Hepatobiliary Pancreat Dis Int

	2019 Vol. 18 No. 4
	Published: 2019-08-15


	Pages 303-402
	EDITORIAL META-ANALYSIS REVIEW ARTICLES ORIGINAL ARTICLES/Transplantation ORIGINAL ARTICLES/Liver ORIGINAL ARTICLES/Biliary ORIGINAL ARTICLES/Pancreas LETTERS TO THE EDITOR GUIDELINES VIEWPOINTS

EDITORIAL

	303	Li Z, Zhu JY
		Hepatocellular carcinoma: Current situation and challenge ^Hot!
		Hepatocellular carcinoma (HCC) ranks the fourth cause of cancer-related death worldwide [1] . More than 50% newly diagnosed HCC patients are in China, while 70% of them are at advanced stage when they are diagnosed [2] . These patients have lost the opportunity of radical surgery and can only receive palliative care. Currently, the modality for these advanced stage HCC patients mainly include: targeted therapy, interventional therapy, chemotherapy, radiotherapy, and immunotherapy.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 303-304 . [Abstract] ( 108 ) [HTML 1KB] [PDF 0KB] ( 165 )

	305	Heinrich S
		Pathological tumor response to neoadjuvant therapy in borderline resectable pancreatic cancer
		Surgery is the standard therapy for pancreatic ductal adenocarcinoma (PDAC). After the dramatic decline of operative mortality over the past decades, the indications for pancreas resections have been continuously extended: currently resections of the portal/superior mesenteric vein are considered standard by many centers, and even arterial resections are under debate. Following these changes, different expert groups have defined resectability criteria containing a grey zone (“borderline resectable disease”) of tumors, which may be technically resectable with appropriate surgical expertise, but resection inherits an increased risk of an R1-resection [1].
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 305-306 . [Abstract] ( 94 ) [HTML 1KB] [PDF 0KB] ( 171 )

GUIDELINES

	307	Xu X, Chen J,Wei Q, Liu ZK, Yang Z, Zhang M,Wang GY, Gao J, Yang ZX, Guo WY, Xing TH, Shao Z, Xie QF, Zheng SS
		Clinical practice guidelines on liver transplantation for hepatocellular carcinoma in China (2018 edition) ^Hot!
		Over 3 00 000 people in China die each year of hepatocellular carcinoma (HCC), which accounts for approximately half of HCC- related deaths worldwide. Liver transplantation (LT) is generally recognized as one of the most effective therapeutic approaches for end-stage liver diseases. Since the beginning of the second LT boom in the 1990s, LT in China has been developed rapidly with professional and large-scale trends, and it is approaching or has reached the level of developed countries in terms of quantity and quality. According to the China Liver Transplant Registry, the num- ber of transplants for HCC accounted for 36.8% of the total number of LT cases during the past 5 years in the mainland of China. In or- der to develop an effective, safe and standardized protocol to guide the national LT practice, the clinical guidelines of LT for HCC was launched in 2014 by multidisciplinary experts from Chinese Society of Organ Transplantation, Chinese Medical Association and Chinese Association of Organ Transplantation, Chinese Medical Doctor As- sociation. Recently, there have been new clinical and scientific ad- vances in the field of LT and to keep abreast of these achievements, the original clinical practice guidelines need to be updated.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 307-312 . [Abstract] ( 102 ) [HTML 1KB] [PDF 0KB] ( 179 )

