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Validation and utilization of NGS-based HEMEaccuTest panel and analysis software for hematological malignancies. 基于ngs的HEMEaccuTest面板和血液恶性肿瘤分析软件的验证和应用。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.29
Hyun-jeung Choi, Inseon Lee, M. Lee, K. Jung, Keunsook K Lee, YoungJoon Moon, Kwang Joong Kim
29 Background: Hematological malignancies are forms of cancer that originates in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Detection of genetic alteration in hematological malignancies are increasingly important because of diverse variants associated with classification and diagnosis of subtypes, and prognostic and therapeutic-response prediction. Next-generation sequencing (NGS) is a powerful technology to simultaneously analyze multiple genes to identify clinically well-described variants, as well as rare variants related to hematological malignancies for clinical diagnostics. Methods: We developed the targeted NGS panel (HEMEaccuTest) and automatic analysis software (NGeneAnalySys) for estimating pathogenicity of genetic variants related to hematological malignancies. HEMEaccuTest covers entire coding region of 108 genes that have putatively known for associations with the diseases according to the WHO, NCCN and ELN guidelines. The diagnostic utility of HEMEaccuTest and NGeneAnalySys were validated using reference materials and clinical specimens. Results: The results showed that pathogenic variants were effectively detected with an average coverage depth of 600X and a minimum coverage depth of 100X. It demonstrated an excellent limit of detection, with 100% sensitivity for SNVs at 2% VAF and for indel at 4% VAF. In addition, the analytical sensitivity, specificity and precision of the panel were higher compared to conventional methods such as Sanger sequencing, FISH, and real-time PCR. Noticeably, the approximately 300-bp-size insertions of FLT3-ITD was efficiently detected by a simulating algorithm. Conclusions: This analytical validation study demonstrated that HEMEaccuTest and NGeneAnalySys can be an excellent and useful tool for disease definition and therapeutic strategy in hematological malignancies. NGeneAnalySys provides the evidence-based categorization and clinical interpretation supported by Tier classification (Therapeutic, Prognostic, Diagnostic) of professional guidelines (ACMG/AMP, AMP/ASCO/CAP. etc).
29背景:血液系统恶性肿瘤是癌症的一种形式,起源于血液形成组织,如骨髓或免疫系统细胞。由于与亚型的分类和诊断以及预后和治疗反应预测相关的多种变异,检测血液系统恶性肿瘤的基因改变变得越来越重要。下一代测序(NGS)是一种强大的技术,可以同时分析多个基因,以识别临床上描述良好的变异,以及用于临床诊断的与血液系统恶性肿瘤相关的罕见变异。方法:我们开发了靶向NGS面板(HEMEaccuTest)和自动分析软件(NGeneAnalySys),用于评估与血液系统恶性肿瘤相关的遗传变异的致病性。根据世界卫生组织、NCCN和ELN指南,HEMEaccuTest覆盖了108个基因的整个编码区,这些基因被认为和疾病有关。使用参考材料和临床标本验证了HEMEaccuTest和NGeneAnalySys的诊断实用性。结果:平均覆盖深度为600倍,最小覆盖深度为100倍,可有效检测致病性变异株。它证明了一个极好的检测极限,在2%的VAF下对SNVs和4%的VAF对indel的灵敏度分别为100%。此外,与桑格测序、FISH和实时PCR等传统方法相比,该小组的分析灵敏度、特异性和精密度更高。值得注意的是,通过模拟算法有效地检测到了大约300bp大小的FLT3-ITD插入。结论:这项分析验证研究表明,HEMEaccuTest和NGeneAnalySys可以作为血液系统恶性肿瘤疾病定义和治疗策略的一种优秀而有用的工具。NGeneAnalySys提供基于证据的分类和临床解释,并得到专业指南(ACMG/AMP、AMP/ASCO/CAP等)的Tier分类(治疗、预后、诊断)的支持。
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引用次数: 0
Genetic mutations associated with lung cancer metastasis to the brain. 基因突变与癌症脑转移相关。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.41
C. Su, Juan Zhou, X. Chu, Jinrong Zhao
41 Background: Lung cancer is the most common cause of mortality in both men and women, accounting for one-quarter of all cancer deaths. Most lung cancer-associated deaths result from metastasis, especially brain metastasis. Metastasis associated mutations are important biomarkers for metastasis prediction and outcome improvement. The current study aimed to reveal the molecular mechanisms and the genetic alterations involved in metastasis from lung tumors to the brain. Methods: We carried out whole exome sequencing (WES) of the primary tumors and the corresponding brain metastases from 15 patients with metastatic non-small-cell lung carcinoma. Results: We identified novel lung cancer metastases associated genes (CHEK2P2, BAGE2, AHNAK2) and epigenetic factors (miR-4436A, miR-6077). Lung-brain metastasis samples have more similar Ti/Tv(transition/transversion) profile with brain cancer. Focal adhesion, PI3K-Akt signaling pathway, MAPK signaling pathway are some of the most important tumor onset and metastasis pathways. Alternative splicing, Methylation and EGF-like domain are important metabolic abnormal for the lung-metastasis cancers. Conclusions: We conducted a pairwise lung-brain metastasis based WES and identified some novel metastasis related mutations which provided potential biomarkers for prognosis and targeted therapeutics.
