Introduction

Hilar cholangiocarcinoma(HCCA)accounts for 50−80% of biliary malignancies and associates with high mortality[1,2].For early HCCA,surgical resection is undoubtedly the optimal choice[3].However,most patients have advanced disease at presentation due to the special anatomic characteristics of the hepatic hilum.Among them,few patients are candidates for curative resection because of the invasion of HCCA into portal vein and/or hepatic artery.Most patients are treated palliatively,including endoscopic retrograde cholangiopancreatography(ERCP)or percutaneous transhepatic cholangiodrainage(PTCD),to attenuate obstructive jaundice.With the advances in liver surgery,negative-margin(R0)resection is possible for some patients with advanced HCCA by performing resection and reconstruction of both the hepatic artery and portal vein[4–6].However,the 5-year survival remains unsatisfactory[7].On the other hand,the majority of HCCA patients are concomitant with hyperbilirubinemia at presentation,while the role of preoperative biliary drainage in jaundiced patients remains controversial.

In the past three years,we have treated 176 patients with advanced HCCA,of whom 90 underwent surgical treatment.The present study reviewed their clinical outcomes with emphasis on therapeutic modalities,survival analysis and prognostic assessment.

第二种是对Thread子类进行定义，也对run方式进行重写：clasMyThread extends Thread{public void run(){}}

Methods

Patients and ethical guidelines

A total of 176 patients with HCCA treated in our hospital between January 2013 and December 2015 were enrolled in this study.Inclusion criteria were as follows:(i)histologically(surgical cohort)or cytologically(conservative cohort)diagnosed HCCA;(ii)advanced HCCA(stage III-IV);(iii)with complete clinicopathologic and follow-up data.Exclusion criteria:patients with early HCCA(stages I and II)or those with advanced HCCA receiving radiotherapy and/or chemotherapy preoperatively.All patients underwent CT,MRI and MRCP for preoperative evaluation.Hilar obstruction was characterized by the Bismuth classi fication.The clinical classi fication of tumors was determined according to the TNM classi fication system of International Union Against Cancer.

The study was approved by the Medical Ethics Committee of our hospital and conducted in accordance with the Declaration of Helsinki.The data of patients were extracted from their medical records and a database established by our department.

Statistical analysis was performed with SPSS software,version 17.0(IBM,Armonk,NY,USA).Pearson’s Chi-square test or Fisher’s exact test was used to compare morbidity and mortality among groups.The cut-off of continuous variables was calculated by X-tile software(Yale University,New Haven,CT)in the“minimum P value”approach referring to overall survival(OS)of patient[8].Kaplan–Meier curves were used to visualize differences between OS.The signi ficance among patient groups was analyzed using the log-rank test.We used multivariate Cox proportional hazards models to identify independent prognostic factors.Pearson’s or Spearman’s coefficients tests were carried out to assess the correlation of total bilirubin level with survival time and of clinicalpathological parameters with morbidity.The predictive performance of predictor alone or in combination was assessed by receiver operating characteristic(ROC)curve analysis.A P value of＜0.05 was considered statistically signi ficant.

Managements

Univariate analysis showed that age(P=0.001),preoperative total bilirubin(P=0.003),Bismuth type(P=0.041),treatment modalities(P=0.000)and hepatic artery invasion(P=0.011)were signi ficantly associated with the OS of advanced HCCA patients(Table 3 and Fig.2).

“诗佛”王维擅作山水田园诗，但也写过“莫嫌旧日云中守，犹堪一战取功勋”这样激昂慷慨的颂歌。以你对王维的了解，你能猜出下面哪句诗不是出自王维之手吗？

ERCP or PTCD was performed to reduce bilirubin level for HCCA patients.All endoscopic examinations were performed using a therapeutic duodenoscope(TJF-260V or JF-260V,Olympus Medical,Tokyo,Japan).The strategy used for biliary decompression was selected at the discretion of the endoscopist,based on the location and complexity of the obstruction as well as the expected time of survival of the patient.Unilateral drainage was done with 7-French nasal biliary drainage catheter,8.5-French stent,or self-expandable metal stent with luminal diameter of 10 mm.If the patient had bilateral plastic stents placed,at least one of the stents had a diameter of 8.5-French.Decision on unilateral vs bilateral endoscopic drainage was left to the discretion of the endoscopist based on location and complexity of the obstruction.The technique of PTCD in this series involves the use of ultrasound guidance,a thin Chiba needle and a 0.014-in.guidewire to gain access to the biliary system.Then,8.5-French drainage catheter was placed unilaterally or bilaterally.

