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小百科  ›  肿瘤领域全球研究热点——基于ESI 热点论文的计量分析
期刊论文 癌症 癌症复发 癌症的原因 肿瘤
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Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2020 Dec 25; 37(6): 1012–1024.
Chinese. doi: 10.7507/1001-5515.202009083
PMCID: PMC9929992
PMID: 33369340

Language: Chinese | English

肿瘤领域全球研究热点——基于 ESI 热点论文的计量分析

Global research hotspots on oncology–bibliometric analysis based on the ESI hot papers

雪娇 韩 , 1 雪梅 李 , 2 小清 龚 , 3 柏宏 李 , 4, * 蓓 白 , 5 龙浩 张 , 4, * 剑 蒲 , 4 音 李 , 4 and 鸣明 张 6

雪娇 韩

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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雪梅 李

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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小清 龚

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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柏宏 李

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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蓓 白

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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龙浩 张

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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剑 蒲

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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音 李

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

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鸣明 张

四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China 四川大学华西医院 肿瘤中心 生物治疗科（成都 610041）, Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P.R.China 陆军军医大学第一附属医院 质量管理科（重庆 400038）, Quality Management Department, Southwestern Hospital, Army Medical University, Chongqing 400038, P.R.China 四川大学华西医院 临床研究管理部（成都 610041）, Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu 610041, P.R.China 四川大学华西医院“双一流”建设办公室（成都 610041）, Double First-class Construction Office, West China Hospital, Sichuan University, Chengdu 610041, P.R.China 四川大学华西医院 院长办公室（成都 610041）, Dean’s Office/Department of Emergency Management, West China Hospital, Sichuan University, Chengdu 610041, P.R.China 四川大学华西医院 中国循证医学中心（成都 610041）, Chinese Evidence Based Med Ctr, West China Hospital, Sichuan University, Chengdu 610041, P.R.China

李柏宏，Email： moc.361@4891ilhb
张龙浩，Email： moc.liamtoh@0991oahgnolgnahz

Keywords: 肿瘤学, 研究热点, 文献计量分析

Abstract

With the increasing global burden of various cancer, an abundance of papers emerged every year in the research hotspots of oncology, covering a wide range of research types and topics. In order to facilitate interested readers to quickly grasp the frontier and hotspots of cancer research, it would be helpful to sort out and summarize the research topic in a timely manner. According to the classification of disciplines, we screened the Essential Science Indicators (ESI) hot papers released in 2019 for the ones in the oncology field, utilized methods such as bibliometrics, statistical description, hierarchical induction, analysis and interpretation to further reveal the context and characteristics of research in the field of oncology, summarized the latest progresses and future directions in the field, and provided information and hints for the trajectory of future research. A total of 549 papers were included, which were mainly from the field of clinical medicine; the country with the most publications was the United States, while China ranked the fourth in terms of contribution; the research institution with the highest number of published papers was University of Texas system; N Engl J Med published the most papers, with contribution also from highly influential journals in the field of oncology such as Lancet Oncol , J Clin Oncol , JAMA Oncol and Cancer Discov . Oncology remained the most popular research topic in the medical research and spanned a wide spectrum of sub-topics. In this study, we demonstrated and sorted out research frontiers in the field of oncology in 12 different research directions including the basic cancer research, cancer epidemiology, and various tumors types related to different systems and organs.

Keywords: oncology, research hotspot, bibliometric analysis

引言

据美国癌症学会 2018 年发布的《全球癌症统计 2018》显示，2018 年全球新增 1 800 万例癌症患者，同时有超过 960 万人因癌症死亡。在所有癌症种类中，肺癌发病率最高（占比 11.6%），其次为女性乳腺癌（占比 11.6%）、前列腺癌（占比 7.1%）、结直肠癌（占比 6.1%）。各癌症种类的死亡率方面，肺癌仍然占据首位（占比 18.4%），其次为结直肠癌（占比 9.2%）、胃癌（占比 8.2%）、肝癌（占比 8.2%） [ 1 ] 。作为最主要的非传染类致死原因之一，肿瘤的发病率逐年增加，并有可能成为 21 世纪最主要致死原因 [ 2 ] 。因此，全球有大量研究者开展肿瘤相关研究，肿瘤领域也成为医学研究最热门的方向。2019 年，仅在 Web of Science 核心合集数据库收录的肿瘤领域相关论文就多达 104 485 篇，被引也高达 174 972 次 [ 3 ] 。但海量的研究呈现质量参差不齐、研究方向分散等问题，对感兴趣的读者造成了不小的信息负担。同时，由于肿瘤自身的独特性，根据其原发病灶所在组织器官系统不同，其病理机制以及涉及基因差异较大，也给感兴趣的读者造成很大的困扰。

通过持续跟踪全球最具影响力的科研和学术论文，分析这些热门研究的贡献者和研究内容，能够揭示热门研究和重要领域的主要贡献者和潜在合作者，同时也能够对肿瘤领域不同的重点研究方向有一个综合的了解。

因此，研究前沿热点的分析能提供一个独特的视角来揭示肿瘤领域研究的脉络，可以简明扼要地概括该领域的最新进展和发展方向，为未来研究方向的把握拓展奠定基础。

1. 方法

1.1. 前沿热点的遴选

科睿唯安基本科学指标（Essential Science Indicators，ESI）数据库每 2 个月基于研究成果影响力指标更新一次数据，同时发布一批 ESI 热点论文（即在 2 年内发表且在近 2 个月内被引次数排在相应学科领域全球前 1‰以内的论文），这些论文及相关研究受到了同行高度认可和关注，代表着该领域最具影响力和发展前景的研究方向。ESI 数据库包含 21 个学科大类，其中与医学相关的有 8 个学科分类，分别为临床医学、生物学与生物化学、免疫学、微生物学、分子生物学与遗传学、神经科学与行为学、心理学与精神病学以及药理毒理学。这 8 个领域在 2019 年度共计发布了 3 299 篇 ESI 热点论文，本研究在此基础上根据研究类型及研究内容对肿瘤领域论文作了进一步遴选。

