Association between gut microbiota and hepatocellular carcinoma and biliary tract cancer:A mendelian randomization study

BACKGROUND An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases,yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma(HCC)and biliary tract cancer(BTC).This study aims to explore the relationship between them using Mendelian randomization(MR)analysis method.AIM To assess the relationship between gut microbiota and HCC and BTC.METHODS We obtained Genome-wide association study(GWAS)data for the gut microbiome from the intestinal microbiota genomic library(MiBioGen,https://mibiogen.gcc.rug.nl/).Additionally,we accessed data pertaining to HCC and BTC from the IEU open GWAS platform(https://gwas.mrcieu.ac.uk/).Our analysis employed fundamental instrumental variable analysis methods,including inverse-variance weighted,MR and Egger.To ensure the dependability of the results,we subjected the results to tests for multiple biases and heterogeneity.RESULTS During our investigation,we discovered 11 gut microbiota linked to an increased risk to BTC and HCC.The former included the genus Eubacterium hallii group(P=0.017),Candidatus Soleaferrea(P=0.034),Flavonifractor(P=0.021),Lachnospiraceae FCS020(P=0.034),the order Victivallales(P=0.018),and the class Lentisphaeria(P=0.0.18).The latter included the genus Desulfovibrio(P=0.042),Oscillibacter(P=0.023),the family Coriobacteriaceae(P=0.048),the order Coriobacteriales(P=0.048),and the class Coriobacteriia(P=0.048).Furthermore,in BTC,we observed 2 protective gut microbiota namely the genus Dorea(P=0.041)and Lachnospiraceae ND3007 group(P=0.045).All results showed no evidence of multiplicity or heterogeneity.CONCLUSION This study explores a causal link between gut microbiota and HCC and BTC.These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways,potentially informing therapeutic strategies.

Molecular genetics and targeted therapeutics in biliary tractcarcinoma

The primary malignancies of the biliary tract, cholangio-carcinoma and gallbladder cancer, often present at an advanced stage and are marginally sensitive to radiation and chemotherapy. Accumulating evidence indicates that molecularly targeted agents may provide new hope for improving treatment response in biliary tract carcinoma(BTC). In this article, we provide a critical review of the pathogenesis and genetic abnormalities of biliary tract neoplasms, in addition to discussing the current and emerging targeted therapeutics in BTC. Genetic studies of biliary tumors have identified the growth factors and receptors as well as their downstream signaling pathways that control the growth and survival of biliary epithelia. Target-specific monoclonal antibodies and small molecules inhibitors directed against the signaling pathways that drive BTC growth and invasion have been developed. Numerous clinical trials designed to test these agents as either monotherapy or in combination with conventional chemotherapy have been completed or are currently underway. Research focusing on understanding the molecular basis of biliary tumorigenesis will continue to identify for targeted therapy the key mutations that drive growth and invasion of biliary neoplasms. Additional strategies that have emerged for treating this malignant disease include targeting the epigenetic alterations of BTC and immunotherapy. By integrating targeted therapy with molecular profiles of biliary tumor, we hope to provide precision treatment for patients with malignant diseases of the biliary tract.

Re-expression of RASSF1A by 5-Aza-CdR Induced Demethylation of the Promoter Region in Human Biliary Tract Carcinoma Cells

