Hepatobiliary Pancreat Dis Int

	2020 Vol. 19 No. 6
	Published: 2020-12-15


	Pages 507-606
	META-ANALYSIS REVIEW ARTICLES ORIGINAL ARTICLES/Transplantation ORIGINAL ARTICLES/Liver ORIGINAL ARTICLES/Biliary ORIGINAL ARTICLES/Pancreas LETTERS TO THE EDITOR VIEWPOINTS

META-ANALYSIS

	507	Yang SS, Cai CW, Ma XQ, Xu J, Yu CB
		Efficacy and cost-effectiveness of antiviral regimens for entecavir-resistant hepatitis B: A systematic review and network meta-analysis
		Background: Chronic hepatitis B (CHB) patients who had exposed to lamivudine (LAM) and telbivudine (LdT) had high risk of developing entecavir (ETV)-resistance after long-term treatment. We aimed to conduct a systematic review and a network meta-analysis on the efficacy and cost-effectiveness on antiviral regimens in CHB patients with ETV-resistance. Data sources: We searched PubMed, EMBASE and Web of Science for studies on nucleos(t)ide analogues (NAs) treatment [including tenofovir disoproxil fumarate (TDF)-based rescue therapies, adefovir (ADV)- based rescue therapies and double-dose ETV therapy] in CHB patients with ETV-resistance. The network meta-analysis was conducted for 1-year complete virological response (CVR) and biological response (BR) rates using GeMTC and ADDIS. A cost-effective analysis was conducted to select an economic and effective treatment regimen based on the 1-year CVR rate. Results: A total of 6 studies were finally included in this analysis. The antiviral efficacy was estimated. On network meta-analysis, the 1-year CVR rate in ETV-TDF [odds ratio (OR) = 22.30; 95% confidence interval (CI): 2.78-241.93], LAM-TDF (OR = 70.67; 95% CI: 5.16-1307.45) and TDF (OR = 16.90; 95% CI: 2.28-186.30) groups were significantly higher than that in the ETV double-dose group; the 1-year CVR rate in the LAM-TDF group (OR = 14.82; 95% CI: 1.03-220.31) was significantly higher than that in the LAM/LdT-ADV group. The 1-year BR rate of ETV-TDF (OR = 28.68; 95% CI: 1.70-1505.08) and TDF (OR = 21.79; 95% CI: 1.43-1070.09) therapies were significantly higher than that of ETV double-dose therapy. TDF-based therapies had the highest possibility to achieve the CVR and BR at 1 year, in which LAM-TDF combined therapy was the most effective regimen. The ratio of cost/effectiveness for 1-year treatment was 8526, 17649, 20651 Yuan in the TDF group, TDF-ETV group, and ETV-ADV group, respectively. Conclusions: TDF-based combined therapies such as ETV-TDF and LAM-TDF therapies were the first-line treatment if financial condition is allowed.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 507-514 . [Abstract] ( 68 ) [HTML 1KB] [PDF 0KB] ( 80 )