META-ANALYSIS

	313	Wang SJ, Si XY, Cai ZB, Zhou YM
		Survival after repeat hepatectomy for recurrent colorectal liver metastasis: A review and meta-analysis of prognostic factors
		Background: Frequent recurrent hepatic metastasis after hepatic metastasectomy is a major obstacle in the treatment of colorectal liver metastasis (CRLM). We performed the present systematic review to eval- uate the short- and long-term outcomes after repeat hepatectomy for recurrent CRLM and determine factors associated with survival in these patients. Data sources: An electronic search of PubMed database was undertaken to identify all relevant peer- reviewed papers published in English between January 20 0 0 and July 2018. Hazard ratios (HR) with 95% confidence interval (95% CI) were calculated for prognostic factors of overall survival (OS). Results: The search yielded 34 studies comprising 3039 patients, with a median overall morbidity of 23% (range 8%–71%), mortality of 0 (range 0–6%), and 5-year OS of 42% (range 17%–73%). Pooled analysis showed that primary T3/T4 stage tumor (HR = 1.94; 95% CI: 1.04–3.63), multiple tumors (HR = 1.49; 95% CI: 1.10–2.01), largest liver lesion ≥5 cm (HR = 1.89; 95% CI: 1.11–3.23) and positive surgical margin (HR = 1.80; 95% CI: 1.09–2.97) at initial hepatectomy, and high serum level of carcinoembryonic antigen (HR = 1.87; 95% CI: 1.27–2.74), disease-free interval ≤12 months (HR = 1.34; 95% CI: 1.10–1.62), multiple tumors (HR = 1.64; 95% CI: 1.32–2.02), largest liver lesion ≥5 cm (HR = 1.85; 95% CI: 1.34–2.56), positive surgical margin (HR = 2.25; 95% CI: 1.39–3.65), presence of bilobar disease (HR = 1.62; 95% CI: 1.19–2.20), and extrahepatic metastases (HR = 1.60; 95% CI: 1.23–2.09) at repeat hepatectomy were significantly associated with poor OS. Conclusions: Repeat hepatectomy is a safe and effective therapy for recurrent CRLM. Long-term outcome is predicted mainly by factors related to repeat hepatectomy.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 313-320 . [Abstract] ( 93 ) [HTML 1KB] [PDF 0KB] ( 194 )

	321	Chen JA, Yu Y, Xue C, Chen XL, Cui GY, Li J, Li KF, Ren ZG, Sun RR
		Low microRNA-139 expression associates with poor prognosis in patients with tumors: A meta-analysis
		Background: microRNA-139 (miR-139) is dysregulated in various types of tumors and plays a key role in carcinogenesis. miR-139 may be used as a diagnostic and prognostic biomarker of cancers. However, the data from the literature are not consistent. The present study aimed to verify the prognostic and diagnostic values of miR-139 in solid tumors. Data sources: PubMed, Web of Science and Embase databases were searched and publications from Jan- uary 2011 to August 2017 were included. We used Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database to further validate this meta-analysis. Results: Eight individual studies from seven articles were included. Pooled analyses showed that low miR- 139 expression was related to worse overall survival (OS) [hazard ratio (HR) = 2.27; 95% confidence intervals (CI): 1.74–2.95; P < 0.001] in solid tumors, including hepatocellular carcinoma (HCC) and glioblastoma multiforme (GBM), consisting with the results of TCGA. However, our results of CRC showed that low miR-139 expression was associated with poor OS which was contradictory with the results in TCGA database and need larger samples to validate the phenomenon; whereas for CRC patients, high miR-139 expression predicted poor RFS, which was in good accordance with TCGA results. The results of 27 mi- croarrays from GEO database showed that miR-139 expression levels were lower in tumor tissues com- pared to adjacent non-tumor tissues or healthy tissues. Decreased miR-139 expression was also significantly correlated with poor differentiation grade (OR = 3.57; 95% CI: 1.44–8.85; P = 0.006). However, the combined data indicated that no associations between miR-139 expression and the following parameters such as age (pooled OR = 1.50; 95% CI: 0.69–3.24; P = 0.304), gender (pooled OR = 0.92; 95% CI: 0.56–1.51; P = 0.738), tumor size (pooled OR = 1.51; 95% CI: 0.69–3.31; P = 0.298), late tumor-node-metastasis stage (pooled OR = 1.63; 95% CI: 0.99–2.68; P = 0.057) and lymph-node-metastasis (pooled OR = 0.66; 95% CI: 0.34–1.28; P = 0.222). Conclusions: Low miR-139 expression was related to poor prognosis in HCC and GBM, which could be regarded as a potential prognostic biomarker. However, its precise functional role in CRC still need to be further investigated through larger samples and multicenter studies.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 321-331 . [Abstract] ( 101 ) [HTML 1KB] [PDF 0KB] ( 179 )

