Hepatobiliary Pancreat Dis Int

	2021 Vol. 20 No. 5
	Published: 2021-10-15


	Pages 409-510
	ORIGINAL ARTICLES/Liver ORIGINAL ARTICLES/Biliary ORIGINAL ARTICLES/Pancreas LETTERS TO THE EDITOR VIEWPOINTS Special issue on nonalcoholic fatty liver disease

Special issue on nonalcoholic fatty liver disease

	409	Liu YX, Liu X, Cen C, Li X, Liu JM, Ming ZY, Yu SF, Tang XF, Zhou L, Yu J, Huang KJ, Zheng SS
		Comparison and development of advanced machine learning tools to predict nonalcoholic fatty liver disease: An extended study
		Background: Nonalcoholic fatty liver disease (NAFLD) is a public health challenge and significant cause of morbidity and mortality worldwide. Early identification is crucial for disease intervention. We recently proposed a nomogram-based NAFLD prediction model from a large population cohort. We aimed to ex- plore machine learning tools in predicting NAFLD. Methods: A retrospective cross-sectional study was performed on 15 315 Chinese subjects (10 373 train- ing and 4942 testing sets). Selected clinical and biochemical factors were evaluated by different types of machine learning algorithms to develop and validate seven predictive models. Nine evaluation indicators including area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC), accuracy, positive predictive value, sensitivity, F1 score, Matthews correlation coefficient (MCC), specificity and negative prognostic value were applied to compare the performance among the models. The selected clinical and biochemical factors were ranked according to the importance in prediction ability. Results: Totally 4018/10 373 (38.74%) and 1860/4942 (37.64%) subjects had ultrasound-proven NAFLD in the training and testing sets, respectively. Seven machine learning based models were developed and demonstrated good performance in predicting NAFLD. Among these models, the XGBoost model revealed the highest AUROC (0.873), AUPRC (0.810), accuracy (0.795), positive predictive value (0.806), F1 score (0.695), MCC (0.557), specificity (0.909), demonstrating the best prediction ability among the built models. Body mass index was the most valuable indicator to predict NAFLD according to the feature ranking scores. Conclusions: The XGBoost model has the best overall prediction ability for diagnosing NAFLD. The novel machine learning tools provide considerable beneficial potential in NAFLD screening.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 409-415 . [Abstract] ( 61 ) [HTML 1KB] [PDF 0KB] ( 69 )

	416	Chang XJ, Shi YW, Wang J, Liu HB, Chen Y, Zhu XN, Chen YP, Yu ZJ, Shang QH, Tan L, Li Q, Jiang L, Xiao GM, Chen L, Lu W, Hu XY, Long QH, An LJ, Zou ZY, Wong VWS, Yang YP, Fan JG
		Influence of weight management on the prognosis of steatohepatitis in chronic hepatitis B patients during antiviral treatment ^Hot!
		Background: Although concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treat- ment. Methods: In the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at base- line and week 72. Results: A total of 10 0 0 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH ( P > 0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P < 0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥23 kg/m 2 (Asian criteria) [odds ratio (OR): 0.414; 95% confidence interval (95% CI): 0.190-0.899; P = 0.012] and weight gain (OR: 0.187; 95% CI: 0.050-0.693; P = 0.026) were less likely to have NASH resolution. Among patients without NASH at baseline, 22 (3.7%) developed NASH. Baseline BMI ≥23 kg/m 2 (OR: 12.506; 95% CI: 2.813-55.606; P = 0.001) and weight gain (OR: 5.126; 95% CI: 1.674-15.694; P = 0.005) were predictors of incident NASH. Conclusions: Lower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 416-425 . [Abstract] ( 93 ) [HTML 1KB] [PDF 0KB] ( 78 )