Hypermethylation of the promoter region is an important mean for the transcriptional repression of a number of cancer-associated genes, and over-expression and/or increased activity of DNA methyltransferase are considered to be the main cause of promoter hypermethylation. In order to further explore the epigenetic mechanism of tumor suppressor gene RASSF1A inactivation, 5-aza-2’-deoxycytidine (5-Aza-CdR), a DNA methyltransferase inhibitor, was used to treat the human biliary tract carcinoma cell line QBC-939 at the concentration of 5 μmol/L for 24 h in this study. Af- ter the chemical intervention with 5-Aza-CdR, the methylation status in the promoter region of RASSF1A gene was detected by methylation specific PCR (MS-PCR), and the expression alteration of RASSF1A mRNA and protein were observed by RT-PCR and Western Blot respectively. Following the treatment with 5-Aza-CdR, methylaiton status in the promoter region of RASSF1A gene was re- versed from methylation to unmethylation. A 280 bp DNA band which represented RASS1FA expres- sion at transcriptional level and a 40 kDa (1kDa=0.9921 ku) protein band which represented RASSF1A expression at protein level were detected by RT-PCR and Western Blot respectively in the experimental group cells and there were no corresponding bands in the control group cells. The ex- perimental results suggest that 5-Aza-CdR can induce demethylation in the promoter region of RASSF1A. It can also reverse epigenetic transcriptional silencing caused by DNA methylation and induce the re-expression of RASSF1A in QBC-939. This study also suggest that the mechanism of RASSF1A inactivation is very closely related to the methylation of the promoter region, which may provide a new epigenetic understanding for tumor related gene inactivation and the pathogenesis of biliary tract carcinoma.

Effect of histone deacetylase inhibitor on proliferation of biliary tract cancer cell lines

AIM: To explore the effect of histone deacetylase inhibitor, trichostatin A (TSA) on the growth of biliary tract cancer cell lines (gallbladder carcinoma cell line and cholangiocarcinoma cell line) in vivo and in vitro, and to investigate the perspective of histone deacetylase inhibitor in its clinical application. METHODS: The survival rates of gallbladder carcinoma cell line (Mz-ChA-l cell line) and cholangiocarcinoma cell lines (QBC939, KMBC and OZ cell lines) treated with various doses of TSA were detected by methylthiazoy tetrazolium (MTT) assay. A nude mouse model of transplanted gallbladder carcinoma (Mz-ChA-l cell line) was successfully established, and changes in the growth of transplanted tumor after treated with TSA were measured. RESULTS: TSA could inhibit the proliferation of gallbladder carcinoma cell line (Mz-ChA-l cell line) and cholangiocarcinoma cell lines (QBC939, KMBC and OZ cell lines) in a dose-dependent manner. After the nude mouse model of transplanted gallbladder carcinoma (Mz- ChA-l cell line) was successfully established, the growth of cancer was inhibited in the model after treated with TSA. CONCLUSION: TSA can inhibit the growth of cholangiocarcinoma and gallbladder carcinoma cell lines in vitro and in vivo.

Effect of antisense DNMT3b gene eukaryotic expression plasmid on expression of the DNMT3b gene in human biliary tract carcinoma cells

BACKGROUND: Hypermethylation of the promoter region is one of the major mechanisms of tumor suppressor gene inactivation. DNA methyltransferase 3b (DNMT3b), an enzyme that participates in the establishment of de novo methylation patterns, is highly expressed in many tumor cells and tissues, and it is closely associated with hypermethylation of the promoter of tumor suppressor genes. The aim of this study was to explore the effect of transfection with antisense DNMT3b gene eukaryotic expression plasmid on the expression of the DNMT3b gene in human biliary tract carcinoma cell. METHODS: The constructed antisense DNMT3b gene eukaryotic expression plasmid was transfected into the human biliary tract carcinoma cell line QBC-939 with lipofectamine transfection reagent, and positive cell clones were formed using G418 selection after transfection. The constructed recombinant plasmid was transfected into QBC-939 cells successfully and was confirmed by amplification of the exogenous neo^R gene with the polymerase chain reaction method. The expression of DNMT3b gene mRNA and protein was detected by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and flow cytometry respectively. RESULTS: Following transfection, the mRNA level of the DNMT3b gene decreased from 0.956±0.053 to 0.209±0.023, and the protein level of the DNMT3b gene also decreased from (75.38±3.22)% to (29.87±3.46)%. Very significant differences were observed both at the transcription and posttranscription levels in the expression of the DNMT3b gene between the non-tranfection group and the antisense DN- MT3b gene eukaryotic expression plasmid transfection group (P<0.01). CONCLUSIONS: Transfection with the antisense DNMT3b gene eukaryotic expression plasmid can significantly reduce the expression level of the DNMT3b gene in the human biliary tract carcinoma cell line QBC-939. This study may provide a valid method to investigate the function of the DNMT3b gene and its role in biliary tract carcinoma.