41背景:肺癌是男性和女性最常见的死亡原因,占所有癌症死亡的四分之一。大多数肺癌相关死亡是由于转移,尤其是脑转移。转移相关突变是预测转移和改善预后的重要生物标志物。本研究旨在揭示肺肿瘤向脑转移的分子机制和基因改变。方法:对15例转移性非小细胞肺癌患者的原发肿瘤及相应脑转移灶进行全外显子组测序(WES)。结果:我们发现了新的肺癌转移相关基因(CHEK2P2, BAGE2, AHNAK2)和表观遗传因子(miR-4436A, miR-6077)。肺-脑转移样本具有与脑癌更相似的Ti/Tv(转移/翻转)谱。局灶性黏附、PI3K-Akt信号通路、MAPK信号通路是最重要的肿瘤发生和转移途径。选择性剪接、甲基化和egf样结构域是肺转移癌的重要代谢异常。结论:我们进行了一项基于肺脑转移的双侧WES研究,发现了一些新的转移相关突变,为预后和靶向治疗提供了潜在的生物标志物。
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引用次数: 0
Survival data following phase 1/2 studies using precision tumor-targeted gene delivery to advanced chemotherapy-resistant malignancies. 使用精确肿瘤靶向基因递送晚期化疗耐药恶性肿瘤的1/2期研究后的生存数据。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.101
E. Gordon, S. Chawla, F. Hall
101 Background: Targeted gene delivery in vivo has long been considered the “Holy Grail” of gene therapy. Methods: We reviewed long-term data of patients with advanced chemotherapy-resistant malignancies, previously-treated patients with two tumor-targeted retrovectors: (1) encoding cytotoxic dominant negative cyclin G1, DeltaRex-G (formerly Rexin-G), and (2) encoding cytokine GMCSF plus suicide gene HStk, DeltaVax (formerly Reximmune-C). Results: Ninety-nine patients received > 5,000 intravenous infusions of DeltaRex-G; another 16 patients received 288 intravenous infusions of DeltaRex-G + 96 infusions of DeltaVax followed by valacyclovir p.o. No therapy-related bone marrow suppression, organ dysfunction or delayed treatment related adverse events were observed. Survival analysis showed 5.0% 10-year overall survival rate for patients who received DeltaRex-G alone, and 18.8% for DeltaRex-G + DeltaVax. Conclusions: Data analysis indicates that tumor-targeted gene delivery in vivo, represented by cytocidal DeltaRex-G, with or without immuno-stimulatory DeltaVax, has induced prolonged ( > 10 years) sustained remissions in cancer patients presenting with advanced chemotherapy-resistant solid and hematologic malignancies—plausibly due to safety, selectivity, and immune modulation. While the curative potential of precision targeted genetic medicine necessarily remains an academic question; it is clear that these initial long-term, cancer-free ( > 10 year) survivors represent a major milestone in both cancer therapy and immunotherapy. Phase 2-3 clinical trials are planned for these hard-to treat malignancies.
