The role of stem cells in airway repair:implications for the origins of lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide.Recently,advancements in our ability to identify and study stem cell populations in the lung have helped researchers to elucidate the central role that cells with stem cell-like properties may have in lung tumorigenesis.Much of this research has focused on the use of the airway repair model to study response to injury.In this review,we discuss the primary evidence of the role that cancer stem cells play in lung cancer development.The implications of a stem cell origin of lung cancer are reviewed,and the importance of ongoing research to identify novel therapeutic and prognostic targets is reiterated.     

Chromodomain-helicase-DNA binding protein 5, 7 and pronecrotic mixed lineage kinase domain-like protein serve as potential prognostic biomarkers in patients with resected pancreatic adenocarcinomas

Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomainhelicase-DNA binding protein 5, chromodomain-helicaseDNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation,and should be validated in future studies.     

The International Agency for Research on Cancer （IARC） evaluation of the carcinogenicity of outdoor air pollution： focus on China

The International Agency for Research on Cancer （IARC） has classified outdoor air pollution and the particulate matter （PM） in outdoor air pollution as carcinogenic to humans, as based on sufficient evidence of carcinogenicity in humans and experimental animals and strong support by mechanistic studies. The data with important contributions to the evaluation are reviewed, highlighting the data with particular relevance to China, and implications of the evaluation with respect to China are discussed. The air pollution levels in Chinese cities are among the highest observed in the world today and frequently exceed health based national and international guidelines. Data from high-quality epidemiologic studies in Asia, Europe, and North America consistently show positive associations between lung cancer and PM exposure and other indicators of air pollution, which persist after adjustment for important lung cancer risk factors, such as tobacco smoking. Epidemiologic data from China are limited but nevertheless indicate an increased risk of lung cancer associated with several air pollutants. Excess cancer risk is also observed in experimental animals exposed to polluted outdoor air or extracted PM. The exposure of several species to outdoor air pollution is associated with markers of genetic damage that have been linked to increased cancer risk in humans. Numerous studies from China, especially genetic biomarker studies in exposed populations, support that the polluted air in China is genotoxic and carcinogenic to humans. The evaluation by IARC indicates both the need for further research into the cancer risks associated with exposure to air pollution in China and the urgent need to act to reduce exposure to the population.     

Highlights of Miami winter symposium 2015:into the era of immunotherapy

Personalized cancer medicine has seen significant improvements over the past decade. Recent Elsevier conference: Miami winter symposium 2015(MWS2015) "Towards Personalized Cancer Medicine" meeting was dedicated to this exciting field, and focused on new progress in personalized drug development and antibody drug against checkpoint pathway. This meeting report summarizes the key developments presented and discussed at the meeting, with a focus on immunotherapy, especially on the CTLA-4 and PD-1/PD-L1 pathways. The monoclonal antibody drugs intervening these checkpoint pathways have the potential to play a larger role in personalize medicine within the near future. Here we intended to provide a comprehensive summary about ongoing trends and future perspectives on personalized medicine in cancer therapy.     

Molecular markers as therapeutic targets in lung cancer

Lung cancer is responsible for 29% of cancer deaths in the United States and has very low 5-year survival rates of approximately 11% in men and 15% in women.Although the early diagnosis of lung cancer may increase the survival rate with adequate treatment,advanced lung cancers are often metastasized and receive limited benefit from therapeutic regimens.As conventional treatments for lung cancer reach their limitations,researchers have attempted to discover novel drug therapies aimed at specific targets contributing to the progression of tumorigenesis.Recent advances in systems biology have enabled the molecular biology of lung carcinogenesis to be elucidated.Our understanding of the physiologic processes of tumor development provide a means to design more effective and specific drugs with less toxicity,thereby accelerating the delivery of new drug therapies to the patient’s bedside.     

