Optimizing Thermal Ablation for Colon Cancer Liver Metastases: Rapid Tissue Analysis Allowing for Immediate Retreatment; Metabolic Imaging Biomarker Validation; and Predictive Genetic Signatures

优化结肠癌肝转移的热消融：快速组织分析可立即进行再治疗；

• 批准号: 10245245
• 负责人: Constantinos Thasos Sofocleous
• 金额: $ 25.19万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245245
• 关键词: 3-Dimensional; Ablation; Address; Adjuvant Therapy; Affect; Age; American Cancer Society; Antibodies; BRAF gene; Biological Markers; Biopsy; Biopsy Specimen; Cell membrane; Cellular Assay; Cessation of life; Characteristics; Clinical; Clinical Trials; Coagulation Process; Colon Carcinoma; Colorectal Cancer; Cytology; Disease; Evaluation; Evolution; Failure; Genes; Genomics; Goals; Hematoxylin and Eosin Staining Method; Image; Injections; Institution; KRAS2 gene; Knowledge; Lead; Left; Liver; Liver neoplasms; Local Therapy; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic; Metastatic Neoplasm to the Liver; Methods; Mitochondria; Modeling; Molecular; Morphologic artifacts; Morphology; Mutation; Necrosis; Needles; Nomograms; Outcome; Patients; Persons; Positron-Emission Tomography; Predictive Value; Race; Radiofrequency Interstitial Ablation; Residual Cancers; Residual Tumors; Residual state; Retreatment; Risk; Safety; Signal Transduction; Site; Specimen; Stains; Technology; Testing; Thermal Ablation Therapy; Time; Tissue imaging; Tissues; Touch sensation; Tumor Biology; United States; Work; anatomic imaging; biomarker validation; cancer therapy; cohort; design; early phase clinical trial; exceptional responders; fluorodeoxyglucose; follow-up; genetic predictors; genetic signature; genome analysis; genomic signature; high risk; image guided; imprint; improved; improved outcome; indexing; metabolic imaging; microwave ablation; microwave electromagnetic radiation; minimal risk; minimally invasive; mortality; mutant; neoplastic cell; next generation sequencing; novel; patient population; patient stratification; predicting response; predictive marker; prognostic; prospective; resistance mechanism; sex; standard of care; success; tumor; tumor progression; uptake; whole genome

Summary/Abstract: Colorectal cancer (CRC) represents 8% of all cancers with over 1,100,000 people living with CRC in the US alone. The American Cancer Society estimates that in 2018 there will be over 140,000 new CRC cases and over 50,000 deaths from this disease in the United States. Approximately 50% of patients with CRC develop liver metastases (CLM) and these patients have the highest mortality. Thermal ablation (TA) is a minimally invasive local therapy used to treat CLM. TA causes coagulation necrosis larger than the target tumor to create at least a 5 mm margin to diminish local tumor progression (LTP) with a highly favorable safety profile and curative potential. Despite technological evolution of TA, LTP rates remain high, ranging from 3% to 60% during follow-up of ablated liver tumors. We have shown that microwave ablation is less affected by the heat sink phenomena than radiofrequency ablation, when treating perivascular CLM; therefore, we will limit this proposal to the use of microwave for thermal ablation to optimize outcomes. The high LTP rates are the main limitation of the widespread use of TA in the treatment of cancer. In prior work, we demonstrated that viable (OXPHOS antibody positive and/or KI-67 positive) tumor within the ablation zone (AZ) after TA, and KRAS mutations, carry significant risk for LTP and effect patient survival. We hypothesize that residual undetected viable tumor and tumor biology are the most likely mechanisms leading to ablation failure and eventual LTP, even in the face of complete ablation with margins, depicted in conventional anatomic imaging. This proposed clinical trial is designed to overcome these mechanisms, optimizing TA as a treatment for CLM through the following three specific aims: AIM 1: Establish real time cytopathologic and fluorescent assessment of the AZ by immediate post TA biopsy; AIM 2: Determine the 18F-FDG uptake level representing viable tumor immediately post TA of CLM; AIM 3: Identify gene signatures that predict response in patients undergoing TA of CLM through a pre-ablation biopsy and genomic analysis of the target CLM. Real-time cytopathologic evaluation of the AZ (guided by 3D-assisted technology and metabolic imaging) immediately after TA, is a novel method that can be used as a prognostic immediate biomarker of outcomes after TA. More importantly, retreatment will be offered to treat identified, visible residual tumor at the same sitting. We also propose a pre-ablation biopsy and next-generation sequencing (that is a standard of care in our institution) of all CLM undergoing TA. A significantly higher risk for LTP for KRAS mutant compared to KRAS wild type CLM has been recently documented by our group and others. Despite these new findings and prior knowledge that molecular characteristics impact outcomes of TA, a prospective genomic analysis is still lacking. Whole-genome analysis is thus proposed to detect unknown genes that may underlie extreme responders (estimated 10% of cohort). Our study is expected to create an ablation practice paradigm change, improving outcomes in the large population of patients with CLM and other cancers treated by TA.