REVIEW ARTICLES

	515	Schizas D, Mastoraki A, Routsi E, Papapanou M, Tsapralis D, Vassiliu P, Toutouzas K, Felekouras E
		Combined hepatocellular-cholangiocarcinoma: An update on epidemiology, classification, diagnosis and management ^Hot!
		Background: Combined hepatocellular-cholangiocarcinoma (CHC) is a rare subtype of primary hepatic malignancies, with variably reported incidence between 0.4%–14.2% of primary liver cancer cases. This study aimed to systematically review the epidemiological, clinicopathological, diagnostic and therapeutic data for this rare entity. Data sources: We reviewed the literature of diagnostic approach of CHC with special reference to its clinical, molecular and histopathological characteristics. Additional analysis of the recent literature in order to evaluate the results of surgical and systemic treatment of this entity has been accomplished. Results: The median age at CHC’s diagnosis appears to be between 50 and 75 years. Evaluation of tumor markers [alpha fetoprotein (AFP), carbohydrate antigen 19–9 (CA19–9) and carcinoembryonic antigen (CEA)] along with imaging patterns provides better opportunities for CHC’s preoperative diagnosis. Reported clinicopathologic prognostic parameters possibly correlated with increased tumor recurrence and grimmer survival odds include advanced age, tumor size, nodal and distal metastases, vascular and regional organ invasion, multifocality, decreased capsule formation, stem-cell features verification and increased GGT as well as CA19–9 and CEA levels. In case of inoperable or recurrent disease, combinations of cholangiocarcinoma-directed systemic agents display superior results over sorafenib. Liver-directed methods, such as transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), hepatic arterial infusion chemotherapy (HAIC), radioembolization and ablative therapies, demonstrate inferior efficacy than in cases of hepatocellular carcinoma (HCC) due to CHC’s common hypovascularity. Conclusions: CHC demonstrates an overlapping clinical and biological pattern between its malignant ingredients. Natural history of the disease seems to be determined by the predominant tumor element. Gold standard for diagnosis is histology of surgical specimens. Regarding therapeutic interventions, major hepatectomy is acknowledged as the cornerstone of treatment whereas minor hepatectomy and liver transplantation may be applied in patients with advanced cirrhosis. Despite all therapeutic attempts, prognosis of CHC remains dismal.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 515-523 . [Abstract] ( 64 ) [HTML 1KB] [PDF 0KB] ( 99 )

ORIGINAL ARTICLES/Transplantation

	524	Zhu HK, Zhuang L, Chen CZ, Ye ZD, Wang ZY, Zhang W, Cao GH, Zheng SS
		Safety and efficacy of an integrated endovascular treatment strategy for early hepatic artery occlusion after liver transplantation
		Background: Hepatic artery occlusion (HAO) after liver transplantation (LT) is typically comprised of hepatic artery thrombosis (HAT) and stenosis (HAS), both of which are severe complications that coexist and interdependent. This study aimed to evaluate an integrated endovascular treatment (EVT) strategy for the resolution of early HAO and identify the risk factors associated with early HAO as well as the procedural challenge encountered in the treatment strategy. Methods: Consecutive orthotopic LT recipients ( n = 366) who underwent transplantation between June 2017 and December 2018 were retrospectively investigated. EVT was performed using an integrated strategy that involved thrombolytic therapy, shunt artery embolization plus vasodilator therapy, percutaneous transluminal angioplasty, and/or stent placement. Simple EVT was defined as the clinical resolution of HAO by one round of EVT with thrombolytic therapy and/or shunt artery embolization plus vasodilator therapy. Otherwise, it was defined as complex EVT. Results: Twenty-six patients (median age 52 years) underwent EVT for early HAO that occurred within 30 days post-LT. The median interval from LT to EVT was 7 (6–16) days. Revascularization time (OR = 1.027; 95% CI: 1.005–1.050; P = 0.018) and the need for conduit (OR = 3.558; 95% CI: 1.241–10.203, P = 0.018) were independent predictors for early HAO. HAT was diagnosed in eight patients, and four out of those presented with concomitant HAS. We achieved 100% technical success and recanalization by performing simple EVT in 19 patients (3 HAT + /HAS- and 16 HAT-/HAS + ) and by performing complex EVT in seven patients (1 HAT + /HAS-, 4 HAT + /HAS + , and 2 HAT-/HAS + ), without major complications. The primary assisted patency rates at 1, 6, and 12 months were all 100%. The cumulative overall survival rates at 1, 6, and 12 months were 88.5%, 88.5%, and 80.8%, respectively. Autologous transfusion < 600 mL (94.74% vs. 42.86%, P = 0.010) and interrupted suture for hepatic artery anastomosis (78.95% vs. 14.29%, P = 0.005) were more prevalent in simple EVT. Conclusions: The integrated EVT strategy was a feasible approach providing effective resolution with ex- cellent safety for early HAO after LT. Appropriate autologous transfusion and interrupted suture technique helped simplify EVT.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 524-531 . [Abstract] ( 67 ) [HTML 1KB] [PDF 0KB] ( 87 )