REVIEW ARTICLES

	332	Ferri V, Vicente E, Quijano Y, Ielpo B, Duran H, Diaz E, Fabra I, Caruso R
		Diagnosis and treatment of pancreas divisum: A literature review ^Hot!
		Background: Pancreas divisum is a congenital embryological disease caused by a lack of fusion between the ventral and dorsal pancreatic ducts in the early stages of embryogenesis. Recurrent acute pancreatitis, chronic pancreatitis or chronic abdominal pain are the main clinical syndromes at presentation and occur in only 5% of the patients with pancreas divisum. This review aimed to discuss diagnosis and treatment strategies in patients with symptomatic pancreas divisum. Data sources: We report a literature review from 1990 up to January 2018 to explore the various di- agnostic modalities and surgical techniques and results reported in the surgical treatment of pancreas divisum. Results: There are limited reports available on this topic in the literature. We analyzed and described the main indications in the treatment of pancreas divisum, focusing on surgical treatment and a discussion of the different approaches. Furthermore, we report the results from our experience in two cases of pancreas divisum treated by pancreatic head resection with segmental duodenectomy (the Nakao procedure). Conclusions: Pancreas divisum is a common pancreatic malformation in which only a few patients de- velop a symptomatic disease. Surgical treatment is needed in case of endoscopic drainage failure and in cases complicated with chronic pancreatitis and local complications. Many techniques, of greater or lesser complexity, have been proposed.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 332-336 . [Abstract] ( 111 ) [HTML 1KB] [PDF 0KB] ( 148 )

ORIGINAL ARTICLES/Transplantation

	337	Kurata N, Ogura Y, Ogiso S, Onishi Y, Kamei H, Kodera Y
		Splenectomy in living donor liver transplantation and risk factors of portal vein thrombosis ^Hot!
		Background: Graft inflow modulation (GIM) during adult-to-adult living donor liver transplantation (LDLT) is a common strategy to avoid small-for-size syndrome, and some transplant surgeons attempt small size graft strategy with frequent GIM procedures, which are mostly performed by splenectomy, in LDLT. However, splenectomy can cause serious complications such as portal vein thrombosis and over-whelming postsplenectomy infection. Methods: Forty-eight adult-to-adult LDLT recipients were enrolled in this study and retrospectively reviewed. We applied the graft selection criteria, which routinely fulfill graft-to-recipient weight ratio ≥0.8%, and consider GIM as a backup strategy for high portal venous pressure (PVP). Results: In our current strategy of LDLT, splenectomy was performed mostly due to hepatitis C and splenic arterial aneurysms, but splenectomy for GIM was intended to only one patient (2.1%). The final PVP values ≤20 mmHg were achieved inall recipients, and no significant difference was observed in patient survival or postoperative clinical course based on whether splenectomy was performed or not. However, 6 of 18 patients with splenectomy (33.3%) developed postsplenectomy portal vein thrombosis (PVT), while none of the 30 patients without splenectomy developed PVT after LDLT. Splenectomy was identified as a risk factor of PVT in this study ( P < 0.001). Our study revealed that a lower final PVP could be risk factor of postsplenectomy PVT. Conclusions: Using sufficient size grafts was one of the direct solutions to control PVP, and allowed GIM to be reserved as a backup procedure. Splenectomy should be avoided as much as possible during LDLT because splenectomy was found to be a definite risk factor of PVT. In splenectomy cases with a lower final PVP, a close follow-up is required for early detection and treatment of PVT.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 337-342 . [Abstract] ( 97 ) [HTML 1KB] [PDF 0KB] ( 163 )