Follow-up

Follow-up continued from surgery or stent insertion to the death of the patient.Follow-up was obtained by reviewing clinical notes provided by regular clinic visits or telephone interviews until the time of manuscript preparation.The last follow-up was completed in December,2016.The majority of patients(124/176)were dead at the last follow-up.The median follow-up time was 10.0 months(range 1.0–41.1).Survival time was de fined as the interval between treatment and death or between treatment and the last follow-up for surviving patients.

Statistical analysis

（3）我们将在未来5年内安排2500人次青年科学家来华从事短期科研工作，培训5000人次科学技术和管理人员，投入运行50家联合实验室。

泥浆既是冷却剂也是润滑剂，可以避免孔壁出现坍塌与脱落现象，旋挖钻进行钻孔施工时，由于钻机速度会对孔壁造成一定的扰动，控制泥浆指标尤为重要。特别是在粉砂与粉土地层存在的情况下。泥浆应尽可能地选择孔隙小且韧性好的优质黏土作为原料，同时在其中添加一定量的膨胀剂，使其共同构成护壁泥浆，同时采取循环泥浆施工方式进行作业。对于孔内泥浆比重，本工程选择的泥浆比重较高，需要控制在1.3～1.5。泥浆黏度会对钻速与排渣造成直接对影响，故将泥浆黏度控制在18～22s。泥浆的pH值也会对钻孔造成直接的影响，如果泥浆pH超过11，会使泥浆出现分层现象，导致其护壁作用无法有效的发挥。因此，应将泥浆pH控制在5～9。

Results

Patient characteristics

The patient median age was 63 years(range 24–88)and 70.5%of them were male(n=124).Most patients presented with jaundice(n=159,90.3%)with median total bilirubin of 234.2 μmol/L(range 11.0–796.5).The hilar lesion was classi fied as Bismuth–Corlette type I(n=17,9.7%),type II(n=34,19.3%),type IIIA(n=9,5.1%),type IIIB(n=24,13.6%),type IV(n=41,23.3%);and 51 patients(29.0%)had an unknown Bismuth–Corlette classi fication.Detailed demographics of patients are summarized in Table 1.

Therapeutic procedures

We then performed multivariate analysis by adding signi ficant parameters in univariate analysis into Cox proportional hazard model.High preoperative total bilirubin(HR=2.00,P=0.009),hepatic artery invasion(HR=1.84,P=0.014)and palliative treatment(HR=0.76,P=0.020)were independent risk predictors(Table 3).

Preoperative biliary drainage was done in 58%(52/90)patients:endoscopic nasobiliary drainage(ENBD)in 39,PTCD in 6,both ENBD and PTCD in 7.The median drainage time was 10 days.In patients unsuitable for resection,ERCP or PTCD were performed(Fig.1).

Survival rate

The 1-,2-and 3-year OS rates were 53%,24%and 13%,respectively for the whole cohort.According to treatment modality,the 1-,2-and 3-year OS rates were 65%,38%and 38%in the radical resection group(n=62),63%,30%and 20%in the palliative resection group(n=28),56%,17%and 0%in the ERCP group,and 29%,10%and 0%in the PTCD group,respectively.

确定白砂糖添加量12%，姜水比1∶1，姜汁添加量14%，柠檬酸添加量0.625%时，在β-环状糊精添加量分别为0，0.02%，0.04%，0.06%，0.08%时，设计单因素试验，进行感官评价。

Morbidity and mortality

Complications occurred in 33 patients(36.7%)after surgery.Bile leakage was the most common complication(n=10,11.1%),followed by abdominal infection(n=7,7.8%)and pulmonary infection(n=6,6.7%).The difference of morbidity was signi ficant between surgery group and non-surgery group(36.7%vs 8.1%,P＜0.001),but not between radical and palliative groups(38.7%vs 32.1%,P=0.412).The morbidity had no difference between HAR group(45.0%)and non-vascular resection group(30.1%,P=0.234)(Table 2).For the radical group,Bismuth type(P=0.026),hepatic artery invasion(P=0.045)and operation time(P=0.049)were weakly associated with morbidity.Multivariate analysis showed that hepatic artery invasion was an independent factor(HR=3.30;95%CI:1.02–10.65;P=0.046).

