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Generic Protocols for Analytical Validation of Tumor-Informed Circulating Tumor DNA Assays for Molecular Residual Disease: The Blood Profiling Atlas in Cancer's Molecular Residual Disease Analytical Validation Working Group Consensus Recommendation. 肿瘤信息循环肿瘤DNA检测分子残留疾病分析验证通用方案:癌症分子残留疾病分析验证工作组共识推荐的血液图谱。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2026-01-01 Epub Date: 2026-01-14 DOI: 10.1200/PO-25-00267
Jonathan Baden, Cheng-Ho Jimmy Lin, Andrew T Anfora, Jonathan Beer, Karl Bisselou, Jennifer Bungo, Adam S Corner, Tyler Danek, Jennifer Dickey, James H Godsey, Donald J Johann, Gregory Jones, George Karlin-Neumann, Jessica L Larson, Jerry S H Lee, Li Liu, Dorys Lopez Ramos, David Merriam, Melanie Palomares, Carol E Pena, Jessica Rathbun, Kate Rhodes, Jaime E Connolly Rohrbach, Banu Saritas-Yildirim, Mark Sausen, Shile Zhang, Lauren C Leiman

The presence of circulating tumor DNA (ctDNA) in patients indicates post-treatment molecular residual disease (MRD). Given the complexity of ctDNA-based MRD detection tests, consensus on analytical validation (AV) criteria is needed. To address this, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium's MRD AV Working Group evaluated existing protocols to develop standardized guidance for tumor-informed assays. Protocols pertaining to blood collection tube types, quantitative output, tissue processing, tumor or matched normal sequencing, software, and clinical validation were considered out of scope. After alignment on objectives and assumptions, study designs on the basis of best practices in the field, available assay validation guidance documents, and unique performance challenges for tumor-informed MRD assays were authored. Each protocol contains introduction, experimental design, statistical analysis, and an example data presentation per the US Food and Drug Administration (FDA) Center for Devices and Radiological Health standard format. Biostatisticians were consulted to define minimal test requirements, sample size, and appropriate statistical analyses. The protocols were submitted to the FDA via the presubmission process for formal written feedback followed by a meeting. BLOODPAC's generic protocols for the AV of tumor-informed ctDNA assays for MRD are designed to provide test developers with a core baseline of standardized AV protocols such that methods described can be adapted and applied for any tumor-informed MRD assay irrespective of technology, panel design algorithm, or workflow component. These protocols aim to optimize test developers' presubmission reviews with the FDA, ensuring productive meetings while enabling reviewers to streamline feedback. As always, test developers are encouraged to communicate with FDA directly around their particular AV methods.

患者体内循环肿瘤DNA (ctDNA)的存在提示治疗后分子残留疾病(MRD)。鉴于基于ctdna的MRD检测测试的复杂性,需要对分析验证(AV)标准达成共识。为了解决这个问题,癌症血液图谱(BLOODPAC)联盟的MRD AV工作组评估了现有的协议,以制定肿瘤检测的标准化指导。有关采血管类型、定量输出、组织处理、肿瘤或匹配正常测序、软件和临床验证的方案被认为不在讨论范围之内。在对目标和假设进行调整后,基于该领域最佳实践的研究设计、可用的分析验证指导文件以及针对肿瘤的MRD分析的独特性能挑战被撰写。每个方案包含介绍,实验设计,统计分析,并根据美国食品和药物管理局(FDA)设备和放射卫生中心标准格式的示例数据演示。咨询了生物统计学家来确定最小测试要求、样本量和适当的统计分析。这些方案通过预提交程序提交给FDA,以获得正式的书面反馈,然后举行会议。BLOODPAC的MRD ctDNA检测的AV通用协议旨在为测试开发人员提供标准化AV协议的核心基线,这样所描述的方法可以适用于任何肿瘤的MRD检测,而不考虑技术、面板设计算法或工作流程组件。这些协议旨在优化测试开发人员与FDA的预提交审查,确保富有成效的会议,同时使审稿人能够简化反馈。与往常一样,鼓励测试开发人员直接与FDA就其特定的AV方法进行沟通。
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引用次数: 0
Genomic Profile and Resistance to Anti-Epidermal Growth Factor Receptor Antibody in RAS-Amplified Colorectal Cancer: A Study Based on a Japanese Cancer Genome Database. 基于日本癌症基因组数据库的ras扩增结直肠癌基因组谱和抗表皮生长因子受体抗体耐药性研究
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2026-01-01 Epub Date: 2026-01-08 DOI: 10.1200/PO-25-00424
Gota Fujisawa, Kenji Tamada, Takeshi Hayashi, Nobumi Suzuki, Takuma Iwata, Yu Miyakawa, Masahiro Hata, Rei Ishibashi, Yoku Hayakawa, Aya Shinozaki-Ushiku, Hidenori Kage, Katsutoshi Oda, Narikazu Boku, Mitsuhiro Fujishiro

Purpose: RAS mutation is a key biomarker of anti-epidermal growth factor receptor (EGFR) antibody resistance in colorectal cancer (CRC). However, the clinical impact of RAS amplification on the efficacy of anti-EGFR therapy remains unclear. This study aimed to characterize RAS-amplified CRC and evaluate the sensitivity of these tumors to anti-EGFR antibodies.

