Cdc2-like kinase 1 (CLK1) has dual-specificity kinase ability to phosphorylate tyrosine and serine/threonine protein residues. CLK1 regulates many physiologic processes and has been shown to contribute to multiple types of cancer. In this study, we investigated the functional role of CLK1 during intrahepatic cholangiocarcinoma (ICC) development. The expression of CLK1 was elevated in ICC tumors, and patients with high expression of CLK1 demonstrated poor prognosis. In hydrodynamically transfected mouse models, CLK1 alone was insufficient to induce ICC, whereas CLK1 cooperated with AKT (AKT/CLK1) to trigger ICC initiation. In addition, overexpression of CLK1 in ICC cells facilitated proliferation in vitro and tumor growth in vivo, whereas loss of CLK1 elicited the opposite effects. Moreover, RNA sequencing analysis indicated that high levels of CLK1 corresponded with activation of the Hippo-Yes-associated protein (YAP) signaling pathway. Consistently, AKT/CLK1 murine tumors displayed upregulation of YAP as well as its downstream targets. Furthermore, loss or pharmacologic inhibition of YAP in ICC cells inhibited CLK1-induced growth, and deletion of Yap completely retarded the induction of AKT/CLK1 tumors. Mechanistically, 4D label-free mass spectrometry and coimmunoprecipitation assays revealed WWC2 as a potential mediator of the CLK1-YAP cascade. Collectively, the current findings identify a critical role for CLK1 in promoting ICC development and indicate that inhibiting YAP might be an effective approach for perturbing CLK1-mediated tumorigenesis.Significance: CLK1 drives intrahepatic cholangiocarcinoma initiation and progression by increasing YAP activity, suggesting that targeting YAP could be a potential strategy for treating and preventing CLK1-driven intrahepatic cholangiocarcinoma.

BACKGROUND:The value of anatomic resection (AR) in intrahepatic cholangiocarcinoma (ICC) remains controversial. This study compares the perioperative safety and long-term outcomes of AR versus nonanatomic resection (NAR) in ICC patients. METHODS:A systematic search was conducted in PubMed, Medline, Embase, Cochrane Library, China National Knowledge Infrastructure(CNKI), and Wanfang database for prospective or retrospective studies comparing the efficacy of AR and NAR in, ICC published to 1 June 2024. Meta-analyses were performed on surgical factors, perioperative outcomes, and long-term prognosis for both the entire cohort and the propensity score-matched (PSM) cohort. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS:Seven studies, including 1801 ICC patients, were analyzed. In both the entire and the PSM cohort, the AR group demonstrated superior OS (HR=0.71, 95% CI=0.57-0.88, P=0.002 and HR=0.70, 95% CI=0.59-0.83, P<0.0001, respectively) and DFS (HR=0.75, 95% CI=0.62-0.91, P=0.004 and HR=0.68, 95% CI=0.58-0.79, P<0.00001, respectively) compared to the NAR group. AR significantly improves 1-year, 3-year, 5-year DFS, and 5-year OS(all P<0.05). In the PSM cohort, AR and NAR groups showed comparable blood loss, operative times, overall complications, and major complications (all P>0.05). Subgroup analysis revealed that among patients with tumor >5 cm, AR achieved better OS and DFS, whereas patients with tumors ≤5 cm did not experience survival benefits from AR. CONCLUSION:This study suggests that AR, compared to NAR, can improve OS and DFS without increasing perioperative risks, particularly in ICC patients with tumors larger than 5 cm.

Hepatectomy is widely considered a potential treatment for hepatocellular carcinoma (HCC). Unfortunately, one-third of HCC patients have tumor recurrence within 2 years after surgery (early recurrence), accounting for more than 60% of all recurrence patients. Early recurrence is associated with a worse prognosis. Previous studies have shown that microvascular invasion (MVI) is one of the key factors for early recurrence and poor prognosis in patients with HCC after surgery. This paper reviews the latest literature and summarizes the predictors of MVI, the correlation between MVI and early recurrence, the identification of suspicious nodules or subclinical lesions, and the treatment strategies for MVI-positive HCC. The aim is to explore the management of patients with MVI-positive HCC.

