Xiao-Ping Chen:the“Master of the Scalpel”who saves lives by entering the forbidden territory of hepatopancreatobiliary surgery

In his 50 years of practice,he has performed more than 20,000 hepatopancreatobiliary surgeries,being the first one to propose the concept of the“auxiliary partial orthotopic liver transplantation”internationally.Furthermore,he developed the“Chen's inserting biliary-enteric anastomosis and pancreato-enteric anastomosis,”“Chen's hepatic vascular occlusion,”“Chen's liver double-hanging maneuver,”and“Chen's hepatic vascular occlusion without liver portal dissection.”He also popularized these theories and techniques both in China and worldwide.His name is Xiao-Ping Chen,an academician of the Chinese Academy of Sciences and honorary president of the Tongji Medical College of Huazhong University of Science and Technology.

Hepatocellular carcinoma occurring in a Crohn’s disease patient

We report a case of hepatocellular carcinoma (HCC) occurring in a patient with Crohn’s disease (CD) without chronic hepatitis or liver cirrhosis, and review the clinicopathological features of HCC in CD patients. A 37-year-old Japanese man with an 8-year history of CD and a medication history of azathioprine underwent resection of a liver tumor. The histopathology of the liver tumor was pseudoglandular type HCC. In the nonneoplastic liver, focal hepatocyte glycogenosis (FHG) was observed, however, there was no evidence of liver cirrhosis or primary sclerosing cholangitis. Only nine cases of HCC in CD patients have been reported previously in the English-language literature. Eight of 10cases (including the present case) had received azathioprine treatment, and four of these cases also showed FHG, which is considered a preneoplastic liver lesion, within the non-neoplastic liver. Although the precise mechanism of the development of HCC in CD patients is controversial, these results suggest that azathioprine therapy and FHG in the non-neoplastic liver contribute to the development of HCC. These findings also indicate that it is important to survey CD patients treated with prolonged azathioprine therapy for potential liver tumors.

Hepatocellular adenoma: An unsolved diagnostic enigma

Hepatocellular adenoma (HCA) is a rare benign liver tumour associated with the use of oral contraceptives or other steroid medications which occurs predominantly in young and middle-aged women. Unlike other benign liver tumours, an HCA may be complicated by bleeding and malignant transformation. HCAs have been divided into four subtypes based on molecular and pathological features: hepatocyte nuclear factor 1α-mutated HCA, inflammatory HCA,β-catenin-mutated HCA, and unclassified HCA.β-cateninmutated HCA has the highest risk of haemorrhage or malignant transformation. In the latest upgrade of the guidelines regarding the management of benign liver tumours published in 2016 by the European Association for the Study of the Liver, magnetic resonance imaging (MRI) was recognized to be superior to all other imaging modalities in detecting HCAs and in being able to subtype HCAs up to 80%, with positive identification of 1α-mutated HCA or inflammatory HCA achievable with > 90% specificity. This review analyzed the imaging features of HCA using MRI with hepato-specific contrast agents, focusing on the limitations in the HCA characterization.

Radiofrequency ablation of hepatocellular carcinoma in difficult locations:Strategies and long-term outcomes

AIM:To investigate the treatment strategies and longterm outcomes of radiofrequency ablation(RFA) of hepatocellular carcinoma(HCC) in difficult locations and to compare the results with non-difficult HCC.METHODS:From 2004 to 2012,a total of 470 HCC patients underwent ultrasound-guided percutaneous RFA.Among these HCC patients,382 with tumors located ≤ 5 mm from a major vessel/bile duct(n = 87),from peripheral important structures(n = 232) or from the liver capsule(n = 63) were regarded as difficult cases.There were 331 male patients and 51 female patients,with an average age of 55.3 ± 10.1 years old.A total of 235 and 147 patients had ChildPugh class A and class B liver function,respectively.The average tumor size was 3.4 ± 1.2 cm.Individual treatment strategies were developed to treat these difficult cases.During the same period,88 HCC patients with tumors that were not in difficult locations served as the control group.In the control group,74 patients were male,and 14 patients were female,with an average age of 57.4 ± 11.8 years old.Of these,62 patients and 26 patients had Child-Pugh class A and class B liver function,respectively.Regular follow-up after RFA was performed to assess treatment efficacy.Survival results were generated from Kaplan-Meier estimates,and multivariate analysis was performed using the Cox regression model.RESULTS:Early tumor necrosis rate in the difficult group was similar to that in the control group(97.6% vs 94.3%,P = 0.080).The complication rate in the difficult group was significantly higher than that in thecontrol group(4.9% vs 0.8%,P = 0.041).The followup period ranged from 6 to 116 mo,with an average of 28 ± 22.4 mo.Local progression rate in the difficult group was significantly higher than that in the control group(12.7% vs 7.1%,P = 0.046).However,the 1-,3-,5-,and 7-year overall survival rates in the difficult group were not significantly different from those in the control group(84.3%,54.4%,41.2%,and 29.9% vs 92.5%,60.3%,43.2%,and 32.8%,respectively,P = 0.371).Additionally,a multivariate analysis revealed that tumor location was not a significant risk factor for survival.CONCLUSION:There was no significant difference in long-term overall survival between the two groups even though the local progression rate was higher in the difficult group.

