Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

BACKGROUND The efficacy and safety of transarterial chemoembolization(TACE)combined with lenvatinib plus programmed cell death protein-1(PD-1)for unresectable hepato-cellular carcinoma(HCC)have rarely been evaluated and it is unknown which factors are related to efficacy.AIM To evaluate the efficacy and independent predictive factors of TACE combined with lenvatinib plus PD-1 inhibitors for unresectable HCC.METHODS This study retrospectively enrolled patients with unresectable HCC who received TACE/lenvatinib/PD-1 treatment between March 2019 and April 2022.Overall survival(OS)and progression-free survival(PFS)were determined.The objective response rate(ORR)and disease control rate(DCR)were evaluated in accordance with the modified Response Evaluation Criteria in Solid Tumors.Additionally,the prognostic factors affecting the clinical outcome were assessed.RESULTS One hundred and two patients were enrolled with a median follow-up duration of 12.63 months.The median OS was 26.43 months(95%CI:17.00-35.87),and the median PFS was 10.07 months(95%CI:8.50-11.65).The ORR and DCR were 61.76%and 81.37%,respectively.The patients with Barcelona Clinic Liver Cancer Classification(BCLC)B stage,early neutrophil-to-lymphocyte ratio(NLR)response(decrease),or early alpha-fetoprotein(AFP)response(decrease>20%)had superior OS and PFS than their counterparts.CONCLUSION This study showed that TACE/lenvatinib/PD-1 treatment was well tolerated with encouraging efficacy in patients with unresectable HCC.The patients with BCLC B-stage disease with early NLR response(decrease)and early AFP response(decrease>20%)may achieve better clinical outcomes with this triple therapy.

Cytokine release syndrome triggered by programmed death 1 blockade(sintilimab)therapy in a psoriasis patient:A case report

BACKGROUND In recent years,immune checkpoint inhibitors(ICIs)have demonstrated remarkable efficacy across diverse malignancies.Notably,in patients with advanced gastric cancer,the use of programmed death 1(PD-1)blockade has significantly prolonged overall survival,marking a pivotal advancement comparable to the impact of Herceptin over the past two decades.While the therapeutic benefits of ICIs are evident,the increasing use of immunotherapy has led to an increase in immune-related adverse events.CASE SUMMARY This article presents the case of a patient with advanced gastric cancer and chronic plaque psoriasis.Following sintilimab therapy,the patient developed severe rashes accompanied by cytokine release syndrome(CRS).Fortunately,effective management was achieved through the administration of glucocorticoid,tocilizumab,and acitretin,which resulted in favorable outcomes.CONCLUSION Glucocorticoid and tocilizumab therapy was effective in managing CRS after PD-1 blockade therapy for gastric cancer in a patient with chronic plaque psoriasis.

Assessment of programmed death-ligand 1 expression in primary tumors and paired lymph node metastases of gastric adenocarcinoma

BACKGROUND Anti-programmed death-1/programmed death-ligand 1(PD-1/PD-L1)immuno-therapy has demonstrated promising results on gastric cancer(GC).However,PD-L1 can express differently between metastatic sites and primary tumors(PT).AIM To compare PD-L1 status in PT and matched lymph node metastases(LNM)of GC patients and to determine the correlation between the PD-L1 status and clinicopathological characteristics.METHODS We retrospectively reviewed 284 GC patients who underwent D2-gastrectomy.PD-L1 was evaluated by immunohistochemistry(clone SP142)using the com-bined positive score.All PD-L1+PT staged as pN+were also tested for PD-L1 expression in their LNM.PD-L1(-)GC with pN+served as the comparison group.RESULTS Among 284 GC patients included,45 had PD-L1+PT and 24 of them had pN+.For comparison,44 PD-L1(-)cases with pN+were included(sample loss of 4 cases).Of the PD-L1+PT,54.2%(13/24 cases)were also PD-L1+in the LNM.Regarding PD-L1(-)PT,9.1%(4/44)had PD-L1+in the LNM.The agreement between PT and LNM had a kappa value of 0.483.Larger tumor size and moderate/severe peritumoral inflammatory response were associated with PD-L1 positivity in both sites.There was no statistical difference in overall survival for PT and LNM according to the PD-L1 status(P=0.166 and P=0.837,respectively).CONCLUSION Intra-patient heterogeneity in PD-L1 expression was observed between the PT and matched LNM.This disagreement in PD-L1 status may emphasize the importance of considering different tumor sites for analyses to select patients for immunotherapy.