	343	Chok KSH, Fung JYY, DaiWC, Sin SL, Ma KW, Chan ACY, Cheung TT, Lo CM
		Donor ductal anomaly is not a contraindication to right liver lobe donation ?
		Background: Data of living-donor liver transplantation (LDLT) suggested that donor ductal anomaly may contribute to postoperative biliary complications in recipients and in donors. This retrospective study aimed to determine if the occurrence of postoperative biliary stricture in donors or recipients in right-lobe LDLT (RLDLT) is related to donor biliary anatomy type. Methods: We analyzed our RLDLT recipients’ clinical data and those of their graft donors. The recipients were divided into 2 groups: with and without postoperative biliary stricture. The 2 groups were compared. The primary endpoints were donor biliary anatomy type and postoperative biliary complication incidence; the secondary endpoints were 1-, 3- and 5-year graft and patient survival rates. Results: Totally 127 patients were included in the study; 25 (19.7%) of them developed biliary anastomotic stricture. In these 25 patients, 16 had type A biliary anatomy, 3 had type B, 2 had type C, 3 had type D, and 1 had type E. In the 127 donors, 96 (75.6%) had type A biliary anatomy, 13 (10.2%) had type B, 6 (4.7%) had type C, 10 (7.9%) had type D, and 2 (1.6%) had type E. Biliary stricture was seen in 2 donors, who had type A biliary anatomy. None of the recipients or donors developed bile leakage. No association between the occurrence of postoperative biliary stricture and donor biliary anatomy type was found ( P = 0.527). Conclusions: The incidence of biliary stricture in donors or recipients after RLDLT was not related to donor biliary anatomy type. As postoperative complications were similar in whatever type of donor bile duct anatomy, donor ductal anomaly should not be considered a contraindication to donation of right liver lobe.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 343-347 . [Abstract] ( 91 ) [HTML 1KB] [PDF 0KB] ( 170 )

	348	Ozono Y, Shide K, Toyoshima F, Takaishi Y, Tsuchimochi M, Kamiunten A, Kameda T, Nakamura K, Miike T, Kusumoto K, Iwakiri H, Hasuike S, Nagata K, Sawaguchi A, Shimoda K
		Monocyte-derived fibrocytes elimination had little contribution on liver fibrosis
		Background: Monocyte-derived fibrocytes play an important role in the progression of fibrosis in the skin, lungs, heart and kidney. However, the contribution of fibrocytes to liver fibrosis is unclear. The aim of this study was to investigate whether fibrocytes contributed to fibrosis progression in the livers of carbon tetrachloride (CCl4)-treated mice. Methods: C57BL/6J mice were divided into 4 groups: normal control group, CCl4-treated group, CCl4+ control liposome-treated group, and CCl4+ clodronate liposome-treated group. For the elimination of systemic monocyte and monocyte-derived fibrocyte, one group was treated with clodronate liposome, and another group with control liposome as a control. After 4 weeks of treatment, hepatic mononuclear cells were subjected to immunofluorescent (IF) staining and fluorescence-activated cell sorter (FACS) analysis to detect fibrocytes. Measurement of collagen-positive Sirius red stained area and collagen-I mRNA expression in the liver were performed to evaluate the degree of liver fibrosis quantitatively. Results: In the liver of the CCl4-treated and CCl4+ control liposome-treated groups, the number of fibrocytes, the area positive for Sirius red staining and collagen-I mRNA expression significantly increased compared with those in the normal control group. In the liver of the CCl4+ clodronate liposome-treated group, few fibrocytes was observed as in the normal control group, but Sirius red staining positive area and collagen-I mRNA expression were increased and equivalent to the CCl4-treated and CCl4+ control liposome-treated groups. Conclusion: Monocyte-derived fibrocytes play a minimal role in CCl4-induced liver fibrosis. Cells other than fibrocytes such as hepatic stellate cells play a central role in liver fibrosis.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 348-353 . [Abstract] ( 117 ) [HTML 1KB] [PDF 0KB] ( 171 )