	426	Yang RX, Zou ZS, Zhong BH, Deng H, He FP, Shi JP, Zhao CY, Mi YQ, Zhou YJ, Di FS, Zheng RD, Du Q, Shang J, Popovic B, Chen J, Fan JG
		The pathologic relevance of metabolic criteria in patients with biopsy-proven nonalcoholic fatty liver disease and metabolic dysfunction associated fatty liver disease: A multicenter cross-sectional study in China ^Hot!
		Background: This study aimed to assess the association between metabolic syndrome (MetS) and severity of nonalcoholic fatty liver disease (NAFLD), and to discuss the pathological relevance of the diagnostic criteria in metabolic (dysfunction) associated fatty liver disease (MAFLD). Methods: This was a multicenter, cross-sectional study. Patients with NAFLD confirmed by liver biopsy were enrolled between July 2016 and December 2018 from 14 centers across the mainland of China. Anthropometric and metabolic parameters were collected to assess the pathological relevance. Results: Of 246 enrolled patients with NAFLD, 150 (61.0%) had the comorbidity of MetS. With the increase of metabolic components, the proportions of nonalcoholic steatohepatitis (NASH) and significant fibrosis were notably increased. The comorbid three metabolic components significantly increased the proportion of NASH, and further increase of metabolic components did not increase the proportion of NASH. However, the increase of metabolic components was parallel to the increase of the proportion of liver fibrosis. Among the 246 patients, 239 (97.2%) met the diagnostic criteria of MAFLD. Although non-MAFLD patients had less NASH, they present with similar proportion of significant fibrosis and cirrhosis. In the diagnostic criteria of MAFLD, BMI ≥23 kg/m 2 was related to NASH (Mantel-Haenszel Common Estimate OR: 2.975; 95% CI: 1.037–8.538; P = 0.043), and T2DM was related to significant fibrosis (Mantel-Haenszel Com- mon Estimate OR: 2.531; 95% CI: 1.388–4.613; P = 0.002). The homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.5 was the most significant factor for NASH (OR: 4.100; 95% CI: 1.772–9.487; P = 0.001) and significant factor for liver fibrosis (OR: 2.947; 95% CI: 1.398–6.210; P = 0.004) after the adjustments of the BMI and diabetes. Conclusions: Metabolic dysregulations are important risk factors in NAFLD progression. The insulin resistance status may play a predominant role in the progression in MAFLD patients.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 426-432 . [Abstract] ( 106 ) [HTML 1KB] [PDF 0KB] ( 62 )

	433	Fan GH, Wei RL, Wei XY, Zhang CZ, Qi ZT, Xie HY, Zheng SS, Xu X
		Key factors and potential drug combinations of nonalcoholic steatohepatitis: Bioinformatic analysis and experimental validation-based study ^Hot!
		Background: Nonalcoholic fatty liver disease and its advanced stage, nonalcoholic steatohepatitis (NASH), are the major cause of hepatocellular carcinoma (HCC) and other end-stage liver disease. However, the potential mechanism and therapeutic strategies have not been clarified. This study aimed to identify po- tential roles of miRNA/mRNA axis in the pathogenesis and drug combinations in the treatment of NASH. Methods: Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R. Then we obtained differentially expressed genes (DE-genes). DAVID database was used for Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis. Protein-protein interaction (PPI) networks were used for the identification of hub genes. We found upstream regulators of hub genes using miRTarBase. The expression and correlation of key miRNA and its targets were detected by qPCR. Drug Pair Seeker was employed to predict drug combinations against NASH. The expression of miRNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database. Results: Ninety-four DE-genes were accessed. GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism. Eleven genes were identified as hub genes in PPI networks, and they were highly expressed in cells with vigorous lipid metabolism. hsa-miR-335-5p was the upstream regulator of 9 genes in the 11 hub genes, and it was identified as a key miRNA. The hub genes were highly expressed in NASH models, while hsa-miR-335-5p was lowly expressed. The correlation of miRNA-mRNA was established by qPCR. Functional verification indicated that hsa-miR-335-5p had inhibitory effect on the development of NASH. Finally, drug combinations were predicted and the expression of miRNA and hub genes in HCC was identified. Conclusions: In the study, potential miRNA-mRNA pathways related to NASH were identified. Targeting these pathways may be novel strategies against NASH.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 433-451 . [Abstract] ( 98 ) [HTML 1KB] [PDF 0KB] ( 66 )