Impact of postoperative intravenous fluid administration on complications following elective hepato-pancreato-biliary surgery

Background: The impact of perioperative intravenous fluid administration on surgical outcomes has been documented in literature, but not specifically studied in the context of hepato-pancreato-biliary(HPB) surgery. This study aimed to investigate the impact of postoperative intravenous fluid administration on intensive care unit(ICU), in this subgroup of patients. Methods: A single-center retrospective cohort of 241 HPB patients was assessed, focusing on intravenous fluid administration in ICU, during the first 24 h. Intravenous fluid variables were compared to hospital stay and postoperative complications. Data were assessed using Spearman's correlation test for bivariate correlations and logistic regression for multivariate analysis. Results: The median volume of intravenous fluid administered in the first 24 h postoperatively was 4380 mL, of which 2200 mL was crystalloid, 1500 mL colloid and 680 mL "other" fluid. Patients with one or more complications had a higher median total intravenous fluid input(4790 vs. 4300 mL), higher colloid volume(20 0 0 vs. 150 0 mL), lower urine output(1595 vs. 1900 mL) and greater overall fluid balance( + 3040 vs. + 2553 mL) than those without complications. There were correlations between total intravenous fluid volume administered( r = 0.278, P < 0.001), intravenous colloid input( r = 0.278, P < 0.001), urine output( r =-0.295, P < 0.001), positive fluid balance( r = 0.344, P < 0.001) and length of hospital stay. Logistic regression model was constructed to predict the occurrence of one or more complications; total intravenous fluid volume and overall fluid balance were both independent significant predictors(OR = 2.463, P = 0.007; OR = 1.001, P = 0.011; respectively). Conclusions: Administration of high volumes of intravenous fluids in the first 24 hours post-HPB surgery, along with higher positive fluid balance is associated with a higher rate of complications and longer hospital stay. Moreover, lower urine output is associated with longer hospital stay. Whether these are the cause of complications or the result of them remains unclear.

A ten-year experience of inferior vena cava reconstruction for malignancy:The importance of a multidisciplinary approach with hepatobiliary surgery

To the Editor,Tumor invasion of the inferior vena cava(IVC)through direct erosion is a rare and poor prognostic feature of aggressive hepatic or perihepatic malignancies[1,2].Literature shows poor response to chemotherapy,such that resection often is the only option for improved survival[3].Multidisciplinary collaborations can expand technical options;incorporation of transplant techniques has led to successful R0 resection involving difficult vascular reconstruction and extended resection[4,5].This study describes and analyzes the ten-year collaborative experience of hepatobiliary(HPB)surgeons in management of malignancies involving the perihepatic IVC.

WJH 6^(th) Anniversary Special Issues(2): Hepatocellular carcinoma Mammalian target of rapamycin inhibition in hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is one of the leading causes of cancer-related death worldwide. It is associated with a poor prognosis and has limited treatment options. Sorafenib, a multi-targeted kinase inhibitor, is the only available systemic agent for treatment of HCC that improves overall survival for patients with advanced stage disease; unfortunately, an effective second-line agent for the treatment of progressive or sorafenib-resistant HCC has yet to be identified. This review focuses on components of the mammalian target of rapamycin(mTOR) pathway, its role in HCC pathogenesis, and dual mTOR inhibition as a therapeutic option with potential efficacy in advanced HCC. There are several important upstream and downstream signals in the mTOR pathway, and alternative tumor-promoting pathways are known to exist beyond mTORC1 inhibition in HCC. This review analyzes the relationships of the upstream and downstream regulators of mTORC1 and mTORC2 signaling; it also provides a comprehensive global picture of the interaction between mTORC1 and mTORC2 which demonstrates the pre-clinical relevance of the mTOR pathway in HCC pathogenesis and progression. Finally, it provides scientific rationale for dual mTORC1 and mTORC2 inhibition in the treatment of HCC. Clinical trials utilizing mTORC1 inhibitors and dual mTOR inhibitors in HCC are discussed as well. The mTOR pathway is comprised of two main components, mTORC1 and mTORC2; each has a unique role in the pathogenesis and progression of HCC. In phase Ⅲ studies, mTORC1 inhibitors demonstrate anti-tumor ac-tivity in advanced HCC, but dual mTOR(mTORC1 and mTORC2) inhibition has greater therapeutic potential in HCC treatment which warrants further clinical investigation.