Unresectable hepatocellular carcinoma:Transarterial chemoembolization combined with lenvatinib in combination with programmed death-1 inhibition is a possible approach

In this editorial,we review the article“Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma”.We specifically focused on whether transarterial chemoembolization combined with lenvatinib in combination with a programmed death 1 inhibitor could be used in patients with unresectable hepatocellular carcinoma.Since both transarterial chemoembolization as well as lenvatinib in combination with programmed death 1 inhibitors play an important role in the treatment of advanced liver cancer,but the combination of all three therapeutic approaches needs more research.

Roles of the tumor microenvironment in the resistance to programmed cell death protein 1 inhibitors in patients with gastric cancer

Despite the continuous developments and advancements in the treatment of gastric cancer(GC),which is one of the most prevalent types of cancer in China,the overall survival is still poor for most patients with advanced GC.In recent years,with the progress in tumor immunology research,attention has shifted toward immunotherapy as a therapeutic approach for GC.Programmed cell death protein 1(PD-1)inhibitors,as novel immunosuppressive medications,have been widely utilized in the treatment of GC.However,many patients are still resistant to PD-1 inhibitors and experience recurrence in the advanced stages of PD-1 immunotherapy.To reduce the occurrence of drug resistance and recurrence in GC patients receiving PD-1 immunotherapy,to maximize the clinical activity of immunosuppressive drugs,and to elicit a lasting immune response,it is essential to research the tumor microenvironment mechanisms leading to PD-1 inhibitor resistance in GC patients.This article reviews the progress in studying the factors influencing the resistance to PD-1 inhibitors in the GC tumor microenvironment,aiming to provide insights and a basis for reducing resistance to PD-1 inhibitors for GC patients in the future.

Efficacy of chemotherapy containing bevacizumab in patients with metastatic colorectal cancer according to programmed cell death ligand 1

BACKGROUND Bevacizumab,an anti-vascular endothelial growth factor(VEGF)monoclonal antibody,inhibits angiogenesis and reduces tumor growth.Serum VEGF-C,lactate dehydrogenase,and inflammatory markers have been reported as predictive markers related to bevacizumab treatment.Programmed cell death ligand 1(PD-L1)could act upon VEGF receptor 2 to induce cancer cell angiogenesis and metastasis.AIM To investigate the efficacy of bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer(CRC)according to the expression of PD-L1.METHODS This analysis included CRC patients who received bevacizumab plus FOLFOX or FOLFIRI as first-line therapy between June 24,2014 and February 28,2022,at Samsung Medical Center(Seoul,South Korea).Analysis of patient data included evaluation of PD-L1 expression by the combined positive score(CPS).We analyzed the efficacy of bevacizumab according to PD-L1 expression status in patients with CRC.RESULTS A total of 124 patients was included in this analysis.Almost all patients were treated with bevacizumab plus FOLFIRI or FOLFOX as the first-line chemotherapy.While 77%of patients received FOLFOX,23%received FOLFIRI as backbone first-line chemotherapy.The numbers of patients with a PD-L1 CPS of 1 or more,5 or more,or 10 or more were 105(85%),64(52%),and 32(26%),respectively.The results showed no significant difference in progression-free survival(PFS)and overall survival(OS)with bevacizumab treatment between patients with PDL1 CPS less than 1 and those with PD-L1 CPS of 1 or more(PD-L1<1%vs PD-L1≥1%;PFS:P=0.93,OS:P=0.33),between patients with PD-L1 CPS less than 5 and of 5 or more(PD-L1<5%vs PD-L1≥5%;PFS:P=0.409,OS:P=0.746),and between patients with PD-L1 CPS less than 10 and of 10 or more(PD-L1<10%vs PD-L1≥10%;PFS:P=0.529,OS:P=0.568).CONCLUSION Chemotherapy containing bevacizumab can be considered as first-line therapy in metastatic CRC irrespective of PD-L1 expression.

