Background:KDM1B, a flavin-dependent histone demethylase, is an epigenetic regulator implicated in tumorigenesis; however, its role in esophageal squamous cell carcinoma (ESCC) remains unclear. We aimed to explore the biological role of KDM1B in ESCC and, on this basis, to develop a prognostic prediction model incorporating KDM1B. Methods:Public transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO; GSE26886 and GSE161533) were analyzed to assess KDM1B expression, prognostic relevance, pathway enrichment, and immune infiltration in ESCC. KDM1B genomic alterations were further examined in 52 ESCC specimens from our center. Functional assays were performed in ESCC cell lines to evaluate the effects of KDM1B on proliferation, migration, and apoptosis. Overall survival (OS) was the primary prognostic outcome. Univariable and multivariable Cox regression analyses were performed to construct a prognostic prediction model for estimating 1-, 3-, and 5-year OS. Results:KDM1B was significantly upregulated in ESCC compared with normal esophageal epithelium and was associated with a higher response rate to systemic therapy. In our cohort, intronic variants and copy-number alterations of KDM1B were detected in a subset of tumors. Functional enrichment analyses suggested that KDM1B may be involved in cell-cycle regulation and apoptosis, and its expression was associated with immune infiltration. Survival analyses showed that elevated KDM1B expression was associated with longer OS. A prognostic prediction model incorporating KDM1B expression, pathologic node stage (N stage), pathologic metastasis stage (M stage), overall pathologic stage, gender, and histologic grade was developed to estimate 1-, 3-, and 5-year OS in patients with ESCC. In vitro experiments showed that KDM1B promoted ESCC cell proliferation and migration while inhibiting apoptosis, suggesting a context-dependent role in ESCC biology, potentially influenced by treatment and the immune microenvironment. Conclusions:KDM1B is upregulated in ESCC and may influence tumor behavior through regulation of the cell cycle, apoptosis, and the tumor immune microenvironment. KDM1B was also incorporated into a prognostic prediction model for OS estimation in ESCC, supporting its potential value in prognostic stratification.

Aim To evaluate the prognostic value of Noggin expression and develop a clinically applicable prediction model for patients with advanced gastric cancer receiving first-line chemotherapy. Methods Noggin expression was analysed using the GTEx and TCGA databases and further assessed by immunohistochemistry in 217 gastric cancer tissue specimens. Associations between Noggin expression and clinicopathological characteristics were evaluated. In patients receiving first-line chemotherapy, independent prognostic factors for overall survival were identified using multivariable Cox regression. A nomogram incorporating these factors was developed and internally validated in terms of discrimination, calibration, and clinical utility. Results Noggin expression was significantly higher in gastric cancer tissues than in normal tissues (46.1% vs 15.1%, p < 0.001) and was associated with tumour differentiation and primary tumour location. Among 165 patients who received first-line chemotherapy, six independent prognostic factors for overall survival were identified: malignant ascites, history of gastrectomy, HER2 status, liver metastasis, mismatch repair status, and Noggin expression. A nomogram based on these variables showed good discriminative ability, calibration, and clinical utility after internal validation. Conclusion Noggin expression is an independent prognostic factor in advanced gastric cancer. The Noggin-based nomogram may serve as a practical tool for survival prediction and risk stratification in patients receiving first-line chemotherapy.

Carcinoma of unknown primary (CUP) is a rare malignancy characterized by metastatic disease without an identifiable primary tumor, even after extensive diagnostic evaluation. This case report described a 70-year-old female patient with squamous cell CUP (SCCUP) who initially presented with elevated carbohydrate antigen 19-9 and a diaphragmatic mass. Despite comprehensive workup, including 18F-fluorodeoxyglucose positron emission tomography-computed tomography and a 90-gene expression assay, the primary site remained unclear. The patient underwent surgical resection followed by two cycles of systematic therapy and achieved a disease-free survival of 14 months. This case underscores the limitations of the current diagnostic tools and the potential role of multimodal therapy in the management of CUP. The discordance between molecular testing and the clinical findings further emphasizes the perplexing nature of CUP. This report also reviews the literature on diagnosis and therapeutic options. Due to the absence of standardized regimens, future international collaboration and comprehensive genomic profiling are warranted to advance the understanding of this heterogeneous disease.