	452	Wang ZH, Zheng KI, Wang XD, Qiao J, Li YY, Zhang L, Zheng MH, Wu J
		LC-MS-based lipidomic analysis in distinguishing patients with nonalcoholic steatohepatitis from nonalcoholic fatty liver
		Background: Nonalcoholic fatty liver disease (NAFLD) is one of the main liver diseases, and its pathologic profile includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). However, there is no reliable non-invasive parameter in distinguishing NASH from NAFL in clinical practice. The present study was to find a non-invasive way to differentiate these two categories of NAFLD via lipidomic analysis. Methods: Lipidomic analysis was used to determine the changes of lipid moieties in blood from 20 NAFL and 10 NASH patients with liver biopsy. Liver histology was evaluated after hematoxylin and eosin stain- ing and Masson’s trichrome staining. The profile of lipid metabolites in correlation with steatosis, inflam- mation, hepatocellular necroptosis, fibrosis, and NAFLD activity score (NAS) was analyzed. Results: Compared with NAFL patients, NASH patients had higher degree of steatosis, ballooning degeneration, lobular inflammation. A total of 434 different lipid molecules were identified, which were mainly composed of various phospholipids and triacylglycerols. Many lipids, such as phosphatidyl- choline (PC) (P-22:0/18:1), sphingomyelin (SM) (d14:0/18:0), SM (d14:0/24:0), SM (d14:0/22:0), phosphatidylethanolamine (PE) (18:0/22:5), PC (O-22:2/12:0), and PC (26:1/11:0) were elevated in the NASH group compared to those in the NAFL group. Specific analysis revealed an overall lipidomic profile shift from NAFL to NASH, and identified valuable lipid moieties, such as PCs [PC (14:0/18:2), PE (18:0/22:5) and PC (26:1/11:0)] or plasmalogens [PC (O-22:0/0:0), PC (O-18:0/0:0), PC (O-16:0/0:0)], which were signifi- cantly altered in NASH patients. In addition, PC (14:0/18:2), phosphatidic acid (18:2/24:4) were positively correlated with NAS; whereas PC (18:0/0:0) was correlated positively with fibrosis score. Conclusions: The present study revealed overall lipidomic profile shift from NAFL to NASH, identified valuable lipid moieties which may be non-invasive biomarkers in the categorization of NAFLD. The cor- relations between lipid moieties and NAS and fibrosis scores indicate that these lipid biomarkers may be used to predict the severity of the disease.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 452-459 . [Abstract] ( 49 ) [HTML 1KB] [PDF 0KB] ( 63 )

ORIGINAL ARTICLES/Liver

	460	Zhou QH, Hu CQ, Shi Y, Wu FT, Yang Q, Guan J, Li AC, Chen Z
		Cryptococcosis in patients with liver cirrhosis: Death risk factors and predictive value of prognostic models
		Background: Liver cirrhosis is associated with immune deficiency, which causes these patients to be susceptible to various infections, including cryptococcus infection. Mortality in cirrhotic patients with cryptococcosis has increased. The present study was to explore the risk factors of mortality and the predictive ability of different prognostic models. Methods: Forty-seven cirrhotic patients with cryptococcosis at a tertiary care hospital were included in this retrospective study. Data on demographics, clinical parameters, laboratory exams, diagnostic methods, medication during hospitalization, severity scores and prognosis were collected and analyzed. Student’s t test and Mann-Whitney test were used to compare characteristics of survivors and non-survivors at a 90-day follow-up and cerebrospinal fluid (CSF) manifestations of cryptococcal meningitis. Multivariate Cox regression analysis was used to identify the independent risk factors for mortality. Kaplan-Meier curves were used to analyze patient survival. Receiver operating characteristic (ROC) curves were used to evaluate the different prognostic factors. Results: The 30- and 90-day survival rates were 93.6% and 80.9%, respectively, in cirrhotic patients with cryptococcosis. Cryptogenic liver diseases [hazard ratio (HR) = 7.567, 95% confidence interval (CI): 1.616-35.428, P = 0.010], activated partial thromboplastin time (APTT) (HR = 1.117, 95% CI: 1.016-1.229, P = 0.022) and Child-Pugh score (HR = 2.146, 95% CI: 1.314-3.504, P = 0.002) were risk factors for 90-day mortality in cirrhotic patients with cryptococcosis. Platelet count (HR = 0.965, 95% CI: 0.940-0.991, P = 0.008) was a protective factor. APTT (HR = 1.120, 95% CI: 1.044-1.202, P = 0.002) and Child-Pugh score (HR = 1.637, 95% CI: 1.086-2.469, P = 0.019) were risk factors for 90-day mortality in cirrhotic patients with cryptococcal meningitis. There was significant difference in the percentage of lymphocytes in CSF between survivors and non-survivors [60.0 (35.0-75.0) vs. 95.0 (83.8-97.2), P < 0.001]. The model of end-stage liver disease-sodium (MELD-Na) score was more accurate for predicting 30-day mortality both in patients with cryptococcosis [area under curve (AUC): 0.826, 95% CI: 0.618-1.0 0 0] and those with cryptococcal meningitis (AUC: 0.742, 95% CI: 0.560-0.924); Child-Pugh score was more useful for predicting 90-day mortality in patients with cryptococcosis (AUC: 0.823, 95% CI: 0.646-1.0 0 0) and those with cryptococcal meningitis (AUC: 0.815, 95% CI: 0.670-0.960). Conclusions: These results showed that cryptogenic liver diseases, APTT and Child-Pugh score were as- sociated with mortality in cirrhotic patients with cryptococcosis and cryptococcal meningitis. MELD-Na score was important for predicting 30-day mortality, and Child-Pugh score was critical for predicting 90- day mortality.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 460-468 . [Abstract] ( 46 ) [HTML 1KB] [PDF 0KB] ( 73 )

