Introduction

Gallbladder cancer(GBC)is the most common biliary tract cancer,accounting for 4% of all gastrointestinal cancers[1].The worldwide age-standardized incidence rate(per 100 000)of GBC varies widely by ethnicity and geography,ranging from 0.4 in Norway to 25.3 in Chile(0.82–1.45 in the United States and 0.4–10.2 in Europe)[2–7].The vast majority of GBCs are adenocarcinomas[8,9]and are very aggressive,accounting for 3710 new deaths in the United States every year[10].

《红高粱家族》中对于高密东北乡有这样一句概括性的话语“高密东北乡无疑是地球上最美丽最丑陋、最超脱最世俗、最圣洁最龌龊、最英雄好汉最王八蛋、最能喝酒最能爱的地方”，①为什么莫言会把自己的故乡描绘成众多矛盾的结合体？因为莫言对这片土地怀着一分矛盾、复杂的情感——爱恨交织，而这都与他本人的童年记忆有着不可分割的关系。

Incidental gallbladder cancer(iGBC)is de fined as gallbladder malignancy identi fied on postoperative histopathologic examination with no pre-or intraoperative findings suspicious of malignancy.The incidence of iGBC after a laparoscopic cholecystectomy(CCY)is 0.7%–2.1%[11,12].Indeed,the majority(50%–70%)of all GBCs are discovered incidentally on pathologic analysis of a gallbladder following CCY[9,13],and as such,represent a unique opportunity for a cure.However,in cases of iGBC the rate of bile spillage is very high(44%)[14]and although robust data are lacking,small studies and registry data show signi ficantly worse survival in iGBC patients when bile spillage occurs[14–17].This corroborates the common-sense notion that spillage may convert curable iGBC into an incurable case of peritoneal carcinomatosis,which can lead to premature death,even in cases of the very earliest stage of iGBC(pT1a)[16].

政府在与社工组织互动的过程中，由于政府控制着社工组织所稀缺的资源如经费、合法性等。因此，政府一直处于强势的地位，拥有着资源依赖学派所指的权力，政府在制定服务指标标准的时候也体现着这种权力的作用。政府在购买社工组织服务的同时也制定了一套评估服务的标准，但政府关注的更多是量，是否完成项目合同里面规定的个案、小组、社区活动的数量，成为了政府衡量社工组织开展服务好与坏的主要标准。社工组织在面对资源获取的不稳定性和组织的依赖性，需要不断改变自身的行动模式，以便获取和维持来自外部环境的资源，以至于造成两者互动地位不平等。

企业内部的和谐最重要的内容就是建立符合自身特点的企业文化。在企业文化比较完善之后，企业管理层可以逐步减小其影响力。企业管理者的权力应随着企业组织的和谐程度递减，只要企业可以保持监督约束的权力，其他的权力就应该尽可能地下放。

The high rate of iGBC among all GBC cases is,unfortunately,a testament to the difficulty in detecting iGBC preoperatively.Although some poorly evidence-based warning signs have been suggested[18],such as irregular gallbladder wall thickening(GBWT),large polyps,nonvisualization of the gallbladder,and lymphadenopathy,there are no widely accepted evidence-based warning signs that may reliably alert the general surgeon to the presence of iGBC.Furthermore,the first-line diagnostic tools such as ultrasonography have a limited ability to differentiate iGBC from cholecystitis[19,20].Pitt et al.[21]reported a more sophisticated analysis,including a scoring system based on predictive factors but the “big-data”design of their study precluded re-review of imaging and reports,and required several assumptions to identify iGBC patients.We took advantage of one of the largest single-institution databases to analyze this important problem while maintaining the ability to re-review imaging and reports,to ensure that the iGBC group is not contaminated with patients who were suspected of having GBC preoperatively(i.e.,non-iGBC cases),and to quantify the effects of bile spillage in cases of iGBC,given that this has hitherto been only poorly described in the literature.

