51例恶性黑色素瘤的治疗和预后分析

我院自1972年1月至1988年12月间收治的51例皮肤及粘膜原发性黑色素瘤(后称恶黑),全部经病理确诊,根据随访资料(其中含失访5例,作死亡论者),对其治疗情况和预后关系加以分析。临床资料1.性别,年龄:男性27例,女性24例,     

结合基因表达谱探讨恶性黑色素瘤免疫微环境分型的预后预测价值

目的：探讨恶性黑色素瘤（malignant melanoma,MM）微环境分型对MM患者预后的评估价值。方法：对2010年7月 至2017年5月在南京鼓楼医院手术切除的87例原发性MM组织进行二代测序,免疫组化法检测PD-1、PD-L1、CD3+TIL、MSH2、 MSH6、PMS2和MLH1的表达。随访患者的生存时间,分析不同免疫微环境分型对患者预后的影响及其基因表达特征。结果： 根据PD-L1和TIL表达水平将87例MM患者的肿瘤微环境分为4个亚型：PD-L1+TIL+ 型或双阳型（15/87,17.24%）、PD-L1+TIL[1]型 （15/87,17.24%）、PD-L1- TIL+ 型（20/87,22.99%）、PD-L1- TIL[1]型或双阴型（37/87,42.53%）。双阳型患者的中位无病生存期显著长 于双阴型患者(P<0.05),此可能与双阴型患者存在更多CDK4、MCL1、MYC、AKT2、CCND1、FGF19等预后不良基因拷贝数扩增 相关;双阳型患者PD-1表达显著高于双阴型患者(P<0.01),可能与PD-L1、TIL分别与PD-1呈共表达和共不表达有关。结论：根 据PD-L1及TIL表达将MM 患者微环境分为4种亚型,能够区分MM患者预后,双阴型患者存在更多预后不良基因拷贝数扩增。     

皮肤恶性黑色素瘤患者预后的影响因素分析

目的分析皮肤恶性黑色素瘤(MM)患者预后的影响因素。方法选取74例接受手术联合免疫治疗的皮肤MM患者,采用Cox比例风险回归模型分析影响皮肤MM患者预后的危险因素。结果 74例皮肤MM患者中,死亡33例。单因素分析结果显示,不同TNM分期、肿瘤破溃情况、淋巴结转移情况、Clark分级皮肤MM患者的2年生存率比较,差异均有统计学意义(P<0.05);不同病理类型皮肤MM患者的2年生存率比较,差异无统计学意义(P>0.05)。Cox比例风险回归模型分析结果显示,TNM分期为Ⅲ～Ⅳ期、有淋巴结转移、有肿瘤破溃、Clark分级为Ⅲ～Ⅴ级是影响手术联合免疫治疗后皮肤MM患者预后的独立危险因素(P<0.01)。结论手术联合免疫治疗对皮肤MM具有较好的效果,临床上应重视患者的TNM分期、淋巴结转移情况、肿瘤破溃情况和Clark分级对皮肤MM患者预后的影响。     

热疗对肿瘤免疫微环境中免疫细胞及免疫相关细胞因子的影响

随着对肿瘤热疗和肿瘤免疫微环境(TIME)的深入研究,近年来热疗对TIME的作用越来越受到学者们的重视。本文就目前国内外研究进展,对热疗与TIME中几类主要免疫细胞和免疫相关细胞因子的影响及作用机制作一综述。全面而透彻的了解热疗对TIME的调控作用,有助于为肿瘤治疗提供新的思路和方法。     

抑郁介导肿瘤免疫微环境诱导肝癌不良预后研究

摘 要：［目的］ 寻找抑郁影响肿瘤预后的相关基因,分析这些基因与肿瘤免疫微环境的相互作用,探讨抑郁影响肝癌预后的可能作用机制。［方法］ 选取倾向评分匹配临床及病理分期相一致的肝癌患者组织17例,其中抑郁组8例、无抑郁组9例,通过转录组基因芯片技术筛选两组间差异基因,采用基因互作网络作图分析肝癌抑郁相关的关键因子和相关信号通路。利用癌症基因图谱（The Cancer Genome Atlas,TCGA）数据库分析抑郁相关关键炎症因子的表达与肝癌肿瘤浸润淋巴细胞( tumor infiltrating lymphocytes,TILs)表型评分及预后的关系。［结果］ 比较两组组织标本基因表达谱,共有286个基因表达水平发生改变,其中上调基因131个、下调基因155个。将差异表达基因进行互作网络作图,发现主要存在两个主要的网络节点,CXCR4-CXCL12轴和ALDH2-DMGDH-ABAT,炎症因子CXCL13、TIMP2、FOS、CD40、CCL25都与CXCR4-CXCL12轴存在相互作用或调控的关系,抑郁相关的CXCR4-CXCL12轴差异基因表达与肝癌患者TILs表型评分相关。生存分析结果显示,TILs表型评分的低评分组生存时间短于中评分组（P＜0.05）。Cox回归分析结果显示,FOS、CXCR4、CXCL13、CD40高表达及CXCL12低表达是影响肝癌患者总生存的危险因素。［结论］ 抑郁可介导激活肝癌组织中FOS、CXCR4、CXCL13、CD40表达、下调CXCL12表达调控TILs表型,影响肿瘤免疫微环境,抑制肿瘤免疫,从而影响预后。     