101背景:体内靶向基因递送长期以来一直被认为是基因治疗的“圣杯”。方法:我们回顾了晚期化疗耐药恶性肿瘤患者的长期数据,这些患者以前用两种肿瘤靶向逆转录病毒载体治疗:(1)编码细胞毒性显性阴性细胞周期蛋白G1,DeltaRex-G(以前的Rexin-G),和(2)编码细胞因子GMCSF加自杀基因HSVk,DeltaVax(以前的Rexin-C)。结果:99例患者接受了超过5000次DeltaRex-G静脉输注;另外16名患者接受了288次DeltaRex-G静脉输注+96次DeltaVax静脉输注,随后接受了伐昔洛韦口服。未观察到与治疗相关的骨髓抑制、器官功能障碍或延迟治疗相关的不良事件。生存分析显示,单独接受DeltaRex-G治疗的患者的10年总生存率为5.0%,DeltaRex-G+DeltaVax治疗的患者为18.8%。结论:数据分析表明,以细胞杀伤性DeltaRex-G为代表的体内肿瘤靶向基因递送,无论是否使用免疫刺激性DeltaVax,都诱导了癌症晚期化疗耐药性实体病和血液病患者的长期(>10年)持续缓解,这可能是由于安全性、选择性和免疫调节。虽然精准靶向基因医学的治疗潜力必然仍然是一个学术问题;很明显,这些最初的长期无癌(>10年)幸存者代表了癌症治疗和免疫疗法的一个重要里程碑。计划对这些难以治疗的恶性肿瘤进行2-3期临床试验。
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引用次数: 1
Analysis of serum by Raman spectroscopy finds changes in blood metabolites of cancer patients in 45 seconds. 通过拉曼光谱分析血清发现癌症患者血液代谢物在45秒内发生变化。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.57
Hiroaki Ito, Tomokazu Miyazaki, N. Uragami, N. Yokoyama, H. Inoue
57 Background: Cancer is an important disease that accounts for many of the causes of death worldwide, and early diagnosis is important for improving treatment results. In medical care, blood test is a simple and excellent test method, but there is still no cancer blood diagnosis method with high accuracy that can be performed in general hospitals. We are trying to detect cancer patients by analyzing serum using Raman spectroscopy. Methods: Among the outpatients who underwent upper gastrointestinal endoscopy or colonoscopy, 236 subjects who agreed to participate in the study were included. Raman scattering spectra were measured by irradiating a 1064 nm wavelength laser for 15 seconds with serum collected from the subject before endoscopic examination. The average value measured a total of three times was taken as the measured value, and the three measured values were averaged to obtain the value of each examinee. In the obtained Raman scattering spectra, the scattering spectral intensities of the wavelength originating in the specific molecules were analyzed. Results: We were able to obtain clear Raman scattering spectra of all serum samples. When comparing the Raman scattering spectral intensities of the wavelength originating in specific molecules, a large number of serum measurement values were gathered at the center, and the measurement values of the cancer patients' serum were over low or high. By setting the appropriate cutoff line, cancer patients (gastric cancer or colon cancer) and non-cancerous persons could be relatively clearly distinguished (sensitivity, 100%; Specificity, 75%). Conclusions: Our micro Raman system is able to acquire Raman scattering spectra of serum samples. Furthermore, it has been suggested that cancer diagnosis using serum could be possible by comparing the scattering spectral intensities caused by specific molecules. Clinical trial information: UMIN000034306.
57背景:癌症是一种重要的疾病,在世界范围内造成许多死亡原因,早期诊断对于提高治疗效果至关重要。在医疗保健中,血液检测是一种简单而优秀的检测方法,但目前还没有综合医院可以进行的高准确度的癌症血液诊断方法。我们试图通过使用拉曼光谱分析血清来检测癌症患者。方法:在接受上消化道内窥镜或结肠镜检查的门诊患者中,236名同意参与该研究的受试者被纳入其中。通过在内窥镜检查之前用从受试者收集的血清照射1064nm波长的激光15秒来测量拉曼散射光谱。将总共测量三次的平均值作为测量值,并对三次测量值进行平均以获得每个受试者的值。在获得的拉曼散射光谱中,分析了源自特定分子的波长的散射光谱强度。结果:我们能够获得所有血清样品的清晰拉曼散射光谱。当比较源自特定分子的波长的拉曼散射光谱强度时,大量血清测量值聚集在中心,癌症患者血清的测量值过低或过高。通过设置适当的截止线,可以相对清晰地区分癌症患者(癌症或癌症)和非癌症患者(敏感性,100%;特异性,75%)。结论:我们的微拉曼系统能够获得血清样品的拉曼散射光谱。此外,有人提出,通过比较由特定分子引起的散射光谱强度,可以使用血清进行癌症诊断。临床试验信息:UMIN000034306。
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引用次数: 1
A transcriptomic landscape of cancer and TME in early-stage lungadenocarcinomaby single-cell sequencing. 癌症和TME在早期肺腺癌单细胞测序中的转录组学景观。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.33
Siwei Wang, Yi-qun Zhou, Jue Fan, R. Yin
33 Background: Immuno-checkpoint inhibition therapies has been revolutionizing cancer treatment. Yet only a fraction of patients show durable responses , whereas the majority of treated patients show relatively low clinical response. This difference is likely to be caused by the heterogeneity of both cancer cells and cells involved in the tumor microenvironment (TME). However, the extent of this heterogeneity, how it is shaped by other factors in the tumor and vice versa, remains poorly understood. Methods: To explore the heterogeneity of lung adenocarcinoma, we obtained tumor tissuesand peripheral blood froma cohort of 30 treatment-naive patients. For each sample, single-cell RNA sequencingand whole exome sequencing(WES) wereperformed. A