In conclusion,iGBC is not easily detected,as evidenced by the high proportion of GBC cases presenting as incidentally,but importantly,having a high index of suspicion may avoid unnecessary reoperations and the high-risk that accompany bile spillage,which commonly occur in cases of iGBC.There are several predictive factors that may help the surgeon diagnose iGBC,including age,GBWT,dilated common bile duct,and elevated alkaline phosphatase.In addition,we found that the number of preoperative imaging modalities and the presence of GBWT without PCCF are useful predictors of iGBC.Furthermore,we have quanti fied the risk of bile spillage,which leads to a signi ficantly increased rate of unresectable carcinomatosis in the majority(72.7%)of cases,and correspondingly,a signi ficantly poorer survival.

Indeed,we and others have found that conversion from laparoscopic to open CCY correlated with higher risk of iGBC on univariate analysis[21].However,a conversion was not considered in our predictive model since it did not precede the CCY.Although several other studies did not assess the correlation between bile spillage and peritoneal carcinomatosis,some did assess survival,and our quantifying the signi ficant correlation between bile spillage and peritoneal carcinomatosis provides a logical mechanism for the worse survival observed in the literature,albeit in mostly small studies[14–17,23].

Methods

There are several limitations in our study.First,this is a retrospective study and is therefore subject to all the biases and other problems that potentially accompany retrospective studies,including the inability to draw causal relationships.The retrospective nature of the study also may lead to the misidenti fication of cases with or without bile spillage.Second,because the incidence of iGBC after CCY is only 0.45%,the small number of patients in the iGBC group lowers the power of the study and introduces the pos-sibility of a type-II error.Third,we have anecdotally observed that a diagnosis of cancer by a pathologist may preclude mention on the pathology report of other benign diagnoses,since they are relatively irrelevant clinically to a patient with GBC,leading to discrepancies,for example,between the proportions of preoperative and pathologic diagnoses of benign conditions,such as cholecystitis.

Variables including patient demographics,comorbidities,preoperative imaging findings,clinical and pathological diagnoses,laboratory results,type of operation,and vital statistics were retrieved.To analyze the most common imaging modality in depth,preoperative ultrasound(US)images for both iGBC cases and 1.7:1 random controls were blindly reviewed by a radiologist.Data of two cases with no available US images were obtained from reports or CT imaging.

Bivariate analyses of patient characteristics,imaging data,laboratory findings perioperative course,and intra-and postoperative findings were compared between iGBC and non-iGBC cases using Chi-square analyses for ordinal,nominal and binary variables and Student’s t test for normally distributed,continuous data.To adjust for multiple comparisons,a Bonferroni correction was applied whereby signi ficance was accepted at a two-tailed level of P≤0.01.

Features found to be statistically different between iGBC groups at P≤0.01 were considered for backward elimination into a multivariable logistic regression analysis.A missing value analysis was conducted to explore biases and patterns in missing data.Variables were removed from the list of considered predictors of iGBC if a)they were not clinically relevant,b)they possessed high correlations with other candidate covariates,c)they did not precede the operation or d)there were too many missing values.The remaining variables were entered in a backward-elimination fashion to build the model that best explained the variation in the outcome of interest,i.e.,iGBC.Goodness of fit and linearity were explored throughout using the Hosmer–Lemeshow and the Cox–Snell R2 methods,respectively.Odds ratio(OR)and their 95%con fidence interval(CI)were computed.Variables were removed if P＞0.1 or if the 95%CI of the OR included 1.A Kaplan–Meier analysis was used to compare differences in the survival function between various groups.Differences in survival curves were assessed using the Log-Rank(Mantel–Cox)test.

