精准医疗时代胰腺癌个体化类器官研究现状与应用前景

目的总结精准医疗时代背景下胰腺癌个体化类器官(organoids)研究现状及其潜在的临床应用前景。方法检索Pub Med数据库获取相关资料,就胰腺癌个体化类器官特征及其在促进胰腺癌精准治疗中的应用进行综述。结果胰腺癌患者个体化类器官模型系统作为测试肿瘤药物和个体化肿瘤疗法的新型平台,利于致癌基因建模、靶基因发现和个体化药物敏感性检测,可用于肿瘤精准治疗。结论个体化肿瘤类器官可用于指导胰腺癌的精准治疗。     

合成致死效应在胰腺癌精准治疗中的应用及研究进展

胰腺癌恶性程度高、手术切除率低、缺乏有效的治疗药物,预后极差。合成致死策略在肿瘤治疗中具有较好前景,有助于根据不同胰腺癌患者的遗传突变背景制定个体化治疗方案,符合肿瘤精准治疗的理念。合成致死策略也是靶向药物研发的方向之一。随着高效低毒的个体化抗肿瘤治疗模式的建立,基于合成致死策略的靶向治疗有望改善胰腺癌系统治疗的现状。...     

人源性肿瘤组织异种移植模型在胰腺癌综合治疗中的应用及展望

胰腺癌预后欠佳,以化疗及分子靶向治疗为代表的全身综合治疗是改善胰腺癌术后预后的关键,也是延长晚期胰腺癌生存时间的重要手段。但是由于胰腺癌细胞的耐药性、异质性等原因,目前的全身综合治疗方案仍未达到理想效果,基于精准医学的个体化胰腺诊疗模式将是解决这个问题的重要途径。随着人源性肿瘤组织异种移植(PDX)模型的应用,胰腺癌的...     

KRAS突变与胰腺癌的发生及治疗的研究进展

目的总结KRAS突变与胰腺癌发生及治疗的研究进展。方法通过阅读近几年国内外的相关文献,对KRAS突变与胰腺癌发生及治疗的研究进展进行归纳总结。结果胰腺癌有"癌症之王"的称谓,超过90%的胰腺癌患者表达KRAS基因突变。KRAS通过下游信号通路Raf(rapidly accelerated fibrosarcoma)-丝裂原活化蛋白激酶激酶(MEK)-细胞外信号调节激酶(ERK)、磷脂酰肌醇3-激酶(PI3K)-蛋白激酶B(AKT)和Ral GDS-Ral,与胰腺癌有着复杂的关系。虽然胰腺癌发生的基础研究不断深入,但仍缺乏有效的分子靶向药物。结论 KRAS基因突变在胰腺癌的发生中扮演着重要的角色,与KRAS突变相关的治疗进展,有利于为胰腺癌患者提供更好的预后。     

精准医疗大环境下血游离DNA突变检测对胰腺癌诊治发展的临床意义

精准医疗是以个体化医疗为基础、随着基因组测序技术快速进步以及生物信息与大数据科学的交叉应用而发展起来的新型医学概念与医疗模式,并且日益在恶性肿瘤临床治疗中显示出价值。胰腺癌是致死率最高的恶性实体瘤之一,近些年胰腺外科手术技术日臻成熟,影像、手术器械、能量平台、辅助治疗、靶向药物等相关学科发展,为胰腺癌治疗跨入个体化阶段提供了基础和可能性。循环游离肿瘤DNA(ctDNA)能反映肿瘤的基因特征,该文阐述检测ctDNA突变对胰腺癌诊疗精准化发展的临床意义。     

胰腺癌靶向治疗的研究现状

胰腺癌是一种恶性程度高、致死性强的疾病,5年生存率小于5％.虽然外科手术和药物的治疗有了较大的进步,但其预后不佳,这与药物的耐药性有密切关系.随着胰腺癌分子生物学研究的进展,目前可以根据患者的肿瘤组织活检特点进行胰腺癌靶向的个体化治疗.基于此,一些靶向于肿瘤细胞和肿瘤微环境的信号通路的新药正在进行前期临床试验.本文就胰腺癌的靶向治疗作简要综述.     

