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Abstract 2603: What's more in serrated lesions: interobserver agreement and molecular features 摘要2603:在锯齿状病变中更重要的是:观察者之间的一致和分子特征
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-2603
F. Ambrosi, C. Ricci, Federico Chiarucci, Stefano Chilotti, Doriana Donatella Di Nanni, A. G. Corradini, Maria Antonietta Cumiento, D. Biase, M. Fiorentino
Introduction: Serrated lesions are a heterogeneous group of lesions routinely evaluated with different morphologic subtypes, and colorectal carcinogenesis has been related to the understanding of the serrated pathway in these lesions. In this setting, BRAF V600E mutation has been demonstrated as a marker for the serrated carcinogenic evolution, while the mismatch repair protein (MMR) was recognized in a small subset of hyperplastic polyps. Design: This study aimed to evaluate the interobserver agreement among 6 pathologists in the morphological diagnosis of the serrated lesion according to WHO Classification; furthermore, the additional MMR (MLH1, PMS2, MSH2, MSH6) and BRAF V600E (VE1) mutation status were studied by immunohistochemistry and NGS analysis. Results: We evaluated 52 serrated lesions of the colon retrieved from our pathology archives in 2019. The cohort included 48 patients: 21 males and 27 females, with a mean age of 67 years (range 50-89), of which 77.1% were identified according to regional screening protocol. All hematoxylin and eosin slides were independently reviewed by each pathologist, who classified all samples according to the WHO Classification of Digestive System Tumor (Fleiss Kappa: 0.75). The immunohistochemical expression of MMR and BRAF was evaluated in 42 samples. Loss of MLH1 and PMS2 was recorded in one serrated sessile lesion (LSS) with dysplasia, but NGS analysis resulted negative. In contrast, BRAF V600E IHC resulted positive in 22 samples (52.4%), specifically in 5 hyperplastic polyps (71.4%), 10 LSS (66.6%), 5 LSS with dysplasia (45.5%) and 2 adenomatous polyps (100%), 1 TSA negative. All BRAF V600E IHC positive cases were confirmed by NGS analysis. Conclusion: To conclude, the interobserver agreement for morphological classification of serrated lesions resulted substantial; however, behind the morphological appearance, BRAF V600E resulted in predominant mutation in LSS and hyperplastic polyps, these observations confirmed the possibility to improve the classification with IHC BRAF V600E; especially for hyperplastic polyps, it may be crucial to identify precancerous lesions and different clinical management. Citation Format: Francesca Ambrosi, Costantino Ricci, Federico Chiarucci, Stefano Chilotti, Doriana Donatella Di Nanni, Angelo Gianluca Corradini, Maria Antonietta Cumiento, Dario De Biase, Michelangelo Fiorentino. What9s more in serrated lesions: interobserver agreement and molecular features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2603.
导读:锯齿状病变是一组异质性病变,通常以不同的形态亚型进行评估,结直肠癌的发生与对这些病变中锯齿状通路的理解有关。在这种情况下,BRAF V600E突变已被证明是锯齿状致癌进化的标志,而错配修复蛋白(MMR)在一小部分增殖性息肉中被识别出来。设计:本研究旨在评估6名病理学家根据WHO分类对锯齿状病变进行形态学诊断时的观察者间一致性;此外,通过免疫组织化学和NGS分析研究了其他MMR (MLH1、PMS2、MSH2、MSH6)和BRAF V600E (VE1)突变状态。结果:我们评估了2019年从病理档案中检索到的52例结肠锯齿状病变。该队列包括48例患者:男性21例,女性27例,平均年龄67岁(50-89岁),其中77.1%根据区域筛查方案确定。所有苏木精和伊红切片由每位病理学家独立审查,他们根据who消化系统肿瘤分类(Fleiss Kappa: 0.75)对所有样本进行分类。在42个样本中评估MMR和BRAF的免疫组织化学表达。MLH1和PMS2的缺失记录在一例发育不良的锯齿状无柄病变(LSS)中,但NGS分析结果为阴性。相比之下,BRAF V600E IHC阳性22例(52.4%),其中增生性息肉5例(71.4%),LSS 10例(66.6%),LSS伴不典型增生5例(45.5%),腺瘤性息肉2例(100%),TSA阴性1例。所有BRAF V600E IHC阳性病例均经NGS分析确诊。结论:总之,观察者之间对锯齿状病变形态学分类的一致意见是实质性的;然而,在形态表象的背后,BRAF V600E导致了LSS和增生性息肉的显性突变,这些观察结果证实了用IHC BRAF V600E改进分类的可能性;特别是对于增生性息肉,鉴别癌前病变和不同的临床处理可能是至关重要的。引文格式:Francesca Ambrosi, Costantino Ricci, Federico Chiarucci, Stefano Chilotti, Doriana Donatella Di Nanni, Angelo Gianluca Corradini, Maria Antonietta Cumiento, Dario De Biase, Michelangelo Fiorentino。锯齿状病变更重要的是:观察者之间的一致和分子特征[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2603。