Given that patients with bile spillage were discovered postoperatively to have had an unrecognized epithelial cancer(iGBC)withinthe gallbladder lumen at the time of bile spillage,a detailed review of all cases of iGBC in the database was performed by two independent authors(CSC and GN)to review operative,pathologic,clinical,and imaging records.Bile spillage during CCY was deemed to have occurred if there was documented evidence on the operative report or if there was evidence in the pathology report of a transmural breach of the gallbladder wall,unless the surgeon recorded opening the gallbladder for inspection after removal or the surgeon speci fically stated that the gallbladder was removed intact without bile spillage,a statement that trumped a pathologist’s description of a transmural breech of the gallbladder wall.These cases were then considered to be at high-risk for peritoneal carcinomatosis.The actual occurrence of peritoneal carcinomatosis was recorded if speci fically con firmed in the medical record.If patients were alive at least 2 years postoperatively without evidence of peritoneal carcinomatosis,the evidence-based assumption was made that they did not have peritoneal carcinomatosis since the median survival for stage-4 patients is 2 months,and the 2-year survival rate is only 2%[22].Thus,these patients were rightcensored from the analysis.When assessing the median survival of patients deemed to be at high-risk for peritoneal carcinomatosis and the correlation between high-risk for peritoneal carcinomatosis and actual development of peritoneal carcinomatosis,patients were excluded from the bile spillage group if the American Joint Committee on Cancer T-stage of the iGBC was Tis,since bile from gallbladders with a merely in situ tumor would not be expected to harbor cancer cells and to progress to peritoneal carcinomatosis.

Table 1 Patient characteristics.

Characteristics iGBC-(n=5770) iGBC+(n=26) P value Age(mean±SD,yr)(n=5713) 52.27±18.45 75.61±11.92 ＜0.001 Gender(n=5772)Male 1593(27.7%) 10(38.5%) 0.271 Female 4153(72.3%) 16(61.5%)Race(n=5767)White 3931(68.5%) 18(69.2%) 0.955 African American 1512(26.3%) 8(30.8%)Asian 62(1.1%) 0 Hispanic 146(2.5%) 0 Other 90(1.6%) 0 ASA score group(n=2096)1 to 2(normal or mild disease) 1217(58.3%) 2(25.0%) 0.057 3 to 5(moderate to moribund) 871(41.7%) 6(75.0%)Preoperative comorbidities(n=5602)Congestive heart failure 277(5.0%) 1(3.8%) 0.630 Hypertension 2258(40.5%) 18(69.2%) 0.003 Cerebrovascular accident 90(1.6%) 0 0.515 Coronary artery disease 716(12.8%) 3(11.5%) 0.831 Chronic obstructive pulmonary disease 375(6.7%) 6(23.1%) 0.001 Renal failure 213(3.8%) 1(3.8%) 0.994 Diabetes mellitus 887(15.9%) 10(38.5%) 0.002 Alcohol abuse 744(13.3%) 1(3.8%) 0.157 Hepatitis infection 168(3.0%) 0 0.812 Cirrhosis 54(1.0%) 1(3.8%) 0.232 Ascites 48(0.9%) 18(69.2%) 0.001 Liver fibrosis 9(0.2%) 0 0.825 Preoperative diagnosis(n=5555)Acute cholecystitis 2044(37.0%) 14(53.8%) 0.041 Chronic cholecystitis 1720(31.1%) 5(19.2%) 0.211 Gangrenous cholecystitis 38(0.7%) 1(3.8%) 0.049 Perforated cholecystitis 3(0.1%) 0 0.907 Hemorrhagic cholecystitis 5(0.1%) 0 0.880 Symptomatic cholecystitis 3197(57.8%) 13(50.0%) 0.428 Biliary dyskinesia 448(8.1%) 0 0.137 Biliary pancreatitis 319(5.8%) 3(11.5%) 0.186 Choledocholithiasis 150(2.7%) 2(7.7%) 0.068 Gallbladder polyp 39(0.7%) 0 0.673 Incidental/asymptomatic stones 154(2.8%) 0 0.453

Results

Predicting iGBC

We identi fied 5796 patients who underwent CCY with a mean age of 52.3 years.The majority of patients were female(72%),and White(68%).After exclusions,26 patients(0.45%)were found to have iGBC.Compared to the controls,patients with iGBC were signi ficantly older(75.61 versus 52.27 years,P＜0.001),had a higher incidence of hypertension(69.2%versus 40.5%,P=0.003),chronic obstructive pulmonary disease(23.1%versus 6.7%,P=0.001),and diabetes mellitus(38.5%versus 15.9%,P=0.002)(Table 1).

