant histological subtypes of lung cancer. Detecting lung cancer at an early stage is essential for successful therapy and increasing survival. There are still no satisfactory biomarkers for the early detection of lung cancer. In this study, tumour tissue paired with tumour-adjacent normal bronchial epithelial tissue was obtained from patients with squamous cell lung carcinoma without metastasis. The proteins extracted from the cell membrane were separated by two-dimensional polyacrylamide gel electrophoresis (2-DE) and were analysed with the Image Master two-dimensional platinum software. Twenty-five significantly different protein spots were selected and identified with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). A total of 19 proteins were successfully identified. Twelve proteins were up-regulated, and seven proteins were down-regulated in the cancerous tissue compared with the tumour-adjacent normal tissue. One up-regulated protein and one down-regulated protein in squamous cell lung carcinoma were verified by Western blot analysis and RT-PCR; the results were consistent with the 2-DE analysis. In conclusion, membrane proteomics identified a number of candidate biomarker proteins that were differentially expressed between squamous cell lung cancer tissue and adjacent normal tissue. These biomarker candidates have the potential to elucidate the underlying pathogenesis of squamous cell lung cancer.     

Pancreatic metastasis and extrahepatic biliary obstruction in squamous cell lung carcinoma

Primary lung cancer frequently metastasizes to distant organs. The pancreas is a relatively infrequent site of metastasis. As a result, extrahepatic bile duct obstruction (EHBDO) resulting from pancreatic metastasis from lung cancer is extremely rare and occurs mostly with small-cell lung cancer (SCLC). We report an unusual case in which a patient presented with jaundice and, after extensive workup, was diagnosed with squamous cell carcinoma of the lung with metastasis to the pancreas causing EHBDO. He underwent endoscopic retrograde cholangiopancreatography (ERCP) and the obstruction was relieved with a stent placement. The patient was treated with combination chemotherapy (carboplatin and paclitaxel) with a good clinical and radiographic response.     

Toward an early diagnosis of lung cancer: an autoantibody signature for squamous cell lung carcinoma

Serum‐based diagnosis offers the prospect of early lung carcinoma detection and of differentiation between benign and malignant nodules identified by CT. One major challenge toward a future blood‐based diagnostic consists in showing that seroreactivity patterns allow for discriminating lung cancer patients not only from normal controls but also from patients with non‐tumor lung pathologies. We addressed this question for squamous cell lung cancer, one of the most common lung tumor types. Using a panel of 82 phage‐peptide clones, which express potential autoantigens, we performed serological spot assay. We screened 108 sera, including 39 sera from squamous cell lung cancer patients, 29 sera from patients with other non‐tumor lung pathologies, and 40 sera from volunteers without known disease. To classify the serum groups, we employed the standard Naïve Bayesian method combined with a subset selection approach. We were able to separate squamous cell lung carcinoma and normal sera with an accuracy of 93%. Low‐grade squamous cell lung carcinoma were separated from normal sera with an accuracy of 92.9%. We were able to distinguish squamous cell lung carcinoma from non‐tumor lung pathologies with an accuracy of 83%. Three phage‐peptide clones with sequence homology to ROCK1, PRKCB1 and KIAA0376 reacted with more than 15% of the cancer sera, but neither with normal nor with non‐tumor lung pathology sera. Our study demonstrates that seroreactivity profiles combined with statistical classification methods have great potential for discriminating patients with squamous cell lung carcinoma not only from normal controls but also from patients with non‐tumor lung pathologies. © 2008 Wiley‐Liss, Inc.     

