Hepatobiliary Pancreat Dis Int

	2017 Vol. 16 No. 1
	Published: 2017-02-15


	pages 1-112
	REVIEW ARTICLES ORIGINAL ARTICLES/Transplantation ORIGINAL ARTICLES/Liver ORIGINAL ARTICLES/Biliary ORIGINAL ARTICLES/Pancreas MEETINGS AND COURSES RELEVANT CONTENT GUIDELINES

GUIDELINES

	10	Ye QF, Senninger N
		The consensus on liver autotransplantation from an international panel of experts

		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 10-16 . [Abstract] ( 208 ) [HTML 41KB] [PDF 679KB] ( 1432 )

REVIEW ARTICLES

	17	Lau WY, Lai ECH, Lau SHY
		Associating liver partition and portal vein ligation for staged hepatectomy: the current role and development ^Hot!
		BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently been developed to induce rapid liver hypertrophy and reduce post-hepatectomy liver failure in patients with insufficient future liver remnant (FLR). ALPPS is still considered to be in an early developmental phase because surgical indications and techniques have not been standardized. This article aimed to review the current role and future developments of ALPPS. DATA SOURCES: Studies were identified by searching MEDLINE and PubMed for articles from January 2007 to October 2016 using the keywords "associating liver partition and portal vein ligation for staged hepatectomy” and “ALPPS”. Additional papers were identified by a manual search of references from key articles. RESULTS: ALPPS induces more hypertrophy of the FLR in less time than portal vein embolization or portal vein ligation. The benefits of ALPPS include rapid hypertrophy 47%-110% of the liver over a median of 6-16.4 days, and 95%-100% completion rate of the second stage of ALPPS. The main criticisms of ALPPS are centered on its high morbidity and mortality rates. Morbidity rates after ALPPS have been reported to be 15.3%-100%, with ≥ the Clavien-Dindo grade III morbidity of 13.6%-44%. Mortality rates have been reported to be 0%-29%. The important questions to ask even if oncologic long-term results are acceptable are: whether the gain in quality and quantity of life can be off balance by the substantial risks of morbidity and mortality, and whether stimulation of rapid liver hypertrophy also accelerates rapid tumor progression and spread. Up till now, the documentations of the ALPPS procedure come mainly from case series, and most of these series include heterogeneous groups of malignancies. The numbers are also too small to separately evaluate survival for different tumor etiologies. CONCLUSIONS: Currently, knowledge on ALPPS is limited, and prospective randomized studies are lacking. From the reported preliminary results, safety of the ALPPS procedure remains questionable. ALPPS should only be used in experienced, high-volume hepatobiliary centers.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 17-26 . [Abstract] ( 240 ) [HTML 59KB] [PDF 381KB] ( 1215 )

	27	Zhang W, Fung J
		Limitations of current liver transplant immunosuppressive regimens: renal considerations
		BACKGROUND: The use of calcineurin inhibitor (CNI)-based immunosuppressive regimens following liver transplantation (LTx) has improved the outcomes of the recipients. However, CNI has nephrotoxicity and causes short- and long-term renal complications. The progressive structural changes can be irreversible in the long-term, leading to chronic kidney dysfunction. The present review was to evaluate the different strategies of CNI application to renal function in liver recipients. DATA SOURCES: PubMed database was searched for relevant articles in English on the issue of immunosuppressive regimen and kidney injury that related to early minimization of CNI after LTx. RESULTS: Total avoidance of CNI from post-LTx immunosuppressive regimens has been associated with unacceptable high rates of acute, steroid resistant rejections; late conversion from CNI to non-nephrotoxic immunosuppressant failed to recover renal function. Early CNI minimization and conversion to non-nephrotoxic immunosuppressant, although had no effect on patient survival rates, improved glomerular filtration rate. The combination of everolimus (a mammalian target of rapamycin inhibitor) and tacrolimus not only maintains immunosuppressive efficacy but also minimizes kidney injury. CONCLUSIONS: Up to now, protocols entirely avoiding CNI have not passed the primary safety endpoint of patient and graft survival, as well as the FDA mandated endpoint of biopsy proven acute rejection. Thus, early CNI minimization after LTx is the most rational approach preserving post-transplant renal function.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 27-32 . [Abstract] ( 222 ) [HTML 38KB] [PDF 256KB] ( 1049 )