1.2. 数据的收集与整理

四川大学华西医院学科信息服务团队于 2019 年 1 月、3 月、5 月、7 月、9 月、11 月分 6 次收集了 ESI 发布的 8 个医学相关领域热点论文，并使用 Office Access 2016 提前设计标准的论文信息提取表，分别对文章的题目、期刊、作者、被引次数、参与国家、研究领域、研究方向、关键词、通信作者国家及单位、文章类型、研究是否为多中心研究或跨国合作研究、基金资助类型、文章主要内容、三级学科分类以及热门研究方向等信息进行提取，每次团队提取结束汇总后，分别由两名研究者独立审核、校对，汇总后根据学科分类筛选出肿瘤领域的文章进行下一步归纳分析。

1.3. 数据分析与研究热点前沿报告撰写

采用文献计量学、统计描述等方法对热点论文的年份、期刊、国家/地区、机构、学科类别、影响因子等信息的分布特征进行分析，通过统计描述和统计图表展示肿瘤领域热门研究的国家级机构贡献以及期刊等分布。选取纳入论文中被引次数排序前 10% 的论文，通过分层归纳分析法梳理总结肿瘤领域的研究热点和前沿。

2. 肿瘤领域热点研究分布

2019 年度发布的 ESI 热点论文中共有 549 篇肿瘤领域相关论文，分别发表于 2016 年（18 篇）、2017 年（163 篇）、2018 年（262 篇）和 2019 年（106 篇），其中被引次数最高的论文是 2018 年在 Ca-A Cancer J Clin 杂志上发表的《2018 年全球癌症统计：GLOBOCAN 对 185 个国家 36 种癌症发病率和死亡率进行的估计》，被引次数达到 15 033 次。肿瘤领域相关热点论文主要分布于临床医学（422 篇）、药理学及毒理学（61 篇）、分子生物学及遗传学（27 篇）、生物学及生物化学（22 篇）等学科领域。它们所采用的研究类型多样，主要为干预性临床试验 175 篇（31.9%）、综述 99 篇（18.0%）、基础研究 91 篇（16.6%）、临床指南/专家共识 43 篇（7.8%）、队列研究 41 篇（7.5%）等。

2.1. 国家贡献

这 549 篇热点论文主要由 38 个国家牵头共计超 106 个国家和地区参与完成。贡献最多的国家分别是美国、澳大利亚、英国、中国、加拿大、法国、比利时、德国、意大利和奥地利等。美国是肿瘤领域热点论文的最主要来源国家，论文数量远高于其他国家和地区；而中国的发文贡献量位列第四，其中中国内地 50 篇，中国台湾 3 篇，中国香港 1 篇（见 图 1 ）。

An external file that holds a picture, illustration, etc. Object name is swyxgcxzz-37-6-1012-1.jpg
图 1

National/regional contributions to the publication of hot papers on oncology

肿瘤领域疾病热点论文国家/地区发表贡献

2.2. 研究机构贡献

共计有 327 所研究机构作为通信单位参与了肿瘤领域热点论文的发表，其中大学或学院发表 273 篇，医院发表 37 篇，科研中心发表 32 篇。发表论文数量最高的研究机构为德州大学系统，共发表了 29 篇热点论文；哈佛大学其次，共发表了 21 篇；斯隆·凯特琳纪念癌症中心、加州大学系统并列第三位，发文数量为 13 篇；约翰霍普金斯大学、华盛顿大学并列第四位，发文数量 7 篇（见 图 2 ）。

An external file that holds a picture, illustration, etc. Object name is swyxgcxzz-37-6-1012-2.jpg

Contributions of research institutions to the publication of hot papers on oncology

肿瘤领域疾病热点论文研究机构发表贡献

2.3. 期刊分布

2019 年入选的肿瘤领域热点论文分别发表在 155 本期刊上，其中既包括 N Engl J Med 、 Lancet 、 JAMA 、 Nature 等综合性顶级期刊，也包括 Lancet Oncol 、 J Clin Oncol 、 JAMA Oncol 、 Cancer Discov 等肿瘤领域的专科顶级期刊。发表热点论文数量最多的期刊是 N Engl J Med ，共有 63 篇，占热点论文总量的 11.5%； Lancet Oncol 发表 43 篇， J Clin Oncol 发表 41 篇， Lancet 发表 30 篇， Nature 发表 24 篇（见 表 1 ）。