Objective The sensitivity of immune checkpoint inhibitors (ICIs) as monotherapy is low in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor ( EGFR ) exon 20 insertion mutations (ex20ins). This study aims at investigating the effectiveness of the combination of ICI and chemotherapy (ICI-combined regimen) in a real-world population of NSCLC patients harboring near-loop insertions of EGFR exon 20. Methods We conducted a retrospective study of advanced NSCLC with EGFR ex20ins from April 2016 to March 2021 at Guangdong Provincial People's Hospital, Southern Medical University, China. A total of 126 cases of EGFR ex20ins were screened from 1610 patients with advanced NSCLC harboring EGFR mutations and 62 cases were further analyzed for different therapeutic efficacy. Results The first-line ICI-combined regimen showed marked efficacy for near-loop insertions of EGFR exon 20, with an ORR of 71.4% and a mPFS of 11.5 months, compared to ORRs of 12.5% for traditional targeted therapy ( P = .003) and 18.8% for chemotherapy ( P = .013). The first-line mPFS of traditional EGFR -TKIs and chemotherapy were only 5.6 and 5.8 months, respectively. Similar results were observed for any-line therapy of ICI-combined regimen, with an ORR of 80%. The median progression-free survival (PFS) of any-line therapy of ICI-combined regimen was 11.5 months, which were significantly longer than that of traditional targeted therapy (4.5 months, P = .026) and chemotherapy (5.0 months, P = .013). Conclusions ICI-combined regimen may be superior compared to targeted therapy and chemotherapy for advanced NSCLC with near-loop insertions of EGFR exon 20. Further exploration is warranted to confirm the efficacy of ICI-combined regimen.

NDC80, a crucial component of the kinetochore, plays a pivotal role in regulating cell mitosis. Recent studies reported that NDC80 regulates the proliferation of cancer cells and may be related to poor prognosis in cancer. However, the biological function and mechanism of NDC80 in esophageal squamous cell carcinoma (ESCC) have not yet been elucidated. In this study, we analyzed the expression and mutation of NDC80 in ESCC tissue and assessed its impact on ESCC cells in vitro. A total of 52 ESCC tissues samples were collected and NDC80 gene status was analyzed by whole exome sequence. shRNA was used to knockdown NDC80 expression in two ESCC cell lines TE1 and ECA109 by targeting silence NDC80 gene. Cellular proliferation, apoptosis, migration, and invasion were examined. Copy number variants (CNVs) of NDC80 were detected in 40.4

BACKGROUND:To treat liver failure, three-dimensional (3D) bioprinting is a promising technology used to construct hepatic tissue models. However, current research on bioprinting of hepatic tissue models primarily relies on conventional single-cell-based bioprinting, where individual functional hepatocytes are dispersed and isolated within hydrogels, leading to insufficient treatment outcomes due to inadequate cell functionality. OBJECTIVE:Here, we aim to bioprint a hepatic tissue model using functional hepatocyte organoids (HOs) and evaluate its liver-specific functions in vitro and in vivo. DESIGN:Human chemically induced pluripotent stem cells (hCiPSCs) were used as a robust and non-genome-integrative cell source to produce highly viable and functional HOs (hCiPSC-HOs). An oxygen-permeable microwell device was used to enhance oxygen supply, ensuring high cell viability and promoting hCiPSC-HOs maturation. To maintain the long-term biofunction of hCiPSC-HOs, spheroid-based bioprinting was employed to construct hepatic tissue models (3DP-HOs). 3DP-HOs were intraperitoneally implanted in mice with liver failure. RESULTS:3DP-HOs demonstrated enhanced cell viability when compared with a model fabricated using single-cell-based bioprinting and exhibited gene profiles closely resembling hCiPSC-HOs while maintaining liver-specific functionality. Moreover, 3DP-HOs implantation significantly improved survival in mice with CCl4-induced acute-on-chronic liver failure and also Fah-/- mice with liver failure. 3DP-HOs significantly reduced liver injury, inflammation and fibrosis indices while promoting liver regeneration and biofunction expression. CONCLUSION:Our bioprinted hepatic tissue model exhibits remarkable therapeutic efficacy for liver failure and holds great potential for clinical research in the field of liver regenerative medicine.