摘要/摘要：结直肠癌 (CRC) 占所有癌症的 8%，有超过 1,100,000 人患有结直肠癌 仅在美国就有 CRC。美国癌症协会估计，2018 年将有超过 140,000 名新癌症患者 美国有 CRC 病例和超过 50,000 人死于该疾病。大约 50% 的患者 CRC 会发生肝转移 (CLM)，这些患者的死亡率最高。热消融（TA）是一种 用于治疗 CLM 的微创局部疗法。 TA引起比靶肿瘤更大的凝固性坏死 创建至少 5 毫米的边缘以减少局部肿瘤进展 (LTP)，并具有非常有利的安全性 和治疗潜力。尽管 TA 的技术不断发展，LTP 率仍然很高，从 3% 到 60% 在消融的肝脏肿瘤的随访期间。我们已经证明微波消融受散热器的影响较小 治疗血管周围CLM时，现象优于射频消融；因此，我们将限制该提案 使用微波进行热消融以优化结果。高 LTP 率是主要限制 TA 在癌症治疗中的广泛应用。在之前的工作中，我们证明了可行的（OXPHOS TA 后消融区 (AZ) 内的抗体阳性和/或 KI-67 阳性）肿瘤和 KRAS 突变携带 LTP 的重大风险并影响患者的生存。我们假设残留的未检测到的活肿瘤和 肿瘤生物学是导致消融失败和最终 LTP 的最可能机制，即使在 传统解剖成像中描绘的带有边缘的完全消融的面部。 这项拟议的临床试验旨在克服这些机制，优化 TA 作为 CLM 的治疗方法 通过以下三个具体目标： 目标 1：建立实时细胞病理学和荧光评估 TA 后立即进行活检，确定 AZ；目标 2：确定代表活肿瘤的 18F-FDG 摄取水平 立即发布 CLM TA；目标 3：识别预测接受 TA 治疗的患者反应的基因特征 CLM 通过预消融活检和目标 CLM 的基因组分析。 AZ 的实时细胞病理学评估（以 3D 辅助技术和代谢成像为指导） TA 后立即进行，是一种新方法，可用作预后的直接生物标志物 TA之后。更重要的是，将提供再治疗，以在同一地点治疗已识别的可见残留肿瘤。 我们还建议进行消融前活检和下一代测序（这是我们的护理标准） 所有接受 TA 的 CLM 机构）。与 KRAS 相比，KRAS 突变体发生 LTP 的风险显着更高 我们的小组和其他人最近记录了野生型 CLM。尽管有这些新发现和先前的发现 目前仍缺乏分子特征影响 TA 结果的认识，但仍缺乏前瞻性基因组分析。 因此，提出全基因组分析来检测可能导致极端反应的未知基因 （估计占队列的 10%）。我们的研究预计将改变消融实践范式，改善 TA 治疗的大量 CLM 和其他癌症患者的结果。

项目成果

Real-Time Split-Dose PET/CT-Guided Ablation Improves Colorectal Liver Metastasis Detection and Ablation Zone Margin Assessments without the Need for Repeated Contrast Injection.

实时分剂量 PET/CT 引导消融可改善结直肠肝转移检测和消融区边缘评估，无需重复注射造影剂。

• 发表时间: 2022-12-19
• 影响因子: 5.2
• 作者: Zirakchian Zadeh, Mahdi;Yeh, Randy;Kunin, Henry S;Kirov, Assen S;Petre, Elena N;Gönen, Mithat;Silk, Mikhail;Cornelis, Francois H;Soares, Kevin C;Ziv, Etay;Solomon, Stephen B;Sotirchos, Vlasios S;Sofocleous, Constantinos T
• 通讯作者: Sofocleous, Constantinos T

Radiation segmentectomy of hepatic metastases with Y-90 glass microspheres.

Y-90 玻璃微球肝转移放射段切除术。

• 发表时间: 2021
• 作者: Kurilova, I;Bendet, A;Fung, E K;Petre, E N;Humm, J L;Boas, F E;Crane, C H;Kemeny, N;Kingham, T P;Cercek, A;D'Angelica, M I;Beets;Sofocleous, C T
• 通讯作者: Sofocleous, C T