Background: Cholangiocarcinoma (CCA) is a highly heterogeneous biliary malignancy with a poor prognosis. Finding early diagnosis and therapeutic targets for CCA is of great importance. The aim of this study was to screen for key genes involved in CCA using bioinformatics analysis, identify establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2) as a core candidate, and validate its role experimentally. Methods: The CCA data were downloaded using the Gene Expression Comprehensive Database and the Cancer Genome Atlas, the core gene ESCO2 with strong correlation with CCA was screened by raw letter analysis, and the prognostic value of key CCA genes was analyzed by Kaplan-Meier. The effects of ESCO2 on CCA cells and its oncogenic effects were investigated by cell and animal experiments. Results: A total of 1,372 differential genes were screened in this study, with 742 up-regulated genes including ESCO2 and 630 down-regulated genes. Patients with high ESCO2 expression had a poorer prognosis and were significantly associated with N stage. Immune infiltration analysis revealed that ESCO2 expression was negatively correlated with CD8A and FGFBP2. Cellular experiments showed that ESCO2 was significantly up-regulated in CCA cells. ESCO2 overexpression promotes CCA cell proliferation and inhibits apoptosis. In vivo experiments confirmed that ESCO2 promotes tumor growth and shortens survival in mice. Conclusions: ESCO2 is a key regulatory gene affecting the development of CCA and plays an important role in CCA cell proliferation, which could be a new target for CCA diagnosis and treatment.

Background: The location relative to the hepatic and peritoneal sides of T2 gallbladder cancer (GBC) clearly affects the prognosis, but it remains unknown whether the location and extent of T3 tumors impact survival. To investigate the influence of a novel T3 subclassification on the prognosis of patients who received radical resection. Methods: This retrospective multicenter cohort study analyzes pT3 data collected between 2013 and 2018. The T3 category is divided into subgroups of T3p (T3p1 and T3p2), T3h, and T3p + 3h. The T3p is defined as an invasion of the peritoneal side alone. T3p1 indicates serosal penetration alone, and T3p2 refers to involvement of one adjacent organ/structure; T3h means liver invasion on hepatic side alone, while T3p + 3h represents a combination of T3p and T3h. Overall survival (OS) and disease-free survival (DFS) of T3 subgroups were calculated and compared. Cox multivariable analysis was performed to identify prognostic factors. Results: A total of 424 patients were included in the derivation (n=252) and validation cohorts (n=172). Subtypes T3p2, T3h, and T3p + 3h (other than T3p1 as T3b) displayed the worst median OS of 15.0, 15.0, and 11.0 months, respectively, compared to T3p1 (T3a) (44.0 months) (P<0.001). This subclassification enabled further prognostic stratification and comparisons in American Joint Committee on Cancer stage IIIA [5-year OS: 58.0% (T3aN0M0) vs. 29.8% (T3bN0M0), P<0.001] and IIIB [32.4% (T3aN1M0) vs. 10.9% (T3bN1M0), P=0.005]. T3b disease was identified as an independent predictor of worse OS or DFS. The prognostic discriminative ability of T3 subclassification was consistent in the validation cohort.Conclusions: A novel T3 subclassification (T3a and T3b) is worthwhile considering for GBC TNM grouping. T3aN0M0 should be distinguished as a new and the foremost subgroup of stage III (ChiCTR2400090220).

Objective: To investigate the effect of the number of positive preoperative serological tumor markers on the surgical approach and prognosis of patients with intrahepatic cholangiocarcinoma. Methods: This is a retrospective case-series study. Data from 548 patients with intrahepatic cholangiocarcinoma after radical resection from October 2010 to April 2019 were retrospectively collected in 10 hospitals of China. There were 277 males and 271 females with an age of (57.8±10.2)years(range:23 to 84 years). Four hundred and twenty-six patients(77.7%) had at least one positive preoperative serum tumor marker. The data collection included the results of 4 preoperative serological tumor markers,other preoperative indicators(5 prodromal symptoms, 6 medical history,8 preoperative serological indicators,5 preoperative imaging indicators,and 14 preoperative pathological examination indicators),baseline data (gender and age),surgical methods,and prognostic follow-up data. Four preoperative results of serologic tumor marker and surgical procedure were converted into categorical variables. The number of positive preoperative serum tumor markers was used as the treatment variable,the surgical method was used as the mediating variable,and the survival time was used as the outcome variable. Univariate and multivariate analysis were used to screen for other preoperative indicators which were independent factors that influenced the surgical procedure and the prognosis of patients as covariates to analyze the mediating effect. Results: Of the 548 patients included in the study, 176 patients (32.1%) underwent partial hepatectomy,151 patients(27.5%) underwent hemihepatectomy, and 221 patients(40.3%) underwent partial hepatectomy or hemihepatectomy combined with other treatments. The results of the univariate and multivariate analysis showed that the number of positive serum tumor markers,intrahepatic bile duct dilatation,portal vein invasion,pathological differentiation,pathological type,vascular invasion,T stage,N stage and maximum tumor diameter were independent factors influencing the surgical procedure(all P<0.05). Intrahepatic bile duct dilatation,pathological differentiation and T stage were independent prognostic factors for patients with intrahepatic cholangiocarcinoma(all P<0.05). Intrahepatic bile duct dilatation,differentiation and T stage were included as covariates in the mediation effect model. The results showed that the number of positive serum tumor markers before surgery had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma (β=-0.092, P=0.039),and had a positive predictive effect on the surgical method (β=0.244,P<0.01). The number of positive serum tumor markers had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma (β=-0.151, P=0.002). Direct and indirect effects accounted for 71.3% and 28.7% of total effects,respectively. Conclusions: The higher the positive number of preoperative tumor markers,the worse the prognosis of patients with intrahepatic cholangiocarcinoma. The number of positive cells not only directly affects the prognosis of patients,but also indirectly affects the prognosis of patients by affecting the surgical method.