Furthermore,several preoperative factors associated postoperatively with iGBC.Preoperative imaging modalities were used more frequently in iGBC patients compared to non-iGBC cases:significantly more of those with iGBC(30.8%)underwent 3 or more imaging modalities than non-iGBC cases(12.8%);similarly,69.2%iGBC cases underwent 0–2 modalities versus 87.2%for non-iGBC cases(P=0.002).In particular,patients with iGBC were nearly 5 times more likely to undergo preoperative ERCP(19.2%versus 4.0%,P＜0.001).In addition,iGBC patients had a signi ficantly larger common bile duct diameter on US(7.13 mm)versus patients without iGBC(5.04 mm,P＜0.001)(Table 2).

The blinded review of preoperative US images was performed to assess variables not captured in the larger database,such as the presence of focal versus diffuse GBWT,which was reasoned to possibly correlate with—and thereby help identify patients with—iGBC.Although patients with iGBC did more frequently have focal GBWT,the number in this analysis was very small[only two iGBC patients(8.7%)were found to have focal GBWT(Table 3)].Any type of GBWT(either focal or diffuse)was signi ficantly associated with iGBC(Table 3).However,given that iGBC is often confused with and misdiagnosed as cholecystitis,and that cholecystitis generally presents with both GBWT and PCCF,we further reasoned that the presence of GBWT without PCCF may support the diagnosis of iGBC.Indeed,73.9%of iGBC patients had this finding(GBWT in the absence of PCCF)versus only 47.4%of non-iGBC patients in the blinded-review subset(P＜0.001)(Table 3).

In the main dataset,in addition to preoperative imaging findings,some preoperative laboratory results are valuable to the diagnosis of iGBC.Patients with iGBC had signi ficantly higher values for white blood cell count,glucose,alanine aminotransferase,alkaline phosphatase,total and direct bilirubin and prothrombin time,and had lower serum albumin,compared with those without iGBC(Table 4).

To this sparse list of predictive factors,we add our novel finding that the presence of GBWT without PCCF was highly signi ficant in bivariate,and persisted as signi ficant in multivariate analysis.That GBWT without PCCF may help distinguish iGBC from cholecystitis is an important finding,given that cholecystitis is a very commonmimicker of GBC.Another novel finding is the number of imaging tests performed preoperatively,which was highly signi ficant on bivariate analysis.Of the five imaging modalities in our database—US,computed tomography(CT),MRI,HIDA scan,and endoscopic retrograde cholangiopancreatography(ERCP)—only two(generally the ubiquitous US and CT)were performed for the vast majority of patients in our database,while fewer patients in the database underwent three,four,or five imaging studies.Indeed,one of the advantages of a large institutional database such as this is that a more granular dataset can be obtained and customized.For example,as noted in a recent analysis of the National Cancer Database(NCDB)[25],several factors essential to the current analysis are not available in NCDB,including the above-mentioned finding of GBWT without PCCF,bile spillage,and even iGBC itself.

