Objective: To investigate the correlation between 18Fluoro-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic parameters and peripheral blood circulating tumour DNA (ctDNA) in patients with diffuse large B-cell lymphoma (DLBCL), and the prognostic value of these two types of parameters in predicting progression-free survival (PFS).
Methods: Clinical, PET/CT and ctDNA data of DLBCL patients who underwent peripheral blood ctDNA testing and corresponding PET/CT scans during the same period were retrospectively analyzed. At the time of ctDNA sampling and PET scan, patients were divided into baseline and relapsed/refractory (R/R) groups according to different disease conditions. CtDNA mutation abundance was expressed as variant allele frequency (VAF), including maximum VAF (maxVAF) and mean VAF (meanVAF). Total metabolic tumour volume (TMTV) and total lesion glycolysis (TLG) were obtained by the 41% maximum normalized uptake value method, and the distance between the two farthest lesions (Dmax) was used to assess the correlation between PET parameters and ctDNA mutation abundance using Spearman correlation analysis. The receiver operating characteristic (ROC) curves were used to obtain the optical cut-off values of those parameters in predicting PFS in the baseline and R/R groups, respectively. Survival curves were outlined using the Kaplan-Meier method and log-rank test was performed to compare survival differences.
Results: A total of 67 DLBCL patients ［28 males and 39 females, median age 56.0(46.0, 67.0) years］ were included and divided into baseline group (29 cases) and R/R group (38 cases). Among these PET parameters, baseline TMTV, TLG, and Dmax were significantly correlated with baseline ctDNA mutation abundance, except for maximum standardized uptake value (SUVmax) (maxVAF vs TMTV: r=0.711; maxVAF vs TLG: r=0.709; maxVAF vs Dmax: r=0.672; meanVAF vs TMTV: r=0.682; meanVAF vs TLG: r=0.677; meanVAF vs Dmax: r=0.646). While in all patients, these correlations became weaker significantly. Among R/R patients, only TMTV had a weak correlation with meanVAF (r=0.376). ROC analysis showed that, the specificity of TMTV, TLG and Dmax in predicting PFS was better than mutation abundance, while the sensitivity of ctDNA mutation abundance was better. Except R/R patients, TMTV, TLG, Dmax, and VAF were significantly different at normal/elevated lactate dehydrogenase in baseline group and all patients (all P<0.05). Survival curves indicated that high TMTV (>109.5 cm3), high TLG (>2 141.3), high Dmax (>33.1 cm) and high VAF (maxVAF>7.74%, meanVAF>4.39%) were risk factors for poor PFS in baseline patients, while only high VAF in R/R patients (both maxVAF and meanVAF >0.61%) was a risk factor for PFS.
Conclusion: PET-derived parameters correlate well with ctDNA mutation abundance, especially in baseline patients. VAF of ctDNA predicts PFS more sensitively than PET metabolic parameters, while PET metabolic tumour burden with better specificity. TMTV, TLG and VAF all have good prognostic value for PFS. PET/CT combined with ctDNA has potential for further studies in prognostic assessment and personalized treatment.
题目: 弥漫大B细胞淋巴瘤18F-FDG PET/CT代谢参数和循环肿瘤DNA突变丰度：相关性和生存分析.
目的: 探讨弥漫大B细胞淋巴瘤（DLBCL）患者18-氟-脱氧葡萄糖正电子发射断层显像/计算机断层扫描代谢参数与外周血循环肿瘤DNA（ctDNA）的相关性，以及这两类参数在预测无进展生存期（PFS）中的预后价值.
方法: 回顾性分析同期行外周血ctDNA检测及相应PET/CT扫描的DLBCL患者的临床、PET/CT及ctDNA资料。ctDNA取样及PET扫描时，根据疾病不同治疗及病情发展情况，将患者分为基线组和复发/难治性（R/R）组。ctDNA突变丰度以变异等位基因频率（VAF）表示，包括最大VAF（maxVAF）和平均VAF（meanVAF）。以41%最大标准化摄取值方法获得总代谢肿瘤体积（TMTV）和糖酵解总量（TLG），并获得两最远病灶距离（Dmax），采用Spearman相关分析评估PET参数与ctDNA突变丰度的相关性。在基线及R/R组中分别采用受试者工作特征（ROC）曲线获得这些参数和预测PFS的最佳截断值。采用Kaplan-Meier法勾画生存曲线并行log-rank检验比较生存差异.
结果: 共纳入67例DLBCL患者，男性33例，女性34例，中位年龄为56.0（46.0，67.0）岁，基线组29例，R/R组38例。PET参数中，除最大标准化摄取值（SUVmax）外，基线TMTV、TLG、Dmax均与基线ctDNA突变丰度显著相关（maxVAF vs TMTV：r=0.711；maxVAF vs TLG：r=0.709；maxVAF vs Dmax：r=0.672；meanVAF vs TMTV：r=0.682；meanVAF vs TLG：r=0.677；meanVAF vs Dmax：r=0.646），而在全部患者中，以上相关性明显减弱。在R/R患者中，仅TMTV与meanVAF具有较弱的相关性（r=0.376）。对各参数进行ROC分析结果表明，TMTV、TLG和Dmax预测PFS的特异性优于突变丰度，而ctDNA突变丰度的敏感性更好。除R/R患者外，在基线患者和全体患者中可观察到在不同乳酸脱氢酶水平下，TMTV、TLG、Dmax、VAF均具有显著差异（均P<0.05）。生存曲线表明，基线患者中，高TMTV（>109.5 cm3）、高TLG（>2 141.3）、高Dmax（>33.1 cm）及高VAF（maxVAF>7.74%、meanVAF>4.39%）均是不良PFS的危险因素，而在R/R患者中仅高VAF（maxVAF和meanVAF均>0.61%）是影响PFS的危险因素.
结论: PET衍生参数与ctDNA突变丰度相关性良好，尤其是在基线患者中。ctDNA的VAF预测PFS较PET代谢参数更敏感，而PET代谢肿瘤负荷具有更好的特异性。TMTV、TLG和VAF均对PFS有良好的预后价值。PET/CT联合ctDNA在预后评估和个性化治疗方面有进一步研究的潜力.
Keywords: circulating tumour DNA; diffuse large B-cell lymphoma; fluorodeoxyglucose; mutation abundance; positron emission tomography/computed tomography.