Six patients died after surgery.The main cause of death is hepatic failure.The mortality of palliative group was not signi ficantly higher compared with radical group(10.7%vs 4.8%,P=0.370;Table 2).The mortality of HAR group had no difference compared with that of non-vascular group(10.0%vs 5.7%;Table 2).

Univariate analysis

The initial therapeutic regimen,surgical or conservative treatment,was determined in a multidisciplinary team meeting.All the operations for HCCA were performed by experienced surgeons.Regular resection consisted of en bloc resection of the common bile duct,the tumor and the gallbladder,and clearance of hepatoduodenal ligament lymph nodes.Caudate resection was routinely performed in patients undergoing hepatectomy.Biliary drainage was completed by Roux-en-Y hepaticojejunostomy.Vascular resection and reconstruction were also planned preoperatively for patients suspected of vascular invasion according to contrast-enhanced CT or MRI,and these procedures were performed if the vasculature was found to be invaded by the tumor during surgery.R0 resections were de fined as those no cancer cells which were found with microscopy at the resection margin,and R1 resections as those with detectable cancer cells microscopically at the resection margins.

Table 1 Demographics of patients with hilar cholangiocarcinoma at advanced stage.

CEA:carcinoembryonic antigen.

Variables The whole cohort(n=176) The radical group(n=62)Median age(yr) 63(24–88) 65(34–80)Gender(male/female) 124/52 45/17 Median preoparative total bilirubin(μmol/L) 234.2(11.0–796.5) 186.5(11.0–796.5)Median CEA(μg/L) 4.1(0.7–936.6) 3.7(0.7–76.9)Median CA19-9(U/mL) 464.3(2–12,000) 306.9(2–12,000)Resection margins R0 66(73.3%) 62(100%)R1 20(22.2%) 0 Unknown 4(4.4%) 0 TNM tumor classi fication IIIa 54(30.7%) 24(38.7%)IIIb 52(29.5%) 16(25.8%)IVa 34(19.3%) 10(16.1%)IVb 36(20.5%) 12(19.4%)Lymph node(positive/negative) 49/39 26/36 Bismuth–Corlette classi fication I 17(9.7%) 6(9.7%)II 34(19.3%) 10(16.1%)IIIa 9(5.1%) 6(9.7%)IIIb 24(13.6%) 14(22.6%)IV 41(23.3%) 26(41.9%)Unknown 51(29.0%) 0 Portal vein invasion 75(42.6%) 27(43.5%)Hepatic artery invasion 59(33.5%) 20(32.3%)Blood loss(mL) 0 605±444 Length of stay(days) 10.2±9.3 18.7±17.5 Postoperative outcome Death within 1 year 49(54.4%) 20(32.3%)Death beyond 1 year 41(45.6%) 42(67.7%)

Fig.1.Flow diagram showing the treatment of all HCCA patients in this study.

Multivariate analysis and establishment of Cox model

Radical resection was performed in 62(35.2%)patients,resection with residual cancer in 28(15.9%).In radical resection group,10 underwent a concomitant portal vein resection(PVR),3 hepatic artery resection(HAR),and 17 PVR plus HAR(Fig.1).

However,the predictive performance of each parameter was far from satisfaction.The area under ROC curve(AUC)of each parameter(preoperative total bilirubin:0.641;hepatic artery invasion:0.584;treatment modalities:0.640)was all lower than 0.7.Therefore,the combined in fluence of the three features was also evaluated.A Cox model,or prognostic index (PI),was built to predict the probability of death:PI=0.692×preoperative total bilirubin+0.609×hepatic artery invasion− 0.274×treatment modalities(preoperative total bilirubin:1 for preoperative total bilirubin＜286 μmol/L,2 for preoperative total bilirubin ≥286 μmol/L;hepatic artery invasion:1=no;2=yes;treatment modalities:1 for palliative treatment,including palliative resection,ERCP and PTCD,2 for radical resection).The AUC of PI was 0.748(95%CI:0.678–0.811;sensitivity:82.3%,speci ficity:53.5%),signi ficantly larger than that of parameter alone(P＜0.05,Fig.3A).Furthermore,using the PI value of 1.088 as the cut-off,patients were classi fied into two groups:low-risk group(PI≤1.088,n=104)and high-risk group(PI＞1.088,n=72).We found greater disparity of survival between the two groups[1-,2-,3-year OS,66%,38%,38%in the low-risk group vs 40%,12%,3%in the high-risk group,respectively(P=0.000);mean survival time(17 vs 6 months);(Fig.3B)was also better than that of any single parameter.These results collectively suggest better predictive performance of combined parameters than parameter alone.