表 1

Journal distribution of hot papers on oncology

肿瘤领域热点论文期刊分布

排名 期刊 论文数量 占比
1 N Engl J Med 63 11.5%
2 Lancet Oncol 43 7.8%
3 J Clin Oncol 41 7.5%
4 Lancet 30 5.5%
5 Nature 24 4.4%
6 JAMA Oncol 21 3.8%
7 Eur Urol 15 2.7%
8 Science 15 2.7%
9 Cancer Discov 10 1.8%
10 Nat Rev Clin Oncol 10 1.8%
11 Ca-A Cancer J Clin 9 1.6%
12 Blood 8 1.5%
13 JAMA 8 1.5%
14 Neurosurgery 8 1.5%
15 Ann Oncol 7 1.3%
16 Clin Cancer Res 7 1.3%
17 Gut 7 1.3%
18 Cell 6 1.1%
19 Nat Rev Cancer 6 1.1%
20 Cancer Res 5 0.9%
21 Hepatology 5 0.9%
22 J Control Release 5 0.9%
23 J Natl Compr Cancer Netw 5 0.9%
24 Nat Rev Drug Discov 5 0.9%
25 Ann Surg 4 0.7%
26 Food Chem Toxicol 4 0.7%
27 Int J Pharm 4 0.7%
28 Nature Med 4 0.7%
29 Nucl Acid Res 4 0.7%
30 Advan Drug Delivery Rev 3 0.5%

2.4. 中国研究

我国研究者在肿瘤领域贡献了 54 篇热点论文，占所有肿瘤领域热点论文数量的 9.8%，分别发表于 2017 年（5 篇）、2018 年（36 篇）和 2019 年（13 篇）。被引次数最高为 367 次，平均被引次数为 23.6 次。从研究类型来看，包括 28 篇基础研究、8 篇综述、3 篇队列研究、3 篇流行病学研究，其他类型研究数量较少。其研究领域主要分布于临床医学（27 篇）、药理学及毒理学（16 篇）、生物学及生物化学（6 篇）。发表期刊方面，发文数量最多的是 Nature ，共计 5 篇，其后是 JAMA Oncol （4 篇）、 Cancer Res （4 篇）、 Biomed Pharmacother （3 篇）和 Biochem Biophys Res Commun （3 篇）等。

2.5. 肿瘤领域全球研究热点

由于肿瘤并不是单一器官/系统疾病，其原发病灶可能出现在人体任何部位，因此其相关研究与其他疾病领域有所差异。2019 年度发布的肿瘤领域热点论文除基础研究及流行病学研究外，根据肿瘤原发病灶所属器官系统不同分为不同的研究方向，主要集中在消化系统肿瘤相关研究（240 篇）、泌尿系统肿瘤相关研究（198 篇）、血液系统肿瘤相关研究（169 篇）等，其他各组织器官系统也均有大量相关研究。本文就肿瘤领域基础研究、肿瘤流行病学研究、神经系统肿瘤、头面部肿瘤、呼吸系统肿瘤、乳腺肿瘤、消化系统肿瘤、泌尿系统肿瘤、生殖系统肿瘤、骨与软组织肿瘤、血液肿瘤、皮肤体表肿瘤 12 个方向的顶级论文（纳入论文按被引次数排序的前 10%，被引次数位于全球前 1‱）进行了梳理和总结（概览见 表 2 ～ 7 ） [ 1 , 4 - 81 ] 。

表 2

Global research hotspots on oncology: basic research and epidemiological research

肿瘤领域全球研究热点——基础与流行病学

研究主题 相关研究 被引次数
2020.09.23 肿瘤领域基础研究
免疫检查点抑制剂治疗肿瘤的不良事件 Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1 [ 4 ] 436 Clin Cancer Res
Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens：a systematic review and meta-analysis [ 5 ] 194 JAMA Oncol
Fatal toxic effects associated with immune checkpoint inhibitors：a systematic review and meta-analysis [ 6 ] 295 JAMA Oncol
Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials：a systematic review and meta-analysis [ 7 ] 87 JAMA Oncol
长链非编码 RNA 和 micro RNA Long non-coding RNA LINC00339 facilitates the tumorigenesis of non-small cell lung cancer by sponging miR-145 through targeting FOXM1 [ 8 ] 31 Biomed Pharmacother
Phase I study of MRX34，a liposomal miR-34a mimic，administered twice weekly in patients with advanced solid tumors [ 9 ] 284 Invest New Drugs
Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells [ 10 ] 68 Int J Nanomed
HER 激酶抑制剂 HER kinase inhibition in patients with HER2- and HER3-mutant cancers [ 11 ] 198 Nature
木耳菜 Antiangiogenic phenylpropanoid glycosides from gynura cusimbua [ 12 ] 6 Nat Prod Res
肿瘤特异性抗原 Noncoding regions are the main source of targetable tumor-specific antigens [ 13 ] 72 Sci Transl Med 肿瘤流行病学
全球 Global surveillance of trends in cancer survival 2000-14 （CONCORD-3）： analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries [ 14 ] 733 Lancet
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [ 1 ] 15 033 CA Cancer J Clin
美国 Cancer screening in the United States，2017：A review of current American cancer society guidelines and current issues in cancer screening [ 15 ] 214 CA Cancer J Clin
Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States [ 16 ] 219 CA Cancer J Clin

表 7

Global research hotspots on oncology: bone and soft tissues, hepatology, skin and body surface