Consequences of iGBC:peritoneal carcinomatosis and survival

Preoperative recognition of patients who are at increased risk to have iGBC is essential for several reasons.First and foremost,it allows the general surgeon to consider whether he/she has the ability to do the potentially difficult and high-oncologic-risk case.The surgeon can make the decision before operation.If the surgeon fails to identify iGBC until the pathology report,or has suspicion raised only intraoperatively,the patient is likely to have an unnecessary operation.Depending on the T-stage and the status of the cystic-duct margin,performing a partial hepatectomy,lymphadenectomy and possibly excision of the extrahepatic biliary tree may be indicated.Avoiding this potentially unnecessary reoperation is a second reason why preoperative recognition is essential.Finally,in cases of iGBC,bile spillage may be a life-threatening event.Without iGBC,bile spillage is of little consequence for the long-term survival of the patient,and while one never wants to spill bile,the consequences of spillage in benign cases are not nearly so grave as in cases of GBC.With preoperatively suspected GBC,increased meticulousness in avoiding bile spillage is essential due to the potentially life-threatening risks of bile spillage,and warrants having a lower threshold to convert the procedure to an open approach if the suspicion for iGBC is high.

Detailed review of the iGBC cases con firmed evidence of intraoperative bile spillage in 10 iGBC cases,which were therefore deemed high-risk for peritoneal carcinomatosis,and its absence in 7 cases,which was deemed low-risk for peritoneal carcinomatosis.Peritoneal carcinomatosis high-risk cases(cases with evidence of bile spillage)were 2.6 times more likely to develop actual peritoneal carcinomatosis than low-risk cases that lacked evidence of bile spillage(72.7%versus 27.3%,P=0.005).A Kaplan–Meier analysis of cases at low-risk versus high-risk for peritoneal carcinomatosis revealed widely diverging lines(Fig.1 A),with patients at low-risk(lacking bile spillage)having a median survival of 45.5 months,compared to 11.4 months for those at high-risk(with bile spillage)(P=0.005),despite having similar distributions of T stage(no-spillage group had 57%stage 2,29%stage 3,and 14%Tis,versus the bile-spillage group having 50%stage 2,40%stage 3,and 10%1b;P=0.7).Patients who developed peritoneal carcinomatosis following bile spillage during CCY for iGBC had a profoundly worse median survival compared to those without peritoneal carcinomatosis(6.7 versus 45.5 months;P=0.006;Fig.1B).

张立民(通信作者) 男,1966年出生于辽宁省开原市.教授,博士生导师.主要研究领域为卫星信号处理、视景仿真与虚拟现实.

Discussion

Having assessed predictors of iGBC,we then assessed the consequences of having missed iGBC preoperatively.Of the 26 iGBC cases,4 were stage Tis,1 was T1b,11 were T2,9 were T3,and 1 was a sarcomatoid carcinoma not otherwise staged.The median survival of the iGBC group was 34.8 months,compared to 25.8 months for 8 patients in the database with non-iGBC.Although the small number precluded finding signi ficance in this comparison,it is expected that,compared with symptomatic GBC,iGBC would have an improved survival in general.However,we sought to investigate these cases of iGBC in more detail,given our hypothesis that the avoidable occurrence of bile spillage may profoundly affect outcomes.

3）注水系统是油田的关键设备，以后要加强对注水水质的监测以及注水设备的定期问题排查。特别是细过滤器的填料漏失情况，要定期通过观察孔进行观察，通过滤料高度的对比（添加填料后已经做了标记），及时分析查找滤料漏失问题。

乔治·桑：生活中的某个时刻，我们争取幸福、获得信任、感受陶醉的能力达到顶点。接下来，疑虑与忧郁就笼罩上来，并把我们永远裹住，就好像我们的灵魂不能再满足它们的需求。或许这就是其实正在黯然隐去的命运，我们被判定要缓缓地步下曾经乘兴勇敢地攀上的高坡。