Expenditure of hospital care on cancer in China,from 2011 to 2015

Objective:A solid understanding of levels and trends of spending on cancer is important to evaluate whether our healthcare resources were wisely spent and to prioritize future resources for cancer treatment and prevention.However,studies on economic burden of cancers in China are scant and the results are inconsistent.Methods:The Chinese hospital information database and nearly 350 million inpatient medical record data were used.As the ratios of cancer inpatient payments to total inpatient payments were mainly influenced by the grades and sites of hospitals,the estimates of payments of cancer inpatients in this study were stratified by hospital grades and provinces.Only the payments of cancer inpatients happened in grade 2,grade 3 and specialized cancer hospitals were included in the analyses.The total medical payments of cancers in China were estimated based on the ratios of outpatient payments to inpatient payments in specialized cancer hospitals.Results:From 2011 to 2015,the payments of cancer inpatients in China have increased by 84.1％ and the total inpatient payments reached 177.1 billion RMB in 2015,accounting for 4.3％ of the total health expenditure in China.Based on the ratio of outpatient payments to inpatient payments,the total payments on cancer treatments in China were estimated to be 221.4 billion RMB in 2015.Among different cancer types,the highest payments were the treatment of trachea,bronchus and lung cancer.The major cancer inpatient payments (67.1％ in 2015) spent in grade 3 general hospitals and this ratio increased continually from 2011 to 2015.The expenditure of cancer treatments also varies by region with the major expenditure in the eastern region of China.Conclusions:This study estimated the total payments of cancer treatments in China and analyzed how the money was spent on cancer treatments in the recent 5 years,which would provide information for decision makings on the allocation of resources to service provisioning,prevention strategies,research funding,and assessing whether the economic burden of cancer is affordable to the governments.     

Epidemiologic studies of particulate matter and lung cancer

Particulate matter （PM） plays an important role in air pollution, especially in China. European and American researchers conducted several cohort-based studies to examine the potential relationship between PM and lung cancer and found a positive association between PM and lung cancer mortality. In contrast, the results regarding PM and lung cancer risk remain inconsistent. Most of the previous studies had limitations such as misclassification of PM exposure and residual confounders, diminishing the impact of their findings. In addition, prospective studies on this topic are very limited in Chinese populations. This is an important problem because China has one of the highest concentrations of PM in the world and has had an increased mortality risk due to lung cancer. In this context, more prospective studies in Chinese populations are warranted to investigate the relationship between PM and lung cancer.     

China’s landscape in oncology drug research:perspectives from research collaboration networks

Objective:Better understanding of China’s landscape in oncology drug research is of great significance for discovering anti-cancer drugs in future.This article differs from previous stuthes by focusing on Chinese oncology drug research communities in co-publication networks at the institutional level.Moreover,this research aims to explore structures and behaviors of relevant research units by thematic community analysis and to address policy recommendations.Methods:This research used social network analysis to define an institutions network and to identify a community network which is characterized by thematic content.Results:A total of 675 sample articles from 2008 through 2012 were retrieved from the Science Citation Index Expanded(SCIE) database of Web of Science,and top institutions and institutional pairs are highlighted for further discussion.Meanwhile,this study revealed that institutions based in the Chinese mainland are located in a relatively central position,Taiwan’s institutions are closely assembled on the side,and Hong Kong’s units located in the middle of the Chinese mainland’s and Taiwan’s.Spatial division and institutional hierarchy are still critical barriers to research collaboration in the field of anti-cancer drugs in China.In addition,the communities focusing on hot research areas show the higher nodal degree,whereas communities giving more attention to rare research subjects are relatively marginalized to the periphery of network.Conclusions:This paper offers policy recommendations to accelerate cross-regional cooperation,such as through developing information technology and increasing investment.The brokers should focus more on outreach to other institutions.Finally,participation in topics of common interest is conducive to improved efficiency in research and development(R&D) resource allocation.     