Drug-eluting beads chemoembolization combined with programmed cell death 1 inhibitor and lenvatinib for large hepatocellular carcinoma

BACKGROUND The combination of transarterial chemoembolization(TACE),lenvatinib,and programmed cell death 1(PD-1)inhibitor has been widely used in the treatment of advanced hepatocellular carcinoma(HCC)and has achieved promising results.However,there are few studies comparing whether drug-eluting beads TACE(DTACE)can bring more survival benefits to patients with large HCC compared to conventional TACE(C-TACE)in this triplet therapy.AIM To compare the efficacy and adverse events(AEs)of triple therapy comprising DTACE,PD-1 inhibitors,and lenvatinib(D-TACE-P-L)and C-TACE,PD-1 inhibitors,and lenvatinib(C-TACE-P-L)in patients with large HCC(maximum diameter≥5 cm),and analyze the prognostic factors.METHODS Following a comprehensive review of our hospital’s medical records,this retrospective study included 104 patients:50 received D-TACE-P-L,and 54 received CTACE-P-L.We employed Kaplan-Meier estimation to assess the median progression-free survival(PFS)between the two groups,utilized Cox multivariate regression analysis to identify prognostic factors,and applied theχ2 test to evaluate AEs.RESULTS The objective response rate(ORR)and median PFS were significantly higher in the D-TACE-P-L group compared to the C-TACE-P-L group(ORR:66.0%vs 44.4%,P=0.027;median PFS:6.8 months vs 5.0 months,P=0.041).Cox regression analysis identified treatment option,portal vein tumor thrombus,and hepatic vein invasion as protective factors for PFS.AEs were comparable between the two CONCLUSION D-TACE-P-L may have significantly better PFS and ORR for large HCC,while exhibiting similar AEs to C-TACE-PL.

Effectiveness and tolerability of programmed cell death protein-1 inhibitor+chemotherapy compared to chemotherapy for upper gastrointestinal tract cancers

BACKGROUND The combination of programmed cell death protein-1(PD-1)inhibitor and che-motherapy is approved as a standard first-or second-line treatment in patients with advanced oesophageal or gastric cancer.However,it is unclear whether this combination is superior to chemotherapy alone.AIM To assess the comparative effectiveness and tolerability of combining PD-1 inhibitors with chemotherapy vs chemotherapy alone in patients with advanced gastric cancer,gastroesophageal junction(GEJ)cancer,or oesophageal carcinoma.METHODS We searched the PubMed and Embase databases for studies that compared the efficacy and tolerance of PD-1 inhibitors in combination with chemotherapy vs chemotherapy alone in patients with advanced oesophageal or gastric cancer.We employed either random or fixed models to analyze the outcomes of each clinical trial,en-compassing data on overall survival(OS),progression-free survival(PFS),objective response rate,and adverse events(AEs).RESULTS Nine phase 3 clinical trials(7016 advanced oesophageal and gastric cancer patients)met the inclusion criteria.Our meta-analysis demonstrated that the pooled PD-1 inhibitor+chemotherapy group had a significantly longer OS than the chemotherapy-alone group[hazard ratio(HR)=0.76,95%confidence interval(CI):0.71-0.81];the pooled PFS result was consistent with that of OS(HR=0.67,95%CI:0.61-0.74).The count of patients achieving an objective response in the PD-1 inhibitor+chemotherapy group surpassed that of the chemotherapy-alone group[odds ratio(OR)=1.86,95%CI:1.59-2.18].AE incidence was also higher in the combination-therapy group than in the chemotherapy-alone group,regardless of whether≥grade 3 only(OR=1.30,95%CI:1.07-1.57)or all AE grades(OR=1.88,95%CI:1.39-2.54)were examined.We performed a subgroup analysis based on the programmed death-ligand 1(PD-L1)combined positive score(CPS)and noted extended OS and PFS durations within the CPS≥1,CPS≥5,and CPS≥10 subgroups of the PD-1 inhibitor+chemotherapy group.CONCLUSION In contrast to chemotherapy alone,the combination of PD-1 inhibitor and chemotherapy appears to present a more favorable option for initial or subsequent treatment in patients with gastric cancer,GEJ tumor,or oesophageal cancer.This holds true particularly for individuals with PD-L1 CPS scores of≥5 and≥10.

