Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review

Background:Perihilar cholangiocarcinoma(phCCC)is a dismal malignancy.There is no consensus regard-ing the best treatment for patients with unresectable phCCC.The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice.Data sources:The search was conducted in PubMed,Embase,Cochrane,and LILACS.The related references were searched manually.Inclusion criteria were:reports in English or Portuguese literature that a)patients with confirmed diagnosis of phCCC;b)patients treated with a curative intent;c)patients with the outcomes of liver resection and liver transplantation.Case reports,reviews,letters,editorials,conference abstracts and papers with full-text unavailability were excluded from the analysis.Results:Most of the current literature is based on observational retrospective studies with low grades of evidence.Liver resection has better long-term outcomes than systemic chemotherapy or palliation ther-apy and liver transplantation is a good alternative for selected patients with unresectable phCCC.All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahep-atic diseases.As a general rule,patients presenting with a tumor having a longitudinal size>3 cm or extending below the cystic duct,lymph node disease,confirmed extrahepatic dissemination;intraoper-atively diagnosed metastatic disease;a history of other malignancies within the last five years,and did not complete chemoradiation regimen and were medically unfit should not be considered for transplan-tation.Some of these criteria should be individually assessed.Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers,and any decision-making must be based on a multidisciplinary evaluation.Conclusions:phCCC is a complex condition with high morbidity.Surgical therapies,including hepatec-tomy and liver transplantation,are the best option for better long-term disease-free survival.

Animal models of hepatitis E infection: Advances and challenges

Hepatitis E virus(HEV)is one of the leading causes of acute viral hepatitis worldwide.Although most of HEV infections are asymptomatic,some patients will develop the symptoms,especially pregnant women,the elderly,and patients with preexisting liver diseases,who often experience anorexia,nausea,vom-iting,malaise,abdominal pain,and jaundice.HEV infection may become chronic in immunosuppressed individuals.In addition,HEV infection can also cause several extrahepatic manifestations.HEV exists in a wide range of hosts in nature and can be transmitted across species.Hence,animals susceptible to HEV can be used as models.The establishment of animal models is of great significance for studying HEV transmission,clinical symptoms,extrahepatic manifestations,and therapeutic strategies,which will help us understand the pathogenesis,prevention,and treatment of hepatitis E.This review summarized the animal models of HEV,including pigs,monkeys,rabbits,mice,rats,and other animals.For each animal species,we provided a concise summary of the HEV genotypes that they can be infected with,the cross-species transmission pathways,as well as their role in studying extrahepatic manifestations,prevention,and treatment of HEV infection.The advantages and disadvantages of these animal models were also emphasized.This review offers new perspectives to enhance the current understanding of the research landscape surrounding HEV animal models.

Xanthogranulomatous cholecystitis managed by laparotomy may go through troublesome clinical course: Reflection of severe inflammation

To the Editor: Xanthogranulomatous cholecystitis(XGC) is an uncommon inflammatory disease of the gallbladder, and its incidence is reported to be 1.3%-5.2% [1]. XGC is diagnosed by histopathological examination, characterized by severe inflammatory destruction followed by a granulomatous reaction, marked proliferative fibrosis, and infiltration of inflammatory cells [2].

ANA-HEp2 pattern evaluation in pancreatic cancer:What can the autoantibodies tell us?

To the Editor:Pancreatic neoplasms are mainly diagnosed by imaging methods and confirmed by biopsies[1].Imaging techniques and the tumor markers carbohydrate antigen 19-9(CA19-9)or carcinoembryonic antigen(CEA)used for follow-up,are expensive and of low sensitivity and specificity[2].

A new prognostic model for drug-induced liver injury especially suitable for Chinese population

Drug-induced liver injury(DILI)is a rare side effect of drugs caused by all kinds of prescription or over-the-counter chemi-cals,biological agents,traditional Chinese medicine(TCM),natu-ral medicine(NM),health products,dietary supplements and their metabolites,and even excipients,which can lead to jaundice,liver failure,or even death.Although it is rare in term of single drug,the occurrence of DILI in all liver injuries is not low due to the wide range of drugs and foods involved.Moreover,there was an increasing trend of incidence of DILI since 2010 worldwide,with Asian regions showing the highest incidence[1].