Methods: We conducted a retrospective observational study using the Center for Cancer Genomics and Advanced Therapeutics database in Japan, which includes clinical and genomic data from patients who underwent comprehensive genomic profiling. We analyzed the data from 9,135 patients with unresectable colorectal adenocarcinoma (CRA) who underwent FoundationOne CDx testing.

Results: RAS amplification was identified in 2.1% (188/9,135) of patients with CRA. Among 1,649 patients with RAS wild-type CRA who received first-line chemotherapy with anti-EGFR antibodies, those with RAS amplification had a lower overall response rate (ORR) and a shorter time to treatment failure (TTF) compared with those without RAS amplification (ORR, 37.5% [21/56] v 52.9% [843/1,593]; median TTF, 195 days [95% CI, 129 to 224] v 274 days [95% CI, 258 to 293]; P = .023 and P = .005, respectively). By contrast, among 4,858 patients treated with bevacizumab, no significant differences were observed in ORR (37.3% [31/83] v 37.1% [1,772/4,775]; P = .964) or TTF (median, 231 days [95% CI, 175 to 273] v 259 days [95% CI, 252 to 270]; P = .445).

Conclusion: RAS amplification is a rare alteration that may confer resistance to anti-EGFR antibodies. Assessing RAS amplification status may help guide the appropriate use of anti-EGFR antibodies in clinical practice.

目的:RAS突变是结直肠癌(CRC)抗表皮生长因子受体(EGFR)抗体耐药的关键生物标志物。然而,RAS扩增对抗egfr治疗效果的临床影响尚不清楚。本研究旨在表征ras扩增的结直肠癌,并评估这些肿瘤对抗egfr抗体的敏感性。方法:我们使用日本癌症基因组学和高级治疗中心的数据库进行了一项回顾性观察研究,其中包括来自接受全面基因组分析的患者的临床和基因组数据。我们分析了9,135例接受FoundationOne CDx检测的不可切除结直肠癌(CRA)患者的数据。结果:2.1%(188/ 9135)的CRA患者检测到RAS扩增。在1,649例接受抗egfr抗体一线化疗的RAS野生型CRA患者中,RAS扩增患者的总有效率(ORR)较低,治疗失败时间(TTF)较无RAS扩增患者短(ORR为37.5% [21/56]vs 52.9%[843/ 1593];中位TTF为195天[95% CI, 129 ~ 224] vs 274天[95% CI, 258 ~ 293]; P = 0.023和P = 0.005)。相比之下,在4858例接受贝伐单抗治疗的患者中,ORR (37.3% [31/83] vs 37.1% [1772 / 4775]; P = 0.964)或TTF(中位,231天[95% CI, 175 ~ 273] vs 259天[95% CI, 252 ~ 270]; P = 0.445)无显著差异。结论:RAS扩增是一种罕见的变异,可能导致对抗egfr抗体产生耐药性。评估RAS扩增状态可能有助于指导临床实践中抗egfr抗体的适当使用。
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引用次数: 0
Molecular Characterization of a Complex PDGFRB Structural Variation in Infantile Myofibroma With Complete Response to Imatinib. 对伊马替尼完全有效的婴儿肌纤维瘤中复杂PDGFRB结构变异的分子特征
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2026-01-01 Epub Date: 2026-01-14 DOI: 10.1200/PO-25-00943
Wynn E Bastianelli, Jinhua Wu, Mian Umair Ahsan, Ava M Szepessy, Jeffery Schubert, Naomi J Balamuth, Joe Chan, Elizabeth H Denenberg, Minjie Luo, Avrum N Pollock, Pierre A Russo, Karleena Rybacki, Feng Xu, Yiming Zhong, Lea F Surrey, Kai Wang, Theodore W Laetsch, Marilyn M Li
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引用次数: 0
Olaparib Response in a Patient With Platinum-Refractory Germ Cell Tumor Harboring a Somatic BRIP1 Mutation. 携带体细胞BRIP1突变的铂难治性生殖细胞肿瘤患者的奥拉帕尼应答
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2026-01-01 Epub Date: 2026-01-08 DOI: 10.1200/PO-25-00768
Camila Bobato Lara Gismondi, Ruchi Agarwal, Maria Fernanda Botelho Teixeira, Alexander Chehrazi-Raffle
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引用次数: 0
Pathway for the Development of ATR Inhibitors in Pediatric Malignancies: An ACCELERATE Multistakeholder Analysis. ATR抑制剂在儿童恶性肿瘤中的发展途径:加速多利益相关者分析。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2026-01-01 Epub Date: 2026-01-15 DOI: 10.1200/PO-25-00642
Susanne A Gatz, Julia Glade-Bender, Andrew D J Pearson, Michael V Ortiz, Ronald Bernardi, Lou Chesler, Steve Clifford, Sarah Cohen-Gogo, Esther De La Cuesta, Teresa de Rojas, Kaat Durinck, Sara Federico, Elizabeth Fox, Sally George, Ioannis Gounaris, Anton George Henssen, Meredith Irwin, Marcel Kool, Alan Lau, Karsten Nysom, Alberto Pappo, Gregory K Pennock, Stefan M Pfister, Nicole Scobie, Emily K Slotkin, Malcolm Smith, Frank Speleman, Elizabeth A Stewart, Brenda J Weigel, Gilles Vassal