目的 探讨消化系统恶性肿瘤中免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)导致免疫相关不良事件(immune-related adverse events,irAEs)的特征及危险因素.方法 回顾性分析2019 年4 月至2021 年10 月北京大学肿瘤医院诊治的 95 例接受ICIs治疗的消化系统恶性肿瘤患者的临床资料和irAEs发生情况.irAEs、内分泌irAEs危险因素分析采用二元Logistic回归分析.结果 95 例患者共应用ICIs治疗458 例次,中位应用3 例次(范围:1～33 例次).irAEs的发生率为55.8％,3～4 级irAEs发生率为 9.5％.最常见的irAEs为皮肤irAEs(27.4％)和内分泌irAEs(22.1％).内分泌irAEs中甲状腺功能减退最常见(16.8％),肾上腺皮质功能减退(2.1％)和垂体炎(1.1％)少见.多数irAEs发生于免疫治疗初期,78.2％发生于 12 周内.过敏反应、皮肤irAEs最早发生,中位发生时间分别为 2 周(范围:0.9～3.1 周)和 3.8 周(范围:0.9～17.9 周),内分泌irAEs中位发生时间为 6.9 周(范围:3.0～52.1 周).多因素分析显示,女性(OR=5.197,95％CI:1.166～23.154,P=0.031)和微卫星高度不稳定(microsatellite instability-high,MSI-H)(OR=35.048,95％CI:2.756～445.787,P=0.006)是内分泌irAEs发生风险增加的独立危险因素,免疫治疗联合化学药物治疗(OR=0.107,95％CI:0.021～0.412,P=0.001)是内分泌irAEs的独立保护性因素.结论 在消化系统恶性肿瘤中应用ICIs具有较好的安全性.女性和MSI-H患者出现内分泌irAEs风险增加,联合化学药物治疗可能降低内分泌irAEs发生风险.

Acquired resistance is a major problem limiting the clinical efficacy of treatments for metastatic colorectal cancer (mCRC). Histological transformation is an important mechanism underlying the acquired resistance of non-small cell lung cancer and prostate cancer to targeted therapy. However, no report has examined the role of histological transformation in mCRC. Here, we report the first case of histologically transformed large cell neuroendocrine carcinoma from primary colon adenocarcinoma during antiangiogenesis and anti-PD-1 combination therapy. The histologic conversion was confirmed by the observation that the transformed large cell neuroendocrine carcinoma lesion retained the original mutational signature found in the primary tumor. Sequential tumor biopsy and dynamic changes in tumor markers demonstrated the transformed process. The histological transformation not only resulted in discordant responses to the same treatment but also significantly shortened overall survival. This case calls for more attention to histological transformation in mCRC. Tumor rebiopsy upon disease progression and monitoring dynamic changes in tumor markers would help to identify such cases.