基于TCGA数据挖掘筛选肺鳞癌预后相关lncRNA分子标签

目的：通过对TCGA数据库的挖掘,筛选与肺鳞癌预后相关的lncRNA。方法：提取TCGA数据库中肺鳞癌患者临床数据以及肺鳞癌和癌旁组织中的lncRNA表达数据,采用LASSO Cox回归筛选肺鳞癌预后相关的lncRNA,并构建lncRNA分子标签。采用Cox模型研究该分子标签的表达水平对肺鳞癌患者预后的影响。结果：首先筛选出322个在癌和癌旁组织中差异表达的lncRNA。经LASSO Cox回归分析从中筛选出6个与肺鳞癌预后相关的lncRNA,分别为KTN1-AS1、FAM83A-AS1、AF131217.1、RP11-108M12.3、CTD-2555C10.3和AC068831.16。根据这6个lncRNA构建的分子标签表达水平中位数-0.09将肺鳞癌病人分为高表达组和低表达组,高表达组病人死亡风险是低表达组的2.14倍（HR=2.14,95%CI：1.50~3.04,P < 0.01）。预测模型的Harrell's C统计量为0.69（95%CI：0.64~0.75）。结论：通过对TCGA数据库的挖掘,发现KTN1-AS1、FAM83A-AS1、AF131217.1、RP11-108M12.3、CTD-2555C10.3和AC068831.16对肺鳞癌的预后有影响,且构建的lncRNA分子标签表达水平与肺鳞癌病人的预后有显著性关联。     

Establishment and comparative characterization of novel squamous cell non-small cell lung cancer cell lines and their corresponding tumor tissue

Background

Cell lines play an important role for studying tumor biology and novel therapeutic agents. Particularly in pulmonary squamous cell carcinoma (SCC) the availability of cell lines is limited and knowledge about their representativeness for corresponding tumor tissue is scanty.

Materials and methods

We established three novel SCC cell lines from fresh tumor tissue of 28 donors, including 8 SCC. Two cell lines were derived from different localizations of the same donor, i.e. primary tumor and lymph node metastasis. This represents a so far unique combination in lung cancer. The genotypes, gene expression profiles and mutational status of epidermal growth factor receptor (EGF-R) and Kirsten rat sarcoma (k-ras) of the cell lines and their corresponding tumor tissue were analyzed and compared. Moreover, the molecular characteristics were related to functional properties of the cell lines. Those comprised proliferation, motility and chemosensitivity. The cell lines were authenticated by single tandem repeat DNA typing. Tumorigenicity was analyzed in a murine xenograft model.

Results

Comparative genomic hybridization and multiplex fluorescence in situ hybridization revealed essential genetic similarities between the cell lines and their corresponding tumor tissue, but indicated also some genetic evolution and clonal selection. EGF-R or k-ras mutations were not detected. Gene expression profiling showed various differences between tumor tissue and cell lines affecting gene clusters associated with immune response, adhesion, proliferation, differentiation and angiogenesis. However, there were also common gene expression patterns reflecting the relationship between cell lines and their corresponding tumor tissue. Moreover, the molecular characteristics of the tumor tissue and the descendent cell line were associated with functional properties of the latter. All cell lines showed a unique, heterozygous human DNA profile and one cell line displayed rapid tumor formation in mice.

Conclusions

Here, we demonstrate that cell lines represent a useful in vitro system for studying basic mechanisms in lung cancer, but cover only distinct molecular characteristics of the original tumor. Moreover, we present three novel, comprehensively characterized SCC cell lines.     

NK细胞及DCs在肺鳞癌组织中的浸润与预后关系的研究

目的 研究肺鳞癌组织中NK细胞和DCs浸润与预后的关系.方法 采用免疫组化S-P法,分别用单克隆CD57抗体和S-100抗体标记NK细胞和DCs,检测肺鳞癌组织中浸润NK细胞和DCs的数量,分别比较NK细胞和DCs浸润的程度与肺鳞癌患者术后生存时间的关系.结果 长期生存组中NK细胞、DCs浸润的密度为(23.3±12.2)/HPF和(7.6±3.3)/HPF,均高于短期生存组的(9.0±11.9)/HPF和(2.9±1.2)/HPF(P=0.027,P=0.016),高浸润的NK细胞和DCs组中,平均术后生存时间分别为45.3个月和50.5个月,显著高于低浸润的NK和DCs,分别为31.9和25.6个月(P=0.032,P=0.006).结论 在肺鳞癌中,NK细胞和DCs在肿瘤组织中的浸润数量与肿瘤患者的预后呈正相关,可作为判断肺鳞癌预后的指标之一,两者联合检测意义较大,但两者不是影响预后的独立因素.     