Sorafenib induced tumor lysis syndrome in an advanced hepatocellular carcinoma patient

A 55-year-old male patient with hepatitis B-related liver cirrhosis was found to have advanced hepatocellular carcinoma.His AFP was initially 9828μg/L and rapidly dropped to 5597μg/L in ten days after oral sorafenib treatment.However,he developed acute renal failure, hyperkalemia,and hyperuricemia 30 d after receiving the sorafenib treatment.Tumor lysis syndrome was suspected and intensive hemodialysis was performed. Despite intensive hemodialysis and other supportive therapy,he developed multiple organ failure(liver, renal,and respiratory failure)and metabolic acidosis. The patient expired 13 d after admission.

Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity among Chinese patients

AIM:To determine the clinicopathological characteristics of nonsteroidal anti-inflammatory drug(NSAID)-induced acute hepato-nephrotoxicity among Chinese patients.METHODS:We conducted a retrospective chart review of patients using the International Classification of Diseases,Ninth Revision diagnosis code for acute kidney injury(AKI)(584.5 or 584.9)and for acute liver injury(ALI)(570.0 or 573.3)from January 2004 to December 2013.Medical records were reviewed to confirm the diagnosis of AKI and ALI and to quantify NSAID administration.RESULTS:Seven of 59 patients(11.8%)were identified with acute hepato-nephrotoxicity induced by NSAIDs.Five patients(71.4%)received over the recommended NSAIDs dose.Compared with NSAIDsassociated mere AKI,the risk factors of NSAIDsinduced acute hepato-nephrotoxicity are age older than 60 years(57.1%),a high prevalence of alcohol use(71.4%)and positive hepatitis B virus(HBV)markers(85.7%).Compared with NSAIDs-associated mere ALI,the risk factors of NSAIDs-induced acute hepatonephrotoxicity are age older than 60 years(57.1%),increased extracellular volume depletion(71.4%),and renin-angiotensin-aldosterone system(RAAS)inhibitor combined use(57.1%).Acute interstitial nephritis and acute tubulointerstitial disease were apparent in three out of six(42.9%)kidney biopsy patients,respectively.Acute hepatitis was found in four out of six(66.7%)liver biopsy patients.Overall complete recovery occurred in four patients within a mean of 118.25±55.42 d.CONCLUSION:The injury typically occurred after an overdose of NSAIDs.The risk factors include age older than 60 years,alcohol use,positive HBV markers,extracellular volume depletion and RAAS inhibitor combined use.

Helicobacter pylori and other Helicobacter species DNA in human bile samples from patients with various hepato-biliary diseases

瞄准：为了由 16S rRNA 基因的嵌套的 PCR 调查 Helicobacter 种类的存在，由 Helicobacter pylori (H pylori ) 的存在跟随了 16S rRNA，脲，在获得在的胆汁的 cagA 基因内视镜后退从 60 印第安人的 cholangio-pancreatography (ERCP ) 使遭到。方法：六十件胆汁样品从在 ERCP 与各种各样的 hepato 胆汁的疾病和控制题目诊断的病人被获得。PCR 分析为 Helicobacter 类 16S rRNA 基因和 H pylori (16S rRNA，脲和 cagA ) 用教材被执行基因。胃的 H pylori 地位也从与各种各样的 hepato 胆汁的疾病和控制从病人在内视镜检查法获得的活体检视被估计。控制组主要与胃的混乱由题目组成了。定序分析被执行证实有 16S rRNA 和 cagA 教材的 PCR 产品从 H pylori 被导出。结果没有 Helicobacters 从胆汁样品在文化被种。Helicobacter DNA 在 96.7% 组和 6.6% 的胆汁被检测我和 II 分别地。十来自组，我为 16S rRNA 和脲是积极的， 9 为 cagA 是积极的基因。在从控制的 2 的对比， 1 与 16S 放大了教材使用了的 rRNA，脲和 cagA。16S rRNA 基因和 cagA 的序列是 99% 类似于 Helicobacter pylori。结论：Helicobacters 与各种各样的 hepato 胆汁的混乱的致病被联系。

