PD-1/PD-L1抑制剂在晚期肝细胞肝癌治疗中的研究进展

晚期原发性肝细胞肝癌(hepatocellular carcinoma,HCC)的系统治疗主要包括靶向治疗、化疗以及免疫治疗。近3年,程序性死亡受体-1(programmed death receptor-1,PD-1)/程序性死亡受体-1配体(programmed death receptor-1 ligand,PD-L1)抑制剂在晚期HCC治疗中取得突破性进展。纳武单抗(nivolumab)和帕博利珠单抗(pembrolizumab)先后被美国食品药品管理局(FDA)批准用于HCC二线治疗。多个PD-1/PD-L1抑制剂联合系统治疗的Ⅰ、Ⅱ期临床研究初步显示出较好的疗效和安全性。阿特珠单抗(atezolizumab)联合贝伐单抗一线治疗成为首个在Ⅲ期临床研究中证实优于现有标准治疗索拉非尼的全新疗法。本文就近年PD-1/PD-L1抑制剂在晚期HCC治疗中的研究进展进行概述。     

程序性死亡受体1/程序性死亡受体配体1抑制剂在三阴性乳腺癌治疗中的研究进展

三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型,具有较高的免疫原性、肿瘤浸润淋巴细胞（TIL）富集及程序性死亡受体配体1(PD-L1)表达的特点,其比多数其他类型的乳腺癌亚型患者可能更早开始受益于免疫检查点的封锁和治疗。目前,程序性死亡受体1(PD-1)/PD-L1已被批准作为一种辅助诊断指标。但PD-1/PD-L1抑制剂在TNBC治疗中的安全性、有效性、稳定性尚不明确。本文就免疫检查点抑制剂（ICI）单药及与化疗、分子靶向治疗和放疗联合治疗在TNBC中的研究进展进行综述。     

免疫治疗后进展的晚期非小细胞肺癌二线继续免疫治疗联合化疗的回顾性分析

摘 要：［目的］ 探讨一线程序性细胞死亡受体1(programmed cell death-1 receptor,PD-1)单抗进展后,二线继续PD-1单抗联合化疗治疗晚期非小细胞肺癌的临床疗效及预后。［方法］ 回顾性分析21例一线治疗采用PD-1单抗（帕博利珠单抗）联合或不联合含铂双联化疗治疗后进展,二线继续PD-1单抗（更换为信迪利单抗）联合化疗的晚期非小细胞肺癌。采用Kaplan-Meier生存曲线分析无进展生存期和总生存期,采用Cox回归模型进行多因素分析和评估预后因素。［结果］ 一线进展后更改为二线化疗方案并继续联合不同的PD-1单抗治疗,临床有效率为38.1%,疾病控制率为66.7%。程序性细胞死亡配体1(programmed cell death-1 ligand,PD-L1)表达阳性者和阴性者之间的疾病控制率并无统计学差异（P=0.217）。二线治疗的无进展生存时间（即二线治疗开始至疾病进展或死亡）为5.1个月。Cox多因素回归分析显示二线治疗的无进展生存时间与病理类型和PD-L1表达均无相关性。21例患者的中位总生存时间为17.6个月。Cox多因素回归分析显示,PD-L1表达是影响患者总生存的独立因素（HR=0.095,95%CI：0.018～0.494,P=0.005）。以PD-L1表达分层,亚组分析显示PD-L1阳性患者的中位总生存期为21.0个月（95%CI：16.003～25.696）;PD-L1阴性患者的中位总生存期为13.1个月（95%CI：10.708～15.492）（P=0.001）。［结论］ 一线进展后更换不同的PD-1单抗联合化疗有效,值得进一步研究。     