MAD2L1在肺腺癌中的表达及对免疫微环境的影响

目的 探讨MAD2L1在肺腺癌组织中的表达对患者预后及免疫微环境的影响。方法 通过TCGA和GEO数据库分析在肺腺癌组织及正常肺组织样本中MAD2L1的表达差异,生存分析评价其表达水平与患者预后的关系,StarBase数据库构建肺腺癌miRNA-MAD2L1调控网络,分析肺腺癌组织中MAD2L1的表达与免疫细胞浸润的关系。结果 肺腺癌组织中MAD2L1表达上调且MAD2L1高表达与肺腺癌的病理分期、淋巴结转移显著相关,MAD2L1表达水平高的肺腺癌患者预后较差,miR-101-3p/MAD2L1轴被确定为MAD2L1在肺腺癌中最有潜力的上游调控相关途径,MAD2L1表达水平与肿瘤免疫细胞浸润和免疫检查点表达呈显著相关。结论 MAD2L1在肺腺癌组织中高表达,与肺腺癌不良预后及肿瘤免疫浸润相关,可作为肺腺癌患者治疗的潜在靶点。     

74例皮肤黑色素瘤的预后及影响因素分析

目的 探讨皮肤恶性黑色素瘤的临床病理特征及预后相关因素。方法 回顾性分析南京鼓楼医院2010年1月至2016年6月收治的74例皮肤黑色素瘤患者的临床病理资料。所有入组患者均接受手术治疗,术后辅助治疗分为联合免疫治疗和未联合免疫治疗,免疫治疗方法包括细胞因子治疗和过继性免疫细胞回输疗法,未联合免疫治疗者包括术后未治疗的以及术后仅行辅助放疗或辅助化疗的患者。根据随访资料分析预后情况,并采用Cox比例风险回归模型分析影响预后的因素。结果 全组患者的中位生存期（OS）和无病生存期（DFS）分别为 32.0个月（95％CI： 20.2～43.8个月）和23.0个月（95％CI： 16.4～29.6个月）。Ⅲ期患者术后联合免疫治疗较未联合免疫治疗中位OS延长（38.0个月 vs. 10.0个月,P=0.002）。多因素分析显示,年龄、分期、淋巴结转移、原发灶溃疡和肿瘤Breslow厚度是影响皮肤黑色素瘤OS的独立因子,分期、淋巴结转移、原发灶溃疡和肿瘤Breslow厚度是影响DFS的独立因子。结论 年龄、分期、淋巴结转移、肿瘤Breslow厚度和原发灶溃疡均与皮肤恶性黑色素瘤患者的预后密切相关。Ⅲ期患者术后联合免疫治疗可延长OS。     

免疫细胞在急性髓系白血病骨髓微环境中的浸润模式及其预后价值

目的:探究免疫细胞在急性髓系白血病骨髓微环境中的浸润模式,以及分析其与临床特征和预后间的关系.方法:从GEO数据库中下载422例急性髓系白血病患者的基因表达谱数据和相关临床数据,采用CIBERSORT算法计算急性髓系白血病患者骨髓微环境中22种免疫细胞的构成比例,然后分别分析浸润性免疫细胞与年龄、FAB分型等临床特征间...     