Hepato-cardiovascular response and its regulation

AIM: To determine the possible existence of a hepatocardiovascular response and its regulatory mechanism in normal rats.METHODS: Systemic hemodynamic changes following intraportal injection of latex microspheres were studied in two modified rat models of hepatic circulation, in which the extrahepatic splanchnic circulation was excluded by evisceration and the liver was perfused by systemic blood via either the portal vein (model 1) or hepatic artery(model 2)in vivo.RFSULTS: In model 1, intraportal injection of two sized microspheres (15-μm and 8O-μm) induced a similar decrease in mean arterial pressure, while extrahepatic portal venous occlusion induced an immediate increase in mean arterial pressure. In model 2, microsphere injection again induced a significant reduction in mean arterial pressure, aortic blood flow and aortic resistance. There were no significant differences in these parameters between liver-innervated rats and liver-denervated rats.The degrees of microsphere-induced reduction in mean arterial pressure (-38.1±1.9% in liver-innervated rats and -35.4±2.1% in liver-denervated rats, respectively)were similar to those obtained by withdrawal of 2.0 mL of blood via the jugular vein (-33.3±2.1%) (P＞0.05).Injection of 2.0 mL Haemaccel in microsphere-treated rats, to compensate for the reduced effective circulating blood volume, led to a hyperdynamic state which, as compared with basal values and unlike control rats, was characterised by increased aortic blood flow (+21.6±3.3%),decreased aortic resistance (-38.1±3.5%) and reduced mean arterial pressure (-9.7±2.8%).CONCLUSION: A hepato-cardiovascular response exists in normal rats. It acts through a humoral mechanism leading to systemic vasodilatation, and may be involved in the hemodynamic disturbances associated with acute and chronic liver diseases.

Hepato-biliary profile of potential candidate liver progenitor cells from healthy rat liver

AIM:To evaluate the presence of progenitor cells in healthy adult rat liver displaying the equivalent advanced hepatogenic profile as that obtained in humans.METHODS:Rat fibroblastic-like liver derived cells (rFLDC) were obtained from collagenase-isolated liver cell suspensions and characterized and their phenotype profile determined using flow cytometry,immunocytochemistry,reverse transcription polymerase chain reaction and functional assays.RESULTS:rFLDC exhibit fibroblastoid morphology,express mesenchymal (CD73,CD90,vimentin,-smooth muscle actin),hepatocyte (UGT1A1,CK8) and biliary (CK19) markers.Moreover,these cells are able to store glycogen,and have glucose 6 phosphatase activity,but not UGT1A1 activity.Under the hepatogenic differentiation protocol,rFLDC display an up-regulation of hepatocyte markers expression (albumin,tryptophan 2,3-dioxygenase,G6Pase) correlated to a down-regulation of the expression of the biliary marker CK19.CONCLUSION:Advanced hepatic features observed in human liver progenitor cells could not be demonstrated in rFLDC.However,we demonstrated the presence of an original rodent hepato-biliary cell type.

Comparative study of IORT and 3D-CRT for hepato-cellular carcinoma

Objective: To investigate the feasibility of intra-operative radiation therapy (IORT) in hepato-cellular carcinoma (HCC). Methods: Based on the dosage distribution of tumor and adjacent sensitive organs, and dose-volume histogram (DVH), Topslane three-dimensional therapy plan was used to compare IORT and three-dimensional conformal radiation therapy (3D-CRT) in 12 cases of HCC. Results: Taking the center of tumors as the isodose center, the V90 (volume of 90% dose distribution) of IORT was significantly better than that of 3D-CRT, and median absorbed doses of normal organs in IORT was significantly lower than that in 3D-CRT. Conclusion: The V90 of IORT is better than that of 3D-CRT in HCC, and neighboring sensitive organs were effectively protected by IORT. The tumors absorbed dose and local control rate are improved in IORT.

Ⅰ型毛-肝-肠综合征小鼠模型构建及表型分析

目的 建立基于Ttc37(Tetratricopeptide Repeat Domain 37)基因缺失的Ⅰ型毛-肝-肠综合征(trichohepato-enteric syndrome,THES)的小鼠疾病模型。方法 利用CRISPR/CAS9技术在小鼠Ttc37基因中插入loxP序列构建Ttc37flox品系,通过与全身表达的CAG-Cre品系交配产生全身敲除小鼠Ⅰ型THES动物模型(Ttc37flox/flox;CAG-Cre),利用荧光定量PCR和Western blot确认敲除效果。选取8周龄小鼠,对皮肤、脾脏、肝脏、膀胱和胃肠道等主要组织进行苏木精-依红染色和病理分析,对血清中的谷草转氨酶(aspartate aminotransferase,AST)和谷丙转氨酶(alanine aminotransferase,ALT)进行酶学检测,对血清中的血红蛋白进行检测,注射抗原后利用ELISA检测免疫球蛋白IgM和IgG水平。结果 Ttc37flox/flox;CAG-Cre表现出与Ⅰ型THES相似的毛发、皮肤、B细胞和眼睛发育异常表型;常规饲养条件下未表现出肝脏、胃肠道、膀胱和血红蛋白异常。结论 Ⅰ型THES的小鼠疾病模型构建成功,可用于病理机制研究。