后PD-1/PD-L1抑制剂时代肿瘤治疗展望

免疫检查点抑制剂能够重启并维持肿瘤-免疫循环,使抗肿瘤免疫反应正常化。目前,以抗PD-1/PD-L1单抗为代表的免疫检查点抑制剂已显著改善多种恶性肿瘤患者的预后,是免疫治疗的新里程碑。然而,单独使用抗PD-1/PD-L1单抗有效率低,与手术、化疗、放疗和靶向治疗等传统治疗手段的联合应用展现出巨大潜力,且新的免疫检查点抑制剂单药或联合使用也在研究中,从而进入后抗PD-1/PD-L1单抗时代。然而,联合方式和生物标志物的筛选仍然是关注的焦点。本文就免疫检查点抑制剂治疗现状作简要综述并对后抗PD-1/PD-L1单抗时代进行展望。     

晚期胃癌及胃食管交界癌的免疫治疗现状及进展

PD-1/PD-L1抑制剂在晚期胃癌（GC）及胃食管交界癌（GEJC）的临床试验中显示出较好的疗效及安全性,为其临床应 用提供了有力的科学依据。单药PD-1/PD-L1抑制剂治疗的疗效欠佳,仅作为后线治疗选择。PD-1/PD-L1抑制剂联合多种治疗 模式能够提高患者的疾病应答率和延长患者生存时间,成为目前GC及GEJC治疗的热点。本文基于最新临床试验结果,对晚期 GC及GEJC的免疫治疗疗效及预测分子进行综述。     

靶向药物治疗上皮性卵巢癌的研究进展

约2/3的晚期上皮性卵巢癌患者经标准治疗后最终会复发。标准治疗后使用靶向药物维持治疗可延长无铂间隔,降低出现继发性铂耐药的风险,增加后续治疗时铂类药物的选择,提高患者下次含铂化疗的应答率,可延长患者的无进展生存期和总生存率。继VEGF抑制剂贝伐珠单抗（bevacizumab）被推荐用于上皮性卵巢癌维持治疗后,多项维持治疗研究成果已公布,维持治疗的方案根据乳腺癌易感基因（breast cancer susceptibility gene,BRCA）状态和初治是否使用贝伐珠单抗进行了更新：BRCA 1/2 突变的患者 ,初始治疗中如果使用贝伐珠单抗 ,维持治疗可以用聚二磷酸腺苷核糖聚合酶[poly(ADP-ribose)polymerase,PARP]抑制剂奥拉帕尼联合贝伐珠单抗或者奥拉帕尼单药或者尼拉帕尼单药,而对于初始治疗时未使用贝伐珠单抗的患者,推荐使用奥拉帕尼或者尼拉帕尼维持;无BRCA突变的患者,在初始治疗中如果使用贝伐珠单抗,推荐用奥拉帕尼联合贝伐珠单抗或单药贝伐珠单抗,初始治疗中未使用过贝伐珠单抗的患者推荐使用尼拉帕尼维持。PD-1/PD-L1抑制剂的多项临床研究也正在开展。本文主要对微血管生成抑制剂、PARP抑制剂、PD-1/PD-L1抑制剂治疗上皮性卵巢癌的最新研究进展进行综述。     

PD-1/PD-L1通路抑制剂治疗进展期胃癌的研究进展

胃癌是危害人类健康的恶性肿瘤之一,对于早期胃癌而言,手术联合化疗效果显著,而对于进展期胃癌,其效果并不理想。程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡受体配体-1（prorammed cell death ligand 1,PD-L1）通路的发现为进展期胃癌患者的治疗提供了希望。目前已有部分研究表明,PD-1/PD-L1抑制剂单药或联合化疗治疗可使胃癌及胃食管交界癌患者受益,预示着PD-1/PD-L1抑制剂联合手术及标准化治疗方案可能是提高胃癌患者治疗疗效的突破点。本文将对PD-1/PD-L1抑制剂治疗进展期胃癌的研究进展作一综述。     