Aim: To evaluate the perioperative outcomes and postoperative survival of applying staging laparoscopy (SL) in intrahepatic cholangiocarcinoma (ICC) patients undergoing surgical resection. Methods: A retrospective analysis was performed on all selected ICC patients who underwent curative-intent resection with/without applying staging laparoscopy from January 2010 to August December 2021. Perioperative outcomes and postoperative survival were analyzed. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to reduce the bias due to confounding variables in the SL group and the non-SL group. Multivariate Cox analysis was used to ascertain the independent predictor of survival for ICC patients. Results: A total of 279 patients (24.1%) were included in the SL group, while 881 patients (75.9%) were included in the non-SL group. Compared with the non-SL group, the SL group had lower blood loss, smaller tumor size, higher R0 resection rate, and shorter hospital stay, but a higher incidence of postoperative complications. The OS of the SL group was better than that of the non-SL group (Median OS: 31 months vs. 20 months). The 1-, 3-, and 5-year overall survival rates of the SL group were 77.9%, 45.1%, and 32.9%, respectively, while the non-SL group had rates of 63.9%, 31.3%, and 18.4%. SL was confirmed as an independent predictor of survival by multivariate Cox analysis. Conclusion: ICC patients receiving SL had better perioperative outcomes and significantly prolonged overall survival after resection surgery. The subgroup analysis results support the use of routine SL.

Objective:To establish a predictive model for survival benefit of patients with intrahepatic cholangiocarcinoma (ICC) who received adjuvant chemotherapy after radical resection.Methods:The clinical and pathological data of 249 patients with ICC who underwent radical resection and adjuvant chemotherapy at 8 hospitals in China from January 2010 to December 2018 were retrospectively collected. There were 121 males and 128 females,with 88 cases>60 years old and 161 cases≤60 years old. Feature selection was performed by univariate and multivariate Cox regression analysis. Overall survival time and survival status were used as outcome indicators,then target clinical features were selected. Patients were stratified into high-risk group and low-risk group,survival differences between the two groups were analyzed. Using the selected clinical features, the traditional CoxPH model and deep learning DeepSurv survival prediction model were constructed, and the performance of the models were evaluated according to concordance index(C-index).Results:Portal vein invasion, carcinoembryonic antigen>5 μg/L,abnormal lymphocyte count, low grade tumor pathological differentiation and positive lymph nodes>0 were independent adverse prognostic factors for overall survival in 249 patients with adjuvant chemotherapy after radical resection (all P<0.05). The survival benefit of adjuvant chemotherapy in the high-risk group was significantly lower than that in the low-risk group ( P<0.05). Using the above five features, the traditional CoxPH model and the deep learning DeepSurv survival prediction model were constructed. The C-index values of the training set were 0.687 and 0.770, and the C-index values of the test set were 0.606 and 0.763,respectively. Conclusion:Compared with the traditional Cox model, the DeepSurv model can more accurately predict the survival probability of patients with ICC undergoing adjuvant chemotherapy at a certain time point, and more accurately judge the survival benefit of adjuvant chemotherapy.