Table 2 Morbidity and mortality of advanced HCCA patients after treatment.

∗Including hepatic artery resection alone and in combined with portal vein resection.

Variables Radical resection(n=62)Palliative resection(n=28)ERCP(n=43) PTCD(n=43) Vascular resection(n=37)Non-vascular resection(n=53)Hepatic artery resection∗(n=20)Total morbidity 24(38.7%) 9(32.1%) 5(11.6%) 2(4.7%) 17(45.9%) 16(30.1%) 9(45.0%)Bile leakage 7 3 5 5 2 Abdominal infection 6 1 5 2 2 Hepatic failure 2 2 2 2 1 Pulmonary infection 5 1 3 3 2 Lymphorrhagia 1 1 Renal failure 1 1 Abdominal hemorrhage 1 1 1 Pancreatitis 3 Cholangitis 1 2 1 1 Ileus 1 1 1 Cerebral infarction 1 1 1 Total mortality 3(4.8%) 3(10.7%) 0 0 3(8.1%) 3(5.7%) 2(10.0%)Hepatic failure 2 2 2 2 1 Cerebral infarction 1 1 1 Pulmonary infection 1 1

Table 3 Univariate and multivariate analysis of OS among HCCA patients at advanced stage according to clinicopathologic parameters.

∗:Parameters were adopted for their prognostic signi ficance by univariate analysis; †:The cut-off of parameter was calculated by X-tile software in the“minimum P value”approach referring to OS of patient; ‡:Palliative treatment includes PTCD,ERCP and palliative resection.OS:overall survival;HR:hazard ratio;CEA:carcinoembryonic antigen;NA:not adopted.

Parameters∗Univariate analysis 1-year OS Multivariate analysis HR 95%CI P value Cox score HR 95%CI P value Whole cohort Age† (＜67/≥67 yr)1.83 1.30–2.74 0.001 61%/39% NA NA NA 0.169 Preoperative total bilirubin† (＜286/≥286 μmol/L) 1.74 1.21–2.53 0.003 60%/43% 0.692 2.00 1.19–3.35 0.009 Bismuth type(I/II/IIIa/IIIb/IV) 0.90 0.77–1.04 0.041 NA NA NA NA 0.832 Treatment modalities(Palliative treatment/radical resection‡) 0.70 0.59–0.85 0.000 46%/65% −0.247 0.76 0.60–0.96 0.020 Hepatic artery invasion(no/yes) 2.21 1.20–4.06 0.011 77%/56% 0.609 1.84 1.13–2.98 0.014 Radical group Age† (＜67/≥67 yr)2.33 1.02–5.32 0.035 64%/39% NA NA NA 0.285 Preoperative total bilirubin† (＜286/≥286 μmol/L) 2.77 1.31–5.88 0.005 71%/38% 1.246 3.48 1.50–8.05 0.004 Bismuth type(I/II/IIIa/IIIb/IV) 0.84 0.64–1.12 0.002 NA NA NA NA 0.656 CEA† (＜4.15/≥4.15 U/mL) 2.58 1.20–5.52 0.010 66%/40% 0.944 2.57 1.01–6.52 0.047