肿瘤领域全球研究热点——骨与软组织肿瘤、血液肿瘤、皮肤体表肿瘤

研究主题 相关研究 被引次数
2020.09.23 骨与软组织肿瘤
临床试验 Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma（SARC028）：a multicentre，two-cohort，single-arm，open-label，phase 2 trial [ 66 ] 233 Lancet Oncol
Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial：data from the HORRAD trial [ 67 ] 100 Eur Urol
临床试验 Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-hodgkin lymphoma [ 68 ] 258 J Clin Oncol
Early positron emission tomography response-adapted treatment in stage I and II hodgkin lymphoma：final results of the randomized EORTC/LYSA/FIL H10 trial [ 69 ] 158 J Clin Oncol
Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia：a non-randomised，open-label，phase 1b study [ 70 ] 213 Lancet Oncol
Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia [ 71 ] 247 N Engl J Med
Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic hodgkin lymphoma [ 72 ] 404 J Clin Oncol
测序 Molecular minimal residual disease in acute myeloid leukemia [ 73 ] 212 N Engl J Med
Prediction of acute myeloid leukaemia risk in healthy individuals [ 74 ] 159 Nature
CAR-T T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma [ 75 ] 169 J Clin Oncol 皮肤体表肿瘤
黑色素瘤 Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab [ 76 ] 297 Ann Oncol
Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events：a pooled analysis of randomized phase II and III trials [ 77 ] 153 J Clin Oncol
Randomized，open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced，unresectable melanoma [ 78 ] 160 J Clin Oncol
Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma（COLUMBUS）：a multicentre，open-label，randomised phase 3 trial [ 79 ] 198 Lancet Oncol
Pembrolizumab versus ipilimumab for advanced melanoma：final overall survival results of a multicentre，randomised，open-label phase 3 study（KEYNOTE-006） [ 80 ] 419 Lancet
皮肤鳞状细胞癌 PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma [ 81 ] 271 N Engl J Med

2.5.1. 肿瘤领域基础研究

肿瘤领域的基础研究（见 表 2 ）最为关注的是免疫检查点抑制剂与肿瘤治疗相关的不良事件 [ 4 - 7 ] ，包括肿瘤超进展 [ 4 ] 、内分泌功能障碍 [ 5 ] ，以及 2 篇不良事件的系统评价与 Meta 分析 [ 6 7 ] 。肿瘤超进展（hyperprogression disease，HPD）是免疫检查点阻断治疗后肿瘤不但没有缩小，反而加速生长的现象，是免疫检查点抑制剂治疗的新的不良反应，其标志物及发生机制尚不清楚 [ 4 ] 。免疫检查点抑制剂治疗的最常见不良反应为疲劳、瘙痒和腹泻 [ 7 ] ；甲状腺功能减退和甲状腺功能亢进症是最常见的内分泌免疫相关不良事件 [ 5 ] ；致命性毒性反应包括心肌炎、神经系统毒性反应、结肠炎等 [ 6 ] 。有 3 篇研究的是长链非编码 RNA（Inc RNA）和 micro RNA（miRNA） [ 8 - 10 ] ，包括 LINC0339 促进非小细胞肺癌的肿瘤发生 [ 8 ] ，外泌体递送 miR-26a 可抑制肝癌细胞生长 [ 10 ] 及评估一种类似于 miR-34a 的脂质体在晚期实体瘤患者中的疗效和安全性 [ 9 ] 。另外 3 篇研究内容分别为：从木耳菜提取出的苯基丙氨酸苷类化合物具有抗血管活性 [ 12 ] ，非编码区是肿瘤特异性抗原的主要来源 [ 13 ] 和 HER 激酶抑制剂在 HER2 和 HER3 突变肿瘤患者中的疗效 [ 11 ] 。

2.5.2. 肿瘤流行病学

肿瘤流行病学研究（见 表 2 ）为肿瘤学各个方向的资源投入奠定了基础。其中有 4 篇 [ 1 , 14 - 16 ] 文献受到了极大的关注，2 篇主要探讨美国的流行病学，包括癌症筛查 [ 15 ] 和潜在危险因素引起的癌症发病和死亡的比例 [ 16 ] ；另外 2 篇则关注全球癌症发病率和死亡率 [ 1 ] 及 5 年生存率的统计 [ 14 ] 。据统计，2018 年有 1 810 万癌症新发病例和 960 万例癌症死亡病例，发病率较高的依次是肺癌、乳腺癌、前列腺癌和结肠直肠癌；死亡率依次是肺癌、结肠直肠癌、胃癌和肝癌 [ 1 ] ；对大多数癌症来说，5 年生存率最高的 8 个国家依次为美国、加拿大、澳大利亚、新西兰、芬兰、冰岛、挪威和瑞典 [ 14 ] 。美国的研究则评估了危险因素（吸烟；二手烟；超重；饮酒；食用红肉及加工肉类；少吃水果/蔬菜、膳食纤维及膳食钙；缺乏身体活动；紫外线辐射及 6 个癌症相关感染）占美国癌症发病例数的 42.0% 和死亡例数的 45.1%，其中吸烟所占比例最高，其次是超重和酒精摄入 [ 16 ] 。

2.5.3. 神经系统肿瘤

神经系统肿瘤（见 表 3 ）最受关注的 4 篇论文 [ 17 - 20 ] 中被引最高的一篇是手术腔内立体定向放射外科手术（stereotactic radiosurgery，SRS）和全脑放射治疗（whole brain radiotherapy，WBRT）在脑转移瘤术后患者中的疗效和安全性比较。结果发现，两组之间的总体生存虽然没有差异，但与 SRS 相比，WBRT 患者的认知功能下降更为常见，提示 SRS 是一种副作用较小的替代 WBRT 的疗法 [ 17 ] 。另一篇研究的是一种靶向 EGFRvIII 的肽类肿瘤疫苗（Rindopepimut）联合替莫唑胺在新诊断的 EGFRvIII 阳性胶质母细胞瘤患者中的疗效和安全性，但最终发现 Rindopepimut 不能延长新诊断胶质瘤患者的生存时间 [ 18 ] 。还有一篇研究肿瘤电场疗法（tumor-treating fields，TTFields）对胶质母细胞瘤的治疗效果，肿瘤电场疗法可通过向肿瘤传递低强度交变电场干扰肿瘤细胞分裂，研究结果发现该疗法改善了胶质母细胞瘤患者的无进展生存率和总生存率 [ 19 ] 。最后一篇基础研究是关于 EGFR 通路调控的 NEAT1 促进胶质母细胞瘤的生长和侵袭 [ 20 ] 。

