精准医疗—肿瘤诊治的新模式

精准医疗（precision medicine）又称为个性化医疗,是根据个体基因特征、环境以及生活习惯,为病人量身设计出最佳治疗方案,以期达到治疗效果最大化和不良反应最小化的一种定制医疗模式。作为一种全新的医学概念与医疗模式,日益在恶性肿瘤临床治疗中显示出价值。人类基因组计划的完成和测序技术的飞速发展,极大地促进了肿瘤基因组测序研究,发现了大量与肿瘤相关的基因组改变,为肿瘤的个体化精准治疗提供理论和技术支撑。本文主要对精准医疗的概念、实施步骤以及在肿瘤治疗中的应用做一简要的概述。     

肿瘤精准细胞免疫治疗：梦想照进现实

精准医疗(precision medicine)作为一种全新的医学概念与医疗模式,已日益在恶性肿瘤临床治疗中显示其价值。精准细胞免疫治疗(precision cell immunotherapy,PCIT)是基于肿瘤患者基因检测,筛选可引起强烈免疫反应的新抗原(neoantigen),进而寻找并富集针对新抗原的精准T细胞(precision T cell for neo-antigen,PNA-T),扩增后回输患者的治疗新策略。相对于其他精准医学治疗方式,精准细胞免疫治疗具有比较独特的优势,有望成为中国肿瘤精准医学治疗的重要突破口。本文围绕肿瘤精准细胞免疫治疗面临的机遇与挑战,从概念、特点、流程、技术难点等方面进行了详细阐述,并对比了其与转基因嵌合抗原受体T细胞(chimeric antigen recepor T cell,CAR-T)的异同,勾勒出肿瘤精准细胞免疫治疗的美好前景。     

组学技术在肿瘤精准诊疗中应用的研究进展：从单组学分析到多组学整合

肿瘤涉及DNA、RNA、蛋白质和代谢物水平的多种异常,是一种复杂的全身性疾病。根据中心法则衍生的组学方法分别为基因组学、转录组学、蛋白质组学和代谢组学。在过去的数十年间,关于肿瘤的单一组学研究取得了显著成绩,但肿瘤发生发展的确切机制尚不清楚。为了更加系统地揭示肿瘤发生发展的过程及其机制,多组学研究应运而生,推动肿瘤研究范式从单参数模型向多参数系统模型的转变。多组学方法的整合有望阐明肿瘤的发生发展机制,发现具有诊断和预后预测功能的生物标志物,探索新的治疗靶点,最终实现肿瘤预测、预防和个体化医疗（PPPM）。本文综述了肿瘤研究中不同组学技术的研究方法和研究进展,特别强调了多组学技术在肿瘤研究和临床相关结果中整合的重要性和科学价值。     

An overview of precision oncology basket and umbrella trials for clinicians

With advancements in biomarkers and momentum in precision medicine, biomarker-guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine—to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.     

Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine

Background

Despite advances in molecular medicine over recent decades, there has been little advancement in the treatment of osteosarcoma. We performed comprehensive molecular profiling in two cases of metastatic and chemotherapy-refractory osteosarcoma to guide molecularly targeted therapy.

Patients and Methods

Hybridization capture of >300 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from tumor samples from two patients with recurrent, metastatic osteosarcoma. The DNA from each sample was sequenced to high, uniform coverage. Immunohistochemical probes and morphoproteomics analysis were performed, in addition to fluorescence in situ hybridization. All analyses were performed in CLIA-certified laboratories. Molecularly targeted therapy based on the resulting profiles was offered to the patients. Biomedical analytics were performed using QIAGEN''s Ingenuity^® Pathway Analysis.

Results

In Patient #1, comprehensive next-generation exome sequencing showed MET amplification, PIK3CA mutation, CCNE1 amplification, and PTPRD mutation. Immunohistochemistry-based morphoproteomic analysis revealed c-Met expression [(p)-c-Met (Tyr1234/1235)] and activation of mTOR/AKT pathway [IGF-1R (Tyr1165/1166), p-mTOR [Ser2448], p-Akt (Ser473)] and expression of SPARC and COX2. Targeted therapy was administered to match the P1K3CA, c-MET, and SPARC and COX2 aberrations with sirolimus+ crizotinib and abraxane+ celecoxib. In Patient #2, aberrations included NF2 loss in exons 2–16, PDGFRα amplification, and TP53 mutation. This patient was enrolled on a clinical trial combining targeted agents temsirolimus, sorafenib and bevacizumab, to match NF2, PDGFRα and TP53 aberrations. Both the patients did not benefit from matched therapy.

Conclusions

Relapsed osteosarcoma is characterized by complex signaling and drug resistance pathways. Comprehensive molecular profiling holds great promise for tailoring personalized therapies for cancer. Methods for such profiling are evolving and need to be refined to better assist clinicians in making treatment decisions based on the large amount of data that results from this type of testing. Further research in this area is warranted.     