Thanks

The editorial staff of the Hepatobiliary&Pancreatic Diseases International are grateful to the listed reviewers for their contributions to the improvement of the manuscripts received and the publication of the journal in the year of 2023(October 1,2022 to September 30,2023).

Robotic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: Analysis of surgical outcomes and long-term prognosis in a high-volume center

Background: Robotic pancreaticoduodenectomy(RPD) has been reported to be safe and feasible for patients with pancreatic ductal adenocarcinoma(PDAC) of the pancreatic head. This study aimed to analyze the surgical outcomes and risk factors for poor long-term prognosis of these patients. Methods: Data from patients who underwent RPD for PDAC of pancreatic head were retrospectively analyzed. Multivariate Cox regression analysis was used to seek the independent prognostic factors for overall survival(OS), and an online nomogram calculator was developed based on the independent prognostic factors. Results: Of the 273 patients who met the inclusion criteria, the median operative time was 280.0 minutes, the estimated blood loss was 100.0 m L, the median OS was 23.6 months, and the median recurrence-free survival(RFS) was 14.4 months. Multivariate analysis showed that preoperative carbohydrate antigen 19-9(CA19-9) [hazard ratio(HR) = 2.607, 95% confidence interval(CI): 1.560-4.354, P < 0.001], lymph node metastasis(HR = 1.429, 95% CI: 1.005-2.034, P = 0.047), tumor moderately(HR = 3.190, 95% CI: 1.813-5.614, P < 0.001) or poorly differentiated(HR = 5.114, 95% CI: 2.839-9.212, P < 0.001), and Clavien-Dindo grade ≥ Ⅲ(HR = 1.657, 95% CI: 1.079-2.546, P = 0.021) were independent prognostic factors for OS. The concordance index(C-index) of the nomogram constructed based on the above four independent prognostic factors was 0.685(95% CI: 0.640-0.729), which was significantly higher than that of the AJCC staging(8th edition): 0.541(95% CI: 0.493-0.589)( P < 0.001). Conclusions: This large-scale study indicated that RPD was feasible for PDAC of pancreatic head. Preoperative CA19-9, lymph node metastasis, tumor poorly differentiated, and Clavien-Dindo grade ≥ Ⅲ were independent prognostic factors for OS. The online nomogram calculator could predict the OS of these patients in a simple and convenient manner.

Impact of cirrhosis-related complications on posttransplant survival in patients with acute-on-chronic liver failure

Background:Acute-on-chronic liver failure(ACLF)is a life-threatening syndrome defined as acute decompensation in patients with chronic liver disease.Liver transplantation(LT)is the most effective treatment.We aimed to assess the impact of cirrhosis-related complications pre-LT on the posttransplant prognosis of patients with ACLF.Methods:This was an observational cohort study conducted between January 2018 and December 2020.Clinical characteristics,cirrhosis-related complications at LT and patient survival post-LT were collected.All liver recipients with ACLF were followed for 1 year post-LT.Results:A total of 212 LT recipients with ACLF were enrolled,including 75(35.4%)patients with ACLF-1,64(30.2%)with ACLF-2,and 73(34.4%)with ACLF-3.The median waiting time for LT was 11(4-24)days.The most prevalent cirrhosis-related complication was ascites(78.8%),followed by hepatic encephalopathy(57.1%),bacterial infections(48.1%),hepatorenal syndrome(22.2%)and gastrointestinal bleeding(11.3%).Survival analyses showed that patients with complications at LT had a significantly lower survival probability at both 3 months and 1 year after LT than those without complications(all P<0.05).A simplified model was developed by assigning one point to each complication:transplantation for ACLF with cirrhosis-related complication(TACC)model.Risk stratification of TACC model identified 3 strata(≥4,=3,and≤2)with high,median and low risk of death after LT(P<0.001).Moreover,the TACC model showed a comparable ability for predicting the outcome post-LT to the other four prognostic models(chronic liver failure-consortium ACLF score,Chinese Group on the Study of Severe Hepatitis B-ACLF score,model for end-stage liver disease score and Child-Turcotte-Pugh score).Conclusions:The presence of cirrhosis-related complications pre-LT increases the risk of death post-LT in patients with ACLF.The TACC model based on the number of cirrhosis-related complications pre-LT could stratify posttransplant survival,which might help to determine transplant timing for ACLF.