ORIGINAL ARTICLES/Transplantation

	33	Kim SH, Lee SD, Kim YK, Park SJ
		Right hepatectomy in living donors with previous abdominal surgery
		BACKGROUND: Few studies have evaluated the impact of previous abdominal surgery (PAS) on living donor right hepatectomy (LDRH). The aim of this study was to investigate the outcomes of liver transplantation using right lobe grafts of living donors with PAS. METHODS: Data were reviewed from LDRH patients at the authors’ institution between March 2008 and November 2014. LDRH patients with PAS were divided into two groups according to upper PAS (group 1) or lower PAS (group 2), and they were compared to those without PAS (group 3) who were matched 1:1 based on age, gender, and body mass index. Perioperative data, complications by the Clavien classification, and the outcomes with more than 14 months follow-up were compared. RESULTS: Twenty-three (4.9%) of a total of 471 LDRH donors had PAS. Eleven donors were assigned to group 1, 12 to group 2, and 23 to group 3. Intraperitoneal adhesions were found in 20 (87.0%) of 23 donors with PAS, of whom 5 (21.7%) had adhesiolysis-related injuries that happened more commonly in group 1 than in group 2 (P=0.025). LDRH was successfully completed under upper midline laparotomy in all donors. No donors received perioperative blood transfusion. The peak postoperative AST, ALT, INR, and total bilirubin levels made no difference between the three groups. Compared with group 3, groups 1 and 2 had a longer operative time (P=0.012) and a higher grade I complication rate (P=0.047). All donors recovered fully to their routine activities. The 23 recipients of grafts from donors with PAS showed good liver function with 1-year graft and patient survivals of 100%. CONCLUSION: A history of PAS is not a contraindication to LDRH in the current era of advanced surgical techniques.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 33-38 . [Abstract] ( 264 ) [HTML 32KB] [PDF 316KB] ( 957 )

	39	Gu LH, Li FH, Xia Q, Fang H, Zhang SJ, Han LZ
		Diagnosis and outcomes of collateral arterial formation after irreversible early hepatic artery thrombosis in pediatric liver recipients
		BACKGROUND: Early hepatic artery thrombosis (eHAT) has been recognized as an important cause of graft loss and mortality. However, the incidence, etiology and outcome are not clear, especially for children. The present study was to investigate the formation of collateral artery flow after irreversible eHAT and its impact on patient’s prognosis. METHODS: We analyzed eHAT after liver transplantation in children from October 2006 to April 2015 in our center, illustrated the formation of collateral hepatic artery flow after irreversible eHAT and explored the diagnosis, complications, treatment and prognosis. The basic and follow-up ultrasonographic images were also compared. RESULTS: Of the 330 pediatric liver recipients, 22 (6.67%) developed eHAT within 1 month. Revascularization attempts including surgical thrombectomy, interventional radiology and conservational treatment (thrombolysis) were successful in 5 patients. Among the 17 who had irreversible eHAT, follow-up ultrasonography revealed that collateral artery flow was developed as early as 2 weeks after eHAT. Liver abscess and bile duct complication occurred secondary to eHAT in variable time. CONCLUSIONS: Collateral arterial formation is a compensatory adaptation to eHAT to supply blood to liver grafts. However, the severe bile duct damage secondary to eHAT is irreversible and retransplantation is unavoidable.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 39-44 . [Abstract] ( 229 ) [HTML 31KB] [PDF 525KB] ( 959 )