Molecular targeted agents—where we are and where we are going

A total of 23 new cancer medicines or indication expansions were approved by the U. S. Food and Drug Administration in 2012. Among these, 12 are new molecular entities (NMEs)-new chemical or biological drugs approved for the first time for oncologic use-and 10 of these NMEs are molecular targeted agents. Among the 10 targeted agents, 4 are anti-angiogenesis agents and 2 are Bcr-Abl pathway inhibitors, targeting well established targets validated by previously approved agents such as bevacizumab (Avastin) or imatinib (Gleevec). Despite this progress, several questions remain: Do these newly approved agents provide sufficient treatment options to manage the broad spectrum of cancers we deal with in the clinic? Where will the next wave of new cancer drugs come from? Where should R&D efforts be invested to continue improve cancer treatment and management, especially for tumor types uniquely prevalent in China? This editorial and the review articles in this special issue of Chinese Journal of Cancer provide an in depth review of the progress and challenges in developing targeted cancer therapies, as well as an outlook of new research areas where near term breakthroughs are expected to overcome some of these challenges.     

Circulating tumor cells in lung cancer:Detection methods and clinical impact

Circulating tumor cells（CTCs） are tumor cells that enter the blood circulation after detaching from the primary tumor and can migrate to reach distant organs, where they can give rise to aggressive metastasis. Clinical studies have revealed that the presence of CTCs in peripheral blood is correlated with disease progression in lung cancer. However, as CTCs are rare cancer cells released from tumors into the bloodstream, both enrichment and sensitive detection methods are technically challenging. In order to best understand how CTCs are currently being deployed, this review mainly focuses on the different detection methods for CTCs. Furthermore, we will describe the clinical impact of circulating tumor cells in lung cancer and discuss their potential use as biomarker to guide the prognosis.     

免疫治疗新浪潮下对中国肺癌免疫临床研究的审思

从抗CTLA-4抗体Ipilimumab在恶性黑色素瘤中获得成功开始,靶向免疫检查点的治疗成为抗肿瘤治疗的有效策略之一,掀起了肿瘤免疫治疗研究的新浪潮.在肺癌领域,国外开展了一系列免疫靶向药物的临床研究,Nivolumab、Pembrolizumab和Atezolizumab相继被批准用于肺癌的治疗,改写了肺癌治疗历史.在中国,也相继开展了肺癌免疫靶向药物的临床研究,本文主要对中国肺癌免疫研究的现状、差距和未来如何创新进行了分析和探讨.     

晚期非小细胞肺癌免疫治疗现状及未来方向

肺癌仍然是中国发病率和死亡率最高的恶性肿瘤,其中非小细胞肺癌（non-small cell lung cancer,NSCLC）约占80%以上。以靶向程序性死亡[蛋白]-1（programmed death protein-1,PD-1）或程序性死亡[蛋白]配体-1（programmed death ligand-1,PD-L1）的免疫检查点抑制剂（immune checkpoint inhibitor,ICI）为基础的治疗已成为了晚期肺癌的标准治疗手段之一。本综述将对晚期NSCLC免疫治疗的现状予以梳理,探讨现阶段面临的问题与挑战,并思考与展望未来发展方向。     

Immune checkpoints and immunotherapy in non-small cell lung cancer: Novel study progression,challenges and solutions

Lung cancer is the most common type of cancer with the highest mortality rate worldwide. Non-small cell lung cancer (NSCLC) accounts for ~85% of the total number of lung cancer cases. In the past two decades, immunotherapy has become a more promising treatment method than traditional treatments (surgery, radiotherapy and chemotherapy). Immunotherapy has been shown to improve the survival rate of patients and to have a superior effect when controlling lung cancer than traditional therapy. However, only a small number of patients can benefit from immunotherapy, and not all patients who qualify experience long-term benefits. In the clinic, the objective response rate of programmed cell death protein 1 treatment without the prior screening of patients is only 15–20%. Immunotherapy is associated with both opportunities and challenges for patients with NSCLC. The current challenges of immunotherapy include the lack of accurate biomarkers, inevitable resistance and insufficient understanding of immune checkpoints. In previous years, several methods for overcoming the challenges posed by immunotherapy have been proposed, but combination therapy is the most suitable choice. A large number of studies have shown that the combination of drugs can significantly improve their efficacy, compared with monotherapy, and that some therapeutic combinations have been approved by the Food and Drug Administration for the treatment of NSCLC. Traditional Chinese medicine (TCM) is a traditional medical practice in China that can play an important role in immunotherapy. Most agents used in TCM originate from plants, and have the advantages of low toxicity and multiple targets. In addition, TCM includes a unique class of drugs that can improve autoimmunity. Therefore, TCM may be a promising treatment method for all types of cancer.     