Background and Objective:Hepatocellular carcinoma (HCC) is a highly heterogeneous and aggressive tumor. In recent years, the incidence of HCC has been increasing worldwide. Despite notable advancements in treatment methodologies, the prognosis of HCC patients remains unsatisfactory. ErbB family proteins play important roles in the occurrence, progression, and metastasis of HCC, and their abnormal expression is often closely associated with poor patient prognosis. This article sought to investigate the current status and research progress of ErbB family protein targeted therapy in HCC in recent years to provide a reference for basic research and clinical treatment. Methods:We performed a comprehensive, narrative review of the latest literature to define the current progress of ErbB family receptors in HCC in both the pre-clinical and clinical arenas. Key Content and Findings:The ErbB family belongs to the tyrosine kinase (TK) receptor family that comprises four members. These members are closely associated with proliferation, cell cycle regulation, and migration during HCC development through multiple signaling pathways. ErbB-targeted therapy has shown tremendous potential and prospects in the treatment of HCC. Conclusions:Through in-depth research and the application of ErbB-targeted therapy, broader avenues will be opened for the treatment of HCC and other tumors, leading to more personalized and precise treatment approaches.

Although laparoscopic hepatectomy (LH) and radiofrequency ablation (RFA) are the 2 principal minimally invasive surgical approaches and the first line of treatments for patients with hepatocellular carcinoma (HCC). It is not clear which one has greater safety and efficacy. In this meta-analysis, we aim to compare the safety and effectiveness of LH versus RFA for patients with HCC, especially where perioperative and postoperative outcomes differrent. In PROSPERO, a meta-analysis with registration number CRD42021257575 was registered. Using an established search strategy, we systematically searched Web of Science, PubMed, and Embase to identify eligible studies before June 2023. Data on operative times, blood loss, length of stay, overall complications, overall survival (OS) and recurrence-free survival (RFS) were subjected to meta-analysis. Overall, the present meta-analysis included 8 retrospective and 6 PSM studies comprising 1,848 patients (810 and 1,038 patients underwent LH and RFA). In this meta-analysis, neither LH nor RFA showed significant differences in 1-year and 3-year OS rate and 5-year RFS rate. Despite this, in comparison to the RFA group, LH resulted in significantly higher 1-year(p<0.0001) and 3-year RFS rate (p = 0.005), higher 5-year OS rate (p = 0.008), lower local recurrence rate (p<0.00001), longer length of stay(LOS) (p<0.0001), longer operative time(p<0.0001), more blood loss (p<0.0001), and higher rate of complications (p=0.001). Comparative studies indicate that LH seemed to provide better OS and lower local recurrence rate, but higher complication rate and longer hospitalization.

Introduction: Laparoscopy splenectomy has been a preferred choice over open surgery, but limited studies dealing with laparoscopy splenectomy plus pericardial devascularization (LSPD) for elderly patients are available. Aim: To assess the safety and long-term efficacy of spleen bed LSPD for elderly patients with portal hypertension. Material and methods: A total of 132 elderly patients (age > 60 years) suffering from portal hypertension were operated on in the department. The patients were divided into 2 groups: those undergoing LSPD, and those undergoing open splenectomy plus pericardial devascularization (OSPD). Results and outcomes were compared retrospectively. Results: The clinical characteristics of the patients belonging to the two groups were studied. No significant difference between the characteristics of patients was reported and the clinical data revealed similarities in their characteristics. There was no significant difference in time taken for performing the operation (p > 0.05). The LSPD group showed less blood loss; started oral intake early; and the duration of post-operative hospital stay was also shorter (p < 0.05). Incidence rates of portal vein thrombosis; pancreatic leakage; pleural effusion; pulmonary infection; and delayed wound healing were also found to be lower in the LSPD group as compared to the OSPD group (p < 0.05). During a follow-up period of 6-70 months, no significant differences were found in the data for the two methods with respect to the incidence of rebleeding; hepatic encephalopathy; and survival (p > 0.05). Conclusions: It was concluded that spleen bed LSPD is a safe and feasible procedure for treating elderly patients. It had a better clinical effect than that of OSPD.

Objective:To analyze the expression of mucin 1 (MUC1) and Ki67 in intrahepatic cholangiocarcinoma (ICC), and to explore the correlations between the expression of MUC1 and Ki67 and the clinicopathological features and prognosis of ICC patients.Methods:Clinical data of 398 patients with ICC admitted to Henan Provincial People's Hospital from January 2013 to March 2020 were retrospectively analyzed. A total of 104 patients were included in this study, including 67 males and 37 females, aged (56.6±9.3) years. Immunohistochemistry was used to detect the expression of MUC1 and Ki67 in cancer tissues. Univariate and multivariate Cox regression analysis were used to study the prognostic factors of ICC patients.Results:The expression of MUC1 was low in 65 patients and high in 39 patients. Ki67 expression was low in 52 patients and high in 52 patients. High expression of MUC1 was correlated with lymph node metastasis ( P<0.05), while high expression of Ki67 was correlated with tumor nodes number, lymph node metastasis and vascular invasion (all P<0.05). Multivariate analysis showed that ICC patients with high MUC1 expression ( HR=2.321, 95% CI: 1.420-3.792, P<0.001) and high Ki67 expression ( HR=2.012, 95% CI: 1.247-3.247, P=0.004) showed a poor prognosis after hepatectomy. ICC patients with high MUC1 expression ( HR=1.664, 95% CI: 1.058-2.618, P=0.028) and high Ki67 expression ( HR=1.883, 95% CI: 1.168-3.035, P=0.009) had a poor prognosis after hepatectomy. Conclusion:High expression of MUC1 and Ki67 is correlated with tumor growth and metastasis. MUC1 and Ki67 are independent risk factors for prognosis of ICC patients after hepatectomy.