graph-based unsupervised clusteringmethod was usedand cell types were assignedto clusters based on marker gene expression. The sub-types of both cancer cells and TME cells along with their gene expression patterns were comparedbetween different cancer stages and mutation status. Results: we presented a landscape of cancer and TME transcriptome in human lung adenocarcinoma at single-cell resolution. We found the expression of cancer cells exhibits distinct characteristics with different TNM stages. For instance, the tumor cells of a patient classified as T1aN2M0 highly express genes enriched in the cell migration pathway. By comparing TME cells among patients with different mutation status, we identified changes in various T cell subtypes and tumor-infiltrating myeloid cells. Conclusions: This study provided a detailed cell atlas of lung adenocarcinoma and identified gene expression patterns that are unique to specific TNM stages. Moreover, single-cell analyses offer valuable knowledgeof immune changes for each patient subgroup, providing ausefultool for the rational design of immunetherapies.
33背景:免疫检查点抑制疗法已经彻底改变了癌症的治疗。然而,只有一小部分患者表现出持久的反应,而大多数接受治疗的患者表现出相对较低的临床反应。这种差异可能是由癌症细胞和参与肿瘤微环境(TME)的细胞的异质性引起的。然而,这种异质性的程度,以及它是如何由肿瘤中的其他因素形成的,反之亦然,仍然知之甚少。方法:为了探讨肺腺癌的异质性,我们从30名未接受治疗的患者中获得了肿瘤组织和外周血。对每个样本进行单细胞RNA测序和全外显子组测序(WES)。使用基于图的无监督聚类方法,并根据标记基因表达将细胞类型分配给聚类。比较了癌症细胞和TME细胞的亚型及其在不同癌症分期和突变状态下的基因表达模式。结果:我们以单细胞分辨率展示了人类肺腺癌中癌症和TME转录组的概况。我们发现癌症细胞的表达表现出不同TNM分期的不同特征。例如,被分类为T1aN2M0的患者的肿瘤细胞高度表达在细胞迁移途径中富集的基因。通过比较不同突变状态患者的TME细胞,我们确定了各种T细胞亚型和肿瘤浸润性骨髓细胞的变化。结论:本研究提供了肺腺癌的详细细胞图谱,并确定了特定TNM阶段特有的基因表达模式。此外,单细胞分析为每个患者亚组的免疫变化提供了有价值的知识,为合理设计免疫疗法提供了参考。
{"title":"A transcriptomic landscape of cancer and TME in early-stage lungadenocarcinomaby single-cell sequencing.","authors":"Siwei Wang, Yi-qun Zhou, Jue Fan, R. Yin","doi":"10.1200/jgo.2019.5.suppl.33","DOIUrl":"https://doi.org/10.1200/jgo.2019.5.suppl.33","url":null,"abstract":"33 Background: Immuno-checkpoint inhibition therapies has been revolutionizing cancer treatment. Yet only a fraction of patients show durable responses , whereas the majority of treated patients show relatively low clinical response. This difference is likely to be caused by the heterogeneity of both cancer cells and cells involved in the tumor microenvironment (TME). However, the extent of this heterogeneity, how it is shaped by other factors in the tumor and vice versa, remains poorly understood. Methods: To explore the heterogeneity of lung adenocarcinoma, we obtained tumor tissuesand peripheral blood froma cohort of 30 treatment-naive patients. For each sample, single-cell RNA sequencingand whole exome sequencing(WES) wereperformed. A graph-based unsupervised clusteringmethod was usedand cell types were assignedto clusters based on marker gene expression. The sub-types of both cancer cells and TME cells along with their gene expression patterns were comparedbetween different cancer stages and mutation status. Results: we presented a landscape of cancer and TME transcriptome in human lung adenocarcinoma at single-cell resolution. We found the expression of cancer cells exhibits distinct characteristics with different TNM stages. For instance, the tumor cells of a patient classified as T1aN2M0 highly express genes enriched in the cell migration pathway. By comparing TME cells among patients with different mutation status, we identified changes in various T cell subtypes and tumor-infiltrating myeloid cells. Conclusions: This study provided a detailed cell atlas of lung adenocarcinoma and identified gene expression patterns that are unique to specific TNM stages. Moreover, single-cell analyses offer valuable knowledgeof immune changes for each patient subgroup, providing ausefultool for the rational design of immunetherapies.","PeriodicalId":15862,"journal":{"name":"Journal of global oncology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41534235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Building a survivorship care plan delivery process: Experience in an academic center. 建立幸存者护理计划交付流程:在学术中心的经验。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.69
Z. Dayao, B. Tawfik, J. Abernathy, C. Wiggins, A. Gundelach, R. Lauer
