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Genomic Landscape of Waldenström Macroglobulinemia and Its Impact on Treatment Strategies.

Waldenstr ö m 巨球蛋白血症的基因组景观及其对治疗策略的影响。

  • 影响因子:11.08
  • DOI:10.1200/JCO.19.02314
  • 作者列表:"Treon SP","Xu L","Guerrera ML","Jimenez C","Hunter ZR","Liu X","Demos M","Gustine J","Chan G","Munshi M","Tsakmaklis N","Chen JG","Kofides A","Sklavenitis-Pistofidis R","Bustoros M","Keezer A","Meid K","Patterson CJ","Sacco A","Roccaro A","Branagan AR","Yang G","Ghobrial IM","Castillo JJ
  • 发表时间:2020-02-21
Abstract

:Next-generation sequencing has revealed recurring somatic mutations in Waldenström macroglobulinemia (WM), including MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%). Deletions involving chromosome 6q are common in patients with mutated MYD88 and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type MYD88 WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of MYD88 and CXCR4 mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.

摘要

: 下一代测序发现 waldenstr ö m 巨球蛋白血症 (WM) 反复出现体细胞突变,包括 MYD88 (95%-97%) 、 CXCR4 (30%-40%) 、 ARID1A (17%) 、和 CD79B (8%-15%)。涉及染色体 6q 的缺失常见于突变 MYD88 患者,包括调节 NFKB 、 BCL2 、 Bruton 酪氨酸激酶 (BTK) 和细胞凋亡的基因。野生型 MYD88 WM 患者表现出转化和死亡风险增加,并表现出弥漫性大 B 细胞淋巴瘤中发现的许多突变。MYD88 和 CXCR4 突变在 WM 中的发现促进了合理的药物开发,包括 BTK 和 CXCR4 抑制剂的开发。对许多常用于治疗 WM 的药物,包括 BTK 抑制剂 ibrutinib 的反应受到 MYD88 和/或 CXCR4 突变状态的影响。MYD88 和 CXCR4 的突变状态均可用于 WM 的精确引导治疗方法。

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DOI:10.1002/ijc.32847
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METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.

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来源期刊:Cancer letters
DOI:10.1016/j.canlet.2019.12.039
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