	45	Meng XQ, Chen XH, Sahebally Z, Xu YN, Yin SY, Wu LM, Zheng SS
		Cytokines are early diagnostic biomarkers of graft-versus-host disease in liver recipients
		BACKGROUND: Graft-versus-host disease (GVHD) is associated with high mortality. Early diagnosis is essential to start treatment and to improve outcomes. Because of the inflammatory nature, we hypothesis that cytokine profile of patients with GVHD may serve as diagnostic markers. The present study was to evaluate the role of cytokine profile in the diagnosis of GVHD. METHODS: An immunoassay was used to detect 29 cytokines simultaneously in the serum; the measuring sensitivity of all cytokines was pg/mL. Healthy subjects undergoing annual routine physical examinations served as negative controls; 23 patients with hepatocellular carcinoma (HCC) who had undergone liver transplantation (the LT group) comprised the test subjects. A total of 22 kidney recipients with biopsy-confirmed GVHD (the RT group) were included for comparison. HCC patients with radical surgery (the HCC group, n=22) served as positive control. The liver contents of the three cytokines, IL-2, IL-18, and IFN-γ, were detected with immunohistochemistry. Serum granzyme B and perforin were measured by flow cytometry. RESULTS: Of the 29 cytokines, the levels of IL-2 and IL-18 were increased significantly in liver recipients with GVHD compared with healthy controls (P<0.05). The serum levels of these three cytokines in the healthy, HCC, LT, and RT groups were IL-2: 0.90±0.02, 4.14±0.61, 5.10±0.89, and 1.48±0.09 pg/mL; IL-18: 80.61±9.35, 109.51±10.93, 230.11±12.92, and 61.98±7.88 pg/mL; IFN-γ: 24.06±3.88, 24.84±3.21, 40.37±5.88, and 15.33±4.72 pg/mL, respectively. Immunohistochemistry showed that these 3 cytokines expressions in the liver were parallel to the serum cytokine. After standard anti-GVHD treatment, the expressions of IL-2, IL-18, and IFN-γ were decreased in the liver (P<0.05). Serum granzyme B and perforin were significantly increased in GVHD patients (P<0.05). CONCLUSIONS: IL-2, IL-18 and IFN-γ were from liver and might serve as biomarkers for monitoring GVHD development and the effects of anti-GVHD treatment. Granzyme B and perforin may play a role in increasing IL-2, IL-18, and IFN-γ levels in GVHD patients.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 45-51 . [Abstract] ( 231 ) [HTML 37KB] [PDF 906KB] ( 965 )

ORIGINAL ARTICLES/Liver

	52	Chok KSH, Ng KK, Cheung TT, Chan ACY, Chan SC, Lo CM
		Resection of T4 hepatocellular carcinomas with adjacent structures, is it justified? ^Hot!
		BACKGROUND: T4 hepatocellular carcinoma (HCC) with invasion to adjacent structure(s) may require resection of not only the tumor but also the invaded structure(s). This study aims to assess whether such combined resection for T4 HCC is justifiable. METHODS: Adult patients with T4 HCC were divided into three groups. Group 1: tumors and invaded adjacent structures were resected together if histopathologically confirmed tumor invasion; group 2: same as group 1 but histopathologically confirmed tumor adhesion; group 3: tumor resection only. Group comparisons were made. RESULTS: Totally 144 patients were included in the study. There were 71, 14 and 59 patients in groups 1, 2 and 3, respectively. The groups were comparable in demographics, complication and survival. Ten hospital deaths occurred (5, 0 and 5 in groups 1, 2 and 3, respectively; P=0.533). The 5-year overall survival (hospital mortality excluded) was 17.8% in group 1, 14.3% in group 2, and 28.9% in group 3 (P=0.191). The 5-year disease-free survival was 10.4% in group 1 and 14.5% in group 3 (no data for group 2 yet) (P=0.565). On multivariate analysis, macrovascular invasion and poor differentiation were risk factors for survival whereas combined resection did not impact patients’ survival. CONCLUSIONS: Combined resection achieved survival outcomes similar to tumor resection only. Patients with tumor invasion and those with tumor adhesion had comparable survival after combined resection. At centers with the required expertise, combined resection should be attempted to treat T4 HCCs with clinically suspected invasion of adjacent structures.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 52-57 . [Abstract] ( 330 ) [HTML 31KB] [PDF 467KB] ( 813 )