Purpose: High levels of DNA replication stress and defects in the DNA damage response (DDR) pathways are vulnerabilities of many poor prognosis childhood malignancies. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of these pathways and constitutes an attractive target, especially in combination. However, the malignancies where ATR inhibitors have maximum benefit and synergistic combinations differ between adults and children.

Design: ACCELERATE convened a multistakeholder meeting and conducted review and analysis to propose the optimal pathway for the development of ATR inhibitors in pediatric malignancies.

Results: Considering the lack of identified biomarkers, the initial evaluation of ATR inhibitors should focus on Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma in view of their high levels of DNA replication stress and defects in DDR pathways. Early phase trials of ATR inhibitors should be iterative, based on a clear hypothesis with responders and nonresponders undergoing detailed molecular analysis and a revised new hypothesis generated. Trial designs should restrict monotherapy evaluation to a brief exposure in a small number of patients and progress rapidly to combinations. Highlighted combination partners are poly(ADP-ribose) polymerase inhibitors and antibody drug conjugates with topoisomerase I inhibitor payloads. Combinations with ALK inhibitors (in ALK/MYCN-aberrant neuroblastoma) and aurora A kinase (in MYCN-amplified) are supported by robust mechanisms of action and preclinical data. Early interactions with regulators are crucial, and early phase clinical trials should be conducted in regulatory-approved, academic-sponsored, industry-supported, platform trials.

Conclusion: ATR inhibitors are a prototype for the development of medicinal products in a limited pediatric population. For the substantial potential of ATR inhibitors in children with malignancy to be realized, strategic planning between academia, industry, regulators, and patient advocates is vital.

目的:高水平的DNA复制应激和DNA损伤反应(DDR)通路的缺陷是许多预后不良的儿童恶性肿瘤的脆弱性。共济失调毛细血管扩张和rad3相关蛋白(ATR)是这些途径的关键调节因子,构成了一个有吸引力的靶标,特别是在联合使用时。然而,ATR抑制剂对恶性肿瘤的最大益处和协同作用组合在成人和儿童之间有所不同。设计:ACCELERATE召集了多方利益相关者会议,并进行了回顾和分析,以提出开发ATR抑制剂治疗儿科恶性肿瘤的最佳途径。结果:考虑到缺乏确定的生物标志物,鉴于Ewing肉瘤、横纹肌肉瘤和神经母细胞瘤的DNA复制应激水平高,DDR通路存在缺陷,ATR抑制剂的初步评估应侧重于这些肿瘤。ATR抑制剂的早期试验应该是迭代的,基于一个明确的假设,对反应者和无反应者进行详细的分子分析,并产生一个修订的新假设。试验设计应限制单药治疗评估在少数患者中的短暂暴露,并迅速进展到联合治疗。重点强调的组合伙伴是poly(adp -核糖)聚合酶抑制剂和抗体药物偶联物与拓扑异构酶I抑制剂有效载荷。与ALK抑制剂(在ALK/ mycn异常的神经母细胞瘤中)和aurora A激酶(在mycn扩增的神经母细胞瘤中)联合使用得到了强大的作用机制和临床前数据的支持。与监管机构的早期互动至关重要,早期临床试验应在监管机构批准、学术赞助、行业支持的平台试验中进行。结论:ATR抑制剂是在有限的儿科人群中开发医药产品的原型。为了实现ATR抑制剂在恶性肿瘤儿童中的巨大潜力,学术界、工业界、监管机构和患者倡导者之间的战略规划至关重要。
{"title":"Pathway for the Development of ATR Inhibitors in Pediatric Malignancies: An ACCELERATE Multistakeholder Analysis.","authors":"Susanne A Gatz, Julia Glade-Bender, Andrew D J Pearson, Michael V Ortiz, Ronald Bernardi, Lou Chesler, Steve Clifford, Sarah Cohen-Gogo, Esther De La Cuesta, Teresa de Rojas, Kaat Durinck, Sara Federico, Elizabeth Fox, Sally George, Ioannis Gounaris, Anton George Henssen, Meredith Irwin, Marcel Kool, Alan Lau, Karsten Nysom, Alberto Pappo, Gregory K Pennock, Stefan M Pfister, Nicole Scobie, Emily K Slotkin, Malcolm Smith, Frank Speleman, Elizabeth A Stewart, Brenda J Weigel, Gilles Vassal","doi":"10.1200/PO-25-00642","DOIUrl":"10.1200/PO-25-00642","url":null,"abstract":"<p><strong>Purpose: </strong>High levels of DNA replication stress and defects in the DNA damage response (DDR) pathways are vulnerabilities of many poor prognosis childhood malignancies. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of these pathways and constitutes an attractive target, especially in combination. However, the malignancies where ATR inhibitors have maximum benefit and synergistic combinations differ between adults and children.</p><p><strong>Design: </strong>ACCELERATE convened a multistakeholder meeting and conducted review and analysis to propose the optimal pathway for the development of ATR inhibitors in pediatric malignancies.</p><p><strong>Results: </strong>Considering the lack of identified biomarkers, the initial evaluation of ATR inhibitors should focus on Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma in view of their high levels of DNA replication stress and defects in DDR pathways. Early phase trials of ATR inhibitors should be iterative, based on a clear hypothesis with responders and nonresponders undergoing detailed molecular analysis and a revised new hypothesis generated. Trial designs should restrict monotherapy evaluation to a brief exposure in a small number of patients and progress rapidly to combinations. Highlighted combination partners are poly(ADP-ribose) polymerase inhibitors and antibody drug conjugates with topoisomerase I inhibitor payloads. Combinations with ALK inhibitors (in <i>ALK</i>/<i>MYCN</i>-aberrant neuroblastoma) and aurora A kinase (in <i>MYCN</i>-amplified) are supported by robust mechanisms of action and preclinical data. Early interactions with regulators are crucial, and early phase clinical trials should be conducted in regulatory-approved, academic-sponsored, industry-supported, platform trials.</p><p><strong>Conclusion: </strong>ATR inhibitors are a prototype for the development of medicinal products in a limited pediatric population. For the substantial potential of ATR inhibitors in children with malignancy to be realized, strategic planning between academia, industry, regulators, and patient advocates is vital.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"10 ","pages":"e2500642"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12834277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Long Short-Term Memory-Driven Modeling of Dynamic Hepatocellular Carcinoma Microenvironments: A Deep Learning Framework for Precision Treatment Prediction. 动态肝细胞癌微环境的长短期记忆驱动建模:用于精确治疗预测的深度学习框架。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-10 DOI: 10.1200/PO-25-00315
Hai Zhong, Bin Wu, Xiaodan Yang, Xiaoguang Wang, Minjie Chen, Lingyu Hu