The Significance of the PD-L1 Expression in Non–Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers

Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non–small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors.     

基于Web of Science的国外免疫检查点抑制剂在肺癌治疗中应用的研究现状及热点分析

目的:对Web of Science自建库至今关于免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)应用于肺癌治疗的相关文献进行计量学分析,并对该领域的热点和研究态势进行探讨.方法:检索Web of Science文献合集,用Excel、VOSviewer对数据进行分析.结果:经检索...     

多色标记免疫组织化学染色和免疫荧光染色在肺癌免疫治疗中的研究进展

肺癌是目前临床上最常见的恶性肿瘤,严重威胁着患者的生命健康及生活质量。程序性细胞死亡受体1(programmed cell death receptor 1, PD-1)及其配体(programmed cell death ligand 1, PD-L1)抑制剂为非小细胞肺癌(non-small cell lung cancer, NSCLC)患者提供了新的治疗策略。现有的生物标志物检测对准确选择免疫治疗受益的患者均有一定的价值,但都存在着局限性。多标记免疫组织化学/免疫荧光(multiplex immunohistochemistry/immunofluorescence,mIHC/IF)技术允许在单一组织切片上同时检测多个抗体,并对细胞组成、细胞功能和细胞-细胞相互作用进行全面研究。国内外已有大量研究使用mIHC/IF技术对肿瘤免疫微环境(tumor immune microenvironment, TIME)下特异性免疫细胞群进行了探索,发现其有助于肺癌患者临床预后判断及疗效预测。肺癌免疫治疗时代,这项技术在转化研究和临床实践中均具有良好的应用前景。本文就mIHC/IF检测方法在肺癌免疫治疗中的研究进展进行了总结和展望。     

肺癌靶向治疗研究:以文献计量学和可视化分析描述的热点与趋势

目的:通过文献计量学分析方法，阐述并分析肺癌靶向治疗的研究热点与趋势。方法:文章检索了万方数据库、Web of Science、SooPAT(中国专利)数据库近10年来国内外肺癌靶向治疗的相关文献，以文献计量学方法，分析并归类了肺癌靶向治疗的研究热点与时效变迁的趋势。结果:在万方数据库3 744篇肺癌靶向治疗的中文文章中，发现作用于表皮生长因子受体基因突变位点的分子靶向药物-吉非替尼治疗非小细胞肺癌的研究是中国学者近10年的主要研究热点；在近10年Web of Science数据库中检索到的810篇英文文章及参考文献显示，西妥昔单抗、贝伐单抗、纳武单抗、吉非替尼、厄洛替尼和环唑替尼为这10年肺癌治疗领域靶向治疗的热点药物，而多种靶向药物的联合治疗、晚期非小细胞肺癌的靶向治疗效果和肺癌靶向治疗后的脑转移也成为近5年该领域的国际关注热点；中国肺癌靶向治疗领域的254项有权专利的分析显示，申报了专利的主要药物包括酸敏感的吉非替尼-氟硼二吡咯衍生物、顺铂抗肺癌主动靶向隐形类脂质体等。结论:文章采用文献计量学的量化分析技术，呈现出近10年肺癌靶向治疗已成为该领域专业研究者持续关注的热点，而如何选择正确的靶向药物或药物组合方案来解决肺癌治疗中的耐药性问题，同时最大程度地减少患者的不良反应，以延长患者的生存率，应是未来集中研究的方向。     