	58	Bai YF, Liu JM, Zhang XM, Jiang CZ, Xu X, Zheng SS
		Percutaneous liver biopsy: retrospective study of primary and secondary hepatic lymphoma in twenty-one patients
		BACKGROUND: Hepatic lymphoma (HL) is categorized as primary and secondary hepatic lymphoma (PHL and SHL). This disorder can present as hepatic mass or mass-like lesion. Chemotherapy often is the first line treatment for patients with HL. Thus, an accurate pre-management histological diagnosis is essential to potentially improve clinical outcomes. The present study was to explore the prevalence of HL in ultrasound guided liver biopsies for hepatic mass or mass-like lesions, to investigate HL associated clinicopathological features, to raise the awareness of early recognition and proper diagnosis of this entity, and to assess specimen adequacy in needle core biopsy. METHODS: Twenty-one cases of HL were enrolled. Clinical and pathological characteristics were evaluated, quality of biopsies was assessed and pertinent literature was reviewed. RESULTS: HL was diagnosed in 0.94% of 2242 liver biopsy cases with ambiguous clinical presentation, laboratory tests and image studies. There were two cases of PHL (0.09%), and nineteen cases of SHL (0.85%). Histopathologically, diffuse large B-cell lymphoma was the most common type, followed by B-cell lymphoma not otherwise specified, T-cell lymphoma, Hodgkin’s lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Additionally, three lymphocytic infiltration patterns were documented microscopically. The nodular infiltration was the most common type. CONCLUSIONS: HL is a rare entity and histopathology along with ancillary tests remains the only way to make the diagnosis. Clinicians’ awareness of this entity and early liver biopsy are essential in patient management.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 58-64 . [Abstract] ( 167 ) [HTML 32KB] [PDF 741KB] ( 952 )

	65	Zhang YJ, Hu Y, Li J, Chi YJ, Jiang WW, Zhang F and Liu YL
		Roles of microRNAs in immunopathogenesis of non-alcoholic fatty liver disease revealed by integrated analysis of microRNA and mRNA expression profiles ^Hot!
		BACKGROUND: The integrative analysis of microRNA and mRNA expression profiles can elucidate microRNA-targeted gene function. We used this technique to elucidate insights into the immunological pathology of non-alcoholic fatty liver disease (NAFLD). METHODS: We analyzed differentially expressed microRNA and mRNA expression profiles of CD4+ T lymphocytes from the liver and mesenteric lymph nodes (MLNs) of mice with NAFLD using microarrays and RNA sequencing. Normal mice were used as controls. The target genes of microRNAs were predicted by TargetScan. Integrative analysis showed that the mRNAs were overlapped with microRNAs. Furthermore, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the key genes and pathways. Then, 16 microRNAs and 10 mRNAs were validated by qRT-PCR. RESULTS: Microarray analysis suggested that 170 microRNAs were significantly de-regulated in CD4+ T lymphocytes from the liver between the two groups. Eighty mRNAs corresponded with microRNA targeted genes. KEGG analysis indicated that the MAPK pathway was consistently augmented in the liver of NAFLD mice. miR-23b, let-7e, miR-128 and miR-130b possibly played significant parts in the MAPK pathways. Furthermore, between the two groups, 237 microRNAs were significantly de-regulated in CD4+ T lymphocytes from MLNs. 38 mRNAs coincided with microRNA target genes. The metabolic pathway was consistently enriched in the MLNs of NAFLD mice. miR-206-3p, miR-181a-5p, miR-29c-3p and miR-30d-5p likely play important roles in the regulation of metabolic pathways. CONCLUSION: The results of this study presented a new perspective on the application of integrative analysis to identify complex regulation means involved in the immunological pathogenesis of NAFLD.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 65-79 . [Abstract] ( 338 ) [HTML 56KB] [PDF 8330KB] ( 1084 )