The effects of radiotherapy on the survival of patients with unresectable non-small cell lung cancer

Introduction: Lung cancer represents the leading cause of cancer mortality across the worlds. At present, less than 30% of the patients can undergo curative surgery, while the majority of them (65%) are diagnosed with metastatic disease and directed to systemic treatments. In this context there is a subset of patients (25%) with locally advanced stage disease whose outcome might be improved by using combined strategies of treatment including chemotherapy, radiotherapy and surgery.

Areas covered: Here we reviewed possible combination strategies aimed to improve the outcome of lung cancer patients, focusing on the role of radiotherapy both in the adjuvant and oligo-metastatic setting and in synergy with immunotherapy, and finally, we afforded the new challenges concerning the advanced RT and precision oncology. We carried out a focused analysis concerning the key clinical management weaknesses as well as the potential that current research holds.

Expert commentary: We believe that the most promising clinical trials in this specific patient subset will build their rationale on the results of well-designed translational models aimed to test the combination of cytotoxic drugs, radiobiology, and immune-pharmacology. In this context, remarkable investigational fields are focused on the attempt to combine radiotherapy with chemo-immunological strategies and precision medicine protocols.     

Parents’ and adolescents’ perspectives and understanding of information about childhood cancer precision medicine

Background

Precision medicine is projected to become integral to childhood cancer care. As such, it is essential to support families to understand what precision medicine entails.

Methods

A total of 182 parents and 23 adolescent patients participating in Precision Medicine for Children with Cancer (PRISM), an Australian precision medicine clinical trial for high-risk childhood cancer, completed questionnaires after study enrollment (time 0 [T0]). Of the parents, 108 completed a questionnaire and 45 completed an interview following return of precision medicine results (time 1 [T1]). We analyzed the mixed-methods data comprising measures exploring families’ perceptions and understanding of PRISM’s participant information sheet and consent form (PISCF), and factors associated with understanding.

Results

Most parents were satisfied with the PISCF, rating it as at least “somewhat” clearly presented (n = 160/175; 91%) and informative (n = 158/175; 90%). Many suggested improvements including the use of clearer language and a more visually engaging format. Parents’ actual understanding of precision medicine was low on average, but scores improved between T0 and T1 (55.8/100-60.0/100; p = .012). Parents from culturally and/or linguistically diverse backgrounds (n = 42/177; 25%) had lower actual understanding scores than those from a Western/European background whose first language was English (p = .010). There was little correlation between parents’ perceived and actual understanding scores (p = .794; Pearson correlation –0.020; 95% CI, –0.169 to 0.116). Most adolescent patients read the PISCF either “briefly” or “not at all” (70%) and had a perceived understanding score of 63.6/100 on average.

Conclusions

Our study revealed gaps in families’ understanding of childhood cancer precision medicine. We highlighted areas for potential intervention such as through targeted information resources.

Plain Language Summary

• Precision medicine is projected to become part of the standard of care for children with cancer. Precision medicine aims to give the right treatment to the right patient and involves several complex techniques, many of which may be challenging to understand.
• Our study analyzed questionnaire and interview data from parents and adolescent patients enrolled in an Australian precision medicine trial.
• Findings revealed gaps in families’ understanding of childhood cancer precision medicine. Drawing on parents’ suggestions and the literature, we make brief recommendations about improving information provision to families, such as through targeted information resources.

     

精确病理诊断在甲状腺癌精准医疗中的意义

甲状腺癌是近年来发病率上升最快的实体恶性肿瘤,其中绝大多数为滤泡细胞来源,以分化型甲状腺癌为主,包括甲状腺乳头状癌（papillary thyroid cancer,PTC）和滤泡癌（follicular thyroid cancer,FTC）。为实现甲状腺癌的精准预防、诊断和治疗,需要以精确病理诊断作为基础。本文分别从评估并降低甲状腺癌发生风险、术前精确诊断、预后和复发风险分层,以及指导晚期患者分子靶向治疗等方面来阐述精确病理诊断在甲状腺癌精准医疗中的意义。      

循环肿瘤细胞纳米检测技术用于肿瘤早期诊断的探索

循环肿瘤细胞(circulating tumor cell,CTC)在外周血中的存在和循环被认为是引起肿瘤远处转移的主要原因.与传统的影像学检测手段相比,CTC检测技术作为一种非侵袭性的检测手段,其操作更简便、更安全和精准.此外,CTC技术也助于研究者深入探讨肿瘤转移复发和耐药的机制.因此,CTC作为一种生物标志物,在肿瘤的早筛、早诊、预后评估和疗效检测等过程中都有着极其重要的临床意义.中科院国家纳米科学中心研发的“肿瘤捕手”技术利用多肽纳米磁珠来捕获外周血中的CTC.目前,CTC检测技术已在国内多家顶级公立医院开展临床研究和试验,大量临床数据表明,其对于肿瘤早期诊断、预后判断和耐药性监测方面具有极大的指导意义.本文就CTC的研究进展,“肿瘤捕手”技术的研发和应用作一阐述.     