ORIGINAL ARTICLES/Liver

	532	Zhao QY, Xie LT, Chen SC, Xu X, Jiang TA, Zheng SS
		Virtual navigation-guided radiofrequency ablation for recurrent hepatocellular carcinoma invisible on ultrasound after hepatic resection ^Hot!
		Background: No reports are available on the technical efficiency and therapeutic response of virtual navigation (VN)-guided radiofrequency ablation (RFA) for patients with recurrent hepatocellular carcinoma (HCC) after hepatic resection. The aim of this study was to investigate the overall technical performance and outcome of VN-guided RFA in recurrent HCC patients. In addition, a nomogram model was developed to predict the factors influencing the overall survival (OS). Methods: This was a prospective study on 76 recurrent HCC patients who underwent VN-guided RFA between June 2015 and February 2018. The technical feasibility, success, and efficiency, OS, local tumor progression, and complications were evaluated. A multivariate Cox regression analysis was conducted to predict the significant factors, and a nomogram including independent predictive factors was subsequently plotted to predict OS. Results: The technical feasibility, success, and efficiency rates of VN-guided RFA were 86.4%, 94.7%, and 97.4%, respectively. The cumulative OS rates at 1-, 2-, and 3-year were 88.1%, 79.7%, and 71.0%, respectively. The cumulative local tumor progression rates at 1-, 2-, and 3-year were 5.5%, 8.7%, and 14.0%, respectively. In addition, the minor and major complication rates were 5.3% and 3.9%, respectively. No intervention-related deaths occurred during the follow-up period. The C-index of the OS nomogram in this study was 0.737. Conclusions: VN-guided RFA is an effective therapeutic option in recurrent HCC patients and improves the long-term outcomes especially for the lesions that cannot be detected in the two-dimensional ultra- sound. Besides, the nomogram may be a useful supporting tool in predicting OS to estimate the individual survival probability, optimize treatment options, and facilitate decision-making.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 532-540 . [Abstract] ( 61 ) [HTML 1KB] [PDF 0KB] ( 92 )

	541	Chan PPY, Levy MT, Shackel N, Davison SA, Prakoso E
		Hepatocellular carcinoma incidence post direct-acting antivirals in hepatitis C-related advanced fibrosis/cirrhosis patients in Australia
		Background: Despite efficacy in HCV eradication, direct-acting antiviral (DAA) therapy has raised controversies around their impact on hepatocellular carcinoma (HCC) incidence. Herein we reported the first Australian data on HCC incidence in DAA-treated HCV patients with advanced fibrosis/cirrhosis. Methods: We conducted a retrospective single center study of DAA-treated HCV patients with advanced fibrosis/cirrhosis from April 2015 to December 2017. Patients with prior HCC were included if they had complete response to HCC treatment. Results: Among 138 patients who completed DAA therapy, 133 (96.4%) achieved sustained virologic response (median follow-up 23.8 months). Ten had prior HCC and 5/10 (50.0%) developed recurrence, while de novo HCC developed in 7/128 (5.5%). Median time from DAA to HCC diagnosis was 34 weeks in recurrent HCC vs. de novo 52 weeks ( P = 0.159). In patients with prior HCC, those with recurrence (vs. without) had shorter median time between last HCC treatment and DAA (12 vs. 164 weeks, P < 0.001). On bivariate analysis, failed sustained virologic response at 12 weeks (SVR12) ( P = 0.011), platelets ( P = 0.005), model for end-stage liver disease (MELD) score ( P = 0.029), alpha fetoprotein (AFP) ( P = 0.013), and prior HCC ( P < 0.001) were associated with HCC post-DAA. On multivariate analysis, significant factors were prior HCC (OR = 4.80; 95% CI: 1.47–48.50; P = 0.010), failed SVR12 (OR = 2.83; 95% CI: 1.71–16.30; P = 0.016) and platelets (OR = 0.97; 95% CI: 0.95–0.99; P = 0.009). Conclusions: Our study demonstrates a high incidence of recurrent HCC in HCV patients with advanced fibrosis/cirrhosis treated with DAA. Factors associated with HCC development post-DAA were more advanced liver disease, failed SVR12 and prior HCC, with higher rates of recurrence in those who started DAA earlier.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 541-546 . [Abstract] ( 79 ) [HTML 1KB] [PDF 0KB] ( 97 )