PD-1/PD-L1抑制剂治疗三阴性乳腺癌的研究进展

PD-1/PD-L1抑制剂作为免疫检查点抑制剂已经改变了多种肿瘤治疗的现状。在三阴性乳腺癌（triple-negative breast cancer,TNBC）中,以阿替利珠单抗和帕博利珠单抗为代表的PD-1/PD-L1抑制剂已经成为晚期患者一线治疗、早期患者新辅助治 疗的标准方案;其是否用于术后高危分型的辅助治疗,目前尚无结论。本文就目前PD-1/PD-L1抑制剂在TNBC中治疗的现状及 应用前景的相关进展进行综述。     

PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的Meta分析

 目的 系统评价PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的疗效及安全性。方法 通过Web of science等国内外数据库，ASCO会议摘要及杂志筛选文献，进行Meta分析。结果 纳入7项RCT研究，4 101例患者，荟萃分析显示抑制剂联合化疗对比化疗可显著延长患者的PFS（HR=0.59, 95%CI: 0.50~0.70, P<0.00001）、OS（HR=0.65, 95%CI: 0.46~0.92, P=0.02）及ORR（RR=1.72, 95%CI: 1.13~2.62, P=0.01）。亚组分析显示，抑制剂联合化疗可显著延长PFS及OS，且PD-L1表达程度越高，疗效获益越显著。而单药抑制剂对比化疗在延长晚期NSCLC患者的PFS（HR=0.87, 95%CI: 0.57~1.31, P=0.50）、OS（HR=0.82, 95%CI: 0.65~1.03, P=0.09）及提高ORR（RR=1.12, 95%CI: 0.55~2.28, P=0.76）方面两组差异无统计学意义。与化疗相比，单药抑制剂一线治疗PD-L1高表达的晚期NSCLC患者可显著延长OS，但在延长PFS方面未见明显优势。与化疗组相比，抑制剂联合化疗组3~4级不良反应发生率无明显改善（HR=1.09，95%CI: 0.99~1.20, P=0.09），而单药PD-1/PD-L1抑制剂组3~4级不良反应发生率低（RR=0.43, 95%CI: 0.36~0.52, P<0.00001）。 结论 PD-1/PD-L1抑制剂联合化疗一线治疗晚期NSCLC患者疗效优于化疗方案；PD-L1高表达者单药PD-1/PD-L1抑制剂可作为一线治疗的优先选择，且具有良好的安全性。     

卡瑞利珠单抗单药治疗晚期肝细胞癌长期缓解1例

<正>自2019年以来,以程序性死亡受体(programmed death-1,PD-1)及其配体(programmed death ligand 1,PD-L1)为代表的免疫检查点抑制剂在晚期/不可切除的肝细胞癌(HCC)的治疗中不断取得突破性进展,不仅提高了治疗后的客观有效率,还明显改善了患者的生存。迄今,国内外已有多个免疫检查点抑制剂单药或联合方案获批用于HCC的治疗。我国自主研发的卡瑞利珠单抗成为第1个在中国获批晚期HCC适应证的PD-1单抗。我科1例应用卡瑞利珠单抗治疗的晚期HCC患者获得长期缓解,现报告如下。     