Programmed cell death 1 inhibitor sintilimab plus concurrent chemoradiotherapy for locally advanced pancreatic adenocarcinoma

BACKGROUND Pancreatic adenocarcinoma,a malignancy that arises in the cells of the pancreas,is a devastating disease with unclear etiology and often poor prognosis.Locally advanced pancreatic cancer,a stage where the tumor has grown significantly but has not yet spread to distant organs,presents unique challenges in treatment.This article aims to discuss the current strategies,challenges,and future directions in the management of locally advanced pancreatic adenocarcinoma(LAPC).AIM To investigate the feasibility and efficacy of programmed cell death 1(PD-1)inhibitor sintilimab plus concurrent chemoradiotherapy for LAPC.METHODS Eligible patients had LAPC,an Eastern cooperative oncology group performance status of 0 or 1,adequate organ and marrow functions,and no prior anticancer therapy.In the observation group,participants received intravenous sintilimab 200 mg once every 3 wk,and received concurrent chemoradiotherapy(concurrent conventional fractionated radiotherapy with doses planning target volume 50.4 Gy and gross tumor volume 60 Gy in 28 fractions and oral S-140 mg/m2 twice daily on days 1-14 of a 21-d cycle and intravenous gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-d cycle for eight cycles until disease progression,death,or unacceptable toxicity).In the control group,participants only received concurrent chemoradiotherapy.From April 2020 to November 2021,64 participants were finally enrolled with 34 in the observation group and 30 in the control group.RESULTS Thirty-four patients completed the scheduled course of chemoradiotherapy,while 32(94.1%)received sintilimab plus concurrent chemoradiotherapy with 2 patients discontinuing sintilimab in the observation group.Thirty patients completed the scheduled course of chemoradiotherapy in the control group.Based on the Response Evaluation Criteria in Solid Tumors guidelines,the analysis of the observation group revealed that a partial response was observed in 11 patients(32.4%),stable disease was evident in 19 patients(55.9%),and 4 patients(11.8%)experienced progressive disease;a partial response was observed in 6(20.0%)patients,stable disease in 18(60%),and progressive disease in 6(20%)in the control group.The major toxic effects were leukopenia and nausea.The incidence of severe adverse events(AEs)(grade 3 or 4)was 26.5%(9/34)in the observation group and 23.3%(7/30)in the control group.There were no treatment-related deaths.The observation group demonstrated a significantly longer median overall survival(22.1 mo compared to 15.8 mo)(P<0.05)and progression-free survival(12.2 mo vs 10.1 mo)(P<0.05)in comparison to the control group.The occurrence of severe AEs did not exhibit a statistically significant difference between the observation group and the control group(P>0.05).CONCLUSION Sintilimab plus concurrent chemoradiotherapy was effective and safe for LAPC patients,and warrants further investigation.

Advances on biological evaluation methods of programmed cell death protein-1/ligand-1 inhibitors

Immuno-oncology represents a groundbreaking and well-established field within cancer treatment.Among the various immuno-oncology targets,the exploration of programmed cell death-1/ligand-1 for drug discovery has proven to be one of the most successful endeavors.Remarkably,it took nearly 30 years from the initial target identification to the clinical approval of monoclonal antibodies.Providing suitable and reliable bioassays for drug candidate evaluation is of paramount importance throughout the early stages of drug discovery,from lead compound identification to in vivo efficacy testing.This assay review aims to shed light on diverse assays reported in the literature for testing antagonism activity and efficacy of programmed cell death-1/ligand-1 inhibitors.Each of these assays possesses inherent advantages and can be applied in different research scenarios.The insights presented in this summary can serve as a valuable resource for scientists in this field,aiding in the selection of appropriate assays for their specific investigations.

Clinical outcomes of lenvatinib plus transarterial chemoembolization with or without programmed death receptor-1 inhibitors in unresectable hepatocellular carcinoma

BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.