	469	Gu YL, Xiao LL, Li DJ, Liu YN, Zhu CJ, Zhang SJ
		Gene knockout or inhibition of macrophage migration inhibitory factor alleviates lipopolysaccharide-induced liver injury via inhibiting inflammatory response
		Background: Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains. Methods: The model of LPS-induced liver injury was established in wild-type and Mif -knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury. Results: Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif−/− mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1 βwere significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1β and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice. Conclusions: In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 469-477 . [Abstract] ( 77 ) [HTML 1KB] [PDF 0KB] ( 65 )

ORIGINAL ARTICLES/Biliary

	478	Chon HK, Park C, Park DE, Kim TH
		Efficacy and safety of conversion of percutaneous cholecystostomy to endoscopic transpapillary gallbladder stenting in high-risk surgical patients
		Background: Endoscopic transpapillary gallbladder stenting (ETGBS) has been used as an alternative to percutaneous cholecystostomy in patients with acute cholecystitis who are considered unfit for surgery. However, there are few data on the efficacy and safety of ETGBS replacement of percutaneous cholecystostomy in high-risk surgical patients. This study aimed to evaluate the feasibility, efficacy, and safety of ETGBS to replace percutaneous cholecystostomy in high-risk surgical patients. Methods: This single center retrospective study reviewed the data of patients who attempted ETGBS to replace percutaneous cholecystostomy between January 2017 and September 2019. The technical success, clinical success, adverse events, and stent patency were evaluated. Results: ETGBS was performed in 43 patients (24 male, mean age 80.7 ±7.4 years) to replace percutaneous cholecystostomy due to high surgical risk. The technical success rate and clinical success rate were 97.7% (42/43) and 90.5% (38/42), respectively. Procedure-related adverse events and stent-related late adverse events occurred in 7.0% (3/43) and 11.6% (5/43), respectively. Of the patients who successfully underwent ETGBS ( n = 42), only one had recurrent acute cholecystitis during follow-up. The median stent patency was 415 days (interquartile range 240–528 days). Conclusions: ETGBS, as a secondary intervention for the purpose of internalizing gallbladder drainage in patients following placement of a percutaneous cholecystostomy, is safe, effective, and technically feasible. Thus, conversion of percutaneous cholecystostomy to ETGBS may be considered as a viable option in high-risk surgical patients.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 478-484 . [Abstract] ( 63 ) [HTML 1KB] [PDF 0KB] ( 67 )