69 Background: The Institute of Medicine endorses delivery of survivorship care plans (SCPs) to the growing number of cancer survivors in order to improve the coordination of care between oncologists and primary care providers (PCPs). In response, the Commission on Cancer (COC) has increased the SCP delivery requirement to >50% of eligible patients, a goal that is difficult to meet given limited resources. Here we outline the initiatives taken to achieve this goal at the University of New Mexico Comprehensive Cancer Center (UNMCCC). Methods: Prior to 2017, SCPs were not routinely delivered. Beginning 2017, providers were tasked to complete and deliver printed SCPs , resulting in a 17% rate of SCP completion. However, there was general lack of provider support and enthusiasm as the process was time consuming with no method for identifying eligible patients and tracking SCP delivery. In 2018, designated staff was assigned to partially complete the SCPs to assist providers, resulting in an increase in SCP delivery rate to 41%. However, the same barriers existed. SCP softwares, although available, were expensive. A cost effective process therefore was needed. A committee was then formed to create a system-wide process utilizing the existing electronic health record (EHR) MOSAIQ. ASCO based SCPs were created. Once providers identify eligible patients, an SCP electronic order was initiated. Designated staff then partially completes the SCPs based on review of medical records. The EHR extracts data items including demographics, PCP information, cancer type and stage. The EHR is programmed to flag SCPs ready for delivery which the provider then edits and approves. This system tracks multiple time points including referral, completion and delivery of SCPs. This new process was implemented in April 2019. Quarterly reviews are set to assess metrics. Results: Utilizing existing EHR (MOSAIQ), a new SCP delivery process was created that allows tracking of assembly, completion and timing of delivery. Conclusions: To overcome existing barriers to SCP completion and delivery, a new cost effective process was created utilizing existing staff and EHR resources. Institutional support is key to the success of this initiative.
69背景:医学研究所批准向越来越多的癌症幸存者提供生存护理计划(SCPs),以改善肿瘤学家和初级护理提供者(PCPs)之间的护理协调。作为回应,癌症委员会(COC)已将SCP交付要求提高到合格患者的50%以上,鉴于资源有限,这一目标很难实现。在这里,我们概述了新墨西哥大学癌症综合中心为实现这一目标而采取的举措。方法:在2017年之前,SCPs不是常规递送的。从2017年开始,供应商的任务是完成并交付打印的SCP,SCP完成率为17%。然而,普遍缺乏提供者的支持和热情,因为这一过程耗时,没有确定合格患者和跟踪SCP交付的方法。2018年,指定工作人员被指派部分完成SCP,以协助供应商,从而使SCP交付率提高到41%。然而,同样的障碍也存在。SCP软件虽然可用,但价格昂贵。因此,需要一个具有成本效益的过程。随后成立了一个委员会,利用现有的电子健康记录MOSAIQ创建一个全系统流程。创建了基于ASCO的SCP。一旦提供者确定了符合条件的患者,就会启动SCP电子订单。然后,指定工作人员根据对医疗记录的审查,部分完成SCP。EHR提取数据项,包括人口统计、PCP信息、癌症类型和分期。EHR被编程为标记准备交付的SCP,然后由提供商编辑和批准。该系统跟踪多个时间点,包括SCP的转诊、完成和交付。这一新流程于2019年4月实施。季度审查旨在评估指标。结果:利用现有的EHR(MOSAIQ),创建了一个新的SCP交付流程,可以跟踪组装、完成和交付时间。结论:为了克服SCP完成和交付的现有障碍,利用现有员工和EHR资源创建了一个新的成本效益流程。体制支持是这一举措取得成功的关键。
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引用次数: 0
PD-1 blockade in neoadjuvant setting of DNA mismatch repair-deficient/microsatellite instability-high colorectal cancer. PD-1阻断在DNA错配修复缺陷/微卫星不稳定性高结直肠癌癌症新辅助治疗中的应用。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.84
Dingxin Liu, D. Li, Wu Jiang, Z. Pan, Xiaoshi Zhang, P. Ding
84 Background: Although PD-1 blockade has significantly improved the survival of metastatic colorectal cancer with DNA Mismatch Repair-Deficient/Microsatellite Instability-High (MSI-H), the data on neoadjuvant setting is limited. Methods: In this retrospective study, we enrolled eight patients with advanced MSI-H colorectal cancer from three hospitals. four patients are locally advanced and four are metastatic. All the patients received at least two doses of PD-1 antibody with or without chemotherapy as neoadjuvant therapy. The aim of the present study was to evaluate the short‐term efficacy and toxicities of this strategy. Results: Neoadjuvant PD-1 Blockade is well tolerated with a few immune-related side-effect profiles. All the enrolled patients had a major response in imaging and/or pathological evaluation. Five of the seven resected patients were evaluated as pathological complete response. One patient without surgery has a cCR tumor response. For the patients with radical surgery, there is no surgery-related complication observed. Conclusions: Neoadjuvant PD-1 blockade induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H colorectal cancer. Further studies are required to evaluate the long-term effect of this strategy.