Objective:To determine the risk factors for development of combined hepatocellular-cholangiocarcinoma (CHC) and intrahepatic cholangiocarcinoma (ICC).Methods:The clinical data of patients with ICC or CHC confirmed by pathology at Henan Provincial People's Hospital from January 2012 to December 2018 were retrospectively analyzed. Of 225 patients with ICC or CHC, there were 90 males and 135 females, aged (58.7±10.4) years old. Based on the pathological type, there were 172 patients in the ICC group and 53 patients in the CHC group. The healthy control group was selected from 450 individuals who underwent routine health examination in the same hospital, and there were 189 males and 261 females, aged (56.7±9.3) years old. Univariate and multivariate logistic regression were used to analyze the risk factors of ICC and CHC.Results:The risk factors of ICC included hepatitis B surface antigen (HBsAg) (+ )/hepatitis B core antibody (anti-HBc) (+ ) ( OR=9.373, 95% CI: 4.784-18.363, P<0.001), hepatitis C virus antibody (HCV-Ab) (+ ) ( OR=7.151, 95% CI: 1.195-42.776, P=0.031), diabetes mellitus ( OR=3.118, 95% CI: 1.733-5.612, P<0.001) and hepatolithiasis ( OR=18.650, 95% CI: 5.210-66.767, P<0.001). The risk factors of CHC included HBsAg (+ )/anti-HBc(+ )( OR=54.891, 95% CI: 17.434-172.822, P<0.001) and HCV-Ab (+ ) ( OR=37.785, 95% CI: 5.720-249.611, P<0.001). Conclusion:HBV infection, HCV infection, hepatolithiasis, diabetes mellitus and cirrhosis were risk factors for ICC. HBV and HCV infection were risk factors of CHC.

Abstract Objective We assess the predictive value impacted by tumor-infiltrating lymphocytes (TILs) for overall survival (OS) and progression-free survival (PFS) in patients with intrahepatic cholangiocarcinoma (ICC) undergoing complete resection. Methods Sixty-eight patients with resectable ICC were included in this study. We studied stromal TIL density and scored it by staining sections from surgically resected ICC patients with hematoxylin and eosin (HE). The clinical data and prognosis of patients with ICC were obtained by searching clinical and follow-up records. Results A stromal TIL negative status was a predictor of poor OS (HR = 0.41, 95% CI 0.20–0.83, p = .01) and poor PFS (HR = 0.47, 95% CI 0.23–0.97, p = .04) independently. Low stromal TIL density was associated with high levels of CA125 (p = .03) and CA19-9 (p < .01). The high level of CA19-9 (p = .05), high differentiation (p = .02), a large diameter (p = .05), a positive bile duct/vascular cancer embolus (p = .03) and positive satellite nodules (p = .02) were tendencies to develop tumors for patients with a negative status of stromal TIL. Conclusion Our data prompt for the prediction of the PFS and OS of patients with ICC after complete resection, stromal TILs play an important role.

目的 评估分层选择性离断在腹腔镜贲门周围血管离断术联合脾切除术的应用价值.方法 回顾性分析2012年6月至2018年12月在郑州大学人民医院行贲门周围血管离断术联合脾切除术治疗肝硬化门脉高压症378例患者的临床资料,分为腹腔镜组126例,开腹组252例.结果 腹腔镜组手术时间(151.6±19.9)min少于开腹组(157.9±16.7)min,术中出血量(268.5±159.4)mL少于开腹组(341.6±160.9)mL,术后住院时间(7.6±1.7)d短于开腹组(9.5±1.8)d,经口进食时间(1.9±0.9)d短于开腹组(3.1±0.9)d(均P＜0.05).术后并发胰瘘、门静脉血栓形成及胸腔积液均少于开腹组(均P＜0.05).术后随访,中位随访时间为16个月,腹腔镜组上消化道再出血率2.4％(3/126)低于开腹组7.1％(18/252)(P＜0.05).结论 采用分层选择性离断腹腔镜贲门周围血管离断术联合脾切除术,安全、有效、易行,可减少术中出血,缩短手术时间,同时降低术后再发消化道出血风险.