目的 分析肝内胆管癌(intrahepatic cholangiocarcinoma,ICC)不同大体病理类型对预后的影响以及不同大体病理类型与临床特征的关系.方法 采用回顾性病例对照研究方法,收集于2010-2020 年中国 13 家三级甲等医院行根治性切除术的 660 例 ICC 病人的临床和病理学资料,进行1∶1倾向性评分匹配(卡钳值:0.02),采用 Kaplan-Meier 法绘制生存曲线,log-rank 检验进行生存分析.单因素分析采用χ2 检验,P＜0.05 为差异有统计学意义.结果 1∶1 倾向性评分匹配后,肿块型 ICC病人与管周浸润型 ICC病人的预后差异有统计学意义(P＜0.05).当 ICC病人处于 T1 分期时,肿块型 ICC病人与管周浸润型 ICC病人的预后差异有统计学意义(P＜0.05).肿块型 ICC 病人(513 例)和管周浸润型 ICC病人(102 例)在地区、年龄、结石病史、Child-Pugh 分级、腹痛、腹胀、黄疸、发热、中性粒细胞计数、淋巴细胞计数、谷丙转氨酶、总胆红素、总白蛋白、肿瘤位置、肿瘤大小方面比较,差异均有统计学意义(均P＜0.05);肿块型 ICC 和管内生长型 ICC 病人(45 例)在地区、年龄、谷丙转氨酶、肿瘤大小情况比较,差异均有统计学意义(均P＜0.05).结论 与肿块型相比,管周浸润型 ICC病人具有更良好的预后.可进一步探究对管周浸润型 ICC病人进行免疫治疗的有效性,以及肿块型 ICC病人对靶向治疗的敏感性.

Objectives:To construct a nomogram for prediction of intrahepatic cholangiocarcinoma (ICC) lymph node metastasis based on inflammation-related markers,and to conduct its clinical verification.Methods:Clinical and pathological data of 858 ICC patients who underwent radical resection were retrospectively collected at 10 domestic tertiary hospitals in China from January 2010 to December 2018. Among the 508 patients who underwent lymph node dissection,207 cases had complete variable clinical data for constructing the nomogram,including 84 males,123 females,109 patients≥60 years old,98 patients<60 years old and 69 patients were pathologically diagnosed with positive lymph nodes after surgery. Receiver operating characteristic curve was drawn to calculate the accuracy of preoperative imaging examinations to determine lymph node status,and the difference in overall survival time was compared by Log-rank test. Partial regression squares and statistically significant preoperative variables were screened by backward stepwise regression analysis. R software was applied to construct a nomogram,clinical decision curve and clinical influence curve,and Bootstrap method was used for internal verification. Moreover,retrospectively collecting clinical information of 107 ICC patients with intraoperative lymph node dissection admitted to 9 tertiary hospitals in China from January 2019 to June 2021 was for external verification to verify the accuracy of the nomogram. 80 patients with complete clinical data but without lymph node dissection were divided into lymph node metastasis high-risk group and low-risk group according to the score of the nomogram among the 858 patients. Log-rank test was used to compare the overall survival of patients with or without lymph node metastasis diagnosed by pathology.Results:The area under the curve of preoperative imaging examinations for lymph node status assessment of 440 patients was 0.615,with a false negative rate of 62.8% (113/180) and a false positive rate of 14.2% (37/260). The median survival time of 207 patients used to construct a nomogram with positive or negative postoperative pathological lymph node metastases was 18.5 months and 27.1 months,respectively ( P<0.05). Five variables related to lymph node metastasis were screened out by backward stepwise regression analysis,which were combined calculi,neutrophil/lymphocyte ratio,albumin,liver capsule invasion and systemic immune inflammation index,according to which a nomogram was constructed with concordance index(C-index) of 0.737 (95% CI: 0.667 to 0.806). The C-index of external verification was 0.674 (95% CI:0.569 to 0.779). The calibration prediction curve was in good agreement with the reference curve. The results of the clinical decision curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.32,the maximum net benefit could be obtained by 0.11,and the cost/benefit ratio was 1∶2. The results of clinical influence curve showed that when the risk threshold of high lymph node metastasis in the nomogram was set to about 0.6,the probability of correctly predicting lymph node metastasis could reach more than 90%. There was no significant difference in overall survival time between patients with high/low risk of lymph node metastasis assessed by the nomogram and those with pathologically confirmed lymph node metastasis or without lymph node metastasis (Log-rank test: P=0.082 and 0.510,respectively). Conclusion:The prediction accuracy of preoperative nomogram for ICC lymph node metastasis based on inflammation-related markers is satisfactory,which can be used as a supplementary method for preoperative diagnosis of lymph node metastasis and is helpful for clinicians to make personalized decision of lymph node dissection for patients with ICC.