血清中PD-L1含量与胃癌病人预后的关系

目的:分析胃癌病人血清中程序性死亡配体1(programmed death-ligand 1,PD-L1)含量及其与肿瘤分期和预后的关系。方法:收集我院2018年8月至2019年12月60例胃癌病人血清,15例健康成人血清作为对照,通过酶联免疫吸附试验(ELISA)检测血清PD-L1的含量,比较胃癌病人与健康成人血清PD-L1含量的差异,分析胃癌病人血清PD-L1的含量与病期及预后的关系。免疫组织化学检测肿瘤组织内PD-L1的表达情况,并分析其与血清中PD-L1含量的相关性。结果:胃癌组血清中PD-L1的含量明显高于对照组。Ⅲ、Ⅳ期胃癌病人血清PD-L1含量明显高于Ⅰ、Ⅱ期胃癌病人。胃癌病人合并腹膜转移者血清PD-L1含量明显升高,提示预后不良。生存分析显示,血清PD-L1含量高的胃癌病人生存期明显短于低者。检测肿瘤组织标本中PD-L1的表达水平,发现其与血清中PD-L1含量无明显相关性。结论:胃癌病人血清中PD-L1含量高于健康成人。随病期进展逐渐升高。胃癌伴腹膜转移的病人血清中PD-L1升高明显。血清中PD-L1含量与肿瘤组织中的PD-L1表达不相关。

ITP患者PD-1/PD-L1表达特点及其在Treg与Breg细胞之间的相互作用机制分析

目的探讨原发免疫性血小板减少症(ITP)患者细胞程序性死亡受体-1(PD-1)/细胞程序性死亡配体1(PD-L1)表达特点及其在调节性T细胞(Treg)、调节性B细胞(Breg)间的相互作用。方法选取2018年12月—2022年1月在我院治疗的ITP患者106例作为观察组,其中轻度患者32例,中度患者44例,重度患者30例。同时选取同期健康志愿者100例作为对照组。检测两组Treg细胞百分比、Breg细胞百分比、Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率等,同时分析观察组不同病情程度患者各指标差异。结果观察组Breg细胞百分比、Treg细胞百分比、TGF-β、IL-10和IL-4水平均明显低于对照组(P<0.05);观察组Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率、可溶性程序性细胞死亡蛋白-1(sPD-1)和IL-17水平均明显高于对照组(均P<0.05);两组可溶性程序性细胞死亡蛋白配体-1(sPD-L1)水平比较差异无统计学意义(P>0.05)。观察组重度患者Breg细胞百分比、Treg细胞百分比均明显低于轻度和中度患者(均P<0.05),而Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率均明显高于轻度和中度患者(均P<0.05)。Treg细胞表面PD-1阳性率与Breg细胞表面PD-L1阳性率呈正相关(r=0.446,P<0.05)。观察组治疗后Breg细胞百分比、Treg细胞百分比、TGF-β、IL-10和IL-4水平有所升高(P<0.05),而Treg细胞表面PD-1阳性率、Breg细胞表面PD-L1阳性率、sPD-1和IL-17水平有所降低(P<0.05),治疗前后sPD-L1水平比较差异无统计学意义(P>0.05)。结论ITP患者Treg细胞表面PD-1和Breg细胞表面PD-L1阳性率明显升高,与患者病情严重程度呈正相关,同时Treg细胞表面PD-1和Breg细胞表面PD-L1表达之间存在相关性。