Abstract Background The occurrence and progression of various solid tumors are associated with the melanoma-associated antigen A (MAGE-A) family. Although it was demonstrated that demethylation at the promoter region usually causes the over-expression of the MAGE-A family, there has been very few research about the detailed mechanisms of how the genetic modification of promoter region promotes MAGE-A expression.Methods A new non-coding RNA (ncRNA) with the ability of binding with melanoma-associated antigen-A6 (MAGE-A6) promoter region was discovered. The expression consistency between MAGE-A6 and this novel ncRNA in different MAGE-A6 highly expressed malignant cell lines was analyzed by RT-qPCR. The full length of this ncRNA was acquired through RACE and were subsequently named as MAGEA6-DT1. Then up- and down-regulation of MAGEA6-DT1 in human malignant melanoma cells were achieved by lentivirus transduction and siRNA transfection respectively and the transcription and expression of MAGE-A6 was detected by RT-qPCR and Western Blot for verifying MAGE-A6 expression regulating function of MAGEA6-DT1. The exact binding site of MAGEA6-DT1 in MAGE-A6 promoter region was analyzed by dual-luciferase reporter system assay after MAGEA6-DT1 transfection in 293T cells. Moreover, by DNA methylation analysis, we tested whether MAGEA6-DT1 has the ability of MAGE-A6 expression regulation by manipulating its promoter region’s methylation. Finally, RNA pull-down assay was performed to identify the functional binding partner of MAGEA6-DT1.Results MAGEA6-DT1 was identified as a long non-coding RNA (lncRNA) with the length of 771 nucleotides and was abnormally expressed in consistency with MAGE-A6 among various cancer cell lines. Manipulation of MAGEA6-DT1 expression level would positively regulates MAGE-A6 expression. Specific binding site of MAGEA6-DT1 located near the enhancer of MAGE-A6, and its function was revealed to demethylate DNA near its binding site, probably with the assistance of relevant binding partners.Conclusion MAGEA6-DT1, as a lncRNA abnormally expressed in different malignant cell lines, could positively regulate MAGE-A6 expression via specifically combining with and subsequently demethylating MAGE-A6 enhancer. This function may be assisted by some of its binding protein such as DNA (cytosine-5)-methyltransferase 1 (DNMT1).

Derivation of human hepatocytes from pluripotent stem cells in vitro has important applications including cell therapy and drug discovery. However, the differentiation of pluripotent stem cells into hepatocytes in vitro was not well recapitulated the development of liver. Here, we developed a differentiation protocol by mimicking the two-stage development of hepatoblasts, which permits the efficient generation of hepatic progenitor cells from chemically induced pluripotent stem cells (hCiPSCs). Single-cell RNA sequencing (scRNA-seq) indicates the similarity between hepatoblasts differentiated in vitro and in vivo. Moreover, hCiPSC-derived hepatic progenitor cells can further differentiate into hepatocytes that are similar to primary human hepatocytes with respect to gene expression and key hepatic functions. Our results demonstrate the feasibility of generating hepatic progenitor cells and hepatocytes from hCiPSCs with high efficiency and set the foundation for broad translational applications of hCiPSC-derived hepatocytes.

BRAF基因突变结直肠癌是一种具有独特临床病理特征的亚型,BRAF突变以BRAFV600E突变最为常见.BRAFV600E突变结直肠癌的疗效和预后较差,晚期一线可选择化疗联合抗血管生成药物的治疗策略,后线治疗采用BRAF抑制剂联合表皮生长因子受体抑制剂方案可为患者带来生存获益.目前BRAFV600E突变转移性结直肠癌的治疗探索包括阻断各种细胞信号传导通路的靶向药物联合以及靶向治疗与免疫治疗联合等治疗策略.文章就BRAF突变转移性结直肠癌的分子生物学特点、临床病理特征以及BRAFV600E突变转移性结直肠癌的治疗进展进行综述.

Purpose Different types of HPV have been associated with cancer in humans, but the role of HPV in esophageal cancer (EC) is controversial. The purpose of this study was to evaluate the correlation between HPV infection and EC in the Chinese population and to provide the scientific basis for the future prevention, control, early diagnosis, and treatment strategies of EC in China. Methods PCR detected HPV infection in 1112 esophageal cancer tissue samples, and 89 HPV-positive samples were detected by genotyping. Proximity ligation assays (PLAs) and immunohistochemistry were used to detect the expression of HPV E6 and E7 proteins. Real-time fluorescent quantitative PCR was used to detect the integration of HPV16 E6. The level of HPV-specific antibody IgG in serum was detected by ELISA and PLA. Results The positive rates of HPV L1, HPV16, HPV18, hpv16 + 18 E6 and hpv16/18 E6 in 1,112 EC tissue samples were 77.6%, 41.4%, 27.2%, 14.2% and 55.4% respectively. Multiple HPV subtypes were detected in HPV-positive EC samples. PLA showed that E6 and E7 were expressed in EC109 and formed complexes with p53 and pRb, respectively. Immunohistochemistry showed that the positive rates of hpv16 + 18 E6 and E7 in HPV-positive EC samples were 56.4% and 37.0%, respectively. HPV-DNA integration rate in HPV-positive EC tissues (88.79%) was higher than that in adjacent tissues (54.17%). HPV antibody was found in the serum of EC patients by a serological test. Conclusion The study suggests that HPV, especially HPV16 and HPV18, the infection may be a risk factor for EC in the Chinese population and that the E6 protein may play a key role in HPV-associated malignancies. These results may be important for the prevention and treatment of HPV-positive EC in China.