Objective: To explore the clinical value of adjuvant therapy in patients with T3 gallbladder cancer (GBC) who have undergone R0 resection. Methods: Clinical and pathological data from 415 patients with T3 GBC who underwent surgical treatment in 7 tertiary centers in China from January 2013 to December 2018 were collected,including 251 males and 164 females,aged (61±11)years (range: 26 to 88 years). Depending on whether to receive adjuvant therapy after radical resection,the patients were divided into the radical resection group alone (group A,n=358) and the radical resection combined with the postoperative adjuvant therapy group (group B,n=57). The general data of the two groups were matched 1∶1 by propensity score matching method,and the caliper value was 0.02.Clinicopathological characteristics,overall survival and disease-free survival of the two groups were compared.The Cox regression model was used for multivariate analysis,and patients with at least one or more independent risk factors were classified as high-risk clinicopathological subtypes. Subgroup analysis was performed to assess the clinical value of adjuvant therapy after radical resection in patients with high-risk clinicopathological subtypes. Results: After the matching,there were 42 patients in each of the two groups. The incidence of gallbladder cancer and the number of dissected lymph nodes in group B after cholecystectomy were higher than those in group A (χ2=9.224,2.570,both P<0.05). There were no significant differences in overall survival rate and disease-free survival rate between the two groups before and after matching (all P>0.05). The results of the univariate and multivariate analysis showed that CA19-9>39 U/ml,nerve invasion,tumor location (liver side or bilateral),TNM stage ⅢB to ⅣB ,poorly differentiated tumor were independent prognostic factors of overall survival and disease-free survival of patients with T3 stage gallbladder cancer (all P<0.05).Three hundred and twenty-nine patients(79.3%) had high-risk clinicopathological subtypes,and the median survival time after curative resection with and without adjuvant therapy was 17 months and 34 months respectively,and the 3-year and 5-year overall survival rates were respectively 40.0%,21.3% and 46.0%,46.0% (χ2=4.042,P=0.044);the median disease-free survival time was 9 months and 13 months,and the 3-year and 5-year disease-free survival rates were 23.4%,13.6% and 30.2%,18.2% (χ2=0.992,P=0.319). Conclusions: Postoperative adjuvant therapy following radical surgery did not yield significant improvements in the overall survival and disease-free survival rates of patients diagnosed with T3 gallbladder cancer. However, it demonstrated a significant extension in the overall survival rate for patients presenting high-risk clinicopathological subtypes.

Background Microvascular invasion (MVI) has been reported to be an independent prognostic factor of recurrence and poor overall survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the preoperative independent risk factors of MVI and establish a Bayesian network (BN) prediction model to provide a reference for surgical diagnosis and treatment.Methods A total of 531 patients with ICC who underwent radical resection between 2010 and 2018 were used to establish and validate a BN model for MVI. The BN model was established based on the preoperative independent variables. The ROC curves and confusion matrix were used to assess the performance of the model.Results MVI was an independent risk factor for relapse-free survival (RFS) (P < 0.05). MVI has a correlation with postoperative recurrence, early recurrence (< 6 months), median RFS and median overall survival (all P < 0.05). The preoperative independent risk variables of MVI included obstructive jaundice, prognostic nutritional index, CA19-9, tumor size, and major vascular invasion, which were used to establish the BN model. The AUC of the BN model was 78.92% and 83.01%, and the accuracy was 70.85% and 77.06% in the training set and testing set, respectively.Conclusion The BN model established based on five independent risk variables for MVI is an effective and practical model for predicting MVI in patients with ICC.

Objective:To investigate the preoperative clinicopathological features of patients who obtained survival benefit from lymph node dissection in resection of intrahepatic cholangiocarcinoma (ICC).Methods:Clinical data of 415 patients who underwent ICC radical resection in 8 hospitals in China from January 2010 to December 2018 were retrospectively analyzed. The informed consents of all patients were obtained and the local ethical committee approval was received. Among them, 225 patients were male and 190 female,aged from 27 to 83 years, with a median age of 59 years. All patients were divided into the dissection and non-dissection groups according to whether intraoperative lymph node dissection was performed. Propensity score matching (PSM) was used to balance the differences between the dissection and non-dissection groups. Survival analysis was performed by Kaplan-Meier method and Log-rank test. Preoperative clinicopathological characteristics of patients obtaining survival benefit in the dissection group were analyzed.Results:Prior to PSM, 283 patients were allocated in the dissection group and 132 cases in the non-dissection group. After 1∶1 PSM, 228 patients were selected, with 114 cases in each group. The median survival in the dissection and non-dissection groups was 35.4 and 25.0 months, and the overall survival rate in the dissection group was significantly higher than that in the non-dissection group (χ2=5.404, P<0.05). Glisson's capsule invasion,CA19-9>37 kU/L, abnormal neutrophil and lymphocyte count were the preoperative clinicopathological features of ICC patients obtaining survival benefit from lymph node dissection (χ2=9.548, 4.800, 13.715, 13.412; P<0.05).Conclusions:Lymph node dissection in ICC radical resection can bring survival benefit to patients with hepatic capsule invasion, preoperative CA19-9>37 kU/L, abnormal neutrophil and lymphocyte count.