Purpose: This study evaluates deep learning (DL) approaches, particularly long short-term memory (LSTM) networks, for analyzing dynamic changes in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) to improve disease understanding and treatment prediction.

Materials and methods: Multimodal HCC TME data (high-throughput sequencing, protein expression, and time-series imaging) were integrated. Spatial features were extracted using convolutional neural networks (CNNs), while temporal patterns were modeled with LSTMs. Generative adversarial networks (GANs) augmented data for robust training. Model performance was assessed on the basis of dynamic TME characterization and outcome prediction accuracy.

Results: LSTMs demonstrated superior performance in analyzing TME time-series data, effectively capturing long-term dependencies and predicting cellular interactions (accuracy: 92.3% v 85.7% for CNNs alone). The integrated DL framework successfully characterized spatiotemporal TME evolution and treatment response patterns.

Conclusion: This study demonstrates that LSTMs are powerful tools for analyzing and understanding the dynamic changes in the HCC immune microenvironment. Their strong capability in time-series data analysis provides new opportunities for uncovering the mechanisms of HCC progression and optimizing therapeutic strategies. However, because of the lack of detailed etiological information, stratified validation across different etiologies such as hepatitis B virus, hepatitis C virus, and non-alcoholic steatohepatitis has not yet been conducted in this study and should be addressed in future work. The findings highlight the important role of DL technologies in future research and treatment of HCC.