Contribution of gut microbiota to drug-induced liver injury

Drug-induced liver injury(DILI)is caused by various drugs with complex pathogenesis,and diverse clinical and pathological phenotypes.Drugs damage the liver directly through drug hepatotoxicity,or indirectly through drug-mediated oxidative stress,immune injury and inflammatory insult,which eventually lead to hepatocyte necrosis.Recent studies have found that the composition,relative content and distribution of gut microbiota in patients and animal models of DILI have changed significantly.It has been confirmed that gut microbial dysbiosis brings about intestinal barrier destruction and microorganisms translocation,and the alteration of microbial metabolites may cause or aggravate DILI.In addition,antibiotics,probiotics,and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut microbiota.In this review,we discussed how the altered gut microbiota participates in DILI.

Surgical exploration with non-resection in the setting of resectable, borderline and locally advanced pancreatic cancer

Pancreatic cancer has an overall dismal prognosis compared to most other malignancies.In general,only about 15%-20%of patients are deemed upfront resectable at time of diagnosis,with a similar proportion presenting with either borderline or locally advanced disease[1].Novel and more effective treatment regimens including FOLFIRINOX have made yet more patients become resectable,with up to 60%reported in some centers[2].

Hepatobiliary & Pancreatic Diseases International

Hepatobiliany&Pancreatic Diseases lntenational is a joumal published bimonthly in the English language by the First Aifliated Hospital,Zhejiang University School of Medicine,Hangzhou,China.We welcome original research articles,review artides,editorials,and others from amy part of the world.Manuscripts are reviewed by members of the international editorial board and our expert peer reviewers,then either accepted for publication or rejected iby the chief editor.

Different characteristics of chronic dibutyltin dichloride-induced pancreatitis and cholangitis in mouse and rat

Background:Current animal models of chronic pancreatitis(CP)often provide only limited pathophysio-logical insights since they incompletely reflect the human disease.CP induced by injection of dibutyltin dichloride(DBTC-pancreatitis)shares with human CP the important feature of extended fibrosis and would be an even more attractive model if it could be transferred from rats to mice,as recently sug-gested in the context of combined ethanol and DBTC application.This study aimed to evaluate the effects of DBTC in pancreas and liver of C57BL/6 mice,a strain commonly used to engineer genetic mouse mod-els.Methods:C57BL/6 mice and Lewis rats were exposed to variable doses of DBTC.After an investigation period of up to 4 weeks,laboratory findings and histopathological changes of pancreas and liver were evaluated.Results:Chronic DBTC-pancreatitis in rats was characterized by acinar cell damage,ductal changes,fi-brosis,and inflammatory cell infiltrates.Mice treated with DBTC at 6–8 mg/kg body weight,the standard doses in rats,showed transient increases of lipase activities but no morphological signs of chronic DBTC-pancreatitis 4 weeks after injection of the drug.Increased doses of 10–12 mg/kg DBTC were intolerable due to their high toxicity.In contrast,mice and rats presented with a similar histopathology of the liver that can be characterized as a chronic-proliferative DBTC-cholangitis with predominating damage and proliferation of the small bile ducts as well as secondary portal inflammatory cell infiltrates and a begin-ning portal fibrosis.Conclusions:The DBTC-model cannot be transferred from rats to C57BL/6 mice with respect to chronic DBTC-pancreatitis,but might be of interest to study DBTC-cholangitis in both species.