84背景:尽管PD-1阻断显著提高了具有DNA错配修复缺陷/微卫星不稳定性高(MSI-H)的转移性癌症的存活率,但关于新佐剂设置的数据有限。方法:在这项回顾性研究中,我们招募了来自三家医院的8名晚期MSI-H结直肠癌患者。4例为局部晚期,4例为转移性。所有患者都接受了至少两剂PD-1抗体,无论是否进行化疗作为新辅助治疗。本研究的目的是评估该策略的短期疗效和毒性。结果:新佐剂PD-1阻断剂耐受性良好,有一些与免疫相关的副作用。所有入选的患者在影像学和/或病理学评估中都有主要反应。7例切除的患者中有5例被评估为病理完全反应。一名未经手术的患者出现cCR肿瘤反应。对于根治性手术的患者,没有观察到与手术相关的并发症。结论:新辅助PD-1阻断剂诱导晚期dMMR/MSI-H结直肠癌癌症的肿瘤消退,具有主要的临床和病理反应。需要进一步的研究来评估这一战略的长期效果。
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引用次数: 13
A signature predictive of early versus late recurrence after radiation (RT) for breast cancer that may inform the biology of early, aggressive recurrences. 癌症放疗后早期和晚期复发的标志性预测,可能为早期、侵袭性复发的生物学提供信息。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.112
C. Speers, S. L. Chang, B. Chandler, A. Pesch, A. Michmerhuizen, K. Wilder-Romans, S. Nyati, L. Pierce
112 Background: Unmet clinical needs in breast cancer (BC) management include the identification of patients at high risk to fail locally despite standard local therapy and an understanding of the biology of these recurrences. We previously reported a radiation response signature and here extend those studies to identify a signature predictive of timing of recurrence after RT. Methods: 2 independent patient cohorts were used for training (119 pts) and validation (112 pts). All patients received RT after BCS and systemic therapy as appropriate. Spearman’s rank correlation to correlate gene expression to recurrence time was used for feature selection. Significant genes were used to train a linear model which was locked before validation. Cox regression was used for both UVA and MVA. Results: Spearman’s correlation identified 485 genes whose expression was significantly associated with recurrence time (+/-3 yrs). Feature reduction refined the list to 41 genes retained within the signature. In training, the correlation of score to recurrence time was 0.85, p-value < 1.3x10-31; AUC of 0.91. External validation in an independent BC validation set accurately identified patients with early vs. late recurrences (correlation= 0.75, p-value = 0.001, AUC = 0.92, sens.=0.75, spec.= 1.0, PPV = 1.0, NPV = 0.8). Unique associations of breast cancer intrinsic subtype to timing of local recurrence were found. In UVA and MVA the signature remained the most significant factor associated with recurrence. GSEA analysis of the 41 genes retained within the signature identified proliferation and EGFR concepts associated with early recurrences and luminal and ER-signaling pathways associated with late recurrences. Knockdown of genes associated with the early and late recurrences demonstrated novel effects on proliferation and clonogenic survival, respectively. Conclusions: We report a BC gene expression signatures that may be useful in identifying patients unlikely to respond to adjuvant RT and may be used to predict timing of recurrences, with implications for potential treatment intensification and duration of follow-up for women with breast cancer treated with RT.