Genomic profiling and the impact of MUC19 mutation in hepatoid adenocarcinoma of the stomach

Dear Editor,Hepatoid adenocarcinoma(HAC)is a rare pathological subtype of extrahepatic tumor,featured by hepatoid differentiation andα-fetoprotein(AFP)-production[1,2].Hepatoid adenocarcinoma of the stomach(HAS),accounting for 0.3%to 1.0%of all gastric cancers(GCs),has attracted increasing attention due to its high degree of malignancy[3].Compared with classic GC,HAS showed a higher rate of vascular invasion,lymph node metastasis,and liver metastasis,with only 9.0%survival rate at 5 years[4].Currently,there is no effective treatment for HAS,and little is known about its pathogenesis.Herein,we investigated the molecular features of HAS and identified potential therapeutic targets for HAS.

Perspectives on immunotherapy utilization for hepatobiliary cancers in the United States

Strategies involving immunotherapy and targeted therapies are emerging in the last years as valuable options for patients with hepatobiliary cancer(HBC)including hepatocellular carcinoma(HCC),gallbladder cancer(GBC),intrahepatic cholangiocarcinoma(ICC),and extrahepatic cholangiocarcinoma(ECC).

An alpha-fetoprotein-negative hepatoid adenocarcinoma of the gallbladder with squamous differentiation

During a routine health examination, a 61-year-old male was incidentally found to have a neoplasm spreading beyond the gallbladder and into the liver on abdominal ultrasound. The ultrasound demonstrated a mixed-echo mass, measuring 7.6 cm × 4.8 cm in diameter, within the capsuled wall of the gallbladder and adhering to the liver. The patient was subsequently admitted to our hospital. His medical, family, and personal history were unremarkable, and serology tests for hepatitis B and C were both negative. Laboratory tumor marker investigations revealed increases in carcinoembryonic antigen (104.7 ng/mL;normal: 0-5 ng/mL), carbohydrate antigen (CA) 125 (421.3 U/mL;normal:0-37 U/mL), CA 242 (220.4 U/mL;normal: 0-20 U/mL), and CA19-9 (2,118.4 U/mL;normal: 0-27 U/mL) levels. Plasma alpha-fetoprotein (AFP) was within the normal range. An enhanced computed tomography (CT) scan revealed a mass in the gallbladder bed with enlarged hilar lymph nodes (Figure 1A,B,C). A cholecystectomy was subsequently performed, along with a liver and lymph node dissection. Histological findings revealed poorly differentiated cells with abundant eosinophilic cytoplasm ( Figure 1D,E ), and positive staining for cytokeratin-7 (CK7) and hepatocyte specific protein (HepPar-1) by immunohistochemistry (Figure 1F,G), suggesting that these cells were hepatoid adenocarcinoma (HAC).

Systemic management for patients with hepatobiliary tumors in a multi-dimensional view

As one of the most leading causes of cancer-related mortality,hepatobiliary tumors(HBT)are featured as limited treatment and poor survival.Due to the complexity and heterogeneity of epidemiologic risk factors,clinicopathological characteristics and cancer genomics,it is still hard to form a normalized clinical management for patients with advanced HBT.Over a long period of time,surgery-oriented comprehensive treatment is the mainstream medical care for clinical treatment for HBT,which emphasizes to categorize HBT into resectable/transplantable stage or unresectable/untransplantable stage.

Segment 6 monosegment-preserving hepatectomy for hepatoblastoma:individualizing treatment beyond the resectability criteria

Monosegment-preserving hepatic resections are very rarely considered in patients with locally advanced tumors given the high risk of liver failure from an inadequate liver remnant(1,2).Where this is considered,the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)technique,a two-staged procedure in order to induce remnant volume hypertrophy,have been reported(1,2).However,ALPPS has been known to have a high complication rate,hence even more infrequently,this complicated technique has been contemplated for pediatric patients(2).In the case we present,we identified an infant with a locally advanced hepatoblastoma with a unique anatomic presentation,that certainly precludes the possibility of ALPPS,but which otherwise provided the team with the opportunity to perform a single-staged monosegment-preserving hepatectomy with curative intent,in lieu of the alternative of liver transplantation(LT).