Objective:To explore the predictive value of tumor burden score (TBS) combined with lymph node staging (TBS-N staging) for postoperative survival of patients with intrahepatic cholangiocarcinoma (ICC).Methods:Clinical data of 335 ICC patients who underwent hepatectomy in Zhongda Hospital of Southeast University School of Medicine, Eastern Hepatobiliary Surgery Hospital and Affiliated Hospital of North Sichuan Medical College from January, 2013 to December, 2019 were retrospectively analyzed. Among them, 169 patients were male and 166 female, aged from 23 to 87 years, with a median age of 62 years. The informed consents of all patients were obtained and the local ethical committee approval was received. The TBS of all patients was calculated. All the patients were divided into stageⅠ, Ⅱ and Ⅲ according to TBS score and lymph node metastasis. The predictive ability of TBS-N staging for clinical prognosis of ICC patients after hepatectomy was analyzed by the receiver operating characteristic (ROC) curve. The risk factors of clinical prognosis of ICC patients after hepatectomy were identified by Cox proportional hazard regression model.Results:The optimal cut-off value of TBS was 4.22, including84 cases of TBS-N stageⅠ, 202 cases of stageⅡand 49 cases of stage Ⅲ. TBS-N staging was correlated with tumor diameter (F=77.639, P<0.05), intraoperative blood loss (Z=11.385, P<0.05), HBV infection rate (χ2=6.590, P<0.05), surgical resection range (χ2=9.796, P<0.05), vascular invasion (χ2=12.332, P<0.05), TNM staging (P<0.05) and postoperative complications (χ2=7.210, P<0.05) of ICC patients. Cox multivariate analysis showed that TBS>4.22, N1 stage and poor tumor differentiation were the independent risk factors for clinical prognosis of ICC patients after hepatectomy (HR=1.529, 2.100, 1.724; P<0.05). The median overall survival of patients with TBS-N stage Ⅰ, Ⅱ and Ⅲ was 51.4, 22.7 and 12.0 months, respectively, where significant differences were observed (χ2=25.797, P<0.05). The area under ROC curve (AUC) of TBS, N staging and TBS-N model for predicting clinical prognosis of ICC patients after hepatectomy was 0.596, 0.602 and 0.660, respectively.Conclusions:TBS and N staging are the independent risk factors for clinical prognosis of ICC patients after hepatectomy. Compared with TBS or N staging alone, TBS-N staging can better evaluate the clinical prognosis of ICC patients after hepatectomy.

Background: This study aims to develop a nodal staging score (NSS) to determine the optimal number of lymph nodes (LNs) examined in intrahepatic cholangiocarcinoma (iCCA) patients. Methods: Clinicopathologic data were collected from the SEER database (development cohort, n = 2782) and seven Chinese tertiary hospitals (validation cohort, n = 363). NSS was constructed based on a binomial distribution to indicate the probability of nodal disease absence. In addition, its prognostic value was examined by survival analysis and multivariable modeling on pN0 patients. Results: A model fit was performed in node-positive patients and a subgroup analysis was performed according to clinical characteristics. Statistically significant differences were only found in the subgroups when divided by the tumor size of 3 cm. As the number of examined lymph nodes (ELNs) increased, the likelihood of missing a metastatic LN decreased. NSS escalated as ELNs increased in groups with different tumor sizes, with plateaus at 7 and 11 LNs ensuring an NSS of 90.0% for <= 3 cm and >3 cm tumors, respectively. For pN0 patients, multivariate analysis revealed that NSS was an independent prognostic factor for overall survival (OS) and recurrence-free survival (RFS). Conclusions: For accurate staging of iCCA, the optimal number of ELNs was related to tumor size. We recommend that at least 7 and 11 LNs should be examined for tumor size <= 3 cm and >3 cm, respectively. Therefore, the NSS model could be helpful to make clinical decisions for pN0 iCCA. (c) 2023 Published by Elsevier Ltd.