目的:本研究评估了深度学习(DL)方法,特别是长短期记忆(LSTM)网络,用于分析肝细胞癌(HCC)肿瘤微环境(TME)的动态变化,以提高对疾病的认识和治疗预测。材料和方法:整合多模式HCC TME数据(高通量测序、蛋白表达和时间序列成像)。空间特征提取使用卷积神经网络(cnn),时间模式建模使用lstm。生成对抗网络(GANs)增强数据鲁棒性训练。根据动态TME表征和结果预测精度评估模型性能。结果:LSTMs在分析TME时间序列数据、有效捕获长期依赖关系和预测细胞相互作用方面表现出优异的性能(准确率:92.3% vs 85.7%单独使用cnn)。综合DL框架成功表征了TME的时空演化和治疗反应模式。结论:本研究表明lstm是分析和理解HCC免疫微环境动态变化的有力工具。他们强大的时间序列数据分析能力为揭示HCC进展机制和优化治疗策略提供了新的机会。然而,由于缺乏详细的病因学信息,本研究尚未对不同病因(如乙型肝炎病毒、丙型肝炎病毒和非酒精性脂肪性肝炎)进行分层验证,并应在未来的工作中加以解决。这些发现突出了DL技术在未来HCC研究和治疗中的重要作用。
{"title":"Long Short-Term Memory-Driven Modeling of Dynamic Hepatocellular Carcinoma Microenvironments: A Deep Learning Framework for Precision Treatment Prediction.","authors":"Hai Zhong, Bin Wu, Xiaodan Yang, Xiaoguang Wang, Minjie Chen, Lingyu Hu","doi":"10.1200/PO-25-00315","DOIUrl":"https://doi.org/10.1200/PO-25-00315","url":null,"abstract":"<p><strong>Purpose: </strong>This study evaluates deep learning (DL) approaches, particularly long short-term memory (LSTM) networks, for analyzing dynamic changes in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) to improve disease understanding and treatment prediction.</p><p><strong>Materials and methods: </strong>Multimodal HCC TME data (high-throughput sequencing, protein expression, and time-series imaging) were integrated. Spatial features were extracted using convolutional neural networks (CNNs), while temporal patterns were modeled with LSTMs. Generative adversarial networks (GANs) augmented data for robust training. Model performance was assessed on the basis of dynamic TME characterization and outcome prediction accuracy.</p><p><strong>Results: </strong>LSTMs demonstrated superior performance in analyzing TME time-series data, effectively capturing long-term dependencies and predicting cellular interactions (accuracy: 92.3% <i>v</i> 85.7% for CNNs alone). The integrated DL framework successfully characterized spatiotemporal TME evolution and treatment response patterns.</p><p><strong>Conclusion: </strong>This study demonstrates that LSTMs are powerful tools for analyzing and understanding the dynamic changes in the HCC immune microenvironment. Their strong capability in time-series data analysis provides new opportunities for uncovering the mechanisms of HCC progression and optimizing therapeutic strategies. However, because of the lack of detailed etiological information, stratified validation across different etiologies such as hepatitis B virus, hepatitis C virus, and non-alcoholic steatohepatitis has not yet been conducted in this study and should be addressed in future work. The findings highlight the important role of DL technologies in future research and treatment of HCC.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500315"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expanding the Understanding of Polymerase Epsilon in Pancreatic Cancer: Immune Checkpoint Inhibitor Response in Polymerase Epsilon P286R-Mutated Metastatic Pancreatic Adenocarcinoma. 扩大对聚合酶Epsilon在胰腺癌中的理解:免疫检查点抑制剂在聚合酶Epsilon p286r突变的转移性胰腺腺癌中的应答
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-10 DOI: 10.1200/PO-25-00521
Karthic Drishna Perumal, Kenneth Chian, Jinesh Gheeya, Asrar Alahmadi, Arjun Mittra, Mingjia Li
{"title":"Expanding the Understanding of Polymerase Epsilon in Pancreatic Cancer: Immune Checkpoint Inhibitor Response in Polymerase Epsilon P286R-Mutated Metastatic Pancreatic Adenocarcinoma.","authors":"Karthic Drishna Perumal, Kenneth Chian, Jinesh Gheeya, Asrar Alahmadi, Arjun Mittra, Mingjia Li","doi":"10.1200/PO-25-00521","DOIUrl":"https://doi.org/10.1200/PO-25-00521","url":null,"abstract":"","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500521"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Clinical Outcomes of Adult Patients With Newly Diagnosed Mixed Phenotype Acute Leukemia. 新诊断的混合表型急性白血病成年患者的临床结果
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-10 DOI: 10.1200/PO-25-00494
Hannah Goulart, Farhad Ravandi, Nicholas J Short, Nitin Jain, Naval Daver, Tapan M Kadia, Courtney DiNardo, Gautam Borthakur, Koichi Takahashi, Naveen Pemmaraju, Fadi G Haddad, Guillermo Montalban Bravo, Yesid Alvarado, Ghayas C Issa, Alex Bataller, Sherry Pierce, Sanam Loghavi, Guilin Tang, Sa A Wang, Beenu Thakral, Elizabeth Shpall, Richard Champlin, Issa Khouri, Partow Kebriaei, Guillermo Garcia-Manero, Koji Sasaki, Elias J Jabbour, Jayastu Senapati

Purpose: Mixed phenotype acute leukemia (MPAL) is a rare clinical entity with historically poor outcomes.

Methods: We conducted a retrospective analysis of adults 18 years and older with newly diagnosed B-cell (B/M) or T-cell/myeloid (T/M) MPAL treated at our institution between 2017 and 2024.