目的 探索药代动力基因单核苷酸多态性(SNP)与食管鳞癌患者术后无病生存期的关系,用于评估手术患者预后.方法 以77例食管鳞癌术后患者为研究对象,选择ATP结合盒亚家族B成员1(ABCB1)rs1045642、rs2032582、rs3213619,ATP 结合盒亚家族 G 成员2(ABCG2)rs2231137、rs2231142,ATP 结合盒亚家族 C 成员 1(ABCC1)rs246221和ATP结合盒亚家族C成员2(ABCC2)rs3740066这7个SNP行基因测序,采用Cox回归模型评估遗传变异和无病生存之间的关系,并采用半贝叶斯收缩方法对多次检验和小样本量进行校正.结果 在显性基因模型下,ABCC2 rs3740066的次要等位基因与无病生存期缩短有关[粗HR(95％CI)为4.623(1.111～19.241),P=0.035;校正HR(95％CI)为4.290(1.010～18.215),P=0.048].结论 药物代谢动力学基因ABCC2 rs3740066单核苷酸多态性与食管鳞癌患者术后无病生存期有关.

目的 评估血液炎症相关指标中性粒细胞-淋巴细胞比值(neutrophil-lymphocyte ratio,NLR)、血小板-淋巴细胞比值(platelet-lymphocyte ratio,PLR)、淋巴细胞-单核细胞比值(lymphocyte-monocyte ratio,LMR)、白蛋白(albumin,ALB)及联合炎症指标在晚期胰腺癌中的预后价值.方法 回顾性收集2012年7月至2020年10月北京大学肿瘤医院VIP-Ⅱ病区收治的晚期胰腺癌患者诊断时的基线资料.根据受试者工作特征(receiver operating characteristic,ROC)曲线确定炎症相关指标临界值,根据曲线下面积(area under curve,AUC)估计预后因素的准确性.通过单因素和多因素分析评估预后价值.结果 50例晚期胰腺癌患者中位生存时间7.2个月(95％CI:3.568～10.699).炎症相关指标的临界值分别为:NLR=4.5(AUC=0.840,95％CI:0.732～0.948,P<0.001),PLR=138(AUC=0.671,95％CI:0.517～0.826,P=0.038),LMR=4.0(AUC=0.873,95％CI:0.770～0.975,P<0.001),ALB=41.5(AUC=0.726,95％CI:0.582～0.870,P=0.006).单因素及多因素分析显示:NLR≥4.5(HR=11.936,95％CI:4.571～31.169,P<0.001)、PLR≥138(HR=2.246,95％CI:1.045～4.828,P=0.038)、ALB<41.5 g/L(HR=3.214,95％CI:1.463～7.060,P=0.004)为独立危险因素;LMR≥4(HR=0.336,95％CI:0.165～0.687,P=0.003)为独立保护因素.联合炎症指标NLR_ALB、PLR_ALB、LMR_ALB为独立预后指标,评分越高,预后越差.结论 NLR、LMR、PLR、ALB可以作为晚期胰腺癌的预后指标,联合血液炎症相关指标有助于简便、迅速地评估预后,有一定的临床应用前景.