	547	Hu YT, Shu ZY, Jiang JH, Xie QF, Zheng SS
		Torin2 overcomes sorafenib resistance via suppressing mTORC2-AKT-BAD pathway in hepatocellular carcinoma cells
		Background: Sorafenib is an oral multi-kinase inhibitor that was approved by the US Food and Drug Administration for the treatment of patients with advanced hepatocellular carcinoma (HCC). However, resistance to sorafenib is an urgent problem to be resolved to improve the therapeutic efficacy of sorafenib. As the activation of AKT/mTOR played a pivotal role in sorafenib resistance, we evaluated the effect of a dual mTOR complex 1/2 inhibitor Torin2 on overcoming the sorafenib resistance in HCC cells. Methods: The sorafenib-resistant Huh7 and Hep3B cell lines were established from their parental cell lines. The synergistic effect of sorafenib and Torin2 on these cells was measured by cell viability assay and quantified using the Chou-Talalay method. Apoptosis induced by the combination of sorafenib and Torin2 and the alteration in the specific signaling pathways of interest were detected by Western blotting. Results: Sorafenib treatment inversely inhibited AKT in parental but activated AKT in sorafenib-resistant Huh7 and Hep3B HCC cells, which underscores the significance of AKT activation. Torin2 and sorafenib synergistically suppressed the viability of sorafenib-resistant cells via apoptosis induction. Torin2 success- fully suppressed the sorafenib-activated mTORC2-AKT axis, leading to the dephosphorylation of Ser136 in BAD protein, and increased the expression of total BAD, which contributed to the apoptosis in sorafenib-resistant HCC cells. Conclusions: In this study, Torin2 and sorafenib showed synergistic cytostatic capacity in sorafenib-resistant HCC cells, via the suppression of mTORC2-AKT-BAD pathway. Our results suggest a novel strategy of drug combination for overcoming sorafenib resistance in HCC.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 547-554 . [Abstract] ( 69 ) [HTML 1KB] [PDF 0KB] ( 95 )

	555	de Oliveira Souza E, D’Amico EA, Flores da Rocha TR, Marcondes Ferreira C, Medeiros Batista J, Carneiro D’Albuquerque LA, Carrilho FJ, Queiroz Farias A
		Preservation of platelet function in patients with cirrhosis and thrombocytopenia undergoing esophageal variceal ligation
		Background: Thrombocytopenia is a possible risk factor for bleeding after band ligation of esophageal varices. However, elevated von Willebrand factor (VWF) in cirrhosis improves platelet function and could decrease this risk. Our objective was to assess platelet function in patients with cirrhosis undergoing esophageal variceal ligation (EVL). Methods: The assessment consisted of platelet count, antigen and activity of VWF and VWF-cleaving protease ADAMTS-13 activity, and a platelet adhesion and aggregation test simulating vascular flow in vivo (Impact-R R ) prior to EVL. Results: Totally 111 patients were divided into three groups according to platelet count: (1) < 50 ×10 9 /L ( n = 38, 34.2%); (2) 50 ×10 9 /L to 100 ×10 9 /L ( n = 47, 42.3%); and (3) > 100 ×10 9 /L ( n = 26, 23.4%). No statistically significant difference was found in the aggregate size of platelets [group 1: 41.0 (31.8–67.3) μm 2 ; group 2: 47.0 (33.8–71.3) μm 2 ; and group 3: 47.0 (34.0–66.0) μm 2 ; P = 0.60] and no significant correlation was found between aggregate size and platelet count (Spearman r = 0.07; P = 0.47). Surface coverage was 4.1% (2.8%–6.7%), 8.5% (4.0%–10.0%), and 9.0% (7.1%–12.0%) ( P < 0.001) in groups 1, 2 and 3, respectively and correlated with platelet count (Spearman r = 0.39; P < 0.0 0 01). There was no signifi- cant difference between groups in VWF or ADAMTS-13. Post-EVL bleeding occurred in six (5.4%) patients ( n = 2 in group 1, n = 1 in group 2, and n = 3 in group 3; P = 0.32). Patients with bleeding had higher MELD scores [15.0 (11.3–20.3) versus 12.0 (10.0–15.0); P = 0.025], but no difference was demonstrated for platelet function parameters. Conclusion: Platelet function is preserved even in the presence of thrombocytopenia, including in the patients with post-EVL bleeding.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 555-560 . [Abstract] ( 77 ) [HTML 1KB] [PDF 0KB] ( 83 )