分子靶向时代胰腺癌综合诊治的现状与展望

胰腺癌发病率呈上升趋势,以早期诊断困难、手术切除率低及预后差为特点,临床诊治极具挑战性。由于其遗传异质性显著,不同患者之间在疾病进展、临床疗效、放化疗敏感性及预后等方面差异巨大,深入探讨胰腺癌分子生物学特征及其与临床表现、放化疗敏感性的相关性,研发相应的靶向药物,是胰腺癌从传统形态学分型转变到分子分型的重要基础,也是实现从"异病同治"到"同病异治"精准治疗模式转变的前提。在分子靶向时代,胰腺癌的治疗模式转变为综合诊治,有望成为胰腺癌治疗的突破口。     

膜联蛋白A5在胰腺癌中的预后意义及机制的生物信息学分析

背景与目的 胰腺癌是一种诊断较晚、预后差的侵袭性疾病，对于胰腺癌的分子机制研究对改善胰腺癌患者的预后具有重要意义。膜联蛋白A5（ANXA5）与人类肿瘤的发生与发展关系密切，但ANXA5与胰腺癌患者预后的关系及具体机制尚不十分清楚。本研究通过生物信息学分析结合实验验证探讨ANXA5的表达与胰腺癌预后的关系及其作用机制。方法 从TCGA和GEO数据库（GSE15471、GSE16515、GSE21501）下载胰腺癌转录组及临床数据，利用R包分析GEO数据库中ANXA5基因在胰腺癌组织与癌旁正常组织的表达情况，并利用GEPIA在线网站分析TCGA数据库中胰腺癌患者组织与GTEx数据库中正常组织ANXA5基因表达情况。采用Kaplan-Meier的方法分析ANXA5的表达水平对胰腺癌患者总生存时间的影响，然后单因素及多因素Cox分析判断胰腺癌相关危险因素，并利用GSEA分析ANXA5在胰腺癌中可能的信号通路并分析其相关性。最后采用免疫组织化学法检测49例胰腺癌组织和癌旁组织中ANXA5的表达，并分析其与预后及胰腺癌临床病理特征的关系。结果 数据库分析显示，在GSE15471与GSE16515数据集，以及TCGA数据库中ANXA5在胰腺癌组织中的均表达明显升高（均P<0.05）；在GSE21501数据集与TCGA数据库中ANXA5高表达的患者总体生存期明显短于低表达患者（均P<0.05）；TCGA中ANXA5表达是胰腺癌患者预后的独立危险因素（HR=1.819，95% CI=1.058~3.126，P=0.03）；ANXA5基因与胰腺癌TGF-β通路及肿瘤上皮-间质转化（EMT）高度相关。胰腺癌组织样本分析结果显示，ANXA5的表达明显高于癌旁组织（P<0.001），且此基因高表达预示着较差的预后（P=0.008 2）；ANXA5表达是胰腺癌患者预后的独立危险因素（HR=3.06，95% CI=1.046~8.952，P=0.041）；ANXA5的表达与肿瘤临床分期（P=0.000 94）及淋巴结转移（P<0.001）明显相关。结论 ANXA5在胰腺癌中表达升高，其高表达是胰腺癌患者预后的危险因素，其机制可能是通过TGF-β通路及EMT进程促进胰腺癌发展有关。     