	80	Ezhilarasan D, Evraerts J, Sid B, Calderon PB, Karthikeyan S, Sokal E, Najimi M
		Silibinin induces hepatic stellate cell cycle arrest via enhancing p53/p27 and inhibiting Akt downstream signaling protein expression
		BACKGROUND: Proliferation of hepatic stellate cells (HSCs) plays a pivotal role in the progression of liver fibrosis consequent to chronic liver injury. Silibinin, a flavonoid compound, has been shown to possess anti-fibrogenic effects in animal models of liver fibrosis. This was attributed to an inhibition of cell proliferation of activated HSCs. The present study was to gain insight into the molecular pathways involved in silibinin anti-fibrogenic effect. METHODS: The study was conducted on LX-2 human stellate cells treated with three concentrations of silibinin (10, 50 and 100 μmol/L) for 24 and 96 hours. At the end of the treatment cell viability and proliferation were evaluated. Protein expression of p27, p21, p53, Akt and phosphorylated-Akt was evaluated by Western blotting analysis and Ki-67 protein expression was by immunocytochemistry. Sirtuin activity was evaluated by chemiluminescence based assay. RESULTS: Silibinin inhibits LX-2 cell proliferation in dose- and time-dependent manner; we showed that silibinin upregulated the protein expressions of p27 and p53. Such regulation was correlated to an inhibition of both downstream Akt and phosphorylated-Akt protein signaling and Ki-67 protein expression. Sirtuin activity also was correlated to silibinin-inhibited proliferation of LX-2 cells. CONCLUSION: The anti-proliferative effect of silibinin on LX-2 human stellate cells is via the inhibition of the expressions of various cell cycle targets including p27, Akt and sirtuin signaling.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 80-87 . [Abstract] ( 206 ) [HTML 47KB] [PDF 695KB] ( 816 )

	88	Kabirifar R, Ghoreshi Z, Safari F, Karimollah A, Moradi A, Eskandari-nasab E
		Quercetin protects liver injury induced by bile duct ligation via attenuation of Rac1 and NADPH oxidase1 expression in rats
		BACKGROUND: Bile duct ligation (BDL) and subsequent cholestasis are correlated with oxidative stress, hepatocellular injury and fibrosis. Quercetin is a flavonoid with antifibrotic, and hepatoprotective properties. However, the molecular mechanism underlying quercetin-mediated hepatoprotection is not fully understood. The current study was to evaluate mechanisms of hepatoprotective effect of quercetin in BDL rat model. METHODS: We divided male Wistar rats into 4 groups (n=8 for each): sham, sham+quercetin (30 mg/kg per day), BDL, BDL+quercetin (30 mg/kg per day). Four weeks later, the rats were killed, the blood was collected for liver enzyme measurements and liver for the measurement of Rac1, Rac1-GTP and NOX1 mRNA and protein levels by quantitative PCR and Western blotting, respectively. RESULTS: Quercetin significantly alleviated liver injury in BDL rats as evidenced by histology and reduced liver enzymes. Furthermore, the mRNA and protein expression of Rac1, Rac1-GTP and NOX1 were significantly increased in BDL rats compared with those in sham (P<0.05); quercetin treatment reversed these variables back toward normal (P<0.05). Another interesting finding was that the antioxidant markers e.g. superoxide dismutase and catalase were elevated in quercetin-treated BDL rats compared to BDL rats (P<0.05). CONCLUSIONS: Quercetin demonstrated hepatoprotective activity against BDL-induced liver injury through increasing antioxidant capacity of the liver tissue, while preventing the production of Rac1, Rac1-GTP and NOX1 proteins.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 88-95 . [Abstract] ( 222 ) [HTML 51KB] [PDF 665KB] ( 1326 )