表 3

Global research hotspots on oncology: nervous system and head/face tumor

肿瘤领域全球研究热点——神经系统与头面部肿瘤

研究主题 相关研究 被引次数
2020.09.23 神经系统肿瘤
临床试验 Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease（NCCTG N107C/CEC·3）：a multicentre，randomised，controlled，phase 3 trial [ 17 ] 260 Lancet Oncol
Rindopepimut with temozolomide for patients with newly diagnosed，EGFRvIII-expressing glioblastoma（ACT IV）：a randomised，double-blind，international phase 3 trial [ 18 ] 231 Lancet Oncol
Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma：a randomized clinical trial [ 19 ] 325 JAMA
长链非编码 RNA Long noncoding RNA NEAT1，regulated by the EGFR pathway，contributes to glioblastoma progression through the WNT/β-catenin pathway by scaffolding EZH2 [ 20 ] 105 Clin Cancer Res 头面部肿瘤
临床试验 Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer：results from a single-arm，phase II study [ 21 ] 222 J Clin Oncol
Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer（De-ESCALaTE HPV）：an open-label randomised controlled phase 3 trial [ 22 ] 162 Lancet
Pembrolizumab versus methotrexate，docetaxel，or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma（KEYNOTE-040）：a randomised，open-label，phase 3 study [ 23 ] 221 Lancet
Nivolumab for recurrent squamous-cell carcinoma of the head and neck [ 24 ] 1 505 N Engl J Med
Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases：a multicentre randomised phase 2 study [ 25 ] 239 Lancet
单细胞转录组分析 Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer [ 26 ] 317 Cell

2.5.4. 头面部肿瘤

研究头面部肿瘤（见 表 3 ）的文献共计 6 篇 [ 21 - 26 ] ，其中临床试验 5 篇 [ 21 - 25 ] ，还有 1 篇研究头颈部鳞状细胞癌的原发灶和转移灶的单细胞转录组分析 [ 26 ] 。临床试验研究中被引最高的是在铂类和西妥昔单抗难治性复发/转移性头颈部鳞状细胞癌患者中，派姆单抗（Pembrolizumab）显示出抗肿瘤活性和良好的安全性 [ 21 ] 。其次是放疗联合顺铂或放疗联合西妥昔单抗治疗低风险人乳头瘤病毒阳性口咽癌的随机对照试验，但结果证明西妥昔单抗不仅没有降低毒性反应，反而降低了生存 [ 22 ] 。另外 3 篇分别是在复发或转移性头颈部鳞状细胞癌患者中，派姆单抗 [ 23 ] 和纳武单抗（Nivolumab） [ 24 ] 比标准疗法（甲氨蝶呤、多西他赛或西妥昔单抗）的疗效和安全性更好，以及纳武单抗联合伊匹单抗（Ipilimumab）或纳武单抗单药治疗对黑色素瘤脑转移患者有效 [ 25 ] 。

2.5.5. 呼吸系统肿瘤

研究呼吸系统肿瘤（见 表 4 ）的文献有 7 篇 [ 27 - 33 ] ，其中 4 篇是临床试验，包括：纳武单抗治疗进展期非小细胞肺癌的 5 年随访结果显示部分患者可获得持续反应及长期生存 [ 27 ] ；派姆单抗在 PD-1 阳性的恶性胸膜间皮瘤患者中耐受性良好，可能具有抗肿瘤活性 [ 28 ] ；德瓦鲁单抗（Durvalumab）在晚期非小细胞肺癌，尤其是在 EGFR 突变或 ALK 重排的患者中的疗效研究 [ 30 ] ；还有吉非替尼与长春瑞滨联合顺铂辅助治疗 II-IIIA（N1-N2）期 EGFR 突变型非小细胞肺癌的疗效分析，结果显示吉非替尼辅助治疗显著延长了患者的无病生存期，降低了毒性反应，但总体生存数据尚不成熟 [ 29 ] 。另外 3 篇分别是在非小细胞肺癌中检验三种商品化 PD-L1 免疫组化染色的一致性程度 [ 31 ] ，使用分子标记评估肺癌脑转移患者的预后 [ 32 ] ，以及免疫检查点抑制剂治疗在晚期非小细胞肺癌患者预后相关的临床和分子特征的 Meta 分析 [ 33 ] 。