胰腺癌肝转移核心基因的筛选与验证

背景与目的 胰腺癌是预后极差的恶性肿瘤,其5年生存率约为11.5%,有将近半数的患者在初诊时已出现远处转移,而肝转移则占到其中的37.0%~41.9%。探索新的胰腺癌肝转移的生物标志物可能有助于提高患者治疗的效果。因此,本研究通过生物信息学方法寻找在胰腺癌肝转移过程起关键作用的基因并验证。方法 下载GEO数据库中的胰腺导管腺癌（PDAC）高通量测序数据集GSE151580（该数据集中包含胰腺癌肝转移病灶组织样本和原发病灶组织样本）,使用R语言“limma”包筛选出肝转移病灶组织样本和原发病灶组织样本间的差异表达基因。对差异表达基因进行GO和KEGG功能富集。利用STRING数据库构建蛋白质间的相关作用关系,使用Cytoscape对蛋白质相互作用网络进行可视化展示并利用CytoHubba插件根据MCC拓扑分析方法,挑选MCC分数最高的前10位基因,确定为候选的核心基因。利用TCGA、GEPIA、UALCAN和HPA数据库的验证对候选的核心基因加以验证。结果 总共纳入分析基因数为46 512个,符合筛选条件的差异表达基因数为491个,其中上调162个,下调329个。挑选MCC分数最高的前10位基因后,通过候选基因经验证显示,APOB基因在肿瘤组织中高表达（P<0.05）,其表达产物主要定位于细胞质和细胞膜,免疫组化中等强度阳性。APOB基因的突变与患者的M分期有关,表现为该基因突变组中,M1患者构成比更大（P=0.022 1）;而该基因的表达与患者的总生存（OS）率和无病生存（DFS）率均无明显关系（均P>0.05）。此外,APOA4基因表达产物也主要定位于细胞质和细胞膜,免疫组化染色呈中等强度阳性。APOA4基因的突变与患者的TNM分期有关,表现为突变组中,TNM分期更早（P=0.018 3）。该基因低表达患者的DFS更高（HR=1.75,P=0.025）,但与患者的OS无关（P>0.05）。结论 APOB基因可能与胰腺癌的肝转移相关,有望作为胰腺癌肝转移早期筛查的分子标志物。APOA4基因与胰腺癌患者的DFS相关,有望成为新的分子标志物用于评价患者预后,监测肿瘤复发,或作为潜在的基因治疗靶点。     

可切除肝细胞癌合并门静脉癌栓的外科治疗

背景与目的 对于肝细胞癌（HCC）合并门静脉癌栓（PVTT）患者而言,手术切除率低,复发率高,预后较差,其治疗方式目前仍有很多争议。笔者总结可切除HCC合并PVTT的外科治疗经验,比较手术与肝动脉化疗栓塞术（TACE）对此类患者的近远期疗效。方法 回顾性分析云南省临沧市人民医院2016年3月—2021年3月收治的39例可切除HCC合并PVTT患者的临床资料,其中23例患者施行手术治疗（手术组）,16例行TACE治疗（TACE组）。比较两组患者的相关临床资料与预后,并分析影响患者预后的因素。结果 手术组除1例肿瘤广泛侵犯仅取材活检,其余均完成手术,无手术死亡;19例示切缘阴性;2例术后肝功能不全,经人工肝及其他支持治疗痊愈出院。TACE组16例肝动脉超选、灌注、栓塞顺利;1例因肝动脉完全栓塞,术后3 d因急性肝衰竭救治无效死亡。手术组8例术后辅助TACE治疗,5例靶向治疗,其中1例I型PVTT患者手术后联合TACE等治疗后仍生存47个月。TACE组13例多次治疗,4例给靶向药物,其中1例II型PVTT患者TACE术后经过7次灌注化疗及栓塞仍然生存25个月。与TACE组比较,手术组住院时间延长、医疗成本增加、术后行TACE的例数更少、术后未做其他治疗的例数以及术后AFP恢复正常的例数更多（均P<0.05）。手术组与TACE组的中位生存期分别为16.2个月与9.5个月;0.5、1、2、3年生存率分别为65.2%、43.5%、34.8%、17.4%与46.7%、33.3.0%、13.3%、0。两组患者中位生存期与累积生存率差异均有统计学意义（均P<0.05）。单因素分析结果显示,PVTT分型、甲胎蛋白（AFP）水平、肿瘤大小、肿瘤数目与患者术后生存时间有关（均P<0.05）;多因素分析结果显示,治疗方式、PVTT分型、肿瘤直径、AFP水平是患者术后生存时间的独立影响因素（均P<0.05）。结论 PVTT分型、肿瘤直径、AFP水平直接影响HCC合并PVTT患者的术后生存,外科手术切除治疗效果明显好于TACE治疗,尤其是对于可切除HCC合并I/II型PVTT的患者,但治疗选择可能受患者意愿、经济因素等的限制。     