炎调方通过PD-1/PD-L1通路抑制脓毒症大鼠T淋巴细胞衰竭的实验研究

目的研究炎调方对脓毒症大鼠T淋巴细胞及T淋巴细胞表面表面程序性死亡蛋白(PD-1)、程序性死亡蛋白配体(PD-L1)表达的影响。方法SD大鼠(雄性)分为正常组、假手术组、模型组和炎调方组。盲肠结扎穿孔(CLP)制备脓毒症大鼠模型,于造模后12、24、48、72 h采集外周血处死大鼠(每个时间点各5只大鼠),采用流式细胞分析法测定CD3^(+)、CD4^(+)、CD8^(+)比例;双抗体夹心酶联免疫吸附法(ELISA)测定CD4^(+)及CD8^(+)表面PD-1、PD-L1表达水平。结果白介素-6(IL-6)在脓毒症模型组12 h分泌达到高峰后逐渐下降,降钙素原(PCT)在模型组24 h达到高峰后逐渐下降;炎调方组在12 h降低IL-6的水平(P<0.05),24 h时明显降低IL-6、PCT的水平(P<0.01)。模型组CD3^(+)、CD4^(+)、CD8^(+)比例早期分泌开始减少,48 h分泌达最低点(P<0.01);炎调方组在48 h时可升高CD3^(+)、CD4^(+)、CD8^(+)比例,提高CD4^(+)/CD8^(+)的比值而具体调节T细胞活化和增殖的功能。模型组CD4^(+)、CD8^(+)表面PD-1、PD-L1表达水平早期24 h即表达增多(P<0.01),72 h表达最多;炎调方组24 h时即可抑制PD-1、PD-L1的表达水平而具体改善T细胞衰竭的作用。CD4^(+)的比例与CD4^(+)表面PD-1、PD-L1的表达呈负相关(P<0.01);CD8^(+)比例与CD8^(+)表面PD-1、PD-L1的表达呈负相关(P<0.01)。结论脓毒症早期48 h内即出现了T细胞活化和增殖的功能衰竭引起的T细胞免疫抑制。炎调方能在脓毒症早期改善T细胞活化和增殖的功能,其机制可能与抑制PD-1/P-L1通路有关。

急性髓系白血病患儿柔红霉素耐药与PD-L1蛋白表达相关

目的研究急性髓系白血病(AML)患儿柔红霉素(DNR)耐药与程序性死亡受体配体-1(PD-L1)蛋白表达的相关性。方法选取2016年1月至2022年12月郑州大学附属儿童医院收治的110例AML患儿骨髓样本作为研究组,以50名骨髓正常供体骨髓样本作为对照组。培养人AML细胞系HL60、THP-1、U-937、Molm-13,Western blot检测PD-L1蛋白表达量。构建LV-PD-L1-shRNA、LV-PD-L1-WT-OE慢病毒载体,分析PD-L1对Molm-13细胞DNR耐药的影响及机制。结果研究组PD-L1蛋白表达量高于对照组,AML细胞系中PD-L1蛋白表达量高于健康骨髓单个核细胞(BMMC)(P<0.05),PD-L1表达与AML患儿白细胞计数、骨髓原始细胞比率、预后危险分层、两个标准化学治疗方案后疾病缓解情况有关(P<0.05)。PD-L1高表达组总生存率低于PD-L1低表达组(P<0.05)。与LV-PD-L1-WT-OE组比较,LV-PD-L1-shRNA组PD-L1 mRNA表达量降低、细胞增殖活性降低、凋亡率升高(P<0.05),LV-PD-L1-shRNA可提高Molm-13细胞对DNR的敏感性。TCGA数据库分析显示,6-磷酸葡萄糖脱氢酶(G6PD)可能为PD-L1潜在的目标基因。结论PD-L1在儿童AML中高表达,与患儿化疗耐药有关,其可能通过调控G6PD引起DNR耐药。

PD1/PD-L1、中性粒细胞弹性蛋白酶、赖氨酰氧化酶在膀胱癌中的表达及其与膀胱癌预后的关系

目的探讨膀胱癌组织中程序性细胞死亡受体1(PD1)、程序性细胞死亡配体1(PD-L1)、中性粒细胞弹性蛋白酶(NE)、赖氨酰氧化酶(LOX)的表达水平及其表达差异与膀胱癌患者临床病理特征和预后的关系。方法选取2018年1月至2020年12月江西省人民医院收治的56例膀胱癌患者的癌组织作为研究对象,并记录患者的复发和死亡情况进行分析研究。采用免疫组织化学染色法检测PD1、PD-L1、NE、LOX的表达情况,分析PD1、PD-L1、NE、LOX与患者的病理特征和预后的关系。结果免疫组化结果显示PD1在肿瘤相关免疫细胞中存在表达(46/56);TNM分期T2-T3期、高级别肿瘤和出现淋巴结转移的患者PD1和PDL-1的表达阳性率均明显升高,差异有统计学意义(P<0.05)。NE与PD1、PDL-1的表达呈正相关(P<0.05);LOX与PD-L1、PDL-1的表达呈正相关(P<0.05)。PD1阳性表达患者3年无进展生存率为58.70%(27/46),PD-L1阳性表达患者3年无进展生存率为43.48%(10/23),不同PD1、PD-L1表达患者的3年无进展生存率比较差异有统计学意义(P<0.05)。结论膀胱癌组织中PD1、PD-L1表达增加可作为膀胱癌患者潜在的预后预测指标,有助于筛选术后复发的高危患者,并为膀胱癌的免疫学治疗提供新靶点。