Effect of Antisense MBD1 Gene Eukaryotic Expression Plasmid on Expression of MBD1 Gene in Human Biliary Tract Carcinoma Cells

Hypermethylation of the promoter region is one of the major mechanism of tumor suppressor gene inactivation. In order to provide a research tool for the study on the function of MBD1 gene in DNA methylation and tumorigenesis, antisense MBD1 gene eukaryotic expression plasmid was constructed and transfected into human biliary tract carcinoma cell line QBC-939 to observe its effect on the expression of MBD1 mRNA and protein by using RT-PCR and FCM respectively. Following the transfection, the mRNA level of MBD1 gene decreased from 0. 912±0.022 to 0. 215±0. 017, and the protein level of MBD1 gene also decreased from （80.19±5.05） %to （35.11±4.05） %. There were very significant differences in the expression both at the transcription and post-transcription levels of MBD1 gene between non-tranfection group and the antisense MBD1 gene eukaryotic expression plasmid transfection group （P〈0.01）. It was suggested that transfection with the antisense MBD1 gene eukaryotic expression plasmid can significantly reduce the expression level of MBD1 gene in QBC-939, and this study may provide a valid tool for the investigation of the function of MBD1 gene and its role in biliary tract carcinoma.

Expression Analysis of Aquaporin-1 (Aqp-1) in Human Biliary Tract Carcinoma

Background: Aquaporins (AQPs) are important in controlling bile water secretion. AQP is related to the invasion and metastasis of cancer. However, the relationship of biliary tract cancer is not clear. The role of AQP-1 in cancer cell is also unknown. Methhods: We analyzed AQP-1 expression using tissue microarray (TMA) in 99 samples immunohistochemically (50 gallbladder carcinoma, 39 bile duct carcinoma and 10 Papilla Vater carcinoma patients who underwent surgery at our department from 1997 to 2011). Gene expressions were evaluated by the combination of the immunohistological intensity and distribution. The expression level is compared to the clinico-pathological data of the patients. Results: In the TMA, depth of tumor invasion and histological type are associated with AQP-1 expression. The group of patients with high AQP-1 expression is associated with higher rates of disease specific survival (log-rank p = 0.013). Cox’s proportional hazard model reveals that AQP-1 expression is an independent prognostic factor (RR, 0.324;p = 0.001) in multivariate analysis. There is a correlation between AQP-1 expression and tumor invasion. Conclusions: These observations of this study suggest that AQP-1 expression may be favorable biomarkers associated with prognosis and tumor invasion in biliary tract carcinoma.

Frequency of Loss Exprssion of DPC4 Protein in Various Locations of Biliary Tract Carcinoma

Objective To clarify the relationship between loss of expression of DPC4 proteins and pathogenesis of biliary tract carcinoma. Methods 71 primary biliary tract carcinomas(BTCa),including 38 common bile duct(CBD) carcinomas,18 gallbladder carcinomas,and 15 hilar bile ducts(HBD) carcinomas were examined by immunohistochemical staining .In addition,the CBD carcinomas were divid-ed into two groups,a trmor group with metastasis(M+ group ,27 cases)and a tumor group without metastasis(M-group,11 cases). Results The frequency of loss expression of DPC4 protein was 32.8% in BTCa ,47.3% in CBD carcinoma ,11% in gallbladder carcino-ma and 13% in HBD carcinoma.A comparison of the frequency of loss expression of DPC4 showed singnificantly statistical difference in the CBD carcinoma versus gallbladder carcinoma and HBD carcinoma (P<0.01).The frequency of loss expression of DPC4 was 48.1% in the M^+ group and 45.4% in the M^-group.There was no significantly statistical difference between them(P>0.05). Conclusion There is a close relationship between the pathogenesis of BTCa and inactivation of DPC4 with different frequencies of DPC4 gene alteration in various locations of the biliary tract,but inactivation of DPC4 is not related with tumor metastasis in BTCa.