胰腺癌精准医疗的实践与挑战

胰腺癌作为世纪顽症,一直受到广泛的关注与研究。近十年来,随着医疗体系的健全及治疗经验的累积,受益于联合化疗及新辅助治疗的研究进展,胰腺癌患者的预后得到了一定程度的改善。但在精准医疗方面,胰腺癌却始终缓步不前,远远滞后于其他肿瘤。因此,结合在胰腺癌精准医疗方面的实际探索经验与体会,综合国内外的最新研究进展,从分子生物学、实验模型等领域,深度认识目前胰腺癌在精准医疗方面的最新进展十分必要。尤其是基于人源肿瘤异种移植模型和类器官模型建立个体化精准治疗平台,将有望切实改善胰腺癌的研究与治疗手段,提高胰腺癌的治疗效果。     

Intratumoral Heterogeneity of Bladder Cancer by Molecular Subtypes and Histologic Variants

Molecular subtyping may inform on prognosis and treatment response in bladder cancer. However, intratumoral molecular heterogeneity is not well studied in this disease and could complicate efforts to use molecular subtyping to guide patient management. To investigate intratumoral heterogeneity in bladder cancer, we examined molecular subtypes in a consecutive, retrospective cystectomy series of histologic variant bladder cancers and conventional urothelial carcinomas co-occurring with them. Molecular subtypes were assigned as per the approach reported by Lund University, an approach that incorporates cell cycle alterations and markers of differentiation, to give the urothelial-like, genomically unstable, basal-squamous, mesenchymal-like, and neuroendocrine-like subtypes. The majority (93%) of tumors were classified as urothelial like, genomically unstable, or basal squamous. Among patients with more than one tumor histology, 39% demonstrated molecular heterogeneity among the different tumor histologies. This was greatest for the basal-squamous subtype, 78% of which co-occurred with either urothelial-like or genomically unstable carcinoma (among cases with multiple histologies). In contrast, there was no co-occurrence of urothelial-like and genomically unstable carcinoma in the same patient. The findings indicate that bladder cancer is often molecularly heterogeneous, particularly in the basal-squamous subtype. This raises the concern for sampling error in laboratory tests that guide therapy based on molecular subtyping.Patient summary: In this report, we investigated molecular diversity among different areas from the same tumor in patients with bladder cancer. We found that different areas from the same tumor are often molecularly different. We conclude that this biological diversity must be taken into account when interpreting clinical molecular tests performed on bladder cancer samples.     

三阴性乳腺癌治疗进展

三阴性乳腺癌(TNBC)是乳腺癌中恶性程度最高的分子亚型,具有侵袭性强,易于早期复发转移,高异质性等特点.目前化疗仍然是TNBC的标准系统治疗方案,但随着组学技术的高速发展,研究者对TNBC分子生物学本质认识不断加深,发现可以将其分为多种亚型,根据各种分型的生物学特征进行分类治疗,同时针对肿瘤细胞自身特征与外部微环境特...     

Assessing the clinical use of clear cell renal cell carcinoma molecular subtypes identified by RNA expression analysis

ObjectivesTo evaluate the clinical use of recently published RNA-based molecular subtyping algorithms. Patients who undergo surgery for clinically localized clear cell renal cell carcinoma can experience very different outcomes, representing a longstanding challenge for the practicing urologist. Two recent publications suggest that molecular subtyping based on the expression of large panels of genes can help clinically localized clear cell renal cell carcinoma prognostication; however, the analyses was not adjusted for routinely collected clinicopathologic indices.Methods and materialsWe obtained level 3 RNA-seq RPKM data and corresponding clinicopathologic features from The Cancer Genome Atlas (TCGA) and assigned patients to the TCGA subtypes as well as to the ccA/ccB subtypes. To determine the prognostic ability of molecular subtyping after adjusting for variables that are collected as routine medical care, we used Cox models and adjusted for the composite Mayo stage, size, grade, and necrosis (SSIGN) score.ResultsBoth the TCGA and the ccA/ccB subtypes are significantly associated with tumor size, category, grade, and presence of necrosis. The association of these subtypes with overall survival is markedly attenuated following adjustment for the composite Mayo SSIGN score.ConclusionsBoth the TCGA and the ccA/ccB subtypes are associated with overall survival after adjusting for the Mayo SSIGN score. However, the effect sizes are similar to what has been reported for single markers, and thus the clinical use and cost-effectiveness of these RNA-based whole-genome signatures are questionable.     