Given these dire consequences of having iGBC and bile spillage,several authors proposed predictive factors to increase the preoperative suspicion of GBC.In a review of the American College of Surgeon-National Surgical Quality Improvement Program(ACSNSQIP),Pitt et al.suggested that when performing CCY for a benign process the surgeon’s level of suspicion for the presence of an iGBC should be elevated in patients who are older than 65 years,female,Asian or African American ethnicity,and with elevated preoperative alkaline phosphatase[21].We found that all of these but ethnicity are correlated with iGBC.Although ethnicity is largely recognized to increase risk of GBC in general[2–7],our study did not show a correlation between ethnicity and the risk of GBC.It could be that ethnicity-related risk of GBC does not necessarily equate with risk of iGBC versus symptomatic GBC,or that the high-risk associated with ethnicity is simply not seen in large North American databases such as ours,as shown in a review of the discordant literature on porcelain gallbladder[7].Koshenkov et al.[24]also published a predictive model for diagnosing iGBC,consisting of age＞65 years,dilated common bile duct,and GBWT.

The perioperative details are shown in Table 5.There was no difference between the groups in duration of operation,length of stay or estimated blood loss.Regarding operative approach,the iGBC group had a higher percentage of open CCY(11.5%versus 5.2%,P＜0.001)and laparoscopic converted to open CCY(23.1%versus 3.9%,P＜0.001)(Table 5).Multivariable logistic regression revealed that age and the variable GBWT without PCCF were the strongest predictors of iGBC.With the yearly increase in age,the OR of having an iGBC increases by 10%(1.1-fold;95%CI:1.04–1.12).Cases with GBWT without PCCF were 3.5 times more likely to have iGBC(95%CI:1.23–10.0).

Table 2 Preoperative imaging modalities.

Data were presented as mean±SD or n(%).US:ultrasound;CT:computed tomography;MRI:magnetic resonance imaging;HIDA:hepatobiliary iminodiacetic acid;ERCP:endoscopic retrograde cholangiopancreatography;GBWT:gallbladder wall thickness;CBD:common bile duct;PCCF:pericholecystic fluid;CCK:cholecystokinin.

Imaging modalities iGBC- iGBC+ P value US Preoperative(n=5580) 3861(69.5%) 26(100%) 0.095 Gallstones and/or sludge(n=2770) 2411(87.6%) 18(100%) 0.116 Gallstone size(mm)(n=301) 15.25±8.03 20.25±4.59 0.381 GBWT(n=2608) 1030(39.8%) 14(63.6%) 0.023 CBD diameter(mm)(n=2622) 5.04±2.47 7.13±3.97 ＜0.001 PCCF(n=4442) 410(9.3%) 0 0.125 Calci fication(n=4402) 145(3.3%) 1(5.3%) 0.635 GBWT without PCCF(n=4032) 853(21.3%) 17(73.9%) ＜0.001 CT Preoperative(n=5579) 1381(24.9%) 11(42.3%) 0.040 GBWT(mm)(n=37) 4.38±3.50 3.40±2.26 0.140 CBD diameter(mm)(n=105) 10.58±9.30 – –PCCF(n=3003) 234(7.8%) 2(16.7%) 0.256 Calci fication(n=3004) 67(2.2%) 0 0.615 MRI Preoperative(n=5575) 479(8.6%) 5(19.2%) 0.043 GBWT(mm)(n=30) 5.54±4.40 – –CBD diameter(mm)(n=229) 7.52±3.60 7.67±2.50 0.945 PCCF(n=2498) 116(4.7%) 2(40.0%) ＜0.001 Calci fication(n=2491) 25(1.0%) 0 0.821 HIDA Preoperative(n=5581) 1384(24.9%) 9(34.6%) 0.254 Symptoms upon CCK injection(n=962) 777(81.3%) 5(83.3%) 0.898 Ejection fraction(%)(n=658) 23.29±24.42 40.00±56.57 0.336 Time to gallbladder visualization(min)(n=1072) 83.73±402.64 97.71±62.90 0.927 Time to duodenum visualization(min)(n=893) 70.35±230.67 110.00±97.97 0.701 ERCP Preoperative(n=5592) 224(4.0%) 5(19.2%) ＜0.001 Postoperative(n=5589) 111(2.0%) 1(3.8%) 0.505 Number imaging modalities(n=5575)0–2 4840(87.2%) 18(69.2%) 0.002 3 or more 709(12.8%) 8(30.8%) 0.002

Table 3 Independent re-review of US images.