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引用次数: 0
Abstract LB013: Clinical validation of a targeted methylation-based multi-cancer early detection test LB013:靶向甲基化多癌早期检测试验的临床验证
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-LB013
E. Klein, D. Richards, A. Cohn, M. Tummala, R. Lapham, D. Cosgrove, G. Chung, J. Clement, Jingjing Gao, N. Hunkapiller, A. Jamshidi, K. Kurtzman, M. Seiden, C. Swanton, Minetta C. Liu
Introduction: A multi-cancer early detection (MCED) test as a complement to existing screening tests could increase the number of cancer cases detected in a population, potentially improving patient outcomes and survival as well as decreasing harmful and aggressive treatments. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was designed to develop and validate a blood-based MCED test analyzing plasma cell-free DNA (cfDNA) to detect cancer signals across multiple cancer types and simultaneously predict their signal origin. Here, the results of the third and final pre-specified CCGA validation sub-study for a refined MCED test in a large cohort in preparation for clinical use are reported. Methods: CCGA is a prospective, multicenter, case-control, observational study with longitudinal follow-up (overall population N=15,254). In this sub-study (n=5309), key primary objectives were to evaluate test performance for cancer signal detection (specificity, overall sensitivity, sensitivity by clinical stage) and signal origin prediction (accuracy). cfDNA from evaluable samples was analyzed using a targeted methylation bisulfite sequencing assay and a machine learning algorithm. The classifier was trained to target a specificity of 99.4% and locked before analysis of the independent validation set. Overall, 4077 participants comprised the independent validation set with confirmed status (cancer: n=2823; non-cancer: n=1254 with non-cancer status confirmed at year-one follow-up). MCED test results are reported for this confirmed status set. Results: Mean (SD) age in the cancer and non-cancer groups was 62.6 (11.76) and 56.2 (12.63) years, respectively. Specificity for cancer signal detection was 99.5% (1248/1254; 95% confidence interval: 99.0-99.8%). Overall sensitivity for cancer signal detection was 51.5% (1453/2823; 49.6-53.3%); sensitivity increased with stage (Stage I: 16.8% [14.5-19.5%], Stage II: 40.4% [36.8-44.1%], Stage III: 77.0% [73.4-80.3%], Stage IV: 90.1% [87.5-92.2%]). Stage I-III sensitivity was 67.6% (593/877; 64.4-70.6%) in a pre-specified set of 12 high-signal cancers accounting for ~63% of annual US cancer deaths [1] and was 40.7% (863/2118; 38.7-42.9%) in all cancers. Cancer signals were detected across >50 cancer types [2]. Overall accuracy of signal origin prediction in true positives was 88.7% (87.0-90.2%). Conclusions: In this pre-specified, large-scale, clinical validation sub-study of CCGA, the MCED test detected cancer signals across >50 cancer types, which is critical to maximize the number of cancer cases detected in a population. This MCED test performed with high specificity and high accuracy of signal origin prediction. These data lay the foundation for population-scale clinical implementation of this test. 1.US Mortality Data 1969-2016 (www.seer.cancer.gov); based on 2015-2016. 2.Amin et al. CA Cancer J Clin. 2017;67:93e99. Citation Format: Eric A. Klein, Donald Richards, Allen Cohn, Mohan Tummala, Rosanna La