局部进展期胰腺癌新辅助治疗的现状与进展

胰腺癌恶性程度高,其总体5年生存率仅约11%。虽然根治性手术切除可能治愈胰腺癌,但仅约15%胰腺癌在首次确诊时为可切除性疾病。新辅助治疗使得有些原本不可切除的局部进展期胰腺癌（LAPC）获得了R0切除的机会。LAPC新辅助治疗是基于目前治疗现状的一种新的治疗模式,逐渐为临床外科医生接受。新辅助治疗方案的出现,使得20%～61%的LAPC经新辅助治疗后转化为可切除病例。奥沙利铂、伊立替康、氟尿嘧啶和亚叶酸钙（FOLFIRINOX）及吉西他滨联合白蛋白紫杉醇（AG）明显提高了LAPC的手术切除率,是LAPC首选一线新辅助治疗方案。各医疗中心关于LAPC新辅助治疗的方案选择、周期、评估指标、手术时机等方面仍存在较大差异。部分术前全身化疗不足以使肿瘤降期达到手术指征的LAPC患者,可将联合化放疗作为初始治疗。对于不能耐受系统性化疗的LAPC患者,可采用立体定向放射治疗（SBRT）控制局部肿瘤进展。胰腺癌的治疗靶点包括KRAS、EGFR、PARP及NTRK等。NCCN指南建议对所有LAPC患者进行基因检测,指导最佳药物治疗方案及参与新药的临床研究。胰腺癌免疫治疗主要包括免疫检查点抑制剂、过继性T...     

Pancreatic cancer in the remnant pancreas following primary pancreatic resection

Purpose

To clarify the clinical features of cancer in the pancreatic remnant.

Methods

We retrospectively reviewed the clinical and pathological findings of 10 patients who developed remnant pancreatic cancer in our hospital between 2002 and 2012. The KRAS sequences in both the initial pancreatic tumor and remnant pancreatic cancer were examined in two patients.

Results

Eight patients underwent a second pancreatectomy for remnant pancreatic cancer (resected group), while two patients were not operated on and underwent chemotherapy (unresected group). The remnant pancreatic cancer developed at the cut end of the pancreas (pancreaticogastrostomy site) in four patients. In the resected group, four patients died 17 months after the emergence of the remnant pancreatic cancer and four patients survived during the median 40.5-month observation period. The median survival of the unresected group after the emergence of the remnant pancreatic cancer was 10 months. The findings of the KRAS sequencing and immunohistological staining of the remnant pancreatic cancer for MUC1 and MUC2 in the two patients were consistent with those of the initial pancreatic tumor in one patient, and not consistent in the other.

Conclusions

Our results suggest that both local recurrence and a new primary cancer can develop in the pancreatic remnant, and repeated pancreatectomy can prolong survival.     

Impact of KRAS and EGFR Gene Mutations on Recurrence and Survival in Patients with Surgically Resected Lung Adenocarcinomas

Background

Oncogenic gene mutations observed in lung adenocarcinomas, such as epidermal growth factor receptor (EGFR) and KRAS, have some predictive value for chemotherapeutic drugs or EGFR–tyrosine kinase inhibitors. However, the influence of these gene alterations on patients’ prognosis remains controversial.

Methods

We retrospectively analyzed the tumors of 180 patients with completely resected pathological stage I–III lung adenocarcinoma which harbored either KRAS codon 12 mutation or EGFR gene mutations within exons 18–21 to investigate the impact of these gene mutations on the patients’ survival. Gene mutations were detected by established methods.

Results

Of 180 patients, 32 had KRAS codon 12 mutations (KRAS group), 148 had EGFR mutations within exon 18–21 (EGFR group). Pathological stage and operation mode were independent factors for disease-free survival. However, the EGFR group had better overall survival than the KRAS group (P = 0.0271). Cox proportional hazard model revealed pathological stage (P = 0.0001) and presence of EGFR gene mutations (P = 0.0408) were independent factors for overall survival. In survival after tumor recurrence, the EGFR group had a better median survival time (46.7 months) after recurrence than the KRAS group (26.0 months).

Conclusions

In patients with completely resected lung adenocarcinomas, KRAS and EGFR gene mutation status of tumors was not associated with disease-free survival. However, the presence of an EGFR gene mutation boded well for the patient’s overall survival, and thus patients with EGFR mutations have a better prognosis than those with KRAS mutations.

     

胰腺癌精准治疗的研究进展

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