ORIGINAL ARTICLES/Pancreas

	485	Busquets J, Lopez-Dominguez J, Gonzalez-Castillo A, Vila M, Pelaez N, Secanella L, Ramos E, Fabregat J
		Pancreas sparing duodenectomy in the treatment of primary duodenal neoplasms and other situations with duodenal involvement
		Background: There are no clearly defined indications for pancreas-preserving duodenectomy. The present study aimed to analyze postoperative morbidity and the outcomes of patients undergoing pancreas-preserving duodenectomy. Methods: Patients undergoing pancreas-preserving duodenectomy from April 2008 to May 2020 were included. We divided the series according to indication: scenario 1, primary duodenal tumors; scenario 2, tumors of another origin with duodenal involvement; and scenario 3, emergency duodenectomy. Results: We included 35 patients. Total duodenectomy was performed in 1 patient of adenomatous duodenal polyposis, limited duodenectomy in 7, and third + fourth duodenal portion resection in 27. The indications for scenario 1 were gastrointestinal stromal tumor ( n = 13), adenocarcinoma ( n = 4), neu- roendocrine tumor ( n = 3), duodenal adenoma ( n = 1), and adenomatous duodenal polyposis ( n = 1); scenario 2: retroperitoneal desmoid tumor ( n = 2), recurrence of liposarcoma ( n = 2), retroperitoneal paraganglioma ( n = 1), neuroendocrine tumor in pancreatic uncinate process ( n = 1), and duodenal infiltration due to metastatic adenopathies of a germinal tumor with digestive hemorrhage ( n = 1); and scenario 3: aortoenteric fistula ( n = 3), duodenal trauma ( n = 1), erosive duodenitis ( n = 1), and biliopancreatic limb ischemia ( n = 1). Severe complications (Clavien-Dindo ≥IIIb) developed in 14% (5/35), and postoperative mortality was 3% (1/35). Conclusions: Pancreas-preserving duodenectomy is useful in the management of primary duodenal tu- mors, and is a technical option for some tumors with duodenal infiltration or in emergency interventions.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 485-492 . [Abstract] ( 63 ) [HTML 1KB] [PDF 0KB] ( 70 )

VIEWPOINTS

	493	Eso Y, Seno H
		Synergistic effects of anti-angiogenesis and immune checkpoint blockade - a new era of systemic chemotherapy for hepatocellular carcinoma
		Tumor growth requires oxygen and nutrient supplementation through angiogenesis from preexisting vascular beds. Hepatocellular carcinoma (HCC) is a hyper-vascularized tumor with a predominant arterial blood flow. Therefore, targeting angiogenesis is essential for treating HCC. Currently approved molecular-targeted agents (MTAs) for HCC affect angiogenic pathways. Sorafenib, which was approved as the first MTA in 2008, targets vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-Kit, and Raf kinases [1]. Sorafenib has a high incidence of adverse events (AEs) that impair quality of life, such as hand-foot skin reaction and diarrhea. Therefore, novel tolerable and effective first-line MTAs and second-line MTAs after sorafenib failure were desired. Lenvatinib was approved as a novel first-line treatment in 2018 [2], and regorafenib and ramucirumab were approved as second-line treatments in 2017 and 2019, respectively [3,4].
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 493-495 . [Abstract] ( 53 ) [HTML 1KB] [PDF 0KB] ( 68 )

	496	Wang KC, Wang ZG, Dai YB, Wu HF, Yi DH
		Bioinformatics: A beacon of hope in identifying molecular target
		Hepatobiliary malignancies are highly heterogeneous with poor prognosis and drug response [1]. It is difficult to diagnose at an early stage. Hence, precise molecular targets are urgently needed to improve the diagnose efficacy and individual treatment response. However, reliable biomarkers that can predict the individual treatment response are still lacking. With the broad application of high-throughput sequencing technology and bioinformatics analysis in scientific research, increasing numbers of diagnosing molecular targets will be found and tested. Such bioinformatics will provide a more rational way to diagnose, prevent, and treat hepatobiliary cancers [2].
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 496-498 . [Abstract] ( 49 ) [HTML 1KB] [PDF 0KB] ( 66 )

	499	Chen ZR, Jin SF, Ma WB, Jiang RL
		Intestinal microecology: A crucial strategy for targeted therapy of liver diseases
		Intestinal microecology is an important part of human internal environment and is an extremely complex ecosystem consisting of gut microbiota, intestinal mucosa and intestinal immune system [1]. Gut is highly specialized for the digestion and absorption of different nutrients. The gut microbiota is the largest and most complex, which not only affects the local function of the intestine, but also plays an important role in the maturation and maintenance of the whole immune system.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 499-500 . [Abstract] ( 59 ) [HTML 1KB] [PDF 0KB] ( 75 )