胃癌精准医疗时代消化内镜工作面临的问题与对策

[摘要] 精准医疗是指与患者分子生物病理学特征相匹配的个体化诊疗策略和过程。规范化的组织标本取材是分子病理学诊断的基础,也是精准医疗的前提。内镜下活检是获取消化道肿瘤（包括胃癌）组织标本的重要途径。本文重点讨论在胃癌精准医疗分子病理学指导下,对胃癌精准医疗过程中组织标本内镜采集工作中的几个问题,并提出相应建议。     

晚期恶性肿瘤基因突变状态二代测序临床意义分析

目的 靶向治疗是晚期恶性肿瘤的重要治疗方法,二代测序能够准确、高通量地检测基因突变情况,对恶性肿瘤治疗有重要意义.本研究运用二代基因测序(next-generation sequencing,NGS)技术检测晚期恶性肿瘤的基因突变情况,并初步分析错义突变的临床意义.方法 2011-09-01-2016-09-30收集陕西省人民医院肿瘤内科93例晚期恶性肿瘤患者病理组织石蜡标本,利用离子个体化基因检测仪(Ion Personal Genome Machine,Ion Torrent PGM)平台检测标本16个肿瘤相关基因428个常见的突变位点的突变状态,并查询临床试验(Clinical Trails)与美国食品与药物管理局(Food and Drug Administration,FDA)官网数据资料.结果 共发现119个错义突变,其中TP53发生频率最高为34.5％(41/119);除TP53突变在各瘤种中均占较大比例外,肺癌突变频率最高为表皮生长因子受体(epidermal growth factor receptor,EGFR) 25.7％(9/35),结直肠癌为KRAS 31.6％ (6/19),胃癌为KDR 3/6,卵巢癌为KRAS 2/7,宫颈癌为KDR 3/5.70例(75.3％,70/93)检测发现＞1个的错义突变位点;93.8％(15/16)的被检测基因有正在研发中的小分子抑制剂和(或)单抗类制剂,75.0％(12/16)的被检测基因已有FDA批准用于特定瘤种的靶向药物,68.8％(11/16)的被检测基因有尚未被FDA批准的靶向药物.结论 晚期恶性肿瘤基因错义突变发生率较高,且不同瘤种的突变谱不同,目前基于NGS指导的恶性肿瘤个体化靶向治疗有广阔的应用前景.     

面向精准医学的医学细胞生物学的教学探索

精准医学是医疗模式最新发展方向,将对肿瘤医疗模式产生重大的影响.同时精准医学的出现也为基础医学教育带来了新的机遇.医学细胞生物学是医学本科教育中一门重要的基础学科,我们在教学中尝试对教学内容和方式进行改革,增加了精准医学及其临床应用相关的技术和知识讲授,同时配合实验课程的改革.通过对调查问卷和随堂抽测对改革效果进行评价.结果表明本次改革不但提升了课堂授课的效果,同时增强了学生对细胞生物学课程重要性的认识,对学习目的、学习态度和学习方法都产生了积极影响.不但对提高课堂授课质量发挥了积极作用,同时也为探索基础学科教育新模式,培养适应未来医学发展的人才做出了一次有益的尝试.     

精准医疗时代早期乳腺癌患者外科治疗的热点问题

乳腺癌是女性最常见的恶性肿瘤之一，对于早期乳腺癌患者，外科治疗仍然有其不可替代的作用。在精准医疗的背景下，通过回顾近期早期乳腺癌外科治疗的若干热点问题，对外科治疗策略制定、保乳手术范围、区域淋巴结处理、乳房重建时机抉择及乳腺微创治疗等方面进行综述，以期多学科合作，实施早期乳腺癌精准外科治疗。      

单细胞转录组测序技术在肿瘤微环境中的应用进展

癌症因其克隆异质性和组成复杂性一直是人类难以攻克的挑战。肿瘤由癌细胞和多种非癌细胞类型形成,它们与细胞外基质一起形成了肿瘤微环境,这些与癌症相关的细胞和成分以及免疫机制的参与影响着癌症的发生发展,并关系着患者的诊断治疗以及预后。单细胞转录组测序(single-cell RNA-sequencing,scRNA-seq)作为理解复杂生物学系统的首选方法,在肿瘤微环境的研究中备受关注。本文我们总结应用scRNA-seq研究肿瘤微环境以及在临床治疗的作用。