表 4

Global research hotspots on oncology: respiratory system and breast cancer

肿瘤领域全球研究热点——呼吸系统与乳腺肿瘤

研究主题 相关研究 被引次数
2020.09.23 呼吸系统肿瘤
临床试验 Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer：results from the CA209-003 study [ 27 ] 204 J Clin Oncol
Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma（KEYNOTE-028）：preliminary results from a non-randomised，open-label，phase 1b trial [ 28 ] 195 Lancet Oncol
Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA（N1-N2） EGFR-mutant NSCLC（ADJUVANT/CTONG1104）：a randomised，open-label，phase 3 study [ 29 ] 140 Lancet Oncol
Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer（ATLANTIC）：an open-label，single-arm，phase 2 study [ 30 ] 170 Lancet Oncol
PD-L1 免疫组化 Agreement between programmed cell death ligand-1 diagnostic assays across multiple protein expression cutoffs in non-small cell lung cancer [ 31 ] 170 Clin Cancer Res
肺癌脑转移预后评估分级 Estimating survival in patients with lung cancer and brain metastases：an update of the graded prognostic assessment for lung cancer using molecular markers（Lung-molGPA） [ 32 ] 179 JAMA Oncol
非小细胞肺癌临床和分子特征 Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma：
a systematic review and meta-analysis [ 33 ] 		134 JAMA Oncol
乳腺癌 Effect of axillary dissection vs no axillary dissection on 10-Year overall survival among women with invasive breast cancer and sentinel node metastasis：the ACOSOG Z0011（Alliance） randomized clinical trial [ 34 ] 299 JAMA
Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer [ 35 ] 447 N Engl J Med
Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer [ 36 ] 388 N Engl J Med
Diagnostic assessment of deep learning algorithms for detection of lymph node metastases in women with breast cancer [ 37 ] 453 JAMA
Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer：a pooled analysis of 3771 patients treated with neoadjuvant therapy [ 38 ] 292 Lancet Oncol
乳房植入物 Breast implants and the risk of anaplastic large-cell lymphoma in the breast [ 39 ] 109 JAMA Oncol

2.5.6. 乳腺肿瘤

研究乳腺肿瘤（见 表 4 ）的文献有 6 篇 [ 34 - 39 ] ，其中 5 篇是关于乳腺癌的研究 [ 34 - 38 ] ；另 1 篇研究的是乳房植入物与乳腺增生性大细胞淋巴瘤（anaplastic large cell lymphoma，ALCL）之间的关联，结果显示乳房植入物与乳腺 ALCL 风险增加有关，但绝对风险仍然很小 [ 39 ] 。在有关乳腺癌的研究中引用率最高的是比较腋窝淋巴结清扫和前哨淋巴结清扫对浸润性乳腺癌前哨淋巴结转移患者 10 年总生存率的影响，最终发现两组总生存率无显著差异 [ 34 ] ；其次是关于内分泌治疗和化学内分泌治疗在雌激素受体阳性、HER2 阴性、腋窝淋巴结无转移乳腺癌患者中疗效相似的研究 [ 35 ] 。另外 3 篇研究内容分别为：在 HER2 阳性、可手术的乳腺癌患者中，帕妥珠单抗（Pertuzumab）联合曲妥珠单抗（Trastuzumab）和化疗，其无侵袭性生存率显著提高，但发生腹泻也更为常见 [ 36 ] ；评估深度学习算法在检测乳腺癌患者淋巴结 HE 组织切片转移方面的性能，并与病理学家的诊断结果进行比较 [ 37 ] ；还有增加的肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes，TILs）与三阴性乳腺癌（triple-negative breast cancer，TNBC）和 HER2 阳性乳腺癌的生存效益有关，但是 HER2 阴性管腔乳腺癌的不利预后因素，表明不同亚型的乳腺癌其免疫浸润的生物学特性不同 [ 38 ] 。

2.5.7. 消化系统肿瘤

与消化系统肿瘤（见 表 5 ）相关的文献共计 13 篇 [ 40 - 52 ] 。其中 6 篇与结直肠癌相关 [ 40 - 45 ] ，包括梭杆菌及其相关微生物群在转移灶中保持定植 [ 40 ] ；结肠癌患者免疫评分评估预后 [ 42 ] ；Ⅲ期结肠癌原发灶定位与 Ras 和 Braf 突变状态的关系 [ 41 ] ；2018 年度结直肠癌患者的癌症死亡率预测 [ 43 ] ；还有 2 篇临床试验，一是研究纳武单抗联合伊匹单抗在治疗错配修复缺陷/高度微卫星不稳定的转移性结直肠癌中取得持久临床获益 [ 45 ] ，另一项是在未治疗的 KRAS 野生型晚期或转移性结直肠癌患者中，西妥昔单抗或贝伐珠单抗联合一线化疗作为初始治疗无明显差异 [ 44 ] 。被引频次最高的文献是研究美国神经内分泌肿瘤患者的发病率、患病率和生存结局 [ 50 ] 。有 2 篇文献研究林奇综合征基因型对肿瘤风险和生存期的影响 [ 52 ] 和家族性腺瘤性息肉病患者含有致瘤菌的结肠生物膜 [ 51 ] 。另外几篇文献分别是：卡博替尼改善了晚期和进展期肝细胞癌患者的生存 [ 48 ] ；胰腺癌长期存活患者的独特新抗原的鉴定 [ 47 ] ；人源类器官（patient-derived organoids，PDO) 分析确定了胰腺癌化疗的常见反应 [ 46 ] ；还有环状 RNA 谱证实 CIRCPVT1 是胃癌的增殖因子和预后标志物 [ 49 ] 。

表 5

Global research hotspots on oncology: digestive system

肿瘤领域全球研究热点——消化系统肿瘤

研究主题 相关研究 被引次数
2020.09.23 		期刊来源
结直肠癌 Analysis of fusobacterium persistence and antibiotic response in colorectal cancer [ 40 ] 253 Science
Association of prognostic value of primary tumor location in stage III colon cancer with RAS and BRAF mutational status [ 41 ] 25 JAMA Oncol
International validation of the consensus immunoscore for the classification of colon cancer：a prognostic and accuracy study [ 42 ] 400 Lancet
European cancer mortality predictions for the year 2018 with focus on colorectal cancer [ 43 ] 80 Ann Oncol
Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer：a randomized clinical trial [ 44 ] 259 JAMA
Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer [ 45 ] 385 J Clin Oncol
胰腺癌 Organoid profiling identifies common responders to chemotherapy in pancreatic cancer [ 46 ] 134 Cancer Discov
Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer [ 47 ] 281 Nature
肝癌 Cabozantinib in patients with advanced and progressing hepatocellular carcinoma [ 48 ] 385 N Engl J Med
胃癌 Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer [ 49 ] 367 Cancer Lett
神经内分泌肿瘤 Trends in the incidence，prevalence，and survival outcomes in patients with neuroendocrine tumors in the United States [ 50 ] 621 JAMA Oncol
家族性腺瘤息肉病 Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria [ 51 ] 189 Science
林奇综合征 Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age：a report from the prospective lynch syndrome database [ 52 ] 117 Gut