Background In China, most esophageal cancer patients are squamous cell carcinomas and are treated with taxane-containing regimens; however, few studies have examined taxane pharmacokinetics genes and esophageal squamous cell carcinoma (ESCC) prognosis. Methods In total, 227 pathologically confirmed ESCC patients receiving chemotherapy with taxane were included in the analysis. We genotyped seven SNPs (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; and ABCC1 rs246221 and ABCC2 rs3740066) and analyzed their relationship with overall survival. Results With a retrospective cohort study design, by Cox regression and semi-Bayesian shrinkage, in the genetic recessive model, the variant homozygote of ABCB1 rs1045642 was inversely associated with survival (semi-Bayesian shrinkage crude hazard ratio = 1.82, 95% confidence interval = 1.00, 3.31; p = 0.0482). Conclusions Because of inherent defects of the research itself, the finding that the ABCB1 rs1045642 variant was related to poor prognosis in ESCC patients treated with taxane-containing regimens needs to be tested in a larger population and by using more genetic and molecular mechanism experiments.

Background: Chemotherapy-related adverse events may restrain taxane/cisplatin administration as a regimen for patients with esophageal squamous cell carcinoma. Genetic polymorphisms may contribute to adverse event susceptibility. Method & results: The authors genotyped ten SNPs from five genes (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; rs246221 of ABCC1; rs3740066 of ABCC2; and rs10771973, rs12296975 and rs1239829 of FGD4) in 219 patients with esophageal squamous cell carcinoma treated with taxane/cisplatin. Patients with severe toxicities were compared with those with minor or no adverse events by unconditional logistic regression models and semi-Bayesian shrinkage. After adjustment for age and sex, with the null prior, FGD4 rs1239829 was statistically significantly related to grade 3-4 leukopenia (odds ratio [95% CI] in dominant model = 1.77 [1.04-3.03]). Conclusion: The minor allele of FGD4 rs1239829 was related to grade 3-4 leukopenia in patients with esophageal squamous cell carcinoma treated with taxane/cisplatin, with unclear biological mechanism.

Cytochrome P450 (CYP) is the most important phase I drug-metabolizing enzyme, and the effect of drugs on CYP enzymes can lead to decreased pharmacological efficacy or enhanced toxicity of drugs, but there are many deficiencies in the evaluation models of CYP enzymes in vitro. Human-induced hepatocytes (hiHeps) derived from human fibroblasts by transdifferentiation have mature hepatocyte characteristics. The aim was to establish a novel evaluation system for the effect of drugs on CYP3A4, 1A2, 2B6, 2C9, and 2C19 in vitro based on hiHeps. Curcumin can inhibit many CYP enzymes in vitro, and so the inhibition of curcumin on CYP enzymes was compared by human liver microsomes, human hepatocytes, and hiHeps using UPLC-MS and the cocktail method. The results showed that the IC50 values of CYP enzymes in the hiHeps group were similar to those in the hepatocytes group, which proved the effectiveness and stability of the novel evaluation system in vitro. Subsequently, the evaluation system was applied to study the inhibitory activity of notoginseng total saponins (NS), safflower total flavonoids (SF), and the herb pair of NS-SF on five CYP enzymes. The mechanism of improving efficacy after NS and SF combined based on CYP enzymes was elucidated in vitro. The established evaluation system will become a powerful tool for the research of the effect of drugs on the activity of CYP enzymes in vitro, which has broad application prospects in drug research.

Metastasis of esophageal squamous cell carcinoma (ESCC) spread to uncommon sites is increasing in recent years. Metachronous renal metastasis of ESCC was reported before and relatively easy to be diagnosed. But synchronous renal parenchyma metastasis of ESCC is rare and of importance before make treatment plan. Here we present one case of synchronous and one case of metachronous renal parenchyma of ESCC. In the synchronous renal metastasis case, the patient was diagnosed ESCC in August 2016. Though CT scan was normal, PET-CT scan found a small lesion in right renal cortex with increased FDG uptake. The patient refused biopsy of renal lesion. Two cycles of neoadjuvant chemotherapy were given with stable response. Then esophagectomy and adjuvant radiation were given. Seven months later, CT scan revealed renal and spleen lesions and biopsy confirmed squamous cell carcinoma. The patient refused systematic treatment and died 5 months later. In the metachronous renal metastasis case, the patient was diagnosed ESCC in March 2015 and PET/CT scan showed no distant metastasis. Esophagectomy and adjuvant radiotherapy were given. CT scan revealed solitary renal and multiple lung metastasis 23 months later. Biopsy of renal lesion confirmed squamous cell carcinoma (SCC). Chemotherapy was given but with only stable response. The patient died 7 months later after relapse. Both patients had not urinary symptoms. Together with published literatures, renal parenchyma metastasis of ESCC is often asymptomatic. Disease history and biopsy are helpful in diagnosis. And present cases suggested that PET-CT is more sensitive than CT to identify unusual metastasis of ESCC.