Results: We identified 42 patients (median age 70 years); 20 (48%) had B/M MPAL, and 22 (52%) had T/M MPAL; 57% of patients had adverse risk cytogenetics, and 41% had a TP53 mutation. Sixty-two percent of patients were treated with a hybrid regimen, and 45% of patients received intensive therapy. A composite complete remission (CRc; CR + CRi) was achieved in 57% of patients (86% measurable residual disease [MRD]-negative). After a median follow-up of 27.9 months, the median relapse-free survival in patients achieving an overall response (CRc + morphological leukemia-free state) was 10.1 months, 17.8 months in those who achieved a CRc, and not reached (NR) in patients with MRD-negative CRc. The median overall survival (OS) for all patients was 9.5 months and NR for patients achieving a CRc. Although patients with T/M MPAL had a trend toward improved survival compared with those with B/M MPAL (median OS of 9.1 v 25 months P = .28), this difference abrogated when comparison was stratified by treatment intensity. Twelve patients (29%) underwent allogeneic hematopoietic stem-cell transplantation (HSCT); on landmark analysis, HSCT trended to improve OS (NR v 22.8, P = .12). Multivariate Cox analysis demonstrated that TP53 mutation was associated with increased hazards for death (hazard ratio [HR], 3.5, P = .01), whereas the use of intensive chemotherapy trended to be favorable (HR, 0.45, P = .11).

Conclusion: Overall, these data demonstrate the need for treatment intensification in MPAL with HSCT in first remission for best outcomes.

目的:混合表型急性白血病(MPAL)是一种罕见的临床实体,其预后历来较差。方法:我们对2017年至2024年间在我院治疗的18岁及以上新诊断的B细胞(B/M)或T细胞/骨髓(T/M) MPAL的成年人进行了回顾性分析。结果:我们确定了42例患者(中位年龄70岁);B/M型MPAL 20例(48%),T/M型MPAL 22例(52%);57%的患者有不良的细胞遗传学风险,41%的患者有TP53突变。62%的患者接受混合方案治疗,45%的患者接受强化治疗。57%的患者实现了复合完全缓解(CRc; CR + CRi)(86%可测量残留疾病[MRD]阴性)。在27.9个月的中位随访后,达到总体缓解(CRc +形态无白血病状态)的患者的中位无复发生存期为10.1个月,达到CRc的患者为17.8个月,mrd阴性CRc患者未达到NR。所有患者的中位总生存期(OS)为9.5个月,达到结直肠癌的患者为NR。虽然与B/M MPAL患者相比,T/M MPAL患者有改善生存的趋势(中位OS为9.1 v 25个月P = 0.28),但当按治疗强度进行分层比较时,这种差异消失了。12例患者(29%)接受了同种异体造血干细胞移植(HSCT);在地标性分析中,HSCT有改善OS的趋势(NR v 22.8, P = .12)。多因素Cox分析显示,TP53突变与死亡风险增加相关(风险比[HR], 3.5, P = 0.01),而使用强化化疗倾向于有利(风险比,0.45,P = .11)。结论:总的来说,这些数据表明,MPAL患者在首次缓解时进行HSCT治疗需要加强,以获得最佳结果。
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引用次数: 0
Magnetic Resonance Imaging-Detected High-Risk Markers in Rectal Cancer Patients With a Pathologic Complete Response After Neoadjuvant Therapy. 磁共振成像在新辅助治疗后病理完全缓解的直肠癌患者中检测高风险标志物。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2025-12-01 Epub Date: 2025-12-10 DOI: 10.1200/PO-25-00357
Ke Zhao, Minning Zhao, Qing-Yang Li, Jing Yang, Lili Feng, Xiaomei Wu, Zhenhui Li, Yanfen Cui, Xinjuan Fan, Ying-Shi Sun, Zaiyi Liu

Purpose: Pathologic complete response (pCR) is a surrogate end point for prognosis in rectal cancer, yet a subset of pCR patients still face recurrence or poor outcomes. The identification of high-risk pCR patients and the effectiveness of adjuvant therapy remain contentious. This study aimed to evaluate pretreatment magnetic resonance imaging (MRI) markers, identify high-risk pCR patients, and assess the benefit of adjuvant therapy.

Materials and methods: This retrospective multicenter study analyzed 384 pCR patients (2010-2019) to assess pretreatment MRI markers' prognostic value. Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan-Meier curves, with group differences evaluated via the log-rank test.

Results: Among the MRI markers evaluated, magnetic resonance with tumor deposits (mrTD) emerged as the strongest prognostic factor. Positive mrTD was associated with a five-fold increased risk of recurrence (adjusted hazard ratio, 5.16 [95% CI, 2.67 to 9.97]; P < .001) and significantly reduced OS (5.04 [1.80 to 14.1]; P = .002). Patients with mrTD+ had a 3-year DFS of 74.5% and a 5-year OS of 83.6%, compared with 96.6% and 98.6%, respectively, in mrTD- patients. Notably, adjuvant therapy did not improve prognosis in pCR patients, regardless of their MRI marker status.

Conclusion: Positive mrTD is a critical prognostic marker in pCR patients. Adjuvant therapy did not confer benefits, highlighting the need for personalized treatment strategies.