背景与目的:肝内胆管癌(ICC)起病隐匿、侵袭性高,患者往往确诊时已失去了最佳手术时机,接受手术者5年生存率也极低.早期判断患者根治性切除术的生存获益至关重要.本研究依据术前影像学联合血清学指标对ICC根治性切除患者生存获益实行预测,以期对临床判断是否适宜行根治性切除提供指导与参考.方法:回顾性收集2010年1月-2021年12月于中国13家三甲医院行根治性切除的821例ICC患者的影像学与血清学检测资料.影像学指标包括:发现肝脏肿块、肝内胆管扩张、门静脉侵犯、淋巴结侵犯、腹水及结石;血清学指标包括:血红蛋白、白细胞计数、淋巴细胞计数、中性粒细胞计数、甲胎蛋白(AFP)、癌胚抗原(CEA)、糖类抗原19-9(CA19-9)、CA125、丙氨酸氨基转移酶(ALT)、总胆红素(TBIL)、白蛋白(ALB)及凝血酶原时间(PT).通过单因素与多因素Cox回归筛选目标变量,用目标变量构建CoxPH模型并绘制列线图,用Kaplan-Meier生存分析验证评分与患者预后的关系,通过受试者工作特征(ROC)曲线及校准曲线对模型预测效能进行评估.结果:影像学发现腹水、肝内胆管扩张、淋巴结侵犯与血清学指标CEA＞5 μg/L、CA19-9＞37 U/mL、CA125＞40U/mL是独立预后因素(均P＜0.05).用该六个变量构建CoxPH模型,根据该模型所区分的高风险组患者术后1、3、5年生存率均明显低于低风险组患者(均P＜0.05);所构建的列线图具有较好的区分度及有效性.ROC曲线显示,模型1、3、5年预测的曲线下面积分别为0.711、0.721、0.782;模型1、3、5年预测效能均高于独立指标的预测效能.结论:由CA125、腹水、肝内胆管扩张、淋巴结侵犯、CEA、CA19-9这六个术前指标组成的预后模型能较好地对患者进行高低风险分层,并对ICC患者根治性切除术后生存获益进行较精准的个体化预测,对临床医生判断患者是否适宜行根治性切除具有指导意义.

背景与目的:在过去,大血管(门静脉、下腔静脉等)侵犯被认为是肝内胆管癌(ICC)根治性切除的禁忌证,随着手术技术的进步,目前肝切除联合血管切除重建的安全性逐渐被认可,但其疗效如何尚无定论.因此,本研究通过国内多中心数据探讨ICC并血管侵犯患者肝切除联合血管切除重建的安全性和疗效,以及术后辅助治疗的价值.方法:回顾性收集2010年1月-2021年6月国内12家三甲医院收治的1 040例行根治性切除术的ICC患者临床病理资料,包括未发生血管侵犯872例,血管侵犯168例(其中行联合血管切除重建35例,行常规ICC根治术未行血管切除133例).分析全组及不同类型患者的总生存(OS)时间;在血管侵犯的患者中,分析血管切除重建对患者的主要临床指标与OS时间的影响,以及术后辅助治疗对患者OS时间的影响.结果:全组患者中位OS时间为18(9.4～30.6)个月,无血管侵犯患者中位OS时间为18.51(10～32)个月,血管侵犯患者中,未血管切除患者中位OS时间为16.3(9.4～28)个月,血管切除患者中位OS时间为10(5.5～21.6)个月.生存分析结果显示,血管侵犯患者无论是否行血管切除,OS时间均低于无血管侵犯患者(均P＜0.05),血管切除重建对血管侵犯患者的OS无明显改善作用(P=0.662);两两1:1倾向评分匹配后分析显示,血管侵犯患者无论是否行血管切除,中位OS时间均低于无血管侵犯患者,但差异无统计学意义(无血管侵犯vs.血管切除:26个月vs.21.8个月,P=0.087;无血管侵犯vs.未血管切除:27个月vs.16个月,P=0.068),血管切除重建对血管侵犯患者的OS无明显改善作用(P=0.293).在血管侵犯的患者中,血管切除重建患者手术时间及术后住院时间均长于未血管切除患者(均P＜0.05),而术后并发症等其他临床指标均无明显差异(均P＞0.05);同种类型血管侵犯患者的亚组分析结果显示,血管切除重建对不同类型的血管侵犯患者的OS均无改善作用(均P＞0.05);无论是否行血管切除重建,术后辅助治疗对患者的OS均有一定的改善作用,但差异均无统计学意义(均P＞0.05).结论:血管侵犯是ICC患者预后的危险因素,血管切除重建不能明显改善患者预后,且可能增加患者手术时间及术后住院时间.对血管侵犯是ICC患者术后进行辅助治疗可能有助于改善预后.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver cancer with limited treatment options and poor prognosis. Although gemcitabine combined with cisplatin (GEMCIS) or newly GEMCIS plus durvalumab is the first-line systemic therapy for iCCA, several promising treatment targets have been identified in the past decade in both first- and subsequent-line settings, including neurotrophic tropomyosin-receptor tyrosine kinase (NTRK) fusions, RET fusions, high microsatellite instability (MSI-H), high tumor mutation burden (TMB-H), as well as fibroblast growth factor receptor 2 (FGFR2) fusions, BRAF V600E mutation, isocitrate dehydrogenase (IDH)-1 and IDH-2 mutations, and human epidermal growth factor receptor 2 [HER2 (ERBB2)] amplifications. Corresponding small molecule inhibitors and monoclonal antibodies have demonstrated improved efficacy and survival benefits in phase 2 or phase 3 studies, gained regulatory approvals or recommendations in guidelines, and reshaped the therapeutic management for advanced cholangiocarcinoma. Numerous novel targeted drugs and combination therapies have been developed and are under evaluation. Despite the progress made in targeted therapy, it still faces challenges such as acquired drug resistance, precise patient selection, and serious adverse events. Therefore, large-scale randomized phase 3 trials of novel targeted agents and innovative regimens are warranted to benefit this population. Herein, we present a comprehensive review of the literature of clinical significance on targeted therapy for iCCA in recent years, focusing on the advances in mutation-based targeted therapy.

