Clinical efficacy and chemoresistance analysis of precision neoadjuvant chemotherapy for borderline resectable pancreatic cancer: a prospective, single-arm pilot study.

IF 12.5 2区 医学 Q1 SURGERY
Yonggang He, Yinan Zhu, Weiwei Wang, Yuanyue Yi, Zheng Wang, Chongyu Zhao, Jing Li, Xiaobing Huang, Lu Zheng
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引用次数: 0

Abstract

Background: Neoadjuvant chemotherapy (NAC) can improve the survival outcomes of patients with pancreatic cancer, but for borderline resectable pancreatic cancer (BRPC) the proportion of conversion to surgery remains unsatisfactory. This single-arm pilot study aimed to assess the clinical efficacy and safety of NAC based on patient-derived organoids (PDOs) for BRPC.

Methods: Biopsy samples from BRPC patients were collected for generating PDOs. Gemcitabine plus nab-paclitaxel (GnP) as NAC was initially administrated for one cycle, and then the treatment regimen was adjusted based on the PDO drug sensitivity testing. The primary endpoint was the objective response rate (ORR). Secondary endpoints included R0 resection rate, NAC-related adverse events (AEs) and postoperative complications. Exploratory objectives were to assess the chemoresistance to gemcitabine.

Results: Totally 19 of 25 patients were eligible for the study, among whom 16 achieved partial response and received surgical resection, with the ORR of 84.2% (16/19). The R0 resection rate was 81.3% (13/16). During NAC, 8 (42.1%, 8/19) patients experienced different grades of AEs, mainly including grade 2 myelosuppression (26.3%), cutaneous pruritus (5.3%), and diarrhea (5.3%). scRNA-seq analysis of duct cells showed that the transcriptome in aneuploid cells may affect gemcitabine resistance via multiple pathways, among which up-regulation of drug-resistant genes (OLFM4, AGR2, MUC5AC, MUC1, HMGA1, REG4, IL17RB, GCNT3, AKR1B10, ITGA6, HMGCS2, and SQLE) and down-regulation of sensitive genes (SIK1, HEXIM1, SPINT2, GADD45 and TIMP2) played crucial roles. Changes in the interactions between cancer cells and other cell groups may also involve in gemcitabine resistance.

Conclusion: PDO-based NAC shows a promising resectable rate in BRPC patients, with good tolerance. Potential drug-resistant and sensitive genes and cell-cell interaction changes may participate in the development of gemcitabine resistance.

精确新辅助化疗治疗边缘性可切除胰腺癌的临床疗效和化疗耐药分析:一项前瞻性单臂先导研究。
背景:新辅助化疗(NAC)可以改善胰腺癌患者的生存结果,但对于边缘可切除的胰腺癌(BRPC),转化为手术的比例仍然不理想。这项单臂先导研究旨在评估基于患者源性类器官(PDOs)的NAC治疗BRPC的临床疗效和安全性。方法:采集BRPC患者活检标本,生成pdo。吉西他滨联合nab-紫杉醇(GnP)作为NAC初始给药一个周期,然后根据PDO药敏试验调整治疗方案。主要终点为客观缓解率(ORR)。次要终点包括R0切除率、nac相关不良事件(ae)和术后并发症。探索性目的是评估对吉西他滨的化学耐药性。结果:25例患者中有19例符合研究条件,其中16例获得部分缓解并接受手术切除,ORR为84.2%(16/19)。R0切除率为81.3%(13/16)。NAC期间,8例(42.1%,8/19)患者出现不同程度的ae,主要包括2级骨髓抑制(26.3%)、皮肤瘙痒(5.3%)和腹泻(5.3%)。对导管细胞进行scRNA-seq分析发现,非整倍体细胞的转录组可能通过多种途径影响吉西他滨耐药,其中耐药基因(OLFM4、AGR2、MUC5AC、MUC1、HMGA1、REG4、IL17RB、GCNT3、AKR1B10、ITGA6、HMGCS2、SQLE)的上调和敏感基因(SIK1、HEXIM1、SPINT2、GADD45、TIMP2)的下调发挥了至关重要的作用。癌细胞和其他细胞群之间相互作用的改变也可能与吉西他滨耐药有关。结论:基于pdo的NAC在BRPC患者中具有良好的切除率和耐受性。潜在的耐药和敏感基因以及细胞间相互作用的变化可能参与了吉西他滨耐药的发展。
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来源期刊
CiteScore
17.70
自引率
3.30%
发文量
0
审稿时长
6-12 weeks
期刊介绍: The International Journal of Surgery (IJS) has a broad scope, encompassing all surgical specialties. Its primary objective is to facilitate the exchange of crucial ideas and lines of thought between and across these specialties.By doing so, the journal aims to counter the growing trend of increasing sub-specialization, which can result in "tunnel-vision" and the isolation of significant surgical advancements within specific specialties.
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