Subclass analyses according to treatment modalities

According to treatment modalities,we analyzed the subclasses.In radical group,age(P=0.035),Bismuth type(P=0.002),the preoperative total bilirubin(P=0.005)and carcinoembryonic antigen(CEA)(P=0.010)was associated with OS,but the hepatic artery invasion was not(P=0.297;Table 3).Multivariate analysis identi fied that preoperative total bilirubin was still an important independent factor(P=0.004;Table 3).Patients with high level of preoperative total bilirubin had signi ficantly poorer prognosis than those with low level of preoperative total bilirubin(mean survival time:9.7 vs 26.7 months,P=0.005;Fig.4A).However,patients with hepatic artery invasion had the same prognosis as patients without hepatic artery invasion(mean survival time:19.8 vs 20.7 months,P=0.297;Fig.4A).Conversely,preoperative total bilirubin was not a predictor for patients who received palliative treatment(including palliative resection,ERCP and PTCD);hepatic artery invasion indicated signi ficantly poorer prognosis in patients with palliative treatment(P＜0.05,Fig.4B–D).

Discussion

However,the contradictions of surgery for advanced HCCA mainly are:(i)diffuse local or distant metastases;(ii)insufficiency of the future liver remnant;(iii)bilateral ductal extension to the secondary(or segmental)biliary branches;(iv)extensive encasement or occlusion of the portal vein and/or hepatic artery(including main trunk or contralateral branch).

The management of patients with HCCA is complex.Margin negative(R0)resection remains the only treatment that offers the chance of long-term survival[2,9–12].For advanced HCCA patients,vascular invasion is common.Involvement of portal vein or hepatic artery was previously considered as surgical contraindication of HCCA[13].Currently,advances in surgical techniques and knowledge gained from experiences of liver transplantation help us to reconstruct vascular for locally advanced tumors.However,the role of vascular resection,either PVR or HAR,remains controversial.

Although three independent prognostic factors were found,no one was accurate in predicting the prognosis of HCCA patients.In the present study,we combined three independent predictors with their prognostic weight and established a predictive model.This model signi ficantly improved the predictive accuracy of HCCA survival.The model identi fied a subset of patients with worst survival.Most patients died within 1 year with mean survival time less than half year.

Fig.2.Kaplan–Meier analyses of overall survival for preoperative total bilirubin level(A),hepatic artery invasion(B)and treatment modality(C).

Fig.3.(A)Receiver operating characteristic(ROC)curve for prognostic prediction of patients with advanced HCCA.The curves represent preoperative total bilirubin,hepatic artery invasion,treatment modalities and prognostic index(PI)for overall survival.(B)Kaplan–Meier curves of overall survival for patients according to PI.

Fig.4.Subclass analyses according to treatment modalities.(A)In the radical resection group,patients with high level of preoperative total bilirubin(≥286 μmol/L)had signi ficantly poorer prognosis than those with low level of preoperative total bilirubin(＜286μmol/L),while there was no signi ficant difference in survival time between patients with hepatic artery invasion and those without hepatic artery invasion.(B–D)The hepatic artery invasion was a predictor for patients received palliative treatment,including palliative resection(B),ERCP(C)and PTCD(D),but the level of preoperative total bilirubin was not a predictor.

It is documented that HAR is associated with increased morbidity and mortality without an appreciable bene fit in long-term survival and is not performed routinely[10,19–21].However,our study found that HAR signi ficantly improved the median survival time of patients with hepatic artery invasion(Data not shown).Moreover,the morbidity and mortality of cohort receiving HAR were not signi ficantly higher than those of non-vascular resection.These results collectively demonstrated that radical resection combined with artery resection is still effective and safe for advanced HCCA[17,22].

The present study found that preoperative total bilirubin,hepatic artery invasion and treatment modalities are three independent prognostic indicators,and that surgical resection is still the most effective treatment for patients with advanced HCCA.Furthermore,preoperative biliary drainage is essential for highlyjaundiced HCCA patients.