整合多数据库分析NFKBIA在SKCM预后和免疫浸润中的价值

目的：探讨核因子κB抑制因子a(NFKBIA)表达与皮肤黑色素瘤(SKCM)患者预后及其与肿瘤微环境免疫浸润的相关性。方法：利用GEPIA2数据库分析正常皮肤和SKCM组织中NFKBIA的表达差异,GEPIA2和Ualcan数据库分析NFKBIA与SKCM预后关系,TIMER和TISIDB数据库分析NFKBIA与SKCM中TIL和免疫调节基因的关系。选用TISCH和CancerSEA数据库从单细胞水平分析NFKBIA与SKCM细胞亚群及其相关的功能状态关联性。选取湖北省荆门市第二人民医院保存的14例SKCM患者的石蜡组织标本,通过免疫组织化学染色法验证SKCM组织和癌旁组织中NFKBIA蛋白的表达水平。结果：NFKBIA在SKCM组织中呈低表达,并且低表达的SKCM患者预后差(P<0.05)。NFKBIA表达与B细胞、CD8⁺T细胞、CD4⁺T细胞、巨噬细胞、中性粒细胞和DC浸润水平呈正相关关系(均P<0.01)。NFKBIA表达与SKCM中TIL丰度和免疫调节基因呈正相关关系(均P<0.01)。NFKBIA在SKCM单细胞...     

Evaluating prognostic value and relevant gene signatures of tumor microenvironment characterization in esophageal carcinoma

BackgroundTumor microenvironment (TME) cells are an important part of tumor tissues. There is increasing evidence that the TME plays a vital role in tumor prognosis, and is associated with patient survival in various kinds of malignances. To date, very little research has been conducted on how to effectively use TME to better evaluate the prognosis of patients with esophageal carcinoma (EC). The concept of a “TME score” was introduced to better distinguish the prognosis of patients.MethodsWe employed bioinformatic methods to investigate the TME infiltration patterns of 160 patients with EC from the Cancer Genome Atlas (TCGA) cohort. TME clusters were identified using k-means clustering methods with 1,000 resampling times. The significance of the survival difference among patients belonging to different TME clusters was assessed by the log-rank test and Kaplan-Meier survival curves. Correlations between immune cell types and survival were calculated by a Cox regression, and the Pearson correlation coefficient (PCC) was used to measure the relationship among different immune cell types. We classified patient into 2 subtypes based on the optimal breakpoint of TME score determined by R package maxstat.ResultsTwo TME phenotypes were defined based on the immune cell type fractions, and patients with a high TME score phenotype had a better prognosis than those with a low TME score phenotype. Kaplan-Meier analysis for differentially expressed micro ribonucleic acids (RNAs) and messenger RNAs also showed that different TME score subtypes were significantly associated with the prognosis of EC. Just as tumor mutational burden can predict the efficacy of immunotherapy, the TME score can predict the efficacy of immune checkpoint inhibitors (ICIs). The genomic alterations of 2 TME score subtypes of EC further revealed that genomic instability is prevalent in TMEs, and patients with a low TME score subtype have a more unstable chromosome status than those with a high subtype.ConclusionsThus, TME score is an emerging prognostic biomarker for predicting the efficacy of ICIs.     

COX-2/PGE2在肿瘤发生发展和重塑肿瘤微环境中的研究进展

癌症相关炎症(cancer-related inflammation,CRI)在癌症的发生发展中发挥重要作用,前列腺素E2(prostaglandin E2,PGE2)是炎症环境中最为丰富的类花生酸脂质,也是肿瘤微环境中具有免疫调节功能的脂类代谢产物。目前,PGE2合成途径阻断药物联合抗肿瘤药物在肿瘤治疗方面取得一定成效。因此,了解肿瘤微环境中PGE2合成途径的调控环节及其对肿瘤发生发展的作用机制,可为肿瘤防治找寻新方向、提供新靶点。本文就近年来PGE2在肿瘤发生发展和重塑微环境的研究进展进行概述。     

The role of tumor-infiltrating B cells in the tumor microenvironment of hepatocellular carcinoma and its prognostic value: a bioinformatics analysis