2.5.8. 泌尿系统肿瘤

共计 9 篇文献研究泌尿系统肿瘤 [ 53 - 61 ] （见 表 6 ），其中 7 篇关于前列腺癌 [ 53 - 59 ] ，仅 2 篇研究肾癌 [ 60 - 61 ] 。在有关前列腺癌的临床试验中，伊匹单抗虽不能改善无症状或症状轻微的初次化疗、无内脏转移的转移性、去势抗性前列腺癌患者的总生存期，但其无进展生存期和前列腺特异性抗原（prostate specific antigen，PSA）应答率均增加 [ 53 ] 。在非转移性去势耐药前列腺癌患者中，使用雄激素受体抑制剂阿帕鲁胺（Apalutamide）可明显延长患者的无转移生存率和症状进展时间 [ 54 ] 。转移灶定向疗法（metastasis-directed therapy，MDT）与主动检测相比，寡转移复发性前列腺癌患者的无雄激素剥夺治疗（androgen deprivation therapy，ADT）的生存期显著延长 [ 55 ] 。随机进行单一 PSA 筛查与不筛查相比，中位随访 10 年，前列腺癌死亡率无显著差异，但低风险前列腺癌病例的检出率有所上升 [ 56 ] 。对于转移性去势抵抗性前列腺癌（metastatic castration-resistant prostate cancer，MCRPC）患者，服用低剂量醋酸阿比特龙（同时进食低脂早餐）与标准剂量用药相比，其 PSA 反应率与无进展生存率无显著差异 [ 57 ] 。在醋酸阿比特龙加强的松治疗的 MCRPC 患者中再使用恩杂鲁胺，大多数患者观察到两种药剂间的交叉耐药性，但仍有一些受益于恩杂鲁胺治疗 [ 58 ] 。还有一篇基础研究是关于 RB1 和 TRP53 的缺失促进前列腺癌细胞的转移、谱系可塑性和抗雄激素治疗的抵抗 [ 59 ] 。两篇肾癌研究的内容分别为：对肾透明细胞癌患者进行全外显子组测序发现免疫检查点治疗的临床效益与 PBRM1 基因功能缺失突变相关 [ 60 ] ；随机对照临床试验发现在中危或低危转移性肾细胞癌患者中，单用苏尼替尼的疗效并不亚于肾切除联合苏尼替尼治疗 [ 61 ] 。

表 6

Global research hotspots on oncology: urinary system and reproductive system

肿瘤领域全球研究热点——泌尿系统肿瘤与生殖系统肿瘤

研究主题 相关研究 被引次数
2020.09.23 泌尿系统肿瘤
前列腺癌 Randomized，double-blind，phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer [ 53 ] 230 J Clin Oncol
Apalutamide treatment and metastasis-free survival in prostate cancer [ 54 ] 343 N Engl J Med
Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence：a prospective，randomized，multicenter phase II trial [ 55 ] 298 J Clin Oncol
Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality：the CAP randomized clinical trial [ 56 ] 118 JAMA
Prospective international randomized phase II study of low-dose abiraterone with food versus standard dose abiraterone in castration-resistant prostate cancer [ 57 ] 56 J Clin Oncol
Antitumour activity and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with abiraterone acetate plus prednisone for ≥24 weeks in Europe [ 58 ] 36 Eur Urol
Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity，metastasis，and antiandrogen resistance [ 59 ] 281 Science
肾癌 Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma [ 60 ] 247 Science
Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma [ 61 ] 233 N Engl J Med 生殖系统肿瘤
奥拉帕利 Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy：an updated analysis from a randomised，placebo-controlled，double-blind，phase 2 trial [ 62 ] 204 Lancet Oncol
Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer [ 63 ] 391 N Engl J Med
Rucaparib Rucaparib in relapsed，platinum-sensitive high-grade ovarian carcinoma（ARIEL2 Part 1）：an international，multicentre，open-label，phase 2 trial [ 64 ] 439 Lancet Oncol
Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy（ARIEL3）：a randomised，double-blind，placebo-controlled，phase 3 trial [ 65 ] 392 Lancet

2.5.9. 生殖系统肿瘤

有 4 篇文献 [ 62 - 65 ] 研究生殖系统肿瘤（见 表 6 ）且均关于卵巢癌患者的治疗，其中 2 篇研究多聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕利（Olaparib） [ 62 - 63 ] ，另外 2 篇研究 PARP 抑制剂 Rucaparib [ 64 - 65 ] 。奥拉帕利维持治疗铂敏感、复发性卵巢癌患者（包括 BRCA1 和 BRCA2 突变患者）可显著改善生存率且耐受性良好 [ 62 ] ；奥拉帕利维持治疗使新诊断的晚期卵巢癌和 BRCA1/2 突变患者的疾病进展或死亡风险降低了 70% [ 63 ] 。Rucaparib 可显著提高铂类敏感性卵巢癌患者的无进展生存率 [ 65 ] ；Rucaparib 治疗 BRCA 突变或 BRCA 野生型且高杂合性缺失的、铂类敏感的卵巢癌患者的无进展生存要优于 BRCA 野生型且低杂合性缺失的患者 [ 64 ] 。