ORIGINAL ARTICLES/Liver

	354	Sun XL, Jiang X, Kuang Y, Xing L, Bu LY, Yuan SH, Yu JM, Zheng SS
		Potential of Gd-EOB-DTPA as an imaging biomarker for liver injury estimation after radiation therapy
		Background: Hepatic radiation injury severely restricts irradiation treatment for liver carcinoma. The pur- pose of this study was to investigate the clinical application of gadolinium ethoxybenzyl diethylenetri- amine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI (EOB-MRI) in the assessment of liver function after external radiation therapy and to determine the relationship between focal liver reaction (FLR) and liver function. Methods: A total of 47 patients with liver malignancies who underwent external beam radiation therapy were enrolled. EOB-MRI was performed on each patient at approximately one month post-radiotherapy. The hepatobiliary (HPB) phase images from EOB-MRI were fused with the planning CT images, and the isodose lines from the patients’ treatment plans were overlaid onto the fused images. The correlation of the EOB-MR image intensity distribution with the isodose lines was studied. We also compared liver function in patients between pre-treatment and post-treatment. Results: Decreased uptake of Gd-EOB-DTPA, which was manifested by well-demarcated focal hypointensity of the liver parenchyma or FLR to high-dose radiation, was observed in the irradiated areas of 38 patients. The radiotherapy isodose line of decreased uptake area of Gd-EOB-DTPA was 30–46 Gy. The median corresponding dose curve of FLR was 34.4 Gy. Nine patients showed the absence of decreased uptake area of Gd-EOB-DTPA in the irradiated areas. Compared to the 38 patients with the presence of decreased uptake area of Gd-EOB-DTPA, 9 patients with the absence of decreased uptake area of Gd-EOB-DTPA showed significant higher levels of total bile acid, total bilirubin, direct bilirubin and alpha-fetoprotein (P < 0.05). There were no significant differences in alanine transaminase, aspartate aminotransferase, gamma-glutamyl transpeptidase or albumin levels between the two groups (P > 0.05). Conclusions: Visible uptake of Gd-EOB-DTPA by the liver parenchyma was significantly associated with liver function parameters. EOB-MRI can be a valuable imaging biomarker for the assessment of liver parenchyma function outside of radiation area.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 354-359 . [Abstract] ( 106 ) [HTML 1KB] [PDF 0KB] ( 151 )

	360	Wang JJ, Zhang YT, Tseng YJ, Zhang J
		miR-222 targets ACOX1, promotes triglyceride accumulation in hepatocytes
		Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. However, the exact pathogenesis of NAFLD remains to be elucidated. Despite the association with tumors and cardiovascular diseases, the role of miR-222 in NAFLD remains unclear. The present study was to investigate the role of miR-222 in NAFLD. Methods: Wild-type C57BL/6 mice were fed a high-fat diet for 12 weeks to induce NAFLD. Normal human liver cell line (L02) was cultured with free fatty acid (FFA)-containing medium to stimulate cell steatosis. The mRNA levels of miR-222 and acyl Coenzyme A xidase 1 (ACOX1) were detected by quantitative- PCR (Q-PCR). The prediction of ACOX1 as the target gene for miR-222 was conducted via TargetScan. The overexpression or inhibition of miR-222 was mediated by miR-222 mimics or antagomir, and intracellular triglyceride levels were measured using a triglyceride kit. Luciferase reporter assays verified ACOX1 as the target gene for miR-222. Results: miR-222 was significantly elevated in both the in vivo and in vitro NAFLD models. Overexpres- sion of miR-222 significantly increased triglyceride content in the L02 cells, while inhibition of miR-222 expression restricted the accumulation of triglyceride. Overexpression of miR-222 significantly inhibited ACOX1 expression. Transient transfection assays verified that ACOX1 3'-UTR luciferase reporter activity could be inhibited by miR-222 overexpression. Conclusions: The present study suggested that miR-222 promotes the accumulation of triglycerides by inhibiting ACOX1.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 360-365 . [Abstract] ( 90 ) [HTML 1KB] [PDF 0KB] ( 171 )