基于MRI影像组学构建PD-1/PD-L1抑制剂治疗dMMR/MSI-H直肠癌疗效的预测模型

目的:探讨MRI影像组学模型在程序性细胞死亡蛋白-1(PD-1)/程序性细胞死亡-配体1(PD-L1)抑制剂联合全程新辅助治疗(TNT)局部进展期直肠癌(LARC)的疗效预测价值。方法:收集河南中医药大学第一附属医院PD-1/PD-L1抑制剂联合TNT治疗的80例错配修复基因缺陷(dMMR)/微卫星高度不稳定(MSI-H)基因型中低位LARC患者的临床和影像资料。将入组患者按7∶3比例分为训练集和测试集,提取影像组学特征,从中筛选并构建影像组学模型。描绘影像组学模型的Rad-score与病理金标准之间的受试者工作特征(ROC)曲线,计算曲线下面积(AUC),并评价模型的诊断效能。采用决策曲线分析(DCA)计算风险阈值的范围,并评估临床获益情况。收集湖南省人民医院25例dMMR/MSI-H基因型LARC患者的影像资料作为外部验证集。结果:训练集、测试集及外部验证集三者之间的临床特征无统计学差异(P>0.05)。经过降维处理、t检验及一致性检验以及LASSO交叉验证后,筛选出一阶偏度特征和体积2个特征构建影像组学模型。训练集、测试集和外部验证集的影像组学预测模型ROC曲线的AUC、灵敏度、特异度、阳性预测值和阴性预测值分别为0.920、97.1%、85.7%、91.9%、94.7%;0.885、80.0%、88.9%、92.3%、72.7%;0.875、87.5%、88.9%、93.3%、80.0%。DCA曲线显示,当风险阈值范围为0%~82%时,采用影像组学模型预测LARC患者为病理完全缓解(pCR)的获益大于将所有患者都视为pCR或者无病理完全缓解(npCR)。结论:基于MRI影像组学构建的dMMR/MSI-H型局部进展期直肠癌PD-1/PD-L1抑制剂联合全程新辅助放化疗疗效预测模型,有较大潜力为不同基因分型的直肠癌患者制定个体化治疗策略提供量化依据。

通窍汤加减对过敏性鼻炎模型大鼠血清sPD-L1与Tim-1表达的影响

目的:探讨通窍汤加减对过敏性鼻炎(AR)模型大鼠血清可溶性程序性死亡配体1(sPD-L1)、T细胞免疫球蛋白域黏蛋白域蛋白-1(Tim-1)表达的影响。方法:SPF级SD大鼠,建模成功后分为模型组、低剂量组、高剂量组以及地塞米松组。检测各组大鼠行为学评分,ELISA法检测IFN-γ、IL-4水平,H-E染色观察大鼠鼻黏膜组织病理学形态结构,Real time-PCR及免疫印迹检测sPD-L1、Tim-1 mRNA及蛋白表达。结果:与健康组相比,模型组行为学评分、IL-4水平、Tim-1 mRNA及蛋白表达均升高,IFN-γ水平、sPD-L1 mRNA及蛋白表达均降低;与模型组相比,低、高剂量组及地塞米松组行为学评分、IL-4水平、Tim-1 mRNA及蛋白表达均降低,IFN-γ水平、sPD-L1 mRNA及蛋白表达均升高;与低剂量组相比,高剂量组与地塞米松组行为学评分、IL-4水平、Tim-1mRNA及蛋白表达均降低,IFN-γ水平、sPD-L1mRNA及蛋白表达均升高;与高剂量组相比,地塞米松组行为学评分、IL-4水平、Tim-1 mRNA及蛋白表达均升高,IFN-γ水平、sPD-L1 mRNA及蛋白表达均降低。模型组可见鼻黏膜下层水肿,并有大量炎症细胞浸润;与模型组相比,低剂量组、高剂量组以及地塞米松组均有所改善。结论:通窍汤加减对模型AR大鼠具有提高血清sPD-L1水平,以及降低Tim-1水平和调控Th1/Th2水平比例的功效。