Background: Identification of novel biomarkers is crucial for the diagnosis and treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to reveal the clinical significance and molecular characteristics of MYC-associated factor X dimerization protein 1 (MXD1) in ESCC. Patients and methods: We collected 3 ESCC cohorts to investigate the effect of MXD1 on clinical outcomes. In addition, we compared and analyzed the possible transcription changes between MXD1-low and MXD1-high ESCC patients using bioinformatics. Moreover, immunohistochemical analysis was conducted to confirm the potential impact of MXD1 on the prognosis and tumor immune microenvironment (TIME). Results: MXD1 messenger RNA (mRNA) expression was significantly lower in tumors than in normal tissues. Low expression of MXD1 in ESCC was associated with a more aggressive tumor stage and worse prognosis at both the mRNA and protein levels. Moreover, MXD1-low ESCC showed upregulation of epithelial-mesenchymal transition and extracellular matrix-related gene sets, and significantly higher NFE2L2 and KIAA1324L mutation frequencies. In contrast, MXD1-high ESCC showed upregulation of tumor differentiation and immune-related gene sets. Furthermore, the CIBERSORT approach showed that high expression of MXD1 was associated with a higher proportion of neutrophils but a lower proportion of M2 macrophages. At the protein level, MXD1 expression was positively correlated with programmed cell death 1 ligand 1 (PDL1) and CD8 expression. In silico analysis predicted that MXD1-high ESCC was more likely to benefit from immunotherapy. Conclusion: This study suggests that MXD1 is a crucial prognostic factor in ESCC patients and is closely associated with specific transcriptional changes and TIME features.

目的:探讨不可手术切除的局部进展期或转移性胃癌患者外周血中CEA、CA19-9、CA72.4及CA125在预后评估中的价值.方法:回顾性收集2013年7月-2015年5月行一线化疗的109例不可手术切除的局部进展期或转移性胃癌患者的临床资料及化疗前CEA、CA19-9、CA72.4及CA125肿瘤标志物的检测结果,分析其与患者临床病理学特征及预后的关系.结果:109例胃癌患者中CEA、CA19-9、CA72.4及CA125的初诊阳性率分别为46.8％、40.2％、53.5％及35.0％,4种标志物联合检测阳性率高达87.2％.女性患者中CA72.4的阳性率明显高于男性(75.0％ vs.48.6％,P=0.049);CEA阳性与肝转移(P=0.014)、CA125阳性与腹膜转移有关(P=0.005).单因素分析显示,CA72.4阳性者比阴性者的中位无进展生存期(PFS)(6.3个月vs.11.1个月,P=0.020)及中位总生存期(0S)(9.9个月vs.16.9个月,P=0.007)均显著缩短,CA125阳性者比阴性者的中位PFS(6.2个月vs.7.8个月,P=0.002)及中位OS(9.8个月vs.15.6个月,P=0.009)也明显缩短.多因素分析显示,患者预后差的因素有肿瘤分化差(RR=42.282,95％CI=3.385～528.159,P=0.004)、腹膜转移(RR=8.736;95％ CI=1.314～58.097,P=0.025)、CA72.4＞6.7 U/mL (RR=6.718,95％ CI=1.643～27.466, P=0.008)和CA125＞35.0 U/mL (RR=5.483, 95％ CI=1.016～29.601, P=0.048).109例患者中,49例(45.0％)为低危人群(0或1个危险因素),60例(55.0％)为高危人群(2至4个危险因素).低危和高危人群的中位生存期分别为18.5个月和9.9个月(P=0.001).结论:对于不可手术的局部进展期或转移性胃癌患者,CA72.4及CA125与患者预后有关;预后模型有利于将患者进行风险分层并为每个患者制定最佳治疗方案提供帮助.