ORIGINAL ARTICLES/Biliary

	366	Lee HW, Song TJ, Park DH, Lee SS, Seo DW, Lee SK, Kim MH, Jun JH, Moon JE, Song YH
		Diagnostic performance of the current risk-stratified approach with computed tomography for suspected choledocholithiasis and its options when negative finding
		Background: Several studies evaluated the current guideline of the American Society for Gastrointestinal Endoscopy (ASGE) and reported only suboptimal accuracy. This study evaluated the diagnostic performance of the ASGE guideline based on computed tomography (CT) and role of endoscopic ultrasonography (EUS) and magnetic resonance cholangiopancreatography (MRCP) in patients with suspected choledocholithiasis but negative CT finding. Methods: Patients with suspected choledocholithiasis undergoing ERCP between January 2016 and January 2017 were retrospectively analyzed. All patients underwent CT to detect choledocholithiasis. EUS or MRCP was performed when the CT scan showed negative findings. Patients were classified into the high and intermediate-risk groups, based on predictors from the ASGE criteria. Results: Of 583 patients with suspected choledocholithiasis, 340 (58.3%) had stones on ERCP (65.9% in the high-risk group and 40.6% in the intermediate-risk group). The accuracy of ASGE guideline for CT was 63.98% (79.12% sensitivity, 42.80% specificity) and 36.02% (20.88% sensitivity, 57.20% specificity) in the high-risk and intermediate-risk groups, respectively. In 103 patients in the high-risk group underwent both CT and US, the accuracy of CT was higher than that of US for detecting choledocholithiasis (78.64% vs. 53.40%), with a significant difference in area under the curve (AUC) (0.78 vs. 0.59, P < 0.001). Of 339 with negative CT finding, the accuracy of EUS was higher than that of MRCP (90.91% vs. 82.76%), but with no significant difference in AUC (0.91 vs. 0.83, P = 0.347). Conclusions: CT-based ASGE guideline showed superior diagnostic performance than US for predicting choledocholithiasis. The diagnostic options, EUS or MRCP, with negative CT finding showed comparable performance. Therefore, the diagnostic modality should be selected based on availability, experience, cost, and contraindications.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 366-372 . [Abstract] ( 103 ) [HTML 1KB] [PDF 0KB] ( 171 )

ORIGINAL ARTICLES/Pancreas

	373	Peng JS, Wey J, Chalikonda S, Allende DS, Walsh RM, Morris-Stiff G
		Pathologic tumor response to neoadjuvant therapy in borderline resectable pancreatic cancer ^Hot!
		Background: Previous studies have demonstrated the prognostic significance of pathologic tumor response in pancreatic adenocarcinoma following neoadjuvant therapy (NAT). The aim of this study was to determine the incidence of significant pathologic response to NAT in borderline resectable pancreatic cancer (BRPC), and association of NAT regimen and other clinico-pathologic characteristics with pathologic response. Methods: Patients with BRPC who underwent NAT and pancreatic resection between January 2012 and June 2017 were included. Pathologic response was assessed on a qualitative scale based on the College of American Pathologists grading system. Demographics and baseline characteristics, oncologic treatment, pathology, and survival outcomes were compared. Results: Seventy-one patients were included for analysis. Four patients had complete pathologic responses (tumor regression score 0), 12 patients had marked responses (score 1), 42 had moderate responses (score 2), and 13 had minimal responses (score 3). Patients with complete or marked responses were more likely to have received neoadjuvant gemcitabine chemoradiation (62.5%, 38.1%, and 23.1% of the complete/marked, moderate, and minimal response groups, respectively; P = 0.04). Of the complete/marked, moderate, and minimal response groups, margins were negative in 75.0%, 78.6%, and 46.2% ( P = 0.16); node negative disease was observed in 87.5%, 54.8%, and 15.4% ( P < 0.01); and median overall survival was 50.0 months, 31.7 months, and 23.2 months ( P = 0.563). Of the four patients with pathologic complete responses, three were disease-free at 66.1, 41.7 and 31.4 months, and one was deceased with metastatic liver disease at 16.9 months. Conclusions: A more pronounced pathologic tumor response to NAT in BRPC is correlated with node negative disease, but was not associated with a statistically significant survival benefit in this study.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 373-378 . [Abstract] ( 102 ) [HTML 1KB] [PDF 0KB] ( 170 )