	561	Feng HL, Li Q, Cao WK, Yang JM
		Changes in thyroid function in patients with liver failure and their clinical significance: A clinical study of non-thyroidal illness syndrome in patients with liver failure
		Background: Non-thyroidal illness syndrome (NTIS) develops in a large proportion of critically ill patients and is associated with high risk for death. We aimed to investigate the correlation between NTIS and liver failure, and the short-term mortality of patients with these conditions. Methods: The clinical data of 87 patients with liver failure were collected retrospectively, 73 of them were randomly selected for an observational study and to establish prognostic models, and 14 for model validation. Another 73 sex- and age-matched patients with mild chronic hepatitis were randomly selected as a control group. Serum free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were measured. The clinical characteristics of patients with liver failure and NTIS were analyzed. The follow-up of patients lasted for 3 months. Additionally, the values for predicting short-term mortality of model for end-stage liver disease (MELD), Child-Turcotte-Pugh (CTP), chronic liver failure-sequential organ failure assessment (CLIF-SOFA) scores, FT3-MELD model, and FT3 were evaluated. Results: The observation group had significantly lower FT3 (2.79 ± 0.71 vs. 4.43 ± 0.75 pmol/L, P < 0.001) and TSH [0.618 (0.186-1.185) vs. 1.800 (1.570-2.590) mIU/L, P < 0.001], and higher FT4 (19.51 ± 6.26 vs. 14.47 ±2.19 pmol/L, P < 0.001) than the control group. NTIS was diagnosed in 49 of the patients with liver failure (67.12%). In the observation group, patients with NTIS had a higher mortality rate than those without (63.27% vs. 25.00%, P = 0.002). Across the whole cohort, the 3-month mortality was 50.68%. The international normalized ratios (INR) were 2.40 ± 1.41 in survivors and 3.53 ± 1.81 in deaths ( P = 0.004), the creatinine (Cr) concentrations were 73.27 ± 36.94 μmol/L and 117.08 ± 87.98 μmol/L ( P = 0.008), the FT3 concentrations were 3.13 ±0.59 pmol/L and 2.47 ± 0.68 pmol/L ( P < 0.001), the MELD scores were 22.19 ±6.64 and 29.57 ±7.99 ( P < 0.001), the CTP scores were 10.67 ± 1.53 and 11.78 ± 1.25 ( P = 0.001), and the CLIF-SOFA scores were 8.42 ± 1.68 and 10.16 ± 2.03 ( P < 0.001), respectively. FT3 was negatively correlated with MELD score ( r = −0.430, P < 0.001). An FT3-MELD model was established by subjecting FT3 concentration and MELD score to logistic regression analysis using the following formula: Logit( P ) = −1.337 × FT3 + 0.114 ×MELD + 0.880. The areaunder the receiver operating characteristic (ROC) curve was 0.827 and the optimal cut-off value was 0.4523. The corresponding sensitivity and specificity were 67.6% and 91.7%. The areas under the ROC curve for FT3 concentration, MELD score, CTP score, and CLIF-SOFA score were 0.809, 0.779, 0.699, and 0.737, respectively. Conclusions: Patients with liver failure often develop NTIS. FT3-MELD score perform better than CTP and CLIF-SOFA scores in predicting mortality in patients with liver failure. Thus, the FT3-MELD model could be of great value for the evaluation of the short-term mortality of such patients
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 561-566 . [Abstract] ( 74 ) [HTML 1KB] [PDF 0KB] ( 77 )