Establishment of various biliary tract carcinoma cell lines and xenograft models for appropriate preclinical studies

We recently reported several driver genes of biliary tract carcinoma(BTC) that are known to play important roles in oncogenesis and disease progression. Although the need for developing novel therapeutic strategies is increasing, there are very few BTC cell lines and xenograft models currently available for conducting preclinical studies. Using a total of 88 surgical BTC specimens and 536 immunodeficient mice, 28 xenograft models and 13 new BTC cell lines, including subtypes, were established. Some of our cell lines were found to be resistant to gemcitabine, which is currently the first choice of treatment, thereby allowing highly practical preclinical studies to be conducted. Using the aforementioned cell lines and xenograft models and a clinical pathological database of patients undergoing BTC resection, we can establish a preclinical study system and appropriate parameters for drug efficacy studies to explore new biomarkers for practical applications in the future studies.

New trends in diagnosis and management of gallbladder carcinoma

Gallbladder(GB)carcinoma,although relatively rare,is the most common biliary tree cholangiocarcinoma with aggressiveness and poor prognosis.It is closely associated with cholelithiasis and long-standing large(>3 cm)gallstones in up to 90%of cases.The other main predisposing factors for GB carcinoma include molecular factors such as mutated genes,GB wall calcification(porcelain)or mainly mucosal microcalcifications,and GB polyps≥1 cm in size.Diagnosis is made by ultrasound,computed tomography(CT),and,more precisely,magnetic resonance imaging(MRI).Preoperative staging is of great importance in decisionmaking regarding therapeutic management.Preoperative staging is based on MRI findings,the leading technique for liver metastasis imaging,enhanced three-phase CT angiography,or magnetic resonance angiography for major vessel assessment.It is also necessary to use positron emission tomography(PET)-CT or ^(18)F-FDG PET-MRI to more accurately detect metastases and any other occult deposits with active metabolic uptake.Staging laparoscopy may detect dissemination not otherwise found in 20%-28.6%of cases.Multimodality treatment is needed,including surgical resection,targeted therapy by biological agents according to molecular testing gene mapping,chemotherapy,radiation therapy,and immunotherapy.It is of great importance to understand the updated guidelines and current treatment options.The extent of surgical intervention depends on the disease stage,ranging from simple cholecystectomy(T1a)to extended resections and including extended cholecystectomy(T1b),with wide lymph node resection in every case or IV-V segmentectomy(T2),hepatic trisegmentectomy or major hepatectomy accompanied by hepaticojejunostomy Roux-Y,and adjacent organ resection if necessary(T3).Laparoscopic or robotic surgery shows fewer postoperative complications and equivalent oncological outcomes when compared to open surgery,but much attention must be paid to avoiding injuries.In addition to surgery,novel targeted treatment along with immunotherapy and recent improvements in radiotherapy and chemotherapy(neoadjuvant-adjuvant capecitabine,cisplatin,gemcitabine)have yielded promising results even in inoperable cases calling for palliation(T4).Thus,individualized treatment must be applied.