多种癌症早期检测(MCED)测试作为现有筛查测试的补充,可以增加人群中检测到的癌症病例数量,潜在地改善患者的预后和生存率,并减少有害和积极的治疗。循环无细胞基因组图谱研究(CCGA);NCT02889978)旨在开发和验证基于血液的MCED测试,分析血浆游离DNA (cfDNA),以检测多种癌症类型的癌症信号并同时预测其信号来源。本文报告了第三个也是最后一个预先指定的CCGA验证子研究的结果,该子研究是在一个大型队列中为临床应用做准备的一项改进的MCED试验。方法:CCGA是一项前瞻性、多中心、病例对照、观察性的纵向随访研究(总人群N=15,254)。在这个子研究中(n=5309),主要目的是评估癌症信号检测的测试性能(特异性、总体敏感性、临床分期敏感性)和信号起源预测(准确性)。使用靶向甲基化亚硫酸酯测序法和机器学习算法分析可评估样品中的cfDNA。经过训练,分类器的特异性为99.4%,并在独立验证集分析之前锁定。总体而言,4077名参与者组成了确认状态的独立验证集(癌症:n=2823;非癌症:n=1254,在一年随访中确认非癌症状态)。MCED测试结果将报告此确认状态集。结果:肿瘤组和非肿瘤组的平均(SD)年龄分别为62.6(11.76)岁和56.2(12.63)岁。肿瘤信号检测特异性为99.5% (1248/1254;95%置信区间:99.0-99.8%)。肿瘤信号检测的总灵敏度为51.5% (1453/2823;49.6 - -53.3%);敏感性随分期升高(ⅰ期:16.8%[14.5-19.5%],ⅱ期:40.4%[36.8-44.1%],ⅲ期:77.0%[73.4-80.3%],ⅳ期:90.1%[87.5-92.2%])。I-III期敏感性为67.6% (593/877;64.4-70.6%),在一组预先指定的12种高信号癌症中占美国每年癌症死亡人数的约63%[1],为40.7% (863/2118;38.7-42.9%)。在超过50种癌症类型中检测到癌症信号[2]。真阳性患者信号源预测的总体准确率为88.7%(87.0-90.2%)。结论:在这个预先指定的、大规模的、临床验证的CCGA子研究中,MCED检测检测了超过50种癌症类型的癌症信号,这对于最大限度地提高人群中癌症病例的检测数量至关重要。该MCED测试具有高特异性和高准确度的信号起源预测。这些数据为该测试在人群规模的临床实施奠定了基础。1.1969-2016年美国死亡率数据(www.seer.cancer.gov);基于2015-2016年。2.阿明等人。中华肿瘤杂志,2017;37(3):391 - 391。引文格式:Eric A. Klein, Donald Richards, Allen Cohn, Mohan Tummala, Rosanna Lapham, David Cosgrove, Gina Chung, Jessica Clement, jing Gao, Nathan Hunkapiller, Arash Jamshidi, Kathryn Kurtzman, Michael V. Seiden, Charles Swanton, Minetta C. Liu靶向甲基化多癌早期检测试验的临床验证[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要nr LB013。
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引用次数: 0
Abstract 2579: Links between obesity and secreted frizzled-related protein 4 (Sfrp4) in a murine model of colon cancer 摘要:在小鼠结肠癌模型中,肥胖与分泌卷曲相关蛋白4 (frp4)之间的联系
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-2579
Elaine M Glenny, Laura W. Bowers, Diana Li, J. Roper, S. Hursting
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引用次数: 0
Abstract 110: Planned versus observed effect sizes in early phase chemoprevention trials 110:早期化学预防试验的计划效应量与观察效应量
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-110
J. Eickhoff, Jen Birstler, Guanhua Chen, Zhumin Zhang, V. Sahasrabuddhe, E. Szabo, KyungMann Kim
{"title":"Abstract 110: Planned versus observed effect sizes in early phase chemoprevention trials","authors":"J. Eickhoff, Jen Birstler, Guanhua Chen, Zhumin Zhang, V. Sahasrabuddhe, E. Szabo, KyungMann Kim","doi":"10.1158/1538-7445.AM2021-110","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-110","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79448392","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
Abstract 2568: Use of kinase inhibitors in Fanconi anemia oral cancercell lines 2568:激酶抑制剂在范可尼贫血口腔癌细胞系中的应用
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-2568
W. N. Jungbauer, Mustafa M. Ali, B. Wuertz, F. Ondrey
Successful Fanconi anemia (FA) treatment allows greater longevity for these patients. However, there is a greatly increased risk of squamous malignancies of the head and neck which are quite deadly in these young patients. There is an unmet need for non DNA damaging therapies for this malignancy which could augment surgery. Our approach has been to examine potential treatments based on known pathophysiology of the disease which would be acceptable for this population so we examined the effects of metformin and pioglitazone, as well as two cell cycle kinase inhibitors, in FA and leukoplakia cell lines. We examined dose-dependent and combination effects on cell proliferation, as judged by MTT assay. We examined metformin, pioglitazone, the polo-like kinase 1 inhibitor, GSK461364, and Wee1 kinase inhibitor, AZD1775.In single agent studies, we observed dose-dependent decreases in cell proliferation with all 4 single agents. We observed decreased cell proliferation in all cell lines at 72 hours at clinically achievable serum levels of 85% to 55% of control levels (P Citation Format: Walter N. Jungbauer, Mustafa M. Ali, Beverly R. Wuertz, Frank G. Ondrey. Use of kinase inhibitors in Fanconi anemia oral cancercell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2568.