自然杀伤细胞2组成员A、程序性死亡因子配体1表达检测对PD-L1阻断免疫治疗肌层浸润性膀胱癌反应性的预测价值

目的:探究自然杀伤细胞2组成员A(NKG2A)及程序性死亡因子配体1(PD-L1)表达检测对PD-L1阻断免疫治疗肌层浸润性膀胱癌反应性的预测价值。方法:选取100例肌层浸润性膀胱癌患者作为研究对象,对其行PD-L1阻断免疫治疗后,根据治疗反应性将其分为缓解组和未缓解组;对缓解组患者随访3个月,将其分为复发组和未复发组。比较两组患者NKG2A和PD-L1在CD4^(+)和CD8^(+)上的表达水平,采用ROC曲线分析NKG2A和PD-L1预测膀胱癌患者治疗反应性的价值。结果:100例研究对象中,缓解组患者72例(72.00%),未缓解组患者28例(28.00%),两组性别、年龄比较无统计学差异(均P>0.05),但缓解组患者肿瘤直径小于未缓解组,NKG2A、PD-L1/CD4^(+)和PD-L1/CD8^(+)表达水平均低于未缓解组(均P<0.05)。膀胱癌患者NKG2A、PD-L1/CD4^(+)和PD-L1/CD8^(+)表达预测免疫治疗后缓解的AUC值分别为0.771、0.724、0.710;联合诊断的AUC为0.836。72例缓解患者中,出现复发29例(40.28%),未出现复发43例(59.72%),两组性别、年龄以及肿瘤直径比较无统计学差异(均P>0.05),但复发组NKG2A、PD-L1/CD4^(+)和PD-L1/CD8^(+)表达水平均高于未复发组(均P<0.05)。NKG2A、PD-L1/CD4^(+)和PD-L1/CD8^(+)表达预测膀胱癌患者缓解后复发的AUC值分别为0.775、0.740、0.728;联合诊断的AUC为0.874。结论:NKG2A、PD-L1/CD4^(+)和PD-L1/CD8^(+)在不同治疗反应性肌层浸润性膀胱癌患者外周血中表达水平不同,三者对于膀胱癌患者PD-L1阻断免疫治疗反应性均有一定的预测价值,且三者联合预测效能最佳。

血清SIRT1、sICAM-1及PD-L1联合检测对难治性弥漫性大B细胞淋巴瘤患者预后的评估效能

目的探讨血清沉默信息调节因子1(SIRT1)、可溶性细胞间黏附分子-1(sICAM-1)及细胞程序性死亡-配体1(PD-L1)联合检测对难治性弥漫性大B细胞淋巴瘤(DLBCL)患者预后的评估效能。方法选取2022年1月至2023年10月在郑州大学第一附属医院诊治的84例难治DLBCL患者作为研究对象,根据治疗后1个月的疾病状态将患者分为预后良好组(57例)和预后不良组(27例),收集患者的一般临床资料;采用酶联免疫吸附法(ELISA)检测患者血清SIRT1、sICAM-1及PD-L1水平;分析血清SIRT1、sICAM-1及PD-L1水平与患者临床特征、治疗效果及预后的关系;采用多因素logistic回归分析,筛选出患者预后不良的影响因素。绘制受试者工作特征(ROC)曲线,计算曲线下面积(AUC),评价血清SIRT1、sICAM-1及PD-L1水平对难治DLBCL患者预后的预测能力。结果预后不良组血清SIRT1、sICAM-1及PD-L1水平均高于预后良好组(P<0.05)。多因素logistic回归分析显示,血清SIRT1、sICAM-1及PD-L1水平是影响难治性DLBCL患者预后不良的独立危险因素(P<0.05);ROC结果显示,血清SIRT1、sICAM-1及PD-L1单独及三者联合预测难治性DLBCL患者预后不良的AUC分别为0.851、0.843、0.924、0.980,且三者联合的预测价值高于单独预测(P<0.05)。结论血清SIRT1、sICAM-1及PD-L1水平可作为难治DLBCL患者预后评估的重要指标,且三者联合检测的效能优于单项检测,对指导临床治疗及监测疾病进展有重要意义。