2023年ESMO会议肝胆肿瘤治疗研究进展

2023年欧洲肿瘤内科学会(European Society for Medical Oncology,ESMO)年会于2023年10月20~24日在西班牙马德里召开。本次大会报道多项肝胆恶性肿瘤的临床研究结果,涵盖系统治疗、局部联合系统治疗和围手术期治疗等。这些研究结果将改变临床实践并推动肝胆恶性肿瘤领域的发展。本文重点介绍大会肝细胞癌和胆管恶性肿瘤的相关研究结果,探讨当前的治疗热点、问题和未来发展方向。

Interventional radiology in the management of malignant biliary obstruction

Malignant biliary obstruction is commonly due to pancreatic carcinoma,cholangiocarcinoma and metastatic disease which are often inoperable at presentation and carry a poor prognosis.Percutaneous biliary drainage and stenting provides a safe and effective method of palliation in such patients,thereby improving their quality of life.It may also be an adjunct to surgical management by improving hepatic and,indirectly,renal function before resection of the tumor.

Biomarkers for response to immunotherapy in hepatobiliary malignancies

Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies.The identification of reliable predictors of the response to immunotherapy is urgently needed.Data sources:Literature search was conducted in Pub Med for relevant articles published up to May 2022.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence.Tumor programmed death-ligand 1(PD-L1)expression is the most widely studied biomarker in hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs),but there are conflicting results on its predictive potential.Tumor mutational burden(TMB)is generally low both in HCC and BTCs,and the clinical trials of TMB are rare in hepatobiliary malignancies.Promisingly,mismatch repair deficiency(dMMR)/high microsatellite instability(MSI-H)may be a predictive biomarker of response to antiPD-1 therapy in BTCs.Furthermore,some emerging biomarkers,such as gut microbiota,show predictive potential in the preliminary studies.Radiomics and liquid-biopsy biomarkers,including circulating tumor cells,circulating tumor DNA(ct DNA)and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response,showing a new promising direction.Conclusions:Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic.Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies.The identification of predictors for response to ICIs is an urgent need and major challenge.Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.

The relationship between loss expression of DPC4/Smad4 gene and carcinogenesis of pancreatobiliary carcinoma

Objective: To clarify the relationship between loss of DPCA gene expression and pathogenesis of pancreato- biliary carcinoma. Methods: 75 slides of normal duct (20), hyperplasia (15), dysplasia (15), invasive carcinoma (25) from patients with pancreatic diseases including pancreatic carcinoma (25 patients), chronic pancreatitis (6), pancreas injury (2) and 71 slides of common bile duct (CBD) carcinoma (38), gallbladder carcinoma (18), hilar bile duct (HBD) carcinoma (15) from patients with primary biliary tract carcinoma were analyzed for the expression of DPC4 protein by im- munohistochemical staining. Results: All specimens from 20 cases of normal duct and 15 cases of hyperplasia showed marked expres- sion of DPC4 protein. The frequency of loss expres- sion of the DPC4 gene was 33 % in dysplasia, and 48% in invasive carcinoma. There was a significant statistical difference between byperplasia and dyspla- sia (P<0.01) and in dysplasia vs invasive carcinoma (P<0.05). The frequency of loss expression of the DPC4 gene was 47.3% in CBD carcinoma, 11% in gallbladder carcinoma, and 13% in HBD carcinoma. The frequency of loss expression of the DPCA gene was significantly different in CBD carcinoma vs gall- bladder carcinoma and HBD carcinoma (P<0.01). Conclusions: Inactivation of the DPC4 gene occurs late in the neoplastic progression of pancreatic carci- noma. The frequency of DPC4 gene alternation was different in various locations of biliary tract carcino- ma. In CBD carcinoma, this frequency is similar to that in pancreatic carcinoma, indicating their similar molecular alternations.