Immunotherapy and the concept of a clinical cure

Immunotherapy has entered a new phase in its history, i.e. the phase of being broadly accepted as a key component of therapeutic strategies to control and cure cancer. Immune-modulation by checkpoint inhibitors have demonstrated to be capable of inducing long lasting tumour responses. Breaking tolerance by ipilimumab has been a crucial event in the past recent years, but PD-1/PD-L1 antibodies have forever changed the landscape in oncology in 2013. The most mature results have been obtained in advanced melanoma patients. High response rates of high quality with prolonged duration have been demonstrated in melanoma, renal cancer and in lung cancer. The broad potential is now being explored across a wide range of tumours. Importantly, synergy with ipilimumab has been demonstrated in melanoma, indicating a bright further future. Long term tumour control now seems achievable and thus the concept of a “clinical cure” is emerging. These antibodies bring immunotherapy to the forefront and indicate that immune-modulation will be a key component of therapeutic strategies from now on. All these observations indicate that “clinical cures” can only be achieved when the immune system is involved, and so the true renaissance of immunotherapy has arrived.     

病理学指导下的非小细胞肺癌个体化免疫治疗

在肺癌个体化免疫治疗时代，如何有效地筛选程序性死亡［蛋白］-1（programmed death-1，PD-1）/程序性死亡［蛋白］配体-1（programmed death ligand-1，PD-L1）免疫检查点抑制剂潜在获益人群成为免疫治疗时代面临的新挑战。病理科医师通过免疫组织化学检测非小细胞肺癌（non-small cell lung cancer，NSCLC）组织中PD-L1的表达水平，可为预测PD-1/PD-L1免疫检查点抑制剂治疗晚期NSCLC的疗效和预后提供准确可靠的依据。此外，病理科医师可通过传统病理学方法观察主要病理学缓解（major pathological response，MPR）程度，进一步评价早中期肺癌免疫新辅助治疗的效果。对目前病理学诊断指导下的NSCLC个体化免疫治疗的进展以及未来的发展方向进行综述。     

Predictive Capability of PD-L1 Protein Expression for Patients With Advanced NSCLC: Any Differences Based on Histology?

Lung cancer is responsible for 1.8 million annual deaths. Non–small cell lung cancers (NSCLC) represent 85% of lung cancer tumors. While surgery is an effective early-stage treatment, the majority of newly identified US lung cancer cases are stage III/IV.Immunotherapy, using programmed death-ligand 1 (PD-L1) or programmed death 1 (PD-1) receptor antibody therapeutics, has increased survival for patients with NSCLC. PD-L1 protein expression is widely used as a predictive biomarker informing treatment decisions. However, only a minority of patients (27%-39%) respond to PD-L1/PD-1 treatment. PD-L1 protein expression by immunohistochemistry assay has deficiencies in identifying responding and refractory patients.Given the different characteristics of squamous and nonsquamous NSCLC, the predictability of PD-L1 levels in determining which patients would benefit from immunotherapy could vary between the 2 histologies. We analyzed 17 phase-III clinical studies and a retrospective study to determine if the predictive capability of PD-L1 expression varies between squamous and nonsquamous NSCLC.For patients with NSCLC treated with mono or dual-immune checkpoint inhibitors (ICI), PD-L1 expression was more predictive of benefit for patients with nonsquamous NSCLC than squamous NSCLC. Patients with nonsquamous histology and PD-L1 high tumor proportion scores (TPS) survived 2.0x longer compared to those with low TPS, when treated with monotherapy ICI. Among patients with squamous NSCLC, that difference was 1.2 to 1.3x. For patients treated with ICIs and chemotherapy, there was no clear difference in the predictive value of PD-L1 levels between histologies. We encourage future researchers to analyze the predictability of PD-L1 biomarker expression separately for squamous and nonsquamous NSCLC.