112背景:癌症(BC)管理中未满足的临床需求包括识别尽管进行了标准的局部治疗但局部失败的高风险患者,以及了解这些复发的生物学。我们之前报道了辐射反应特征,并在这里扩展了这些研究,以确定预测RT后复发时间的特征。方法:使用2个独立的患者队列进行训练(119例)和验证(112例)。所有患者均在BCS后接受RT,并酌情进行全身治疗。特征选择采用Spearman秩相关法将基因表达与复发时间相关联。使用重要基因来训练线性模型,该模型在验证前被锁定。UVA和MVA均采用Cox回归。结果:Spearman相关性分析发现485个基因的表达与复发时间(+/-3年)显著相关。特征缩减将列表细化为保留在签名中的41个基因。在训练中,得分与复发时间的相关性为0.85,p值<1.3x10-31;AUC为0.91。独立BC验证集中的外部验证准确识别了早期和晚期复发的患者(相关性=0.75,p值=0.001,AUC=0.92,灵敏度=0.75,规范=1.0,PPV=1.0,NPV=0.8)。发现癌症内在亚型与局部复发时间的独特关联。在UVA和MVA中,特征仍然是与复发相关的最重要因素。对保留在特征中的41个基因的GSEA分析确定了与早期复发相关的增殖和EGFR概念,以及与晚期复发相关的管腔和ER信号通路。早期和晚期复发相关基因的敲除分别显示出对增殖和克隆生存的新影响。结论:我们报告了一个BC基因表达特征,该特征可能有助于识别不太可能对辅助RT有反应的患者,并可用于预测复发的时间,对接受RT治疗的癌症乳腺癌患者的潜在治疗强化和随访时间有影响。
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引用次数: 0
Generation of personalized tumor Biopsy-Derived Natural Killer (BDNK) cells. 生成个性化肿瘤活检衍生的自然杀伤(BDNK)细胞。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.86
Hui Min Vivian Teo, Siu Wei. Goh, Intan Permata Sari, W. Chew, H. Lim, R. Dasgupta, Ankur Sharma
86 Background: Natural killer (NK) cells play promising roles in cancer surveillance and possess multiple unique characteristics for allogenic cell transfer (ACT) in the cancer immunotherapy. However, most studies were applicable to ex vivo expanded NK cells from the peripheral blood, which requires massive amount of cell numbers for the initial isolation and expansion. Moreover, recent studies have demonstrated a phenotypic heterogeneity between peripheral and tissue resident NK cells. Methods: In this study, we aim to establish the ex vivo expansion of tumor infiltrating NK cells directly from diagnostic breast core biopsies followed by functional validation through in vitro assays. Results: A total of 20 breast TILs models, including T and NK cells, were successfully established through genetically modified K562 feeder cells co-culture approach. These models represented all the major sub-types (hormone positive and negative) of breast cancers. Next, we extensively evaluated the tumor-reactivity of the selected NK models via effector:target cytotoxicity assays. Interestingly, non-invasive breast tumor line has exhibited a strong preferential kill by NK cells whereas the invasive line counterpart was able to escape NK cell-mediated cytotoxicity. Conclusions: The resource generated in this study has revealed tumor infiltrating NK cells as a potential tool for cell-based therapy in solid tumors. Furthermore, this study provides a platform to investigate the immune-resistance mechanism involved between tumor and NK cells, thus, paving the way to the discovery of novel cancer immunotherapy targets.