SCC在鼻咽癌患者血清中表达的临床意义

目的 探讨鼻咽癌患者血清中鳞状细胞癌抗原(SCC)的表达及临床意义.方法 用酶联免疫吸附法分析186例鼻咽癌患者检测血清SCC水平,并结合临床资料分析该指标的临床意义.结果 鼻咽癌患者SCC阳性率治疗前为29.03%,临床分期之间阳性率差别有统计学意义(P＜0.05),治疗后阳性率均表现下降,总的阳性率为7.0%.结论 SCC作为早诊手段,其敏感性较低,但在初诊鼻咽癌中的阳性率随病期增高,对病情预后监测有临床意义.     

检测鳞癌相关抗原对肺鳞癌的临床意义

鳞癌相关抗原（ＳＣＣ－Ａｇ）是肿瘤相关抗原（ＴＡ－４）的提纯成分。本文对１４０例肺癌（鳞癌９６例、腺癌２５例、小细胞癌１１例及大细胞癌８例）和４２例良性病变（对照组）进行ＳＣＣ－Ａｇ检测。肺鳞癌阳性率为６６．７％、肺腺癌为１６％，小细胞肺癌为１８．２％、大细胞肺癌为１２．５％，良性病变仅２．４％。ＳＣＣ－Ａｇ阳性率与肺鳞癌分期呈正相关，Ⅰ期为２２．２％、Ⅱ期为５５．６％、Ⅲ期为７４．６％、Ⅳ期为８３．３％。因此ＳＣＣ－Ａｇ是肺鳞癌较特异的标记物。通过手术前后动态观察发现，根治性切除术后ＳＣＣ－Ａｇ在７２小时内转阴，有极显著性差异（Ｐ＜０．０１），而姑息性切除术或探查术者，术后仍高于正常值，因此可早期预测手术效果。术后复发或转移时该抗原复又回升，且早于临床表现，在无转移或复发时，该抗原持续稳定在低于正常水平。     

肺鳞癌信号传导及免疫相关基因表达谱的初步研究

目的探讨肺癌信号传导及免疫相关基因与正常肺组织差异表达。方法采用包含1152个cDNA克隆的基因芯片技术,分别对4例肺鳞癌组织及相对应的正常肺组织进行信号传导及免疫相关特异性基因表达谱的比较。结果3例以上共同表达的差异基因78条,其中上调者共44条,下调者共34条。低表达基因主要集中在蛋白质和脂肪等分子的代谢及趋势化因子等方面。高表达的基因包括细胞表面受体、核受体和离子通道等有关信号机制、cAMP、蛋白激酶及蛋白磷酸化酶的作用、细胞凋亡和蛋白降解等。结论细胞信号传导相关基因在肺癌中表达有较大的个体差异,与癌细胞分化程度有关,生物信号传导及肿瘤免疫有关的基因的差异表达分析,可以了解肺癌的发生机制,为今后的研究工作提供线索。     

The prognostic impact of the amount of tobacco smoking in non-small cell lung cancer—Differences between adenocarcinoma and squamous cell carcinoma

Backgrounds

The purpose of this study was to investigate the relationship between the level of tobacco smoking and the clinicopathological features of non-small cell lung cancer (NSCLC) patients, individually for adenocarcinoma (Ad) and squamous cell carcinoma (Sq).

Patients and methods

We retrospectively reviewed the clinical records of 1825 consecutive lung cancer patients who underwent surgery in our department. Among these, the data sets of 750 Ad patients and 364 Sq patients who received lobectomy or more extensive resection were available.

Results

In Ad patients, those who had never smoked (never-smokers) (n = 309) were more likely to be female, to have less advanced stage tumors, and to have a significantly better prognosis than those who had ever smoked (ever-smokers) (n = 441) (5-year OS: never-smokers, 67.9%; ever-smokers, 53.7%, p < 0.0001). In Sq patients, the never-smokers (n = 15) were more likely to be female than the ever-smokers (n = 349). Among ever-smokers, the light-smokers (PY ≤ 30; n = 56) were associated with more female patients, more advanced stage tumors, and significantly worse prognoses than were the heavy smokers (PY > 30; n = 292) (p = 0.0003). The multivariate survival analysis showed that light smoking was related to a worse prognosis compared with heavy smoking (HR = 2.06, 95% CI 1.43–2.98, p = 0.0001).

Conclusions

The never-smokers had a significantly better prognosis than ever-smokers among Ad patients, whereas the light-smokers had a significantly worse prognosis than heavy smokers among Sq patients. There may be factors other than tobacco carcinogens that influence the development of Sq in never and/or light smokers.     

Chemotherapy response as a prognosticator for survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy

Twenty-two patients with limited unresectable squamous cell lung cancer were treated with 6 courses of combination chemotherapy consisting of cyclophosphamide, adriamycin, cisplatin, and bleomycin (CAP-Bleo) and short-course thoracic irradiation started after the first 4 weeks of chemotherapy. Of 20 patients with visible tumor who were treated with 4 weeks of chemotherapy alone, 10 (50 %) had a tumor regression in that 4 week period and 10 did not. Those patients with tumor regression had significantly better progression free and overall survivals than did patients with no chemotherapy regressions (medians of 258 days vs. 136 days and 356 days vs. 150 days respectively). The original bleomycin dose had to be reduced by 50 % primarily because of excessive radiation esophagitis that has not been reported with use of either the CAP regimen or bleomycin along in conjunction with thoracic irradiation. An initial chemotherapy regression seems to be a good prognosticator for progression-free and overall survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy.     

FEZ1、Survivin在肺小细胞癌及低分化鳞状细胞癌蛋白表达及其在凋亡中的作用

Objective:To detect the expressions of FEZ1 and Survivin in small cell lung cancer (SCLC) and poorly differentiated squamous cell carcinoma (PDSCC),and to approach a theoretical basis for clinical diagnosis and treatment.Methods:Immunohistochemical and flow cytometry method were used to detect the expressions of FEZ1 and Survivin.Apoptosis ratio and cell proliferation index in normal lung tissue,SCLC and POSCC were analyzed.Results:The expressions of FEZ1 and Survivin were significantly different between SCLC and PDSCC (P＜0.05).The apoptosis ratio and proliferation index of normal lung tissue were lower than those of PDSCC and SCLC,with a significant difference (P＜0.05).Conclusion:The expressions of FEZ1 and Survivin are significantly different between SCLC and PDSCC,indicating that detecting the expressions of the two indexes may be helpful for clinical diagnosis.     

Swedish lung cancer radiation study group: predictive value of histology for radiotherapy response in patients with non-small cell lung cancer

The aim of the present study was to evaluate the potential predictive value of histology in non-small cell lung cancer (NSCLC) treated with curatively intended radiotherapy. In a collaborative effort among all the Swedish Oncology Departments, clinical data were collected for 1146 patients with a diagnosed non-small cell lung cancer subjected to curatively intended irradiation (?50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Only patients who did not have a histological diagnosis date and death date/last follow-up date were excluded (n = 141). Among the 1146 patients with non-small cell carcinoma eligible for analysis, 919 were diagnosed with either adenocarcinoma (n = 323) or squamous cell carcinoma (n = 596) and included in this study. The median survival for the 919 patients was 14.8 months, while the 5-year survival rate was 9.5%. Patients with adenocarcinoma had a significantly better overall survival compared with patients with squamous cell carcinoma (p = 0.0062, log-rank test). When comparing different stages, this survival benefit was most pronounced for stages IIA–IIB (p < 0.0001, log-rank test). The difference in survival between the two histological groups was statistically significant in a univariate Cox analysis (p = 0.0063) as well as in two multivariate Cox analyses including demographic and treatment variables (p = 0.037 and p = 0.048, respectively). In this large population based retrospective study we describe for the first time that patients with adenocarcinoma have a better survival after curatively intended radiation therapy in comparison with squamous cell carcinoma patients, particularly those with clinical stages IIA–IIB.     

IGF-1R和IRS-1在肺鳞癌组织中的表达及临床意义

目的 检测胰岛素样生长因子1受体(IGF-1R)和胰岛素受体底物1(IRS-1)在肺鳞癌组织中的表达,探究其在肺鳞癌发生发展中的作用及临床意义。方法 采用免疫组化法检测246例肺鳞癌组织与40例癌旁正常组织中IGF-1R、IRS-1的表达情况,并分析两者的相关性及与临床病理特征和预后的关系。结果 IGF-1R在肺鳞癌组织中的阳性表达率明显高于癌旁组织,其表达率分别为54.07%和32.5%,IRS-1在肺鳞癌组织中的阳性表达率明显低于癌旁组织,其表达率分别为38.21%和70%,各组间差异均有统计学意义(P＜0.05)。IGF-1R的表达与淋巴结转移相关(P＜0.05),IRS-1的表达与肺鳞癌组织的分化程度、淋巴结转移相关(P＜0.05)。IGF-1R阳性表达组患者的生存期明显短于IGF-1R阴性表达组患者,IRS-1阳性表达组患者的生存期明显长于IRS-1阴性表达组患者,差异有统计学意义(P＜0.001,P＜0.05)。IGF-1R与IRS-1在肺鳞癌组织中的表达呈负相关(r=-0.125,P＜0.001)。结论 IGF-1R、IRS-1都参与了肺鳞癌的发生、发展,且IGF-1R为独立预后因子。     

人类乳头状瘤病毒与肺癌的病因关系的研究

目的　研究人类乳头状瘤病毒 (HPV)与肺鳞癌发生的关系。方法　采用聚合酶链反应(PCR)技术检测石蜡包埋肺鳞癌组织标本 50份、肿瘤组织旁鳞状化生上皮标本 3 0份、正常支气管粘膜3 0份中的HPVDNA。结果　三种标本中 ,HPVDNA的检出率分别为 2 6%、3 6.7%和 1 0 % ,其中以HPV1 6型所占比例最高。鳞状细胞癌和鳞状化生上皮标本中 ,HPV1 6与HPV6/ 1 1的检出率无明显差异 (P >0 .0 5)。结论　结果表明HPV感染在肺鳞癌的发生中可能起了重要的作用。鳞状上皮化生似可视为癌前病变。PCR技术较体外杂交技术和DNA探针有更高的敏感性。     

c-erbB-2 oncoprotein expression related to chemoradioresistance in esophageal squamous cell carcinoma

PURPOSE: Esophageal carcinoma is a challenging target for radiotherapy. To improve treatment efficacy, an investigation of a predictive factor is desirable. In this study, we evaluated the significance of apoptosis and immunohistochemical staining for p53, Ki-67, c-erbB-2 (HER-2/neu), Ku (p70/p80), and DNA-PKcs for predictive markers of the responsiveness to chemoradiotherapy in esophageal squamous cell carcinoma. MATERIALS AND METHODS: This retrospective analysis consisted of 34 patients with esophageal squamous cell carcinoma in whom tumor biopsy was performed before treatment. They were divided into chemoradiosensitive (n = 13) and chemoradioresistant (n = 21) groups according to the tumor response evaluated at a total radiation dose of 40 Gy. The biopsy samples were examined with immunohistochemical staining for various factors and with an in situ nick end labeling method for apoptosis. The examined data were compared between the two groups. RESULTS: The difference in the Ki-67, p53, Ku (p70/p80), DNA-PKcs labeling indexes and the apoptosis index in tumor cells between the chemoradiosensitive and chemoradioresistant groups was not statistically significant. The expression of c-erbB-2 oncoprotein was statistically significant in the chemoradioresistant group (p = 0.02), although it did not correlate with survival. CONCLUSIONS: c-erbB-2 immunostaining is useful for the prediction of chemoradioresistance in esophageal squamous cell carcinoma.