成功的范可尼贫血(FA)治疗可以延长这些患者的寿命。然而,头颈部鳞状恶性肿瘤的风险大大增加,这在这些年轻患者中是相当致命的。对这种恶性肿瘤的非DNA损伤治疗的需求尚未得到满足,这可能会增加手术。我们的方法是根据已知的疾病病理生理学来检查潜在的治疗方法,这对这个人群来说是可以接受的,所以我们检查了二甲双胍和吡格列酮,以及两种细胞周期激酶抑制剂对FA和白斑细胞系的影响。通过MTT试验,我们检测了剂量依赖性和联合作用对细胞增殖的影响。我们检测了二甲双胍、吡格列酮、polo样激酶1抑制剂GSK461364和Wee1激酶抑制剂AZD1775。在单药研究中,我们观察到所有4种单药对细胞增殖的剂量依赖性降低。我们观察到,在临床可达到的血清水平为对照水平的85%至55%的情况下,所有细胞系在72小时内的细胞增殖均下降(P引用格式:Walter N. Jungbauer, Mustafa M. Ali, Beverly R. Wuertz, Frank G. Ondrey)。激酶抑制剂在范可尼贫血口腔癌细胞系中的应用[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第2568期。
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引用次数: 1
Abstract 2548: Preclinical development of EARLI-001, a genetic platform producing cancer-activated synthetic biomarkers for the early detection of malignancies 摘要2548:early -001的临床前开发,early -001是一个产生癌症激活的合成生物标志物的遗传平台,用于早期检测恶性肿瘤
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-2548
Badriprasad Ananthanarayanan, Regina Nieu, Evan Bishop, Shireen S. Rudina, A. Harwig, Bijee George, D. Suhy
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引用次数: 1
Abstract 2531: Function-related indicator and outcomes of screening mammography in older women from the BCSC-Medicare Cohort 摘要2531:bscc - medicare队列中老年妇女乳房x光筛查的功能相关指标和结果
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-2531
Dongyu Zhang, L. Abraham, J. Demb, D. Miglioretti, S. Advani, B. Sprague, L. Henderson, Tracy Onega, K. Wernli, L. Walter, K. Kerlikowske, J. Schousboe, E. O'Meara, D. Braithwaite
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引用次数: 0
Abstract 2611: Transcription factor-nucleosome dynamics inferred from plasma cfDNA delineates tumor and tumor-microenvironment phenotype 摘要2611:从血浆cfDNA推断的转录因子-核小体动力学描述了肿瘤和肿瘤微环境表型
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-2611
Satyanarayan Rao, A. Han, Alexis Zukowski, E. Kopin, P. Kabos, S. Ramachandran
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引用次数: 0
Abstract 2596: Stage-specific inhibition of NNK-induced lung carcinogenesis by 1,4-phenylenebis(methylene)seleno-aspirin (p-XS-Asp) 摘要2596:1,4-苯基双(亚甲基)硒-阿司匹林(p-XS-Asp)对nnk诱导的肺癌的阶段性抑制作用
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-2596
A. Raza, Amandeep Singh, C. Aliaga, D. Plano, Shantu Amin, Arun K. Sharma
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引用次数: 0
Abstract 112: Analytical performance of a cfDNA-based targeted methylation multi-cancer early detection test for population-scale screening 112 .基于cfdna的靶向甲基化多癌早期检测在人群规模筛查中的分析性能
Pub Date : 2021-07-01 DOI: 10.1158/1538-7445.AM2021-112
G. Alexander, B. Jung, Lijuan Ji, E. Revenkova, Payal Shah, J. Brooks, Jeremy Carter, Zhao Dong, L. Eubank, Maryam Hosseini, Xin Hou, Hannah M Kiarie, Neda Ronaghi, Fabian E. Ortega, Madhuvanthi Ramaiah, Kate Rhodes, R. Shaknovich, Seyedmehdi Shojaee, S. Parpart-Li, N. Hunkapiller
{"title":"Abstract 112: Analytical performance of a cfDNA-based targeted methylation multi-cancer early detection test for population-scale screening","authors":"G. Alexander, B. Jung, Lijuan Ji, E. Revenkova, Payal Shah, J. Brooks, Jeremy Carter, Zhao Dong, L. Eubank, Maryam Hosseini, Xin Hou, Hannah M Kiarie, Neda Ronaghi, Fabian E. Ortega, Madhuvanthi Ramaiah, Kate Rhodes, R. Shaknovich, Seyedmehdi Shojaee, S. Parpart-Li, N. Hunkapiller","doi":"10.1158/1538-7445.AM2021-112","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-112","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77007511","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
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Prevention Research
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