	379	Homeyer RS, Roberts KJ, Sutcliffe RP, Kaltenborn A, Mirza D, Qu Z, Klempnauer J, Schrem H
		Ventilation after pancreaticoduodenectomy increases perioperative mortality: Identification of risk factors and their relevance in Germany that do not apply in England
		Background: Pre-operative risk factors for post-operative ventilation and their influence on survival after pancreaticoduodenectomy for malignancy are unknown. Methods: Totally 391 patients operated in Hannover, Germany were investigated with multivariable lo- gistic regression and Cox regression modeling to identify independent risk factors for post-operative ventilation ≥6 h, patient survival and 90-day mortality. And 84 patients operated in Birmingham, United Kingdom were analyzed to assess the external relevance of findings. Results: Longer operations, history of thrombosis, intra-operative blood transfusion, lower estimated glomerular filtration rates (eGFR) and higher values of the age at operation divided by the Horovitz Quotient independently increased the risk of post-operative ventilation ≥6 h in German patients ( n = 108; 27.6%) ( P < 0.050). Blood transfusion and lower pre-operative eGFR levels increased the risk of early death in German patients significantly and independently of established prognostic factors. A history of throm- bosis and lower eGFR levels were also independent significant risk factors for 90-day mortality in German patients but not in English patients. None of the English patients received post-operative ventilation. Significantly more German patients were > 75 years, had a history of thrombosis, received blood transfusions, and had significantly worse lung function parameters. pT4 tumors were detected in 18 German patients (4.6%), but not in the English patients. Conclusions: Identified risk factors for post-operative ventilation are clinically relevant in Germany but not in England and may be used to lower mortality risk. The German and the English cohorts displayed significant differences in the approach to patient selection and early post-operative extubation.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 379-388 . [Abstract] ( 108 ) [HTML 1KB] [PDF 0KB] ( 178 )

	389	Serenari M, Ercolani G, Cucchetti A, Zanello M, Prosperi E, Fallani G, Masetti M, Lombardi R, Cescon M, Jovine E
		The impact of extent of pancreatic and venous resection on survival for patients with pancreatic cancer
		Background: Borderline resectable pancreatic cancer may require extended resections in order to achieve tumor-free margins, especially in the case of up-front resections, but it is important to know the limits of surgical therapy in this disease. This study aimed to investigate the impact of extent of pancreatic and venous resection on short- and long-term outcomes in patients with pancreatic adenocarcinoma (PDAC). Methods: This was a retrospective study from a prospectively maintained database of pancreatic resections for PDAC. Short- and long-term outcomes were analyzed in patients having borderline resectable PDAC submitted to up-front total pancreatectomy (TP) or pancreaticoduodenectomy (PD) with simultaneous portal vein (PV) and/or superior mesenteric vein (SMV) resection. Venous resections were carried out as tangential venous resection (TVR) or segmental venous resection (SVR). Patients were divided into 4 groups: (1) PD + TVR, (2) PD + SVR, (3) TP + TVR, (4) TP + SVR. Uni- and multivariate Cox regression analysis were performed to identify factors associated with survival. Results: Ninety-nine patients were submitted to simultaneous pancreatic and venous resection for PDAC. Among them, 25 were submitted to PD + TVR (25.3%), 12 to PD + SVR (12.1%), 23 to TP + TVR (23.2%), and 39 to TP + SVR (39.4%). Overall, major morbidity (Clavien-Dindo grade ≥IIIA) was 26.3%. Thirty- and 90-day mortality were 3% and 11.1%, respectively. There were no significant differences among groups in terms of short-term outcomes. Median overall survival of patients submitted to PD + TVR was significantly higher than those to TP + SVR (29.5 vs 7.9 months, P = 0.001). Multivariate analysis identified TP (HR = 2.11; 95% CI: 1.31–3.44; P = 0.002) and SVR (HR = 2.01; 95% CI: 1.27–3.15; P = 0.003) as the only independent prognostic factors for overall survival. Conclusions: Up-front TP associated to SVR was predictive of worse survival in borderline resectable PDAC. Perioperative treatments in high-risk surgical groups may improve such poor outcomes.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 389-394 . [Abstract] ( 104 ) [HTML 1KB] [PDF 0KB] ( 163 )