	567	Bi HQ, Li ZH, Zhang H
		Long noncoding RNA HAND2-AS1 re duce d the viability of hepatocellular carcinoma via targeting microRNA-300/SOCS5 axis ^Hot!
		Background: Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers with high mortality. Long non-coding RNA heart and neural crest derivatives expressed 2 anti-sense 1 (HAND2-AS1) is down-regulated in several cancers including HCC, yet the precise mechanisms how HAND2-AS1 regulates cell survival in HCC remains poorly understood. Methods: The expression levels of HAND2-AS1 and miR-300 were measured using quantitative real-time PCR. The protein levels of suppressor of cytokine signaling 5 (SOCS5), Bcl-2, Bax and cleaved caspase-3 were determined by Western blot. Cell viability and cell proliferation were assessed using cell counting kit-8 and clone formation assay, respectively. Cell apoptosis was detected using flow cytometry. The interactions between HAND2-AS1 and miR-300, miR-300 and SOCS5 were validated using luciferase reporter assay. Results: HAND2-AS1 was down-regulated in HCC tissues and cell lines, and the expression level of HAND2-AS1 was positively correlated to patient survival. HAND2-AS1 over-expression reduced viability and proliferation in HCC cells. Elevated HAND2-AS1 level induced apoptosis in HCC cells, accompanied with increased Bax and cleaved caspase-3 levels and decreased Bcl-2 level. We also validated that HAND2-AS1 acted as a sponge of miR-300, and there was a negative correlation between expression levels of HAND2-AS1 and miR-300 in HCC tissues. Furthermore, we found that SOCS5 was a downstream target of miR-300. In addition, miR-300 mimics abolished HAND2-AS1-mediated inhibition of cell viability and proliferation. miR-300 mimics also reversed the HAND2-AS1-induced apoptosis in HCC cells. Conclusion: lncRNA HAND2-AS1 inhibits proliferation in HCC through regulating miR-300/SOCS5 axis.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 567-574 . [Abstract] ( 68 ) [HTML 1KB] [PDF 0KB] ( 109 )

ORIGINAL ARTICLES/Biliary

	575	Hwang YJ, Park SM, Ahn S, Lee J, Park YS, Kim N
		Diagnostic accuracy of administrative database for bile duct cancer by ICD-10 code in a tertiary institute in Korea ^Hot!
		Background: Administrative database provides valuable information for large cohort studies, especially when tissue diagnosis is rather difficult such as the diagnosis for bile duct cancer (BDC). The aim of this study was to evaluate the diagnostic accuracy of administrative database for BDC by International Classification of Diseases (ICD)-10 codes in a tertiary institute. Methods: BDC and control groups were collected from 2003 to 2016 at Seoul National University Bundang Hospital. Cases of BDC were identified in the National Health Insurance Service (NHIS) database by ICD 10-code supported by V code. The control group was selected from cases without ICD-10 codes for BDC. A definite or possible diagnosis was defined according to pathologic reports. Medical records, images, and pathology reports were analyzed to evaluate ICD-10 codes for BDC. Sensitivity, specificity, positive predictive value, and negative predictive value for BDC were analyzed according to diagnostic criteria and cancer locations. Results: A total of 1707 patients with BDC and 1707 controls were collected. Among those with BDC, 1320 (77.3%) were diagnosed by definite criteria. Most (99.4%) of them had adenocarcinoma. Rate of definite diagnosis was the highest for ampulla of Vater (88.9%), followed by that for extrahepatic (84.9%) and intrahepatic (68.3%) BDCs. False positive cases commonly had hepatocellular carcinomas. For overall diag- nosis of BDC, sensitivity, specificity, positive predictive value, and negative predictive value were 99.94%, 98.33%, 98.30%, and 99.94%, respectively. Diagnostic accuracies were similar regardless of diagnostic criteria or tumor locations. Conclusions: Administrative database for BDC collected according to ICD-10 code with V code shows good accuracy.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 575-580 . [Abstract] ( 74 ) [HTML 1KB] [PDF 0KB] ( 88 )