Background: This study aimed to evaluate the prognostic value of lymph node dissection (LND) in node -negative intrahepatic cholangiocarcinoma (ICC) and identify the appropriately total number of lymph nodes examined (TNLE). Methods: Data from node-negative ICC patients who underwent curative intent resection in ten Chinese hepatobiliary centers from January 2010 to December 2018 were collected. Overall survival (OS), relapse -free survival (RFS) and postoperative complications were analyzed. Propensity score matching (PSM) was performed to reduce the bias due to confounding variables in LND group and non-lymph node dissection (NLND) group. The optimal TNLE was determined by survival analysis performed by the X-tile program using the enumeration method. Results: A total of 637 clinically node-negative ICC patients were included in this study, 74 cases were found lymph node (LN) positive after operation. Among the remaining 563 node-negative ICC patients, LND was associated with longer OS but not RFS before PSM (OS: 35.4 vs 26.0 months, p = 0.047; RFS: 15.0 vs 15.4 months, p = 0.992). After PSM, patients in LND group had better prognosis on both OS and RFS (OS: 38.0 vs 23.0 months, p < 0.001; RFS: 15.0 vs 13.0 months, p = 0.029). There were no statistically differences in postoperative complications. When TNLE was greater than 8, OS (48.5 vs 31.1 months, p = 0.025) and RFS (21.0 vs 13.0 months, p = 0.043) were longer in the group with more dissected LNs. Conclusion: Routinely LND for node-negative ICC patients is recommended for it helps accurate tumor staging and associates with better prognosis. The optimal TNLE is more than 8. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BackgroundThe influence of different postoperative recurrence times on the efficacy of adjuvant chemotherapy (ACT) for intrahepatic cholangiocarcinoma (ICC) remains unclear. This study aimed to investigate the independent risk factors and establish a nomogram prediction model of early recurrence (recurrence within 1 year) to screen patients with ICC for ACT.MethodsData from 310 ICC patients who underwent radical resection between 2010 and 2018 at eight Chinese tertiary hospitals were used to analyze the risk factors and establish a nomogram model to predict early recurrence. External validation was conducted on 134 patients at the other two Chinese tertiary hospitals. Overall survival (OS) and relapse-free survival (RFS) were estimated by the Kaplan–Meier method. Multivariate analysis was conducted to identify independent risk factors for prognosis. A logistic regression model was used to screen independent risk variables for early recurrence. A nomogram model was established based on the above independent risk variables to predict early recurrence.ResultsACT was a prognostic factor and an independent affecting factor for OS and RFS of patients with ICC after radical resection (p < 0.01). The median OS of ICC patients with non-ACT and ACT was 14.0 and 15.0 months, and the median RFS was 6.0 and 8.0 months for the early recurrence group, respectively (p > 0.05). While the median OS of ICC patients with non-ACT and ACT was 41.0 and 84.0 months, the median RFS was 20.0 and 45.0 months for the late recurrence group, respectively (p < 0.01). CA19-9, tumor size, major vascular invasion, microvascular invasion, and N stage were the independent risk factors of early recurrence for ICC patients after radical resection. The C-index of the nomogram was 0.777 (95% CI: 0.713~0.841) and 0.716 (95%CI: 0.604~0.828) in the training and testing sets, respectively.ConclusionThe nomogram model established based on the independent risk variables of early recurrence for curatively resected ICC patients has a good prediction ability and can be used to screen patients who benefited from ACT.