Data were presented as mean±SD or n(%).∗:US data:Independent re-review of iGBC cases versus 1.7:1 random controls;n represents those with imaging available for re-review.GBWT was de fined as qualitatively labeled abnormally thickened by the radiologist,or quantitatively if＞4 mm.GBWT:gallbladder wall thickness;PCCF:pericholecystic fluid.

iGBC-(n=38∗) iGBC+(n=23∗) P value GBWT 18(47.4%) 17(73.9%) 0.003 Focal 0 2(8.7%) 0.148 Diffuse 18(47.4%) 15(65.2%) 0.147 Gallbladder length(mm) 79.35±17.35 78.93±17.93 0.889 Gallbladder width(mm) 32.00±8.27 37.80±3.44 0.061 GBWT without PCCF 18(47.4%) 17(73.9%) ＜0.001

In brief,when surgeons find themselves reviewing more than these two common preoperative imaging tests,and observing GBWT without PCCF in cases of presumed cholecystitis,for an older patient,with a dilated common bile duct,and elevated alkaline phosphatase,the index of suspicion should increase that a cancer may be lurking in that gallbladder,even if not clearly seen on imaging.In these cases,a prepared surgeon may succeed in converting a would be iGBC case to a known GBC case,thereby avoiding reoperation,or worse,spillage of bile laden with cancer cells.

This study was approved by the local institutional review board.All of the consecutive CCYs performed at our institution from 2000 to 2013 were reviewed.Patients younger than 18 years of age,those with preoperative diagnosis or findings suspicious of GBC and those underwent CCY as part of another procedure(e.g.,Whipple,colectomy,hepatectomy,cytoreductive surgeries)were excluded.

Table 4 Preoperative laboratory findings.

Data were presented as mean±SD.

iGBC- iGBC+ P value White blood cells(1000/μL)(n=3782) 9.43±4.90 12.05±6.21 0.009 Blood urea nitrogen(mg/dL)(n=3699) 14.30±11.06 17.29±17.21 0.189 Creatinine level(mg/dL)(n=3692) 1.02±1.13 1.03±0.75 0.968 Glucose(mg/dL)(n=3701) 119.07±48.22 145.21±55.17 0.008 Lactate(mmol/L)(n=63) 47.99±146.25 – –Aspartate aminotransferase(U/L)(n=3018) 701.07±141.28 122.43±150.54 0.097 Alanine aminotransferase(U/L)(n=3018) 78.15±143.72 154.57±235.93 0.017 Alkaline phosphatase(U/L)(n=3044) 109.47±88.95 216.67±210.53 ＜0.001 Total bilirubin level(mg/dL)(n=3038) 0.94±1.82 3.74±6.96 ＜0.001 Direct bilirubin level(mg/dL)(n=2416) 0.35±0.95 1.28±3.52 ＜0.001 Albumin(g/dL)(n=2974) 3.78±0.99 3.21±0.84 0.009 Prothrombin time(s)(n=2336) 11.88±4.47 14.68±8.30 ＜0.001 International normalized ratio(n=2309) 1.18±2.39 1.35±0.89 0.727

Table 5 Perioperative history.