学校领导班子高度重视未成年人思想道德教育工作，成立了未成年人工作领导小组，制定了《学校加强未成年人思想道德建设工作方案》，对学校未成年人的思想道德建设工作进行总体规划，明确了责任、夯实了任务。学校成立了未成年人思想道德教育活动小组，开展日常教育活动。领导小组定期召开未成年人思想道德教育研讨会，学习各项政策法规，了解学校未成年人思想道德的建设情况，督促各教育活动小组开展日常教育工作，为开展未成年人思想道德建设工作提供了强有力的组织保障。

HCCA patients frequently present with jaundice and elevated bilirubin,which require preoperative endoscopic or percutaneous drainage.However,the utility of preoperative biliary drainage is discordant[23].Many authors,mainly from Asia,prefer to undertake routine preoperative biliary drainage based on the opinion that preoperative biliary drainage decreased the probability of complications including hemorrhages,subphrenic abscesses,sepsis,and liver failure[5,24].In contrast,other authors argued against the utility of preoperative biliary drainage[25,26].Many authors consider that preoperative biliary drainage is associated with increased infectious complications that could outweigh its potential bene fits[27,28].We found negative correlations between the preoperative bilirubin level and overall survival time(Data not shown).Preoperative total bilirubin above 286 mmol/dL was a signi ficant poor prognostic factor for HCCA patient;our data are consistent with a recent study[29].Moreover,in the radical resection group,the level of preoperative total bilirubin is the most in fluential independent factor for the survival of HCCA patients.Therefore,we routinely undertake preoperative biliary drainage for these highly-jaundiced patients by endoscopic or percutaneous transhepatic manner[22].In line with previous reports[30–32],we believe that endoscopic nasobiliary drainage is the most suitable method for initial biliary drainage in HCCA patients due to its higher effi-cacy and safety.

巡视监督要准确把握职能定位，巡视工作的主要任务就是查找问题、开展监督。要把主要时间和主要精力用在了解掌握真实情况、查找发现突出问题上。巡视工作是党委的“耳目”，是“千里眼”“顺风耳”，要走基层、纳真言、查实情，把在巡视过程中了解的情况、发现的问题，客观公正、及时准确予以反映，使党委在决策时“耳聪目明”。

Surgeons now do not consider portal vein invasion as a surgical contraindication.PVR has demonstrated long-term survival advantage in patients with advanced HCCA[14–17].A metaanalysis[18]evaluated the results of 13 studies on PVR in the management of HCCA.The results showed that combined PVR is safe and feasible in the treatment of locally advanced HCCA,and can bene fit the overall survival in certain patients.Our data is not consistent with previous reports[14–16],however,we did not find that PVR bene fited patient survival.The reason might be that our patients had more advanced HCCA.Further randomized controlled trials are necessary to determine the prognostic effects of the addition of PVR on patient survival.

In summary,the prognosis of patients with advanced HCCA was mainly affected by the treatment methods,hepatic arterial invasion and preoperative total bilirubin level.Radical resection combined with hepatic artery resection is still a safe and effective treatment for these patients.Preoperative drainage is inevitable for highlyjaundiced patients.

Contributors

ZSS proposed the study.CKJ and ZSS performed the research and wrote the first draft.CKJ and YFC collected and analyzed the data.All authors contributed to the design and interpretation of the study and to further drafts.ZSS is the guarantor.

Funding

This study was supported by grants from the 12th Five-Year major project of the transformation of the primary health appropriate technology in Zhejiang Province,the National Natural Science Foundation for Young Scientists of China(81402350)and the Natural Science Foundation for Young Scientists of Zhejiang Province(LQ13H160001).

大学的主要功能是人才培养、科学研究、服务社会、文化传承创新，大学的这些功能如何实现、不同大学应如何定位、如何协调各种功能之间的关系是大学发展的前提。随着科技进步和社会发展，大学的使命也在不断发生变化。当前信息爆炸与新媒体应用普及已改变了人们的生活方式，大学不再是象牙塔或世外桃源。全球一体化使大学已经无围墙可言，而大数据、云技术、网络技术已将世界时空缩小到一个屏幕上。大学只有不断改革传统教育与教学理念，改革传统教学方式与评价模式，改革传统办学思想，才能在未来社会中不断前行。

Ethical approval

This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine(2017-0392).

农村金融是现代农村经济的核心，要实现农业发展、农村繁荣和农民增收，离不开金融的强有力支持。由于农业是弱质产业，受自然因素影响较大，商业银行开展农村金融业务的成本高、风险大、回报率低，往往面临更大的经营压力，因此仅仅靠商业性金融机构服务农业和农村发展显然不够。而且，农业的外部性特征较强，也要求政府给予必要的支持。政府可以通过开发性、政策性金融，为农业发展、乡村振兴提供强大的支持。

Competing interest

No bene fits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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