背景:自然杀伤细胞(NK)在肿瘤监测中发挥着重要作用,在肿瘤免疫治疗中具有多种独特的异体细胞转移(ACT)特性。然而,大多数研究适用于体外扩增的外周血NK细胞,这需要大量的细胞数进行初始分离和扩增。此外,最近的研究表明外周NK细胞和组织NK细胞之间存在表型异质性。方法:在本研究中,我们旨在通过诊断性乳腺核心活检直接建立肿瘤浸润NK细胞的体外扩增,然后通过体外实验进行功能验证。结果:通过转基因K562饲养细胞共培养方法,成功建立了包括T细胞和NK细胞在内的20只乳腺TILs模型。这些模型代表了乳腺癌的所有主要亚型(激素阳性和阴性)。接下来,我们通过效应靶细胞毒性试验广泛评估了选定NK模型的肿瘤反应性。有趣的是,非侵袭性乳腺肿瘤细胞系表现出NK细胞强烈的优先杀伤,而侵袭性乳腺肿瘤细胞系则能够逃避NK细胞介导的细胞毒性。结论:本研究中产生的资源揭示了肿瘤浸润NK细胞作为实体瘤细胞基础治疗的潜在工具。此外,本研究为研究肿瘤与NK细胞之间的免疫抵抗机制提供了一个平台,从而为发现新的癌症免疫治疗靶点铺平了道路。
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引用次数: 0
Clinical factors associated with comprehensive genomic variation profiling of cervical cancer. 与宫颈癌综合基因组变异谱相关的临床因素。
Pub Date : 2019-10-07 DOI: 10.1200/jgo.2019.5.suppl.62
Qin Xu, Yi-Bin Lin, Xian Lin, Jing Liu, Li Li, Peng Zheng, Bin Liu, H. Shi
62 Background: To better understand the mechanism contributing to cervical carcinogenesis, we perform a comprehensive analysis of genomic alterations in cervical cancer (CC). Methods: We conducted whole-exome sequencing of 43 CCs and established strict integrated workflow of genomic analysis. Correlation analysis was performed to measure the relationships between gene mutations and clinical characteristics of CC patients. Results: Genomic analysis revealed 28 genes frequently mutated in CC including BRD4 (4/43), AXL (4/43), MED12 (4/43), which are undetermined genomic features in CC, and identified recurrent genetic mutations in PIK3CA (16/43), KMT2D (11/43), KMT2C (6/43), FBXW7 (5/43), FAT1 (5/43), ERBB2 (4/43), EP300 (3/43) and NFE2L2 (3/43). Intriguingly, CC patients harbored high frequent mutations in BRCA2 (7/43), but not in BRCA1. The relationship between BRCA2 mutations and clinical factors is yet to be determined. The identified mutations predominately resulted in the dysregulation of the PI3K/AKT/mTOR pathway. Interestingly, we found that AXL mutations were positively correlated with FIGO stage ( P = 0.028), regional lymph node metastasis ( P = 0.011) and distant metastasis ( P = 0.022). KMT2C mutations were positively correlated with FIGO stage ( P = 0.004) and distant metastasis ( P = 0.009). SF3B1 mutations were positively correlated with regional lymph node metastasis ( P = 0.027) and distant metastasis ( P< 0.001). NFE2L2, ERBB2, RAC1, MED12, MET, BAP1, PTPRD and HNF1Amutations were positively correlated with distant metastasis ( P = 0.045, P = 0.004, P = 0.022, P = 0.001, P< 0.001, P< 0.001, P = 0.014, P< 0.001, respectively). POLD1 mutations were positively associated with regional lymph node metastasis ( P = 0.029). However, NOTCH1 mutations were negatively associated with regional lymph node metastasis ( P = 0.047). STK11 mutations were negatively associated with FIGO stage ( P = 0.013). Conclusions: Our results highlight the application of deep sequencing for understanding the molecular mechanisms and uncovering potential diagnostic and therapeutic targets of CC.
62背景:为了更好地了解导致宫颈癌发生的机制,我们对宫颈癌症(CC)的基因组改变进行了全面分析。方法:我们对43个CC进行了全外显子组测序,并建立了严格的基因组分析集成工作流程。进行相关分析以测量CC患者的基因突变与临床特征之间的关系。结果:基因组分析揭示了28个CC中频繁突变的基因,包括BRD4(4/43)、AXL(4/43。有趣的是,CC患者在BRCA2(7/43)中有高频率突变,但在BRCA1中没有。BRCA2突变与临床因素之间的关系尚待确定。已鉴定的突变主要导致PI3K/AKT/mTOR通路的失调。有趣的是,我们发现AXL突变与FIGO分期呈正相关(P=0.028),KMT2C突变与FIGO分期(P=0.004)和远处转移(P=0.009)呈正相关。SF3B1突变与区域淋巴结转移(P=0.027)和远处淋巴结转移呈正相关(P<0.001)。NFE2L2、ERBB2、RAC1、MED12、MET、BAP1、,PTPRD和HNF1Amutation与远处转移呈正相关(分别为P=0.045、P=0.004、P=0.022、P=0.001、P<0.001、P<0.001,P=0.014、P<0.001)。POLD1突变与局部淋巴结转移呈正相关(P=0.029),NOTCH1突变与区域淋巴结转移负相关(P=0.047)。STK11突变与FIGO分期负相关(P=0.013)。结论:我们的研究结果强调了深度测序在理解CC的分子机制和揭示潜在诊断和治疗靶点方面的应用。
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引用次数: 0
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Journal of global oncology
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