Data were presented as mean±SD or n(%).∗25 cases had valid values.CCY:cholecystectomy;IOC:interaoperative cholangiogram.

iGBC- iGBC+ P value Duration of operation(min)(n=1576) 92.21±51.87 76.68±37.26 0.896 Estimated blood loss(mL)(n=4665) 64.90±144.26 81.94±75.42 0.617 Urgency(n=5564)Urgent/emergent 3363(60.7%) 10(38.4%) ＜0.001 Elective/outpatient 2173(39.2%) 15(57.7%)Length of stay(n=2640)Total length of stay(d) 4.6±7.0 6.6±4.4 0.233 Postoperative length of stay(d) 0.19±0.29 0.27±0.81 0.112 Conversion(n=5796) 197(3.9%) 6(23.1%) ＜0.001(Laparoscopic versus Open CCY)Type of operation(n=5038)Laparoscopic CCY only 4023(80.3%) 13(50.0%) ＜0.001 Laparoscopic CCY with IOC 550(11.0%) 4(15.4%) ＜0.001 Open CCY(begun open) 204(4.1%) 2(7.7%) ＜0.001 Open CCY(begun open)with IOC 55(1.1%) 1(3.8%) ＜0.001 Laparoscopic converted to open CCY 121(2.4%) 5(19.2%) ＜0.001 Laparoscopic converted to open CCY with IOC 76(1.5%) 1(3.8%) ＜0.001 Histopathology findings Acute cholecystitis(n=5672) 1028(18.2%) 6∗(24.0%) 0.454 Chronic cholecystitis(n=5726) 4857(85.2%) 10(38.5%) ＜0.001 Gangrenous cholecystitis(n=5661) 281(5.0%) 0 0.251 Perforated cholecystitis(n=5660) 18(0.3%) 0 0.777 Hemorrhagic cholecystitis(n=5661) 236(4.2%) 0 0.296 Cholelithiasis(n=5716) 4324(76.0%) 13∗(52.0%) 0.005 Adenomyosis(n=5664) 25(0.4%) 0 ＜0.001 Diverticulosis(n=5661) 12(0.2%) 0 0.817 Gallbladder polyp(n=5661) 66(1.2%) 1∗(4.0%) 0.192 Cholesterolosis(n=5676) 1056(18.7%) 0 0.017 Sludge(n=5661) 336(6.0%) 4∗(16.0%) 0.035 Other(n=5665) 404(7.2%) 1∗(4.0%) 0.540

We hypothesized that there may exist preoperative factors that are able to predict cases at high-risk of iGBC.These factors help general surgeons to avoid cases of unsuspected iGBC,and also to avoid spillage of cancer-cell-laden bile during CCY that would be associated with worse outcome,due to carcinomatosis.

(3)H3PO2的工业制法是:将白磷(P4)与Ba(OH)2溶液反应生成PH3气体和Ba(H2PO2)2,后者再与H2SO4反应。写出白磷与Ba(OH)2溶液反应的化学方程式:___。

Fig.1.Kaplan–Meier survival analysis of bile spillage(n=10)versus no bile spillage(n=7)(A)and peritoneal carcinomatosis(n=8)versus no carcinomatosis(n=9)(B).Both bile spillage and the presumably resultant carcinomatosis signi ficantly correlated with survival after cholecystectomy.

Contributors

CSC conceived and designed the study.GN,MH,FH,MN and CSC collected the data.PK,FH,SAM,KGC and CSC analyzed the data.GN,MH and CSC wrote the first draft.All authors contributed to the design and interpretation of the study and to further drafts.CSC is the guarantor.

走入金杯印刷有限公司位于东莞的生产车间，印刷机械整齐地排列在车间里，灯光明亮，地面干净，没有一丝刺鼻的油墨味。要不是机器运转的轰鸣声和操作台上偶尔闪过的工人身影，我会以为自己正置身于窗明几净的实验室。我把问题抛给了一直陪在我们身边的金杯印刷董事长杨金溪。他笑答道：“因为金杯印刷一直使用不含乙醇的植物油墨和水性油墨，同时配以无水胶印工艺，所以闻不到异味。”言语中，杨金溪透着自豪。

Funding

None.

Ethical approval

This study was approved by the Institutional Review Board of Saint Agnes Hospital(No.2013-008).

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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