Objective We aimed to evaluate the prognosis and adjuvant chemotherapy (ACT) in intrahepatic cholangiocarcinoma (ICC) patients with different etiology after radical resection. Methods A total of 448 patients with ICC who underwent radical resection between 2010 and 2018 at ten Chinese tertiary hospitals were analyzed in the study. These patients were divided into conventional ICC (Con-ICC, n = 261, 58.2%), hepatitis B virus ICC (HBV-ICC, n = 102, 22.8%) and hepatolithiasis (Stone-ICC, n = 85,19.0%) subtypes according to different etiology. Propensity score matching (PSM) was conducted to mitigate the baseline differences between Con-ICC and HBV-ICC, Con-ICC and Stone-ICC, HBV-ICC and Stone-ICC subtypes. Results Univariate and multivariate analysis showed that different etiology was a prognostic factor for overall survival and relapse-free survival, and different etiology was an independent risk factor for overall survival in ICC patients, respectively ( P < 0.05). In addition, there was a statistical difference for overall survival in early recurrence patients among the three etiological subtypes ( P < 0.05). After PSM, the overall survival of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes ( P < 0.05), while the relapse-free survival of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC ( P > 0.05). In Stone-ICC patients, the median overall survival was 16.0 months and 29.7 months, and the median relapse-free survival was 9.0 months and 20.0 months for non-ACT and ACT patients, respectively ( P < 0.05). Conclusion The prognosis of Stone-ICC patients was significantly worse than those of Con-ICC and HBV-ICC patients. Interestingly, postoperative adjuvant chemotherapy can improve the prognosis of Stone-ICC patients effectively.

Background and purpose Index cholecystectomy is insufficient for curing T3 incidental gallbladder cancer (IGC), and once residual cancer (RC) is found, the prognosis is often poor. The purpose of this study was to investigate the effect of RC on the prognosis and the optimal choice of adjuvant therapy for R0 reresection patients with T3 IGC. Methods We retrospectively reviewed data from patients with T3 IGC who underwent radical reresection from January 2013 to December 2018. RC was defined as histologically proven cancer at reresection. Demographics and tumour treatment-related variables were analysed in correlation with RC and survival. Adjuvant (Adj) chemoradiotherapy (CRT) was correlated with overall survival (OS) and disease-free survival (DFS). Results Of the 167 patients with IGC who underwent surgery, 102 underwent radical extended resection. Thirty-two (31.4%) RCs were found. Hepatic side tumours (T3h) and both side tumours (T3h + T3p) were associated with the presence of RC. In multivariate analysis, RC and lymph node metastasis were independent prognostic factors for DFS and OS (P < 0.05). RC was associated with a significantly shorter median OS (20 vs. 53 months; P < 0.01) and DFS (11 vs. 40 months; P < 0.001) despite R0 resection. For R0 reresection patients with RC and/or lymph node metastasis, Adj CRT significantly improved OS (P = 0.024). Conclusion Residual cancer and lymphatic metastasis are important factors for the poor prognosis of T3 IGC despite R0 resection, and these patients should actively receive adjuvant therapy.

Objective: The aim of this study was to explore the clinical value of lymph node dissection (LND) for intrahepatic cholangiocarcinoma (ICC). Methods: Clinical and pathological data were collected from 147 ICC patients who attended two tertiary centers over the past 5 years. The patients were classified into two groups: the LND group (group A) and the no-performance LND (NLND) group (group B). Clinical and pathological parameters were compared between the two groups to analyze the impact of LND on the prognosis of ICC patients. Results: Of the 147 patients, 54.4% (80) received LND and 42.5% (34/80) of these were found to have lymph node metastasis (LNM) in postoperative pathological diagnosis. Patients undergoing LND usually have a larger surgical range, including hemihepatectomy and enlarged hemihepatectomy ( P = 0.001 ). LND did not increase postoperative complications (27.5%, P = 0.354), but postoperative hospital stays were longer (12.2 ± 6.3 d, P = 0.005) in group A compared with group B (20.9%, 9.5 ± 3.5 d). The 5-year survival rates of groups A and B are almost similar (21% vs 29%, P=0.905 ). The overall survival rate of cN0 (diagnosis obtained by imaging) is better than pN1 (diagnosis obtained by histopathology), but lower than pN0. (all P < 0.05 ). Elevated CA19-9 level (HR = 1.764, 95% CI: 1.113 ~ 2.795 , P = 0.016 ), vascular invasion (HR = 2.697, 95% CI: 1.103 ~ 6.599, P = 0.030 ), and T staging (HR = 1.848, 95% CI: 1.059 ~ 3.224, P = 0.031 ) were independent risk factors for poor ICC prognosis (all P values > 0.05). Conclusion: ICC patients with cN0 may have LNM, and the prognosis of LNM patients is usually poor. Our data may support routine lymphadenectomy for ICC.