目的:病理完全缓解(pCR)是直肠癌预后的替代终点,但一部分pCR患者仍然面临复发或预后不良的问题。高风险pCR患者的识别和辅助治疗的有效性仍然存在争议。本研究旨在评估预处理磁共振成像(MRI)标志物,识别高危pCR患者,并评估辅助治疗的益处。材料和方法:本回顾性多中心研究分析了384例pCR患者(2010-2019),以评估预处理MRI标志物的预后价值。使用Kaplan-Meier曲线估计无病生存期(DFS)和总生存期(OS),通过log-rank检验评估组间差异。结果:在评估的MRI标记物中,肿瘤沉积物磁共振(mrTD)成为最强的预后因素。mrTD阳性与复发风险增加5倍相关(校正风险比为5.16 [95% CI, 2.67 ~ 9.97]; P < .001), OS显著降低(5.04 [1.80 ~ 14.1];P = .002)。mrTD+患者的3年DFS为74.5%,5年OS为83.6%,而mrTD-患者分别为96.6%和98.6%。值得注意的是,辅助治疗并没有改善pCR患者的预后,无论他们的MRI标记状态如何。结论:mrTD阳性是pCR患者预后的重要指标。辅助治疗并没有带来益处,这凸显了个性化治疗策略的必要性。
{"title":"Magnetic Resonance Imaging-Detected High-Risk Markers in Rectal Cancer Patients With a Pathologic Complete Response After Neoadjuvant Therapy.","authors":"Ke Zhao, Minning Zhao, Qing-Yang Li, Jing Yang, Lili Feng, Xiaomei Wu, Zhenhui Li, Yanfen Cui, Xinjuan Fan, Ying-Shi Sun, Zaiyi Liu","doi":"10.1200/PO-25-00357","DOIUrl":"10.1200/PO-25-00357","url":null,"abstract":"<p><strong>Purpose: </strong>Pathologic complete response (pCR) is a surrogate end point for prognosis in rectal cancer, yet a subset of pCR patients still face recurrence or poor outcomes. The identification of high-risk pCR patients and the effectiveness of adjuvant therapy remain contentious. This study aimed to evaluate pretreatment magnetic resonance imaging (MRI) markers, identify high-risk pCR patients, and assess the benefit of adjuvant therapy.</p><p><strong>Materials and methods: </strong>This retrospective multicenter study analyzed 384 pCR patients (2010-2019) to assess pretreatment MRI markers' prognostic value. Disease-free survival (DFS) and overall survival (OS) were estimated using Kaplan-Meier curves, with group differences evaluated via the log-rank test.</p><p><strong>Results: </strong>Among the MRI markers evaluated, magnetic resonance with tumor deposits (mrTD) emerged as the strongest prognostic factor. Positive mrTD was associated with a five-fold increased risk of recurrence (adjusted hazard ratio, 5.16 [95% CI, 2.67 to 9.97]; <i>P</i> < .001) and significantly reduced OS (5.04 [1.80 to 14.1]; <i>P</i> = .002). Patients with mrTD<sup>+</sup> had a 3-year DFS of 74.5% and a 5-year OS of 83.6%, compared with 96.6% and 98.6%, respectively, in mrTD<sup>-</sup> patients. Notably, adjuvant therapy did not improve prognosis in pCR patients, regardless of their MRI marker status.</p><p><strong>Conclusion: </strong>Positive mrTD is a critical prognostic marker in pCR patients. Adjuvant therapy did not confer benefits, highlighting the need for personalized treatment strategies.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2500357"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pediatric Oncology Patients With Germline Pathogenic Variants in Adult-Onset Cancer Predisposition Genes. 儿童肿瘤患者的生殖系致病性变异在成人发病的癌症易感基因。
IF 5.6 2区 医学 Q1 ONCOLOGY Pub Date : 2025-12-01 DOI: 10.1200/PO-24-00749
Michelle F Jacobs, Sarah Austin, Andrea M Murad, Erika Koeppe, Chandan Kumar-Sinha, Dan R Robinson, Yi-Mi Wu, Josh N Vo, Carl Koschmann, Patricia Robertson, Andrea Franson, Denise Leung, Arul M Chinnaiyan, Rajen J Mody

Purpose: Cancer predisposition syndromes caused by germline pathogenic variants (GPV) in adult-onset cancer predisposition genes (aoCPG) are those for which there is low risk of cancer in children, with genetic testing and screening for these conditions typically deferred until adulthood. GPV in aoCPG have been identified in pediatric oncology patients, but in these cases the potential contribution of the aoCPG to cancer development is often unknown. We investigated the role GPV in aoCPG may play in childhood cancer development.

Methods: Results of paired tumor-germline sequencing from pediatric oncology patients enrolled from May 2012 to October 2023 were analyzed for frequency of GPV in aoCPG. Germline testing included analysis of up to 182 cancer predisposition genes. Tumor loss-of-heterozygosity, presence of second somatic pathogenic variant, immunohistochemical stain for protein expression, and/or tumor mutation burden were used to determine possible causation.