BackgroundAccumulating evidence indicates that tumor heterogeneity is characterized by distinct immunosubtypes. However, prior studies have mainly focused on the functions of T cells. The role of tumor-infiltrating B cells in the microenvironment of hepatocellular carcinoma (HCC) requires further investigation.MethodsWe conducted an integrative analysis of single cell RNA sequencing (scRNA-seq) datasets in HCC tumor samples from Gene Expression Omnibus database. We analyzed the features of B cells in normal liver tissue and HCC. Additionally, we conducted a deconvolution analysis using the matrix of scRNA-seq datasets and the RNA-seq datasets in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database. The survival analyses of the TCGA-LIHC cohort with different B cell infiltration rates and was further validated. Finally, we performed immunohistochemistry analysis of primary tumor tissue of HCC patients using antibodies against CD79A and validated the impact of tumor-infiltrating B cells in the prognosis of LIHC.ResultsWe identified several subtypes of B cells in the microenvironment of HCC, including the plasma cells and naïve B cells. The relative ratio of B cells, but not the plasma cells, was significantly decreased in HCC as compared to the normal liver tissue (P<0.05). In addition, genes related to antigen presentation and cell proliferation were decreased in tumor-infiltrating B cells (P<0.05). The observation of B cell infiltration was further validated with the TCGA-LIHC cohort. The overall survival and disease-free survival in HCC patients with higher B-cell infiltration rate were significantly longer than those in the lower infiltration group (P<0.05) in the TCGA-LIHC cohort. Moreover, we demonstrated higher infiltration rates of B cells were significantly associated with a better prognosis of HCC in our cohort.ConclusionsTumor-infiltrating B cells potentially exert a tumor-suppressive function in the microenvironment of HCC and the higher levels of B cell infiltration are associated with a favorable outcome of HCC. Targeted activation of B cells may improve the tumor immune-targeted therapy.     

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),...     

High expression of lncRNA HSD11B1-AS1 indicates favorable prognosis and is associated with immune infiltration in cutaneous melanoma

Cutaneous melanoma is an aggressive malignant cancer associated with poor prognosis. Identification of reliable biomarkers for predicting prognosis of melanoma contributes to improved clinical outcome and disease management. Long non-coding RNAs (lncRNAs) serve a crucial regulatory role of oncogenesis and tumor suppression in melanoma. Using data from The Cancer Genome Atlas database, novel lncRNA 11β-hydroxysteroid dehydrogenase type 1-antisense RNA 1 (HSD11B1-AS1) was identified, which was significantly downregulated in malignant melanoma and its downregulation was significantly associated with poor clinicopathological characteristics, including advanced T and pathological stage, Clark level, Breslow depth and ulceration and worse prognosis. Multivariate analysis showed that HSD11B1-AS1, as well as N stage and Breslow depth, were independent prognostic factors in cutaneous melanoma, and nomograms suggested a good predictive value of 1-, 3- and 5-year overall survival, progression-free interval and disease-specific survival. In vitro experiments verified the decreased HSD11B1-AS1 expression in melanoma cell lines compared with human epidermal melanocytes. Moreover, cell experiments in vitro, including Cell Counting Kit-8, colony formation, wound healing and Transwell assay, suggested that overexpression of HSD11B1-AS1 significantly inhibited melanoma cell proliferation, migration and invasion. Functional enrichment showed significantly enriched pathways in IFN-γ and -α response, TNF-α signaling via NF-κB and IL-2/STAT-5 and IL-6/JAK/STAT-3 signaling. In addition, immune infiltration analysis demonstrated that HSD11B1-AS1 may function by accelerating immune response regulation and the immune cell infiltration of various immunocytes, especially T, T helper 1, activated dendritic and B cells. The present study revealed HSD11B1-AS1 as a potential therapeutic target and promising biomarker for diagnosis and prognosis of cutaneous melanoma.     

Clinical significance and immune landscape of KIR2DL4 and the senescence‐based signature in cutaneous melanoma

Senescence is an effective barrier to tumor progression. Mutations that inhibit senescence and promote cell division are mandatory for the development of cancer. Therefore, it is particularly important to explore the differences between cutaneous melanoma (CM) patients with severe and mild degrees of senescence. We clustered all the patients with CM in the Cancer Genome Atlas (TCGA) database based on all the genes of the senescence pathway in the CellAge and MSigDB database. The prognosis, immunotherapy effect, tumor microenvironment score, NRAS mutation rate, expression of CD274, CTLA4, and PDCD1, and abundance of CD8⁺ T and natural killer (NK) cell infiltration in the younger group of patients (YG) were higher than those in the older group (OG). Compared with the American Joint Committee on Cancer (AJCC) stage, the risk scoring system stratified the risk of CM patients and guided immunotherapy more accurately. The nomogram model, which combined the AJCC stage and risk score, greatly improved the ability and accuracy of prognosis prediction. As KIR2DL4 is the core molecule in the risk scoring system (RSS), knocking down the KIR2DL4 of human NK cells in vitro can inhibit the cytotoxicity of NK cells and can also inhibit the secretion of tumor necrosis factor‐α and interferon‐γ by NK cells. In contrast, upregulation of KIR2DL4 can activate the MEK/ERK signaling pathway, which is the activation pathway of NK cells. Our RSS and nomogram model can accurately stratify the risk of CM patients and effectively predict the effect of immunotherapy and prognosis in CM patients.