2023年ASCO肝胆胰恶性肿瘤治疗进展

2023年美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)年会于2023年6月2日至6日在芝加哥召开。本次大会报道了多项肝胆胰恶性肿瘤领域的重磅研究,涵盖晚期系统治疗、局部联合系统治疗和围手术期治疗等。这些结果将改变临床实践,推动肝胆胰恶性肿瘤领域的发展。本文重点介绍大会肝细胞癌(hepatocellular carcinoma,HCC)、胆管恶性肿瘤(biliary tract cancer,BTC)和胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDAC)相关研究结果,探讨当前的治疗热点、问题和未来发展方向。

细胞游离DNA在胆道癌诊断中的价值:一项meta分析

目的·采用meta分析方法全面评价细胞游离DNA(cell-free DNA,cfDNA)对胆道癌(biliary tract cancer,BTC)的诊断准确性,探究样本来源、检测方法以及截断值选择等对诊断效果的影响,为更好开展临床应用提供依据。方法·检索8个中英文数据库中关于cfDNA对BTC诊断价值的前瞻性或回顾性研究,截止时间为2023年4月。根据纳入和排除标准进行筛选和数据提取,用Spearman秩相关分析评估阈值效应,运用Cochran Q检验、I^(2)检验分析纳入研究间的异质性。拟合双变量混合效应模型,计算总体敏感度、特异度和曲线下面积(area under the curve,AUC)等统计量,判断诊断性能。同时,基于研究类型、样本量大小、检测方式、样本来源和诊断参照标准进行亚组分析。结果·共纳入28项诊断性试验,用诊断性试验准确性质量评价工具2(Diagnostic Accuracy Studies Tool Version 2,QUADAS-2)评价均属于中-高等质量研究,Spearman秩相关分析提示存在阈值效应,合并统计量后求得敏感度(Sen合并)为0.80(95%CI 0.67~0.88),特异度(Spe_(合并))为0.96(95%CI 0.92~0.98),阳性似然比(PLR合并)为22.7(95%CI 9.4~55.2),阴性似然比(NLR合并)为0.21(95%CI 0.12~0.36),诊断比数比(DOR合并)为108(95%CI 31~374)。综合受试者工作特征(summary receiver operating characteristic,SROC)曲线的AUC为0.96(95%CI 0.94~0.98),提示cfDNA对BTC的诊断效能较高。亚组分析结果提示,选择不同的检测方式和样本来源的准确度和敏感度有所不同。结论·cfDNA检测对诊断BTC敏感度和特异度较高,适用于经影像学和常规肿瘤标志物初筛怀疑有恶性风险的患者,但检测方法和样本来源的选择仍需进一步开展面向更广泛人群的临床研究来进一步规范。

晚期胆道癌免疫检查点抑制剂治疗的研究进展

胆道恶性肿瘤(biliary tract cancers,BTC)主要包括胆囊癌和肝内外胆管癌,绝大多数为腺癌,侵袭性较强且预后较差。BTC发病隐匿,即便可手术切除患者仍面临较高复发风险,术后辅助化疗生存获益有限。系统抗肿瘤药物治疗是不可手术切除或转移性BTC的主要治疗手段。近年来,除传统化疗外,免疫检查点抑制剂和分子靶向药物在晚期BTC治疗中也取得较大进展,极大丰富了临床治疗选择,也进一步改善了患者预后。一线化疗联合免疫治疗较传统化疗已成为优势治疗策略,化疗联合免疫治疗和抗血管生成靶向治疗以及化疗联合双免疫治疗显示出较好的前景,二线免疫联合治疗也进行了积极探索。本文就晚期胆道癌的免疫治疗现状与最新进展进行综述。