Expression of CYP1A1 and GSTP1 in Human Brain Tumor Tissues in Pakistan

Most of the exogenous and endogenous chemical compounds are metabolized by enzymes of xenobioticprocessing pathways, including the phase I cytochrome p450 species. Carcinogens and their metabolites aregenerally detoxified by phase II enzymes like glutathione-S-transferases (GST). The balance of enzymesdetermines whether metabolic activation of pro-carcinogens or inactivation of carcinogens occurs. Under certainconditions, deregulated expression of xenobiotic enzymes may also convert endogenous substrates to metabolitesthat can facilitate DNA adduct formation and ultimately lead to cancer development. In this study, we aimed totest the association between deregulation of metabolizing genes and brain tumorigenesis. The expression profile ofmetabolizing genes CYP1A1 and GSTP1 was therefore studied in a cohort of 36 brain tumor patients and controlsusing Western blotting. In a second part of the study we analyzed protein expression of GSTs in the same studycohort by ELISA. CYP1A1 expression was found to be significantly high (p<0.001) in brain tumor as comparedto the normal tissues, with ~4 fold (OR=4, 95%CI=0.43-37) increase in some cases. In contrast, the expressionof GSTP1 was found to be significantly low in brain tumor tissues as compared to the controls (p<0.02). Thisdown regulation was significantly higher (OR=0.05, 95%CI=0.006-0.51; p<0.007) in certain grades of lesions.Furthermore, GSTs levels were significantly down-regulated (p<0.014) in brain tumor patients compared tocontrols. Statistically significant decrease in GST levels was observed in the more advanced lesions (III-IV,p<0.005) as compared to the early tissue grades (I-II). Thus, altered expression of these xenobiotic metabolizinggenes may be involved in brain tumor development in Pakistani population. Investigation of expression of thesegenes may provide information not only for the prediction of individual cancer risk but also for the preventionof cancer.     

DNA切除修复交叉互补基因1、乳腺癌易感基因、核苷酸还原酶1与非小细胞肺癌

 阐述了近年来非小细胞肺癌（NSCLC）化疗敏感性与DNA 切除修复交叉互补基因1 （ERCC1）、乳腺癌易感基因（BRCA1）、核苷酸还原酶1（RRM1）基因表达关系的研究进展，分析3个基因对NSCLC个体化化疗潜在的指导意义     

Polymorphisms in GSTM1, GSTT1 and CYP1A1 and risk of pancreatic adenocarcinoma

A prospective study of 149 unselected incident cases of pancreatic adenocarcinoma and 146 ethnically-matched controls found no associations between GSTM1 (adjusted odds ratio (AOR) 1.14), GSTT1 (AOR: 1.19) and CYP1A1 (AOR: 1.08) polymorphisms and pancreatic cancer susceptibility. Smoking and drinking status did not affect results. These polymorphisms do not appear to be important gene modifiers in pancreatic cancer.     

Association between exposure-relevant polymorphisms in CYP1B1, EPHX1, NQO1, GSTM1, GSTP1 and GSTT1 and risk of colorectal cancer in a Czech population

Associations of functional single nucleotide polymorphisms in cytochrome P450 1B1, epoxide hydrolase 1, NAD(P)H:quinone oxidoreductase 1, glutathione S-transferase Pi-1 and deletions of glutathione S-transferases Mu-1 and θ-1 with colorectal cancer risk were investigated in a hospital-based case-control study on 495 matched pairs of Czech Caucasians. Polymorphisms were assessed by polymerase chain reaction restriction fragment length polymorphism-based methods, allele-specific multiplex and allelic discrimination by real-time polymerase chain reaction. Carriers of variant Ser allele in codon 453 of cytochrome P450 1B1 (rs1800440) were at a significantly lower risk of colorectal cancer compared to carriers of the wild-type allele (adjusted odds ratio, aOR=0.68, CI=0.51-0.89, p=0.006). The combination of polymorphisms in codons 453 and 432 (rs1056836) of cytochrome P450 1B1 further increased the protective effect (aOR=0.53, CI=0.34-0.83, p=0.005). The glutathione S-transferase Mu-1 deletion was associated with a moderately elevated colorectal cancer risk (aOR=1.30, CI=1.01-1.68, p=0.044). Combination of glutathione S-transferase Mu-1 and θ-1 deletion was associated with a significantly higher colorectal cancer risk compared to the presence of both full-length genes (aOR=1.58, CI=1.01-2.47, p=0.044). Genetic polymorphisms in glutathione S-transferase Pi-1, NAD(P)H:quinone oxidoreductase 1, epoxide hydrolase 1 and deduced epoxid hydrolase 1 activity did not modify the risk of colorectal cancer. These results provide further evidence that interaction between metabolic gene variants contributes to colorectal carcinogenesis.     

Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer

Oral cancer ranks first among all cancers in males and is the third most common among females in India. Tobacco-derived carcinogens are involved in the development of oral cancer. Environment-gene interaction in oral carcinogenesis is well demonstrated by phase I and II enzymes that are involved in the metabolism of carcinogens. This study looked at the significance of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in patients with oral cancer. The study included 98 oral cancer patients and 60 age and sex matched healthy controls. Genotypes of CYP1A1, GSTM1 and GSTT1 were determined by PCR-RFLP. GSTM1 null deletion was observed in 49% of oral cancer cases and 33% of control subjects. For GSTT1, 18% of carcinomas and 8% of controls had the null genotype. In the case of CYP1A1 m2 allele, 51% of oral cancers and 17% of normal controls, respectively, had one or both alleles with the isoleucine-->valine substitution. Digestion of the PCR products with enzyme Nco1 revealed polymorphism for CYP1A1 m2 with bands at 263 bp. There was no association between genotypes with tumor size, stage, grade, and age. Since null genotype individuals may possibly be poor detoxifiers with reduced ability to neutralise the reactive carcinogenic intermediates, they may be a high risk category. The frequency distribution of CYP1A1 m2 (Ile/val) genotypes among oral cancer patients was significantly different that from normal controls. The risk of CYP1A1 can be supported by the functional difference between presence of valine and isoleucine; valine type has higher catalytic and mutagenic activity towards benzo[a] pyrene than the isoleucine type. In conclusion, our results suggest that polymorphism in CYP1A1 m2 gene and/or GSTM1 and GSTT1 null genotype may confer an increased risk for oral cancer.     

VEGFR1和MDR1在胃癌中的表达及意义

目的：探讨VEGFR1和MDR1在胃癌中的表达及意义。方法：采用免疫组化SP法检测VEGFR1和MDR1在胃癌中的表达及与分化程度的关系;比较VEGFR1和MDR1在胃癌中的表达相关性。结果：VEGFR1在高、中、低度分化胃癌的表达率依次为15／53（28％）、19／43（44％）、37／54（68％）;在低分化胃癌组织中的表达明显高于高分化和中分化胃癌组织（P〈0．05）。MDR1在高、中、低度分化胃癌的表达率依次为18／53（34％）、21／43（48％）、41／54（76％）;在低分化胃癌组织中的表达明显高于高分化和中分化胃癌组织（P〈0．05）。结论：VEGFR1和MDR1在胃癌中的表达具有一致性,可能在胃癌的多药耐药中扮演重要角色。     

Distribution and metabolism of 1-propyl-1-nitrosourea in rats

The carcinogen 1-[14C]propyl-1-nitrosourea (PNU) was readily absorbed from the rat gut, and the radioactivity was excreted mainly in the urine and expired air. The urinary metabolites of PNU were 1-propylurea and urea. 1-Propylurea was shown to be excreted largely unchanged in the urine. Both [14C]PNU and 1-[14C]propylurea were found to be eliminated rapidly from the rat body. Besides cO2 from PNU, isopropyl alcohol was identified as a volatile metabolite in the expired air. Specific high concentrations (%/g) in main organs and tissues were not observed in adult rats 24 hr after single p.o. doses (20 mg/kg) of labeled PNU. The ureido carbon of PNU showed considerable retention in the blood, while relatively high residual levels were found in the liver for the propyl carbon. Autoradiographic studies on pregnant rats showed a uniform distribution between maternal and fetal bodies a short time after dosing. A relatively high concentration of 14C label was found in the maternal blood 24 hr after treatment with [carbonyl-14C]PNU. Localization of radioactivity in bone systems such as the fetal sterna and vertebrae was noted 6 hr after treatment with [propyl-1-14C]PNU. Metabolic pathways of PNU in the rat are proposed.