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Hepatobiliary&Pancreatic Diseases International

Hepatobiliary&Pancreatic Diseases International is a journal published bimonthly in the English language by the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China.We welcome original research articles,review articles,editorials,and others from any part of the world.Manuscripts are reviewed by members of the international editorial board and our expert peer reviewers,then either accepted for publication or rejected by the chief editor.Manuscripts should be submitted via https://mc03.manuscriptcentral.com/hbpdint.

Comparison of efficacy and safety of transpancreatic septotomy, needle-knife fistulotomy or both based on biliary cannulation unintentional pancreatic access and papillary morphology

Background: Precut sphincterotomy has been widely performed to facilitate selective biliary access when standard cannulation attempts failed during endoscopic retrograde cholangiopancreatography(ERCP). However, scarce data are available on different precut techniques for difficult biliary cannulation. This study aimed to evaluate the efficacy and safety of transpancreatic septotomy(TPS), needle-knife fistulotomy(NKF) or both based on the presence of unintentional pancreatic access and papillary morphology. Methods: Between March 2008 and December 2016, 157 consecutive patients undergoing precutting for an inaccessible bile duct during ERCP were identified. Precut techniques were chosen depending on repetitive inadvertent pancreatic cannulation and the papillary morphology. We retrospectively assessed the rates of cannulation success and procedure-related complications among three groups, namely TPS, NKF, and TPS followed by NKF. Results: The baseline characteristics of the three groups were comparable. The overall success rate of biliary cannulation reached 98.1%, including 111 of 113(98.2%) with TPS, 35 of 36(97.2%) with NKF and 8 of 8(100%) with NKF following TPS, without significant difference among groups. The incidences of total complications and post-ERCP pancreatitis were 9.6% and 7.6%, respectively. There was a trend towards less frequent post-ERCP pancreatitis after NKF(0%) compared with 11 cases(9.7%) after TPS and one case(12.5%) after NKF following TPS, but not significantly different( P = 0.07). No severe adverse event occurred during this study period. Conclusions: The choice of precut techniques by the presence of unintended pancreatic access and the papillary morphology brought about a high success rate without increasing risk in difficult biliary cannulation.

Reply to: Comment on “The role of graft reperfusion sequence in the development of non-anastomotic biliary strictures following orthotopic liver transplantation: A meta-analysis”

The Author Reply:Thank you for extending the opportunity of discussion among interested scientists.We received with interest and curiosity the letter submitted by Dr Pietersen and his colleagues in response to our recently published study addressing the impact of reperfusion sequence on the non-anastomotic biliary stricture[1].

CD4+Foxp3+CD25+/-Tregs characterize liver tissue specimens of patients suffering from drug-induced autoimmune hepatitis:A clinical-pathological study

Background: The diagnosis of drug-induced autoimmune hepatitis(DIAIH) and its differentiation from idiopathic autoimmune hepatitis(AIH) is challenging. This study aimed to differentiate DIAIH from AIH by comparing the biochemical changes, histological features, and frequencies of CD4~+Foxp3~+CD25+/-regulatory T cells(Tregs) in liver tissues or peripheral blood lymphocytes.Methods: A total of 15 DIAIH patients and 24 AIH patients who underwent liver biopsies at initial presentation were enrolled in this study. The liver histological changes were assessed by HE staining. The phenotypic recognition and distribution of CD4~+Foxp3~+CD25+/-Tregs in liver tissues were evaluated by single/double immunostains in serial sections. The CD4~+Foxp3~+CD25+/-Tregs in peripheral blood were analyzed by flow cytometry.Results: The median values of ALT and AST were 404.50 U/L and 454.10 U/L in DIAIH patients and309.50 U/L and 315.00 U/L in AIH patients, respectively. More importantly, for the first time we found that patients with DIAIH had higher levels of serum ALT and AST, more severe degree of lobular inflammation,higher frequencies of zone 3 necrosis and higher number of lobular CD4~+Foxp3~+CD25~-Tregs compared with AIH(P < 0.05). Furthermore, there were positive correlations in DIAIH between the degree of lobular inflammation and either the AST/ALT level or the number of lobular CD4~+Foxp3~+CD25~-Tregs(P < 0.05).However, the frequency of peripheral blood CD4~+Foxp3~+CD25+/-Tregs were not significantly different between DIAIH and AIH.Conclusions: The differences of ALT, AST and the number of lobular CD4~+Foxp3~+CD25~-Tregs between patients with DIAIH and those with AIH are clinically helpful in differentiating these two diseases in their early stage.