Objective. To evaluate the efficacy of pars plana vitrectomy (PPV) combined with episcleral cryotherapy in treating vasoproliferative tumors of the retina (VPTR) with macular complications. Methods. In this retrospective noncomparative interventional case-series analysis, we included 11 eyes of ten patients diagnosed with VPTR. All patients underwent comprehensive ophthalmic examinations and were treated with PPV combined with episcleral cryotherapy. Best-corrected visual acuity (BCVA), tumor activity, retinal morphological structure, and postoperative complications were evaluated. Results. Macular complications included epimacular membrane (n = 10), macular hole (n = 3), and macular edema (n = 1). Tumors were treated with triple freeze-thaw episcleral cryotherapy during PPV. The mean logarithm of minimal angle of resolution (logMAR) BCVA dropped from 0.62 ± 0.58 to 0.39 ± 0.46. The difference between the mean values of logMAR BCVA before and after treatment was statistically significant (t = 2.48, P=0.033 ). The tumor activity was controlled effectively in nine cases. Compared with preoperative tumor activity, tumor activity after treatment was significantly lower ( P<0.01 ). The increase of central retinal thickness and the disruption of retinal layers were associated with macular holes, macular edema, and retinal proliferative membrane. After the treatment, visual acuity improved in 91% of the cases, and 73% had no long-term complications. Conclusion. PPV combined with episcleral cryotherapy promoted tumor regression, preserved retinal integrity, and improved visual acuity. Thus, the combination of PPV with episcleral cryotherapy can be considered effective and safe for the management of VPTR with macular complications.

Objective:To analyze the clinicopathological features, diagnosis and treatment of neuroendocrine carcinoma of gallbladder (GB-NEC).Methods:The clinical data of 17 patients with GB-NEC confirmed by postoperative pathology managed at the People's Hospital of Zhengzhou University from March 2013 to January 2020 were analyzed retrospectively. There were 9 males and 8 females, with an age of (68.9±11.2) years. The clinical and follow-up data were analyzed.Results:The main clinical manifestations were abdominal pain ( n=9, 52.9%), anorexia ( n=5, 29.4%), jaundice ( n=2, 11.8%), abdominal mass ( n=2, 11.8%), and asymptomatic ( n=2, 11.8%). Radical resection of gallbladder carcinoma was performed in 9 patients, and palliative resection in 8 patients. Postoperative chemotherapy was given to 4 patients. Postoperative pathology showed small cell type in 11 patients and large cell type in 6 patients. Immunohistochemical staining showed synaptophysin positivity in 17 patients (100.0%), chromogranin A positivity in 12 (70.6%), Ki67 positivity in 17 patients (100%, >50% was defined as positive). All 17 patients were followed-up from 78 to 745 days, with a median of 237 days. At the time of censor of this study, 13 patients had died. The 1-and 2-year cumulative survival rates were 26.5% and 19.9%, respectively. The 1- and 2-year cumulative survival rates of radical gallbladder carcinoma resection ( n=9) were 44.4% and 33.3%, respectively. Eight patients underwent palliative resection, and the longest follow-up time was 276 days. Conclusion:This study showed the incidence of GB-NEC was low. There was no specific clinical manifestations, and the diagnosis mainly depended on immunohistochemistry. Patients with GB-NEC had high expressions of Ki67 and had poor prognosis. Early radical resection was helpful to improve survival of these patients.

BACKGROUND:The aim of this study was to investigate the prognostic value of arginase-1 (Arg-1) and glypican-3 (GPC-3) in patients with intrahepatic cholangiocarcinoma (ICC).METHODS:Two hundred and thirty-seven patients with ICC were included in this study. All patients had undergone radical surgery and had complete clinical information. Immunohistochemistry was used to assess the levels of Arg-1 and GPC-3 in ICC tissues. Univariate and multivariate analyses were conducted to identify independent risk factors in ICC. The relationship between Arg-1 and GPC-3 levels and patient survival was determined using the Kaplan-Meier method.RESULTS:High Arg-1 and GPC-3 expression levels were associated with poor prognosis in patients with ICC, and they could be as new prognostic biomarkers in ICC.CONCLUSION:Arg-1 and GPC-3 can serve as independent prognostic biomarkers in ICC.