	501	Xu YW, Fu H
		Application of intraoperative ultrasound in liver surgery
		With the development of color Doppler and laparoscopic ultrasound, now intraoperative ultrasound (IOUS) plays an important role in liver surgery. Compared to percutaneous ultrasound (US), IOUS is conducted directly on the liver surface, with no blind spots or dead ends, thus improves the detection, localization and characterization of lesions without influencing factors, such as obesity, ascites and meteorism [1]. Besides, most IOUS uses high frequency ultrasonic probe which provides high resolution so that it can find smaller lesion than computed tomography (CT) and magnetic resonance imaging (MRI) [2,3]. This is very helpful in patients with liver cirrhosis because it is very difficult to distinguish the lesion from normal liver tissue. IOUS detects up to 30% more nodules in cirrhotic livers. But since such nodules are more often regenerative nodules than tumors, IOUS may overestimate the disease. Contrast-enhanced intraoperative ultrasound (CEIOUS) becomes an important supplemental measure in recent years. It may be used for the differentiation of small lesion which is difficult for IOUS by observing the dynamic image of micro perfusion.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 501-502 . [Abstract] ( 47 ) [HTML 1KB] [PDF 0KB] ( 72 )

LETTERS TO THE EDITOR

	503	Bonaccorsi-Riani E, Gillooly A, Bruggenwirth IMA, Martins PN
		Delivery of genetic load during ex situ liver machine perfusion with potential for CRISPR-Cas9 gene editing: An innovative strategy for graft treatment
		Over the years, the shortage of suitable donor organs has challenged the transplant community in performing life-saving liver transplantation (LT). Recent reports from European and American liver transplant registries show persistently high waitlist mortality rates ranging between 10% and 18% [1,2]. To cope with this, liver transplant surgeons are increasingly forced to transplant organs from extended criteria donors. However, it is well known that these organs are more susceptible to the consequences of ischemia-reperfusion injury (IRI), including primary non-function (PNF) and non-anastomotic biliary strictures (NAS) after transplantation, which, by consequence, can increase the number of retransplantations, making organ shortage an endless cycle [3]. This unfavorable scenario has created a fertile environment for the development of organ machine perfusion (MP) strategies aiming to assess and optimize organs before transplantation [4]. A large amount of research has resulted in the development of different perfusion devices and protocols, which have been tested in preclinical and clinical studies, and, more recently, in randomized clinical trials [5]. Currently, hypothermic oxygenated machine perfusion (HOPE) is mainly used to improve mitochondrial status by decreasing oxidative stress and increasing cellular adenosine triphosphate (ATP) levels [6,7], whereas normothermic MP is better suited for evaluation of graft quality during the perfusion session by measuring different biological and physiological parameters.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 503-505 . [Abstract] ( 71 ) [HTML 1KB] [PDF 0KB] ( 64 )

	506	Rizzo A, Ricci AD, Brandi G
		Combination therapy of dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer
		In the last decade, next-generation sequencing (NGS)-based molecular profiling has shed light on the molecular landscape of biliary tract cancer (BTC), revealing the presence of several potentially actionable mutations [1]. According to ClinicalTrials.gov, there are at least 40 phase I to IV ongoing trials aimed at evaluating the role of targeted treatments in BTC, as monotherapy or in combination with other anticancer agents [2]. Early encouraging results have been observed with therapies targeting IDH mutations, FGFR fusions, HER family and, more recently, BRAF mutations [3].
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 506-507 . [Abstract] ( 55 ) [HTML 1KB] [PDF 0KB] ( 69 )

	508	Sun HY, Tong HJ, Cui DW
		Acute hepatitis associated with increased atypical lymphocyte
		Hepatitis A and hepatitis E are acute infectious diseases caused by hepatitis A virus (HAV) and hepatitis E virus (HEV), which are mainly transmitted through the fecal-oral route [1]. The early clinical symptoms of patients with hepatitis A or E are nonspecific, including fever, chills, abdominal pain, diarrhea, and rash [2]. Moreover, the levels of specific laboratory diagnostic biomarkers, such as serum anti-HAV/HEV IgM antibodies, are too low to be detectable which make the early diagnosis difficult [1,3]. These patients are sometimes misdiagnosed in the early stage which result in inappropriate treatments [1]. Atypical lymphocyte is most common in Epstein-Barr virus (EBV) infection [4,5]. However, there are few reports of atypical lymphocyte caused by hepatitis virus. In this study, we report two cases of acute hepatitis with atypical lymphocyte to provide values for the diagnosis of the disease.
		Hepatobiliary Pancreat Dis Int. 2021; 20(5): 508-510 . [Abstract] ( 61 ) [HTML 1KB] [PDF 0KB] ( 66 )

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