Implementing Real-World RECIST-based Tumor Response Assessment in Patients With Metastatic Non-small Cell Lung Cancer

BackgroundTo accelerate drug approvals while maintaining scientific rigor in the evaluation of a therapeutic's efficacy and safety, the United States Food and Drug Administration now considers real-world data (RWD) to support New Drug Applications and expanded indications. Response Evaluation Criteria in Solid Tumors (RECIST) are the gold standard in clinical trials, but the derivation of RECIST-based treatment response from RWD is unproven. This study investigated the feasibility of implementing RECIST criteria in RWD by comparing lung cancer response assessments from RECIST-based measurement of lesions on archived radiologic films with results from medical oncologist and radiologist narratives recorded in electronic health records (EHR).Materials and MethodsResponse to index treatment via different assessment approaches was compared among 30 metastatic non-small cell lung cancer (mNSCLC) patients receiving systemic treatment (index) after progression on a platinum or anti-PD(L)-1-containing regimen. Specifically, responses based on assessments documented in the medical oncologists’ narratives were compared to a radiologist's assessments of archived images using RECIST v1.1 criteria. Each patient's best overall response was characterized as complete or partial (CR/PR), stable disease (SD), progressive disease (PD), or not evaluable (NE).ResultsSimilar distributions of best overall response and substantial concordance (77%) between medical oncologist-reported and radiologist re-assessed responses were observed. There were no instances of CR/PR to PD or PD to CR/PR discordance.ConclusionsResults suggest that accurate treatment responses, similar to RECIST, may be derived using RWD. Further validation and improvement of real-world response assessment are needed to develop a scalable real-world approach for response assessment.     

TRIM59 通过结合 BCLAF1 调控人皮肤黑色素瘤 SK-MEL-2 细胞的恶 性生物学行为

目的：探究三结构域蛋白59（TRIM59）调控人皮肤黑色素瘤细胞SK-MEL-2增殖、细胞周期、凋亡及迁移侵袭的作用机制，及其与Bcl2相关转录因子1（BCLAF1)之间的关系。方法：qPCR和WB法检测人表皮黑色素细胞HEMn-LP、人皮肤黑色素瘤细胞SK-MEL-2、UACC903、A375及36例邢台市人民医院2019年2月至2021年7月收集的皮肤黑色素瘤组织中TRIM59的mRNA和蛋白表达，使用脂质体将si-con、si-TRIM59转染至SK-MEL-2细胞中，WB法检测干扰TRIM59表达对细胞中周期蛋白D1（CCND1）、细胞周期素依赖性激酶2（CDK2）、肿瘤抑制蛋白基因（TP53）和 BCLAF1 蛋白表达的影响，CCK-8法、流式细胞术、划痕愈合实验、Transwell实验检测对细胞的活性、凋亡、迁移和侵袭的影响，免疫共沉淀（Co-IP）实验检测对细胞中TRIM59蛋白与BCLAF1结合能力的影响。结果：与HEMn-LP细胞相比，SK-MEL-2、UACC903、A375细胞中TRIM59 mRNA和TRIM59、BCLAF1蛋白均呈高表达（均P<0.05），SK-MEL-2细胞中TRIM59表达水平最高。相较于si-con组和Normal组，沉默TRIM59后，SK-MEL-2细胞的活性显著降低，细胞周期阻滞于G2期，CCND1、CDK2的蛋白表达显著降低，TP53蛋白和细胞凋亡率均显著升高，划痕抑制率明显升高，迁移侵袭细胞数明显降低（均P<0.05）。免疫共沉淀实验结果显示，TRIM59与BCLAF1之间存在蛋白结合关系。TRIM59与 BCLAF1 在肿瘤组织中的表达呈显著的正相关（r=0.878，P<0.001）。结论：干扰TRIM59表达能够抑制人皮肤黑色素瘤SK-MEL-2细胞的增殖、迁移和侵袭而促进凋亡，抑制SK-MEL-2细胞的恶性生物学行为，其机制可能与TRIM59结合BCLAF1有关。     

Neutrophil-to-Lymphocyte Ratio Predicts Cancer Outcome in Locally Advanced Clear Renal Cell Carcinoma

BackgroundTo evaluate the association of neutrophil-to-lymphocyte ratio (NLR) with recurrence-free survival (RFS) and overall survival (OS) in patients with locally advanced nonmetastatic clear cell renal cell carcinoma (ccRCC) undergoing radical nephrectomy.Material and MethodsWe retrospectively identified 880 nephrectomies performed between January 2009 and December 2016 in a single center, reviewed data from 478 radical nephrectomies for kidney tumors and identified 187 patients with locally advanced nonmetastatic ccRCC (pT3-T4 N0M0). NLR was obtained preoperatively and calculated by dividing absolute neutrophil count by absolute lymphocyte count. OS and RFS were evaluated by the Kaplan–Meier method. Cox proportional-hazards regression models were used to evaluate predictors of RFS and OS.ResultsAmong 187 patients with ccRCC (mean age 63.4 ± 11.5 years; 118 [63.1%] male), the median follow-up was 48.7 months. On univariate analysis, in patients with Fuhrman nuclear grade of differentiation 3-4, the median time to recurrence was significantly shorter with NLR ≥ 4 than < 4 (24 vs. 55 months, P = .045). On multivariable analysis adjusted for NLR ≥ 4, among all variables analyzed (NLR, microvascular invasion, sarcomatoid differentiation, tumor size and body mass index), only nuclear grade of differentiation was an independent predictor of recurrence (hazard ratio 2.18; 95% confidence interval 1.07-4.92, P = .03). The 3-year OS had no statistically significant difference between patients with NLR ≥ 4 or < 4.ConclusionFor patients with locally advanced, nonmetastatic ccRCC, RFS was reduced with high nuclear grade of differentiation and high preoperative NLR. These findings suggest an association between higher NLR and worse outcomes in locally advanced ccRCC.