ORIGINAL ARTICLES/Pancreas

	581	Hori Y, Ikeura T, Yamaguchi T, Yoshida K, Matsuzaki K, Ishida M, Satoi S, Okazaki K
		Role of phosphorylated Smad3 signal components in intraductal papillary mucinous neoplasm of pancreas ? ^Hot!
		Background: Malignant intraductal papillary mucinous neoplasm (IPMN) has poor prognosis. The carcinogenesis of IPMN is not clear. The aim of this study was to clarify transitions in phosphorylated Smad3 signaling during IPMN carcinogenesis. Methods: By using immunohistochemistry, we examined the expression of pSmad3C and pSmad3L from 51 IPMN surgical specimens resected at our institution between 2010 and 2013. We also examined the expression of Ki-67, c-Myc and p-JNK. Results: The median immunostaining index of pSmad3C was 79.2% in low-grade dysplasia, 74.9% in high-grade dysplasia, and 42.0% in invasive carcinoma ( P < 0.01), whereas that of pSmad3L was 3.4%, 4.3%, and 42.4%, respectively ( P < 0.01). There was a negative relationship between the expression of pS- mad3C and c-Myc ( P < 0.001, r = -0.615) and a positive relationship between the expression of pSmad3L and c-Myc ( P < 0.001, r = 0.696). Negative relationship between the expression of pSmad3C and Ki-67 ( P < 0.01, r = -0.610) and positive relationship between the expression of pSmad3L and Ki-67 ( P < 0.01, r = 0.731) were confirmed. p-JNK-positive cells were frequently observed among pSmad3L-positive cancer cells. The median of pSmad3L/pSmad3C ratio in the non-recurrence group and the recurrence group were 0.58 (range, 0.05–0.93), 3.83 (range, 0.85–5.96), respectively ( P = 0.02). The median immunostaining index of c-Myc in the non-recurrence group and the recurrence group were 2.91 (range, 0–36.9) and 82.1 (range, 46.2–97.1), respectively ( P = 0.02). The median immunostaining index of Ki-67 in the non-recurrence group and the recurrence group were 12.9 (range 5.7–30.8) and 90.9 (range 52.9–98.5), respectively ( P = 0.02). Conclusions: pSmad3L was upregulated in malignant IPMN. pSmad3L/pSmad3C ratio may be a useful prognostic factor in IPMN.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 581-589 . [Abstract] ( 77 ) [HTML 1KB] [PDF 0KB] ( 85 )

	590	Kang J, Lee SH, Choi JH,Paik WH, Ahn DW, Jeong JB, Ryu JK, Kim YT
		Folfirinox chemotherapy prolongs stent patency in patients with malignant biliary obstruction due to unresectable pancreatic cancer
		Background: Stent insertion for biliary decompression to relieve jaundice and subsequent biliary infection is necessary for patients with biliary obstruction caused by pancreatic cancer, and it is important to keep the stent patent as long as possible. However, few studies have compared stent patency in terms of chemotherapy in patients with pancreatic cancer. This study aimed to evaluate the differences in stent patency in terms of recently evolving chemotherapy. Methods: Between January 2015 and May 2017, 161 patients with pancreatic cancer who had undergone biliary stent insertion with a metal stent were retrospectively analyzed. The relationship between chemotherapy and stent patency was assessed. Additionally, overall survival according to the treatment, risk factors for stent patency, and long-term adverse events were evaluated. Results: Median stent patency was 42 days for patients with the best supportive care and 217 days for patients with chemotherapy (conventional gemcitabine-based chemotherapy and folfirinox) ( P < 0.001). Furthermore, the folfirinox group showed the longest median stent patency and overall survival, with 283 days and 466 days, respectively ( P < 0.001) despite higher adverse events rate. Patients who underwent folfirinox chemotherapy after stent insertion had better stent patency in multivariate analysis (HR = 0.26; 95% CI: 0.12–0.60; P = 0.001). Conclusions: Compared with patients who received best supportive care only, patients who underwent chemotherapy after stent insertion had better stent patency. More prolonged stent patency can be expected for patients with folfirinox than conventional gemcitabine-based chemotherapy.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 590-595 . [Abstract] ( 65 ) [HTML 1KB] [PDF 0KB] ( 81 )

VIEWPOINTS

	596	Zhou HQ, Li JH, Liu LW, Lou JM, Ren ZG
		Increased CMTM4 mRNA expression predicts a poor prognosis in patients with hepatocellular carcinoma
		Hepