非小细胞肺癌免疫治疗的研究进展

肺癌(lung cancer)是全球发病率及死亡率最高的恶性肿瘤之一,非小细胞肺癌(non-small cell lung cancer,NSCLC)占肺癌的85%,其五年生存率只有15%,传统的抗肿瘤治疗方法(手术、放疗和化疗等)在抑制肿瘤进展中的作用有限,即使有手术机会,也有40%以上患者出现局部复发或远处转移。目前多学科治疗较大程度提高了晚期NSCLC的生存期,研究表明,免疫治疗(immunotherapy)可改善肺癌的预后,有望成为肺癌的重要辅助治疗方式。其中,治疗性肿瘤疫苗(vaccination)如MAGE-A3、L-BLP25、Belagenpum atucel-L等、免疫检查点抑制剂(immune checkpoint inhibition)如ipilimumab、nivolumab、pembrolizumab等得到广泛关注。一系列临床试验表明免疫治疗可以使非小细胞肺癌的死亡率得到缓解,本文就其原理、临床试验、不良反应及有待解决问题的临床研究作系统综述。     

Clinical implication of p53 mutation in lung cancer

Lung cancer development involves multiple genetic abnormalities leading to malignant transformation of the bronchial epithelial cells, followed by invasion and metastasis. One of the most common changes is mutation of the p53 tumor suppressor gene. The frequency of p53 alterations in lung cancer is highest in small cell and squamous cell carcinomas. A genetic “signature” of the type of p53 mutations has been associated with carcinogens in cigarette smoke. The majority of clinical studies suggest that lung cancers with p53 alterations carry a worse prognosis, and may be relatively more resistant to chemotherapy and radiation. An understanding of the role of p53 in human lung cancer may lead to more rational targeted approaches for treating this disease. P53 gene replacement is currently under clinical investigation but clearly more effective means of gene deliver to the tumor cells are required. Novel approaches to lung cancer therapy are needed to improve the observed poor patient survival despite current therapies.     

非小细胞肺癌6号染色体长臂的杂合性缺失的微卫星扫描分析

为探讨6号染色体长臂上与非小细胞肺癌发生相关的微卫星位点,应用多重PCR对41例非小细胞肺癌中6号染色体长臂上的36个微卫星位点进行扩增。PCR产物应用聚丙烯酰胶凝胶电泳分离,电泳结果用GeneScan^TM、Genotyper^TM软件进行分析。结果发现各个位点有明显不同的LOH频率,除D6S1579在41例非小细胞肺癌中未发现杂合性缺失外,其余35个位点均有至少一个位点发生突变,LOH频率从3.57%到75%不等,总LOH频率为78%（32/41）,其中D6S302位点的LOH频率最高（75%）。LOH频率超过20%的位点共有14个,主要分布在2个区域。其中有6个位点：D6S458（21.43%)、D6S1694（26.92%）、D6S1717（35.71%）、D6S1565（40%）、D6S302（75%）、D6S1706（36.36%）分布在6q21附近,具体区域是6q16.3-q21;有5个位点：D6S1550（38.4%）、D6S264（20%）、DS1585（25%）、D6S446（33.3%）、D6S281（30.77%）分布在6q27附近,具体区域是6q26-q27。因此6q21、q27附近可能存在与非小细胞肺癌发生相关的巳知或未知肿瘤抑制基因。     

Epithelial cell plasticity defines heterogeneity in lung cancer

Lung cancer is the leading cause of cancer death for both men and women and accounts for almost 18.4% of all deaths due to cancer worldwide, with the global incidence increasing by approximately 0.5% per year. Lung cancer is regarded as a devastating type of cancer owing to its high prevalence, reduction in the health-related quality of life, frequently delayed diagnosis, low response rate, high toxicity, and resistance to available therapeutic options. The highly heterogeneous nature of this cancer with a proximal-to-distal distribution throughout the respiratory tract dramatically affects its diagnostic and therapeutic management. The diverse composition and plasticity of lung epithelial cells across the respiratory tract are regarded as significant factors underlying lung cancer heterogeneity. Therefore, definitions of the cells of origin for different types of lung cancer are urgently needed to understand lung cancer biology and to achieve early diagnosis and develop cell-targeted therapies. In the present review, we will discuss the current understanding of the cellular and molecular alterations in distinct lung epithelial cells that result in each type of lung cancer.     

肺癌生存质量量表在晚期肺癌中使用的研究进展

近几年来,肺癌的发病率呈现逐年上升的趋势,成为癌症中的头号杀手。临床上针对不同类型肺癌有不同的治疗策略,由于临床上大部分病人在确诊为肺癌时已经为晚期,对于常规治疗方法难以达到效果时,关注肺癌患者的生存质量就显地尤为必要。肺癌生存质量量表可以反映病人临床治疗后的生存质量状况,达到反馈治疗效果的目的。在临床实验中使用肺癌生存质量量表可以帮助临床医师制定最优化的治疗方案。国际上的研究大多不是以生存质量为主要终点的研究,生存质量也不能全面的反映病人预后的状况,希望在今后的研究中,肺癌生存质量量表能够在临床中的使用更加普及、更加全面。本文就肺癌生存质量量表在晚期肺癌中使用的研究进展作一综述,以期更加促进我们对于晚期肺癌患者生存质量的思考与关注,更有利于适合我国国情的生存质量量表的研究和发展。     

Analysis of microsatellite mutations in buccal cells from a case-control study for lung cancer

Exposure to tobacco carcinogens is the major cause of human lung cancer, but even heavy smokers have only about a 10% life-time risk of developing lung cancer. Currently used screening processes, based largely on age and exposure status, have proven to be of limited clinical utility in predicting cancer risk. More precise methods of assessing an individual's risk of developing lung cancer are needed. Because of their sensitivity to DNA damage, microsatellites are potentially useful for the assessment of somatic mutational load in normal cells. We assessed mutational load using hypermutable microsatellites in buccal cells obtained from lung carcinoma cases and controls to test if such a measure could be used to estimate lung cancer risk. There was no significant association between smoking status and mutation frequency with any of the markers tested. No significant association between case status and mutation frequency was observed. Age was significantly related to mutation frequency in the microsatellite marker D7S1482. These observations indicate that somatic mutational load, as measured using mutation frequency of microsatellites in buccal cells, increases with increasing age but that subjects who develop lung cancer have a similar mutational load as those who remain cancer free. This finding suggests that mutation frequency of microsatellite mutations in buccal cells may not be a promising biomarker for lung cancer risk.     

Prevention: a real possibility to repress lung cancer

In the lack of effective treatment, the role of prevention has increased in the repressing of lung cancer. Smoking being a pathogenetic factor in the development of lung cancer is an accepted fact. Because of this, primer prevention means first of all the reduction of smoking both with the help of preventing smoking and cessation. A bigger - historical - debate has developed around secunder prevention: the effective screening of lung cancer. Although it was observed that staging rate and resecability had been more advantageous in the screened group, the screening of lung cancer was declared ineffective, because mortality did not improve. The change of approach can be felt from the middle of the 90's. Nowadays the creation of a multimodal lung cancer preventional strategy is in the center of researches. The screening of risk groups can mean the solution with the aid of biomarkers, chest X-ray and spiral CT. In Hungary, with the infrastructure of existing lung-screening network the up-to-date screening of risk groups seems to have reality in the near future.     

肺结核合并肺癌患者的临床分析

目的：探讨肺结核合并肺癌的临床特点,提高临床医师诊断肺结核合并肺癌的警惕性。方法：对2000年1月至2009年12月在我院诊断为肺结核、肺结核合并肺癌、肺癌患者各40例进行回顾性分析。结果：三组之间的临床表现与实验室检查进行相互比较,发现其临床表现并无统计学差异,影像学与支气管镜检查有明显统计学差异外,其他实验室检查无差异。结论：结核合并肺癌与肺结核、肺癌等临床表现、实验室检查近似,易造成漏诊、误诊,临床医师应提高警惕,及时行影像学及支气管镜等检查。     

Impediment in upper airway stabilizing forces assessed by phrenic nerve stimulation in sleep apnea patients

Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-γ as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-γ ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases.     

Associations between season of birth and the risk of lung cancer: epidemiological findings from Hungary

Lung cancer is the leading cause of cancer deaths worldwide. Both incidence and mortality of lung cancer are especially high in Hungary. Several investigations suggested recently that month of birth (MOB) is associated with the risks of several nonmalignant disorders as well as some malignant disorders. Only a few studies investigated previously the association between MOB and risk of lung cancer, but they provided inconsistent results. We, therefore, decided to investigate this issue in a large sample of individuals who died from lung cancer. Accordingly, we determined the MOB-associated risk of death by lung cancer between the years 1970 and 2009 among all individuals born in Hungary between 1925 and 1934. The final sample included about two million people. A total of 61,904 deaths by lung cancer occurred in this sample during the period investigated. Using analysis of variance (ANOVA), we did not find significant association between MOB and risk of lung cancer death, either in the whole population investigated (F?=?1.492; p?=?.145) or in the female subpopulation (F?=?1.535; p?=?.129). However, those males born in late spring (May-June) had a lower risk of lung cancer development (F?=?2.577; p?=?.006). Results of the Edwards test also did not suggest consistent association between MOB and risk of lung cancer death in the whole investigated period (1925-1934) in any populations (i.e., whole population or male and female subpopulations). In conclusion, we did not find significant association between MOB and risk of lung cancer in our total sample (although results alluded to a weak association between MOB and risk of lung cancer development among males). The possible associations between MOB and the risk of lung cancer development (or smoking) would require confirmation (or refutation) in large studies from other populations.     

Diagnosis of lung cancer

Lung cancer is the most common malignant tumor among male and second among female. The most effective diagnostic tool would be the early detection of the lung cancer. The diagnosis of tumors has to be based on patho-morphological findings. The invasive diagnostic tools can be used if the proved lung process has any therapeutic consequence. Only an experienced team has the chance to examine quickly and effectively the patients.In Hungary there are pulmonological centers where these teams consisting of pneumonologist, radiologists and pathologists are working effectively.     

Financial aspects of targeted therapy of lung cancer as compared to conventional chemotherapy

Lung cancer is the leading cause of cancer death worldwide, and it is responsible for 20-25% of all cancer deaths. In Hungary, more than 4,000 lung cancer patients receive chemotherapy every year, and of them 3,000 suffer from non-small cell lung cancer. Despite the rapid development in antitumor treatment options, the response rates of chemotherapies in non-small cell lung cancer still remain between 15-35%. Recently, EGFR tyrosine kinase inhibitor therapy has been introduced with a response rate of 15% when used in unselected patients. However, this ratio may increase up to 70% when only patients with tumors containing EGFR mutation are treated. Therefore, results of translational research that could help pulmonologists and oncologists to apply tailored therapy in lung cancer patients are of great importance. The purpose of our work was to establish a model in order to study the relevance of immunohistochemical and molecular biological analyses of tumor specimens in treatment and patient selection, and to investigate their cost-sparing effects. We concluded that the most cost-effective type of patient selection could be achieved with EGFR mutation status analysis of the tumor tissue. Our results may help to determine the most cost-effective way of patient selection in case of non-small cell lung cancer patients requiring second line therapy; moreover, they might serve as a basis for further economic analyses.     

Changes in algorythm of surgical management for non-small cell lung cancer (NSCLC)

In Hungary the incidence of lung cancer is growing further and the proportion of patients undergoing surgery is less than 30%. Some improvement is indicated by the rate of explorations decreasing to less than 10%. On the other hand the number of adenocarcinomas has grown to take over the position of the squamous cell carcinomas among the patients operated on. In the recent few decades only some minor changes have occurred in the surgical treatment. For this reason when operability has been established new perspectives have been reviewed before drawing conclusions on the number of cases qualifying for resection. Phrenic and recurrent nerve lesions and in some cases metastases in some other organs do not mean inoperability in the absolute sense any more. Based on the new TNM system the criteria of the qualification for and the date of resection are identified by staging implemented reliably and in details. Palliative surgery may also be possible in some selected cases. A complex approach to the treatment of lung cancer is clearly coming into the focus of our attention. Though a resection is the most important episode here an adjuvant (post-operative) therapy and most recently added that a neoadjuvant (pre-operative) therapy shall improve the patient's chances for survival further, enhancing the favorable result caused by the resection itself. Both the limits and the options of he surgical treatment administered in the cases of metastases in the lung, the brain and the solitary suprarenal gland are discussed in details in the cases of NSCLC.     

Recent advances of novel targeted therapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths world-wide. Recent advances in cancer biology have led to the identification of new targets in neoplastic cells and the development of novel targeted therapies. At this time, two targeted agents are approved by the FDA in advanced non-small cell lung cancer (NSCLC): the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, and the anitangiogenic bevacizumab. A third agent, cetuximab, which was recently shown to enhance survival when used with cisplatin and vinorelbine as first line therapy for advanced NSCLC, will likely be approved by regulatory agencies. With more than 500 molecularly targeted agents under development, the prospects of identifying novel therapies that benefit individual patients with lung cancer are bright.     

Occupational epidemiological study of workers in an acrylonitrile using factory with particular attention to cancers and birth defects

An occupational epidemiological study was organised among workers in an acrylonitrile using factory in Hungary. Of the 888 workers, 783 were included in the study and three groups were differentiated: Group A (N = 452) with direct and continuous exposure, Group B (N = 171) with direct but occasional exposure and Group C (N = 160) without direct exposure, as referent. There were two main objectives: to determine the occurrence of cancer in workers and congenital abnormalities in their liveborn infants. The study did not indicate a higher occurrence of cancer among workers: only one lung cancer patient was found, prostate cancer did not occur. Among congenital abnormalities, the group of specified multiple congenital abnormalities showed a higher rate than expected but characteristic defect-pattern was not found among seven multimalformed babies, though five had cardiovascular malformations. In conclusion, our study did not indicate the carcinogenic, mutagenic and teratogenic effect of acrylonitrile among workers using this chemical in the factory.     

Role of cyclooxygenase-2 in tumor progression and immune regulation in lung cancer

Lung cancer is the leading cause of cancer death all over the world. The low 5-year survival rate (under 15%) has changed minimally in the last 25 years. Amongst different types of lung cancers, non-small cell lung carcinoma (NSCLC) types account 25-40%. To improve the survival of lung cancer patients, new therapeutic strategies are needed. The search for improved therapies has led to the investigation of agents that target novel pathways involved in tumor proliferation, invasion, survival and immune regulation. Cyclooxygenase-2 (COX-2) is one of the novel targets under evaluation for NSCLC therapy and chemoprevention. Although multiple genetic alterations are necessary for lung cancer invasion and metastasis, COX-2 may act as central element in orchestring these processes. COX-2 plays an important role in all aspects of tumor development and growth. It also plays a pivotal role in regulation of cytokines and immune responses in NSCLC patients. In this article, we review the experimental and clinical evidences on the possible link between COX and NSCLC.     

The role of companion diagnostics in the development and use of mutation-targeted cancer therapies

Among all the known differences between cancer and normal cells, it is only the genetic differences that unequivocally distinguish the former from the latter. It is therefore not surprising that recent therapeutic advances are based on agents that specifically target the products of the genes that are mutated in cancer cells. The ability to identify the patients most likely to benefit from such therapies is a natural outgrowth of these discoveries. Development of companion diagnostic tests for this identification is proceeding but should receive much more attention than it currently does. These tests can simplify the drug discovery process, make clinical trials more efficient and informative, and be used to individualize the therapy of cancer patients.     

Establishment and characterization of a lung cancer cell line,SMC-L001, from a lung adenocarcinoma

Lung cancer cell lines are a valuable tool for elucidating lung tumorigenesis and developing novel therapies. However, the majority of cell lines currently available were established from tumors in patients of Caucasian origin, limiting our ability to investigate how cancers in patients of different ethnicities differ from one another in terms of tumor biology and drug responses. In this study, we established a human non-small cell lung carcinoma cell line, SMC-L001, and characterized its genome and tumorigenic potential. SMC-L001 cells were isolated from a Korean lung adenocarcinoma patient (male, pStage IIb) and were propagated in culture. SMC-L001 cells were adherent. DNA fingerprinting analysis indicated that the SMC-L001 cell line originated from parental tumor tissue. Comparison of the genomic profile of the SMC-L001 cell line and the original tumor revealed an identical profile with 739 mutations in 46 cancer-related genes, including mutations in TP53 and KRAS. Furthermore, SMC-L001 cells were highly tumorigenic, as evidenced by the induction of solid tumors in immunodeficient mice. In summary, we established a new lung cancer cell line with point mutations in TP53 and KRAS from a Korean lung adenocarcinoma patient that will be useful for investigating ethnic differences in lung cancer biology and drug response.     

Erythropoietin is a novel therapeutic option in the treatment of anemia caused by small cell lung cancer

Anemia is very common among patients with malignant tumors, due to the disease and chemotherapy. Anemia decreases the patient's quality of life. Erythropoietin therapy is accessible in Hungary for the treatment of chemotherapy-induced anemia in patients suffering from small cell lung cancer. In our case report we present the case of a 62-year-old female small cell lung cancer patient with severe anemia, treated by erythropoietin-beta. The erythropoietin treatment provided the possibility of effective chemo- and radiotherapy. The patient's quality of life greatly improved due to the lack of the symptoms of anemia. The adequate use of erythropoietin is of great help to the physician in the management of small cell lung cancer patients, by improving the quality of life.     

Unraveling the Post-Translational Modifications and therapeutical approach in NSCLC pathogenesis

Non-Small Cell Lung Cancer (NSCLC) is the most prevalent kind of lung cancer with around 85% of total lung cancer cases. Despite vast therapies being available, the survival rate is low (5 year survival rate is 15%) making it essential to comprehend the mechanism for NSCLC cell survival and progression. The plethora of evidences suggests that the Post Translational Modification (PTM) such as phosphorylation, methylation, acetylation, glycosylation, ubiquitination and SUMOylation are involved in various types of cancer progression and metastasis including NSCLC. Indeed, an in-depth understanding of PTM associated with NSCLC biology will provide novel therapeutic targets and insight into the current sophisticated therapeutic paradigm. Herein, we reviewed the key PTMs, epigenetic modulation, PTMs crosstalk along with proteogenomics to analyze PTMs in NSCLC and also, highlighted how epi‑miRNA, miRNA and PTM inhibitors are key modulators and serve as promising therapeutics.