Results: Of the 954 participants, 42 (4.4%) had GPV in aoCPG. Six (14.3%) of these 42 participants had tumor findings indicating their GPV in an aoCPG likely contributed to cancer development: three patients with Lynch syndrome (two anaplastic astrocytomas, one giant cell glioblastoma) and one each with GPV in ATM (craniopharyngioma and diffuse high-grade glioma), BRIP1 (atypical teratoid rhabdoid tumor), and CHEK2 (mixed germ cell tumor of pineal gland).

Conclusion: These findings contribute to the literature suggesting that, rarely, GPV in aoCPG may contribute to cancer diagnoses in children, raising the question of how tumors in these cases may present differently in children than adults. Increased knowledge about potential childhood cancer risks related to what have historically been considered aoCPG could modify predictive genetic testing recommendations for children and enhance existing cancer screening protocols.

目的:由成人发病的癌症易感基因(aoCPG)的种系致病变异(GPV)引起的癌症易感综合征是那些在儿童中癌症风险较低的疾病,这些疾病的基因检测和筛查通常推迟到成年。在儿科肿瘤患者中已经发现了aoCPG中的GPV,但在这些病例中,aoCPG对癌症发展的潜在贡献通常是未知的。我们研究了GPV在aoCPG中可能在儿童癌症发展中的作用。方法:对2012年5月至2023年10月纳入的儿科肿瘤患者配对肿瘤-种系测序结果进行分析,以确定aoCPG中GPV的频率。生殖系检测包括对多达182种癌症易感基因的分析。肿瘤的杂合性缺失、第二体细胞致病变异的存在、蛋白质表达的免疫组织化学染色和/或肿瘤突变负担被用来确定可能的原因。结果:954名参与者中,42名(4.4%)在aoCPG中出现GPV。这42名参与者中有6名(14.3%)的肿瘤发现表明他们在aoCPG中的GPV可能导致了癌症的发展:3名患者患有Lynch综合征(2名间变性星形细胞瘤,1名巨细胞胶质母细胞瘤),1名患者患有ATM中的GPV(颅咽管瘤和弥漫性高级别胶质瘤),BRIP1(非典型畸胎瘤样横纹肌样瘤)和CHEK2(松果体混合生殖细胞瘤)。结论:这些发现有助于文献提示,在罕见情况下,aoCPG中的GPV可能有助于儿童的癌症诊断,这就提出了这些病例中的肿瘤在儿童和成人中的表现如何不同的问题。增加对儿童癌症潜在风险的认识,可能会改变对儿童的预测性基因检测建议,并加强现有的癌症筛查方案。
{"title":"Pediatric Oncology Patients With Germline Pathogenic Variants in Adult-Onset Cancer Predisposition Genes.","authors":"Michelle F Jacobs, Sarah Austin, Andrea M Murad, Erika Koeppe, Chandan Kumar-Sinha, Dan R Robinson, Yi-Mi Wu, Josh N Vo, Carl Koschmann, Patricia Robertson, Andrea Franson, Denise Leung, Arul M Chinnaiyan, Rajen J Mody","doi":"10.1200/PO-24-00749","DOIUrl":"10.1200/PO-24-00749","url":null,"abstract":"<p><strong>Purpose: </strong>Cancer predisposition syndromes caused by germline pathogenic variants (GPV) in adult-onset cancer predisposition genes (aoCPG) are those for which there is low risk of cancer in children, with genetic testing and screening for these conditions typically deferred until adulthood. GPV in aoCPG have been identified in pediatric oncology patients, but in these cases the potential contribution of the aoCPG to cancer development is often unknown. We investigated the role GPV in aoCPG may play in childhood cancer development.</p><p><strong>Methods: </strong>Results of paired tumor-germline sequencing from pediatric oncology patients enrolled from May 2012 to October 2023 were analyzed for frequency of GPV in aoCPG. Germline testing included analysis of up to 182 cancer predisposition genes. Tumor loss-of-heterozygosity, presence of second somatic pathogenic variant, immunohistochemical stain for protein expression, and/or tumor mutation burden were used to determine possible causation.</p><p><strong>Results: </strong>Of the 954 participants, 42 (4.4%) had GPV in aoCPG. Six (14.3%) of these 42 participants had tumor findings indicating their GPV in an aoCPG likely contributed to cancer development: three patients with Lynch syndrome (two anaplastic astrocytomas, one giant cell glioblastoma) and one each with GPV in <i>ATM</i> (craniopharyngioma and diffuse high-grade glioma), <i>BRIP1</i> (atypical teratoid rhabdoid tumor), and <i>CHEK2</i> (mixed germ cell tumor of pineal gland).</p><p><strong>Conclusion: </strong>These findings contribute to the literature suggesting that, rarely, GPV in aoCPG may contribute to cancer diagnoses in children, raising the question of how tumors in these cases may present differently in children than adults. Increased knowledge about potential childhood cancer risks related to what have historically been considered aoCPG could modify predictive genetic testing recommendations for children and enhance existing cancer screening protocols.</p>","PeriodicalId":14797,"journal":{"name":"JCO precision oncology","volume":"9 ","pages":"e2400749"},"PeriodicalIF":5.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12671920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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JCO precision oncology
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