2.5.10. 骨与软组织肿瘤

骨与软组织肿瘤（见 表 7 ）中有两项研究 [ 66 - 67 ] 最受关注。一篇是研究派姆单抗治疗晚期软组织肉瘤和骨肉瘤的安全性和活性，结果显示派姆单抗在未分化多形性肉瘤或去分化脂肪肉瘤患者中显示出良好的活性 [ 66 ] 。另一篇则比较了雄激素剥夺治疗联合前列腺同步放疗与单独雄激素剥夺治疗对原发性骨转移性前列腺癌患者生存率的影响，但结果发现增加前列腺同步放疗并不能提高总体生存率 [ 67 ] 。

2.5.11. 血液肿瘤

共计 8 篇文献致力于血液肿瘤（见 表 7 ）的研究 [ 68 - 75 ] ，其中 5 篇是临床试验 [ 68 - 72 ] 。BCL-2 抑制剂 Venetoclax 在非霍奇金淋巴瘤（non-Hodgkin lymphoma，NHL）中进行了首次Ⅰ期临床试验以确定其安全性、药代动力学和疗效 [ 68 ] 。Venetoclax 联合地西他滨或阿扎胞苷在初治老年急性髓系白血病患者中进行了疗效和安全性研究 [ 70 ] 。Venetoclax 联合 Rituximab 治疗复发或难治性慢性淋巴细胞白血病 [ 71 ] ，Venetoclax 均表现出良好的疗效。派姆单抗在复发/难治性经典霍奇金淋巴瘤中表现出良好的疗效和安全性 [ 72 ] 。根据早期正电子发射计算机断层扫描（positron emission tomography，PET）结果改变治疗方案可改善霍奇金淋巴瘤患者的预后，Ⅰ期和Ⅱ期霍奇金淋巴瘤患者接受 2 个周期的 ABVD 化疗方案后，PET 阳性者治疗转为 BEACOPP ESC 和累及淋巴结放疗（involved-node radiotherapy，INRT），可显著改善 5 年无进展生存率；PET 转为阴性者，单单用 ABVD 并没能达到非劣效性，而免去 INRT 则增加了复发的可能 [ 69 ] 。另外 3 篇研究分别是：用二代测序技术检测急性髓系白血病（acute myelocytic leukemia，AML）患者的微小分子残留病变预测复发的临床价值 [ 73 ] ，用深度测序预测健康人患上 AML 的风险 [ 74 ] 以及表达抗 B 细胞成熟抗原（B-cell maturation antigen，BCMA）的嵌合抗原受体 T 细胞（chimeric antigen receptor T-cell，CAR-T）对复发/难治性多发性骨髓瘤有明显的抑制作用 [ 75 ] 。

2.5.12. 皮肤体表肿瘤

关于皮肤体表肿瘤（见 表 7 ）的文献有 6 篇 [ 76 - 81 ] ，其中 5 篇是关于黑色素瘤 [ 76 - 80 ] ，仅有 1 篇研究 Cemiplimab 在晚期皮肤鳞状细胞癌患者中的疗效和安全性 [ 81 ] 。有关黑色素瘤的研究中引用频次最高的是回顾性分析在患有严重自身免疫性疾病或用伊匹单抗出现严重免疫相关不良事件的黑色素瘤患者中，抗 PD-1 治疗可引起相对频繁的免疫毒性，但这些毒性往往较轻，不需要停止治疗 [ 76 ] 。其次是研究在诱导期因不良反应停止纳武单抗联合伊匹单抗治疗的晚期黑色素瘤患者与未停止治疗的患者疗效相当，提示停药后患者仍可受益于联合治疗 [ 77 ] 。另外 3 篇均为有关黑色素瘤的临床试验，分别为：在晚期黑色素瘤患者中，Talimogene laherparepvec（一种溶瘤病毒）联合伊匹单抗比伊匹单抗单药治疗客观应答率更高 [ 78 ] ；派姆单抗的总体生存率优于伊匹单抗 [ 80 ] ；在 BRAF 突变型晚期、不可切除或转移性黑色素瘤患者中，BRAF 抑制剂 Encorafenib 联合 MEK 抑制剂 Binimetinib 疗效显著，这可能是一种新的治疗选择 [ 79 ] 。

3. 小结

肿瘤领域仍是医学研究最热门的方向，其中免疫检查点抑制剂与肿瘤治疗相关不良事件之间的关系、遗传基因促进肿瘤发生发展的机制仍是基础研究领域的重点研究方向。探究癌症疾病负担以及危险因素相关的流行病学研究也是肿瘤领域研究者重点关注的内容，每年全球癌症统计以及美国癌症统计数据发布后，被大量相关学者引用。此外，各个系统、器官相关的肿瘤，全球学者也在努力探索新的诊疗方式，值得关注的是，提前干预和饮食疗法受到了越来越多的重视。新的药物和手术治疗方式也取得了一些突破性进展。本文概述了肿瘤领域当前最受关注的一些研究，梳理了研究的脉络及其贡献者，为肿瘤研究的兴趣读者提供了一个全面的视角，以了解肿瘤领域的研究前沿和热点。

利益冲突声明：本文全体作者均声明不存在利益冲突。

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