VIEWPOINTS

	395	Li F, Bao QW, Jiang LYQ, Huang QL, Zhang X, Chen JX
		Diagnostic role of microRNA-125b for hepatocellular carcinoma
		It is estimated that there was 841000 new cases of liver cancer and 782000 associated deaths worldwide in 2018, ranking as the sixth most common cancer and the fourth leading cause of cancer-related deaths [1] . With approximately 90% of total cases, hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and is a major public global health challenge at present [1] . The majority of HCC patients are usually at advanced stages when diagnosed, which misses the optimal treatment and prognosis is poor. Alpha-fetoprotein (AFP) is the most widely applied diagnostic serum biomarker to detect HCC at present; however, the diagnostic accuracy of AFP is unsatisfactory, with sensitivity of 53% and specificity of 90% for early stage HCC [2] . Recently, plenty of studies reported that microRNA-125b (miR-125b) might function as potential diagnostic biomarker in HCC [3–8] . miR-125 family, consisting of miR-125a, miR-125b-1, and miR-125b-2, is closely associated with differentiation, proliferation, invasion, and metastasis of cancer cells. However, the diagnostic accuracy of miR-125b remains inconsistent.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 395-397 . [Abstract] ( 102 ) [HTML 1KB] [PDF 0KB] ( 149 )

LETTERS TO THE EDITOR

	398	Lao MY, Ma T, Bai XL, Zhang XZ, Tang TY, Liang TB
		Probable sirolimus-induced rupture of arterial anastomosis after liver transplantation in a patient intolerant of tacrolimus
		Liver transplantation remains the only cure for end-stage liver disease. Tacrolimus is widely used as a first-line immunosuppressive drug to prevent organ rejection after liver transplantation [1–3] . However, tacrolimus has a narrow therapeutic index and wide inter-individual variability in pharmacokinetics, which can result in underimmunosuppression or toxicity. Orally administered tacrolimus is rapidly absorbed from the distal gastrointestinal tract and extensively metabolized in the liver and intestinal walls by cytochrome P450 (CYP) 3A4 and 3A5 [2,4,5] . The activity of these enzymes has significant influence on the pharmacokinetics of tacrolimus. CYP3A5 polymorphism roots the individual differences in tacrolimus bioavailability [1] . Due to the drug’s narrow therapeutic range, dosage adjustments to achieve the desired blood concentration are challenging. Serum concentrations above the therapeutic range may result in nephrotoxicity and neurotoxicity [5] . An alternative to tacrolimus is sirolimus, a newly developed immunosuppressive agent for use in organ transplant recipients [6,7] . However, sirolimus is known to impair wound healing, which limits its early clinical application [8,9] . We report a case of probable sirolimus-induced rupture of arterial anastomoses after liver transplantation in a patient intolerant of tacrolimus.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 398-400 . [Abstract] ( 135 ) [HTML 1KB] [PDF 0KB] ( 172 )

	401	Pietersen LC, van Hoek B, Braat AE
		Comment on “The role of graft reperfusion sequence in the development of non-anastomotic biliary strictures following orthotopic liver transplantation: A meta-analysis”
		With great interest we read the article by Bekheit et al. “The role of graft reperfusion sequence in the development of non-anastomotic biliary strictures following orthotopic liver transplantation: a meta-analysis” [1] . The authors performed a metaanalysis of published studies comparing the outcomes of initial portal reperfusion (IPR) (sequential) versus simultaneous reperfusion (SimR) or initial arterial reperfusion (IAR). The primary objective of the study was to “compare the incidence of nonanastomotic biliary stricture, in both techniques”.
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 401-401 . [Abstract] ( 89 ) [HTML 1KB] [PDF 0KB] ( 171 )

	402	Bekheit M
		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”
		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] .
		Hepatobiliary Pancreat Dis Int. 2019; 18(4): 402-402 . [Abstract] ( 83 ) [HTML 1KB] [PDF 0KB] ( 161 )

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