Introduction and objective: The purpose of this study was to investigate the expression levels and prognostic roles of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and Ki67 in tumor tissues of intrahepatic cholangiocarcinoma (ICC) patients. Patients or materials and methods: The study involved ninety-two ICC patients with complete clinicopathological data and follow-up information, who had previously undergone radical surgery. AFP, CEA, CD10, CD34, and Ki67 were detected in tumor tissues using immunohistochemistry. Statistical tests were used to identify independent risk factors and their associations with overall survival (OS) and disease-free survival (DFS). Results: AFP, CEA and Ki67 were strongly correlated with prognosis. Univariate analysis indicated that higher AFP (P = 0.002), CEA (P < 0.0001), Ki67 (P < 0.0001), CA19-9 (P = 0.039), and CA12-5 (P = 0.002), and larger tumor size (P = 0.001), as well as more advanced tumor node metastasis (TNM) staging (P < 0.0001) were all associated with worse OS. Meanwhile, higher AFP (P = 0.002), CEA (P = 0.001), and Ki67 (P < 0.0001), as well as more advanced TNM staging (P = 0.005) were associated with worse DFS. Multivariate analysis showed that higher AFP (HR = 2.004, 95%CI: 1.146-3.504 P = 0.015), CEA (HR = 2.226, 95%CI: 1.283-3.861 P = 0.004), and Ki67 (HR = 3.785, 95%CI: 2.073-6.909 P < 0.0001), as well as more advanced TNM staging (HR = 2.900, 95%CI: 1.498-5.757 P = 0.002) had associations with worse OS. Furthermore, higher AFP (HR = 2.172, 95%Cl: 1.291-3.654 P = 0.003), CEA (HR = 1.934, 95%Cl: 1.180-3.169 P = 0.009), and Ki67 (HR = 2.203, 95%Cl: 1.291-3.761 P = 0.004) had associations with worse DFS. Conclusion: High AFP, CEA, and Ki67 are significant prognostic indicators in ICC patients, and can be used to evaluate ICC biological behavior and prognosis. (C) 2020 Fundaci on Cl ' nica Medica Sur, A.C. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license.

Objective To evaluate the role of tumor budding in the prognostic value of intrahepatic cholangiocarcinoma(ICC) after radical resection.Methods The clinicopathological data of patients undergoing radical resection for intrahepatic cholangiocarcinoma between 2011 and 2016 were retrospectively analyzed.The number of tumor budding was counted in a ×200 microscopic field (0.785mm2).Based on receiver operation curve (ROC),the number of tumor budding ≥ 15 was defined as high-grade group,and ＜ 15 was low-grade group.Multivariate analysis were performed on predictors of the tumor.Results Low-grade group was observed in 32 cases and high-grade group in 50.High-grade group appeared to develop tumors with higher CA199,poor differentiation,larger tumor diameter,advanced stage and high risks of lymphnode metastasis (respectively x2 =5.470,4.359,5.101,4.696,5.960,all P ＜ 0.05).Univariate analysis showed that tumor budding,CA199,differentiation,tumor diameter,T classification and lymphnode metastasis were related to the overall survival of patients with ICC (respectively x2 =11.704,4.876,5.056,5.152,8.442,16.725,all P ＜ 0.05).On multivariable analysis,high-grade group was a significant independent predictor of worse OS (HR =2.707 95％ CI 1.558-4.705,P ＜ 0.001).Conclusions High-grade tumor budding is an important negative prognostic factor for ICC.

目的 评估加速康复外科(enhanced recovery after surgery,ERAS)在腹腔镜下胰十二指肠切除术(laparoscopic pancreatoduodenectomy,LPD)围手术期的临床应用价值.方法 回顾性分析2016年1月至2018年1月河南省人民医院收治的79例行LPD的患者临床资料,其中围手术期采用ERAS处理方案的患者41例(ERAS组),采用传统处理方案的患者38例(传统组).比较分析两组患者围手术期相关参数.结果 ERAS组的术后AST[(110.38±102.43)U/L]和术后血肌酐[(61.20±16.46)μmol/L]均较传统组轻[(427.09±1434.66)U/L,(74.28±49.58)μmol/L,均P<0.05);住院时间[(17.29±5.44)d]较传统组[(24.68±13.28)d]短(P<0.05).ERAS组术后总并发症发生率、腹腔出血及肺部感染发生率均明显低于传统组(P<0.05).ERAS组绝大部分患者(90.4％)的术后并发症可自愈,而传统组近一半(48.5％)的术后并发症需干预处理(P<0.05).结论 LPD围手术期实施ERAS方案能减少患者肝肾功能损害,降低并发症发生率,缩短住院时间,促进患者早日康复.