A good prognostic predictor for liver transplantation recipients with benign end-stage liver cirrhosis

BACKGROUND： Post-transplant model for predicting mortality（PMPM, calculated as-5.359＋1.988×ln（serum creatinine [mg/d L]）＋1.089×ln（total bilirubin [mg/d L]）） score has been proved to be a simple and accurate model for predicting the prognosis after liver transplantation（LT） in a single center study. Here we aim to verify this model in a large cohort of patients.METHODS： A total of 2727 patients undergoing LT with endstage liver cirrhosis from January 2003 to December 2010 were included in this retrospective study. Data were collected from the China Liver Transplant Registry（CLTR）. PMPM score was calculated at 24-h and 7-d following LT. According to the PMPM score at 24-h, all patients were divided into the low-risk group（PMPM score ≤-1.4, n=2509） and the high-risk group（PMPM score 〉-1.4, n=218）. The area under receiver operator characteristic curve（AUROC） was calculated for evaluating the prognostic accuracy.RESULTS： The 1-, 3-, and 5-year patient survival rates in the low-risk group were significantly higher than those in the high-risk group（90.23%, 88.01%, and 86.03% vs 63.16%, 59.62%, and 56.43%, respectively, P〈0.001）. In the high-risk group, 131 patients had a decreased PMPM score（≤-1.4） at 7-d, and their cumulative survival rate was significantly higher than the other 87 patients with sustained high PMPM score（〉-1.4）（P〈0.001）. For predicting 3-month mortality, PMPM score showed a much higher AUROC than post-transplant MELD score（P〈0.05）.CONCLUSION： PMPM score is a simple and effective tool to predict short-term mortality after liver transplantation in patients with benign liver diseases, and an indicator for prompt salvaging treatment as well.

Differentiation of pyogenic hepatic abscesses from malignant mimickers using multislice-based texture acquired from contrast-enhanced computed tomography

BACKGROUND： Pyogenic hepatic abscess may mimic primary or secondary carcinoma of the liver on contrast-enhanced computed tomography（CECT）. The present study was to explore the usefulness of the analysis of multislice-based texture acquired from CECT in the differentiation between pyogenic hepatic abscesses and malignant mimickers.METHODS： This retrospective study included 25 abscesses in 20 patients and 33 tumors in 26 subjects who underwent CECT. To make comparison, we also enrolled 19 patients with hepatic single simple cyst. The images from CECT were analyzed using a Laplacian of Gaussian band-pass filter（5 filter levels with sigma weighting ranging from 1.0 to 2.5）. We also quantified the uniformity, entropy, kurtosis and skewness of the multislice-based texture at different sigma weightings. Statistical significance for these parameters was tested with oneway ANOVA followed by Tukey honestly significant difference（HSD） test. Diagnostic performance was evaluated using the receiver operating characteristic（ROC） curve analysis.RESULTS： There were significant differences in entropy and uniformity at all sigma weightings（P〈0.001） among hepatic abscesses, malignant mimickers and simple cysts. The significant difference in kurtosis and skewness was shown at sigma 1.8 and 2.0 weightings（P=0.002-0.006）. Tukey HSD testshowed that the abscesses had a significantly higher entropy and lower uniformity compared with malignant mimickers（P=0.000-0.004）. Entropy（at a sigma 2.0 weighting） had the largest area under the ROC curve（0.888） in differentiating abscesses from malignant mimickers, with a sensitivity of 81.8% and a specificity of 88.0% when the cutoff value was set to 3.64.CONCLUSION： Multislice-based texture analysis may be useful for differentiating pyogenic hepatic abscesses from malignant mimickers.