ORIGINAL ARTICLES/Biliary

	96	Sioulas AD, El-Masry MA, Groth S, Schachschal G, Anders M, Rosch T, Denzer U
		Prospective evaluation of the short access cholangioscopy for stone clearance and evaluation of indeterminate strictures
		BACKGROUND: Peroral cholangioscopy facilitates diagnosis and therapy of biliary disorders. This study prospectively evaluated a new short access cholangioscopy. METHODS: Consecutive patients were included as follows: difficult stones (group 1) underwent cholangioscopy with electrohydraulic lithotripsy and indeterminate biliary strictures (group 2) were evaluated with macroscopic assessment and cholangioscopy guided biopsy sampling. We evaluated the complete stone clearance rate (group 1) and diagnostic accuracy (group 2). Follow-up was performed over a median of 13 and 16 months, respectively. RESULTS: Group 1 (n=21): complete stone clearance defined as lack of stones in cholangiography and stone removal during cholangioscopy was achieved in 15 (71.4%) patients. Clinical stone clearance defined as lack of symptoms, laboratory abnormalities and hospital visits during follow-up, irrespective of stone clearance was evident in 17 (81.0%) patients. One serious adverse event occurred (bile duct perforation). Group 2 (n=28): malignancy was confirmed in 15 patients. Sensitivity, specificity and diagnostic accuracy of cholangioscopy were 85.7%, 75.0% and 80.7%, respectively. Sensitivity, specificity and diagnostic accuracy of biopsies were 54.5%, 100.0% and 72.2%, respectively. No serious adverse events occurred, one patient was lost to follow-up. CONCLUSIONS: The novel system enabled complex stone treatment and biliary stricture diagnosis. Cholangioscopy outperformed direct biopsy regarding characterization of indeterminate strictures.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 96-103 . [Abstract] ( 277 ) [HTML 46KB] [PDF 442KB] ( 711 )

ORIGINAL ARTICLES/Pancreas

	104	Yu XZ, Guo ZY, Di Y, Yang F, Ouyang Q, Fu DL, Jin C
		The relationship between SPARC expression in primary tumor and metastatic lymph node of resected pancreatic cancer patients and patients’ survival
		BACKGROUND: Previous researches in pancreatic cancer demonstrated a negative correlation between secreted protein acidic and rich in cysteine (SPARC) expression in primary tumor and survival, but not for SPARC expression in lymph node. In the present study, we aimed to evaluate the SPARC expression in various types of tissues and its impact on patients’ prognosis. METHODS: The expression of SPARC was examined by immunohistochemistry in resected pancreatic cancer specimens. Kaplan-Meier analyses and Cox proportional hazards regression were applied to assess the mortality risk. RESULTS: A total of 222 tissue samples from 73 patients were collected to evaluate the SPARC expression, which included 73 paired primary tumor and adjacent normal tissues, 38 paired metastatic and normal lymph nodes. The proportion of positive SPARC expression in metastatic lymph node was high (32/38), whereas in normal lymph node it was negative (0/38). Positive SPARC expression in primary tumor cells was associated with a significantly decreased overall survival (P=0.007) and disease-free survival (P=0.003), whereas in other types of tissues it did not show a predictive role for prognosis. Univariate and multivariate analyses both confirmed this significance. CONCLUSION: SPARC can serve a dual function role as both predictor for prognosis and potentially biomarker for lymph node metastasis in resected pancreatic cancer patients.
		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 104-109 . [Abstract] ( 206 ) [HTML 33KB] [PDF 616KB] ( 962 )

MEETINGS AND COURSES

	110
		Meetings and courses

		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 110-111 . [Abstract] ( 187 ) [HTML 1KB] [PDF 167KB] ( 552 )

RELEVANT CONTENT

	112
		Relevant content--Liver Cancer (Vol. 5, No. 4, 2016)

		Hepatobiliary Pancreat Dis Int. 2017; 16(1): 112-112 . [Abstract] ( 142 ) [HTML 1KB] [PDF 290KB] ( 388 )

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