帕博利珠单抗联合化疗方案一线治疗晚期或不可切除胆道恶性肿瘤的成本-效用分析

目的从我国卫生体系角度出发,评价帕博利珠单抗联合化疗方案对比安慰剂联合化疗方案一线治疗晚期或不可切除胆道恶性肿瘤(BTC)的经济性。方法根据KEYNOTE-966试验数据构建分区生存模型,模拟周期为21 d,模拟时限为患者终生。以质量调整生命年(QALY)为产出指标,采用成本-效用分析法评价上述两种方案的经济性。通过单因素敏感性分析和概率敏感性分析验证基础分析结果,并探讨有赠药方案情境下的经济性。结果基础分析结果显示,帕博利珠单抗组的成本与效果均高于安慰剂组,增量成本-效果比(ICER)为3909359.78元/QALY,高于以3倍我国2022年人均国内生产总值(GDP)即257094元作为的意愿支付(WTP)阈值,证明没有经济性。单因素敏感性分析结果显示,效用贴现率、无进展生存状态效用值、成本贴现率、帕博利珠单抗成本等对ICER的影响较大。概率敏感性分析验证了基础分析结果的稳健性,并得出当WTP阈值大于1500000元/QALY时,帕博利珠单抗组方案开始具有经济性。情境分析结果表明,当考虑针对低收入人群的帕博利珠单抗慈善赠药方案时,虽然治疗成本大幅下降,但仍不具有经济性。结论在以3倍我国2022年人均GDP作为WTP阈值时,相比于安慰剂联合化疗方案,帕博利珠单抗联合化疗方案治疗晚期或不可切除BTC不具有经济性。

晚期胆道癌抗HER-2治疗临床研究进展

胆道癌(BTC)是起源于胆管上皮的一组恶性肿瘤,异质性高,治疗棘手,预后差,生存期短。晚期BTC的治疗既往主要依赖于化疗,新近免疫联合化疗一线治疗已获得成功;同时,随着对胆道肿瘤的基因组和蛋白组特征认识的不断加深,业已明确其分子分型,且发现了若干分子生物标志物,因此靶向药物在二线治疗BTC的研究如火如荼,正在改变BTC的治疗格局和结局。抗人表皮生长因子受体-2(HER-2)治疗,已在乳腺癌和胃癌等多种肿瘤的治疗中显著改善患者预后,现正在积极探索用于治疗BTC,初步显示了可期的美好前景。本文简要综述了抗HER-2治疗BTC的临床研究进展,提出需要进一步开展基于分子生物标志物HER-2驱动的随机对照、大规模的多中心Ⅲ期研究。

GEMOX方案联合重组人血管内皮抑素一线治疗晚期胆系肿瘤的初步观察

目的：观察吉西他滨（ GEM）、奥沙利铂（ OXA）联合重组人血管内皮抑素（恩度）一线治疗晚期胆系肿瘤（BTCs）的疗效及安全性。方法回顾性分析2009年1月至2013年8月ⅣB期BTCs患者48例，分为联合组（n＝20）和单纯化疗组（ n＝28）。联合组：吉西他滨1000mg／m2静滴，d1、d8；奥沙利铂100mg／m2静滴 d2，3周为1周期；恩度15mg 静滴 d1～d14，3周为1周期。单纯化疗组仅给予GEMOX方案化疗，剂量与使用方法同联合组。2个周期后按照RECIST1.1标准评价近期疗效，参考KPS变化评价生活质量（QoL），根据NCI CTC3.0标准评价不良反应，并观察疾病进展时间（TTP）和总生存时间（ OS）。结果联合组获CR 1例、PR 3例、SD 12例、PD 4例，有效率（ RR）为20.0％，疾病控制率（ DCR）为80.0％；中位TTP为8.6个月，中位OS为14.0个月；QoL改善稳定率为80.0％。单纯化疗组获 CR 1例、PR 5例、SD 15例、PD 7例，RR 为21.5％，DCR 为75.0％；中位TTP为6.0个月，中位OS为10.0个月；QoL改善稳定率为71.4％。两组中位TTP和OS的差异有统计学意义（ P＜0.05）。两组最常见的不良反应为骨髓抑制，其他不良反应包括恶心呕吐、肝功能损害、外周神经炎、皮肤过敏反应等，以1～2级为主，两组比较差异无统计学意义（ P＞0.05）。化疗联合恩度组仅2例出现心电图T波改变，1例出现房性早搏，1例出现轻度血压升高。结论 GEMOX联合恩度方案一线治疗转移性BTCs疗效较好，可以改善或稳定QoL，延长生存时间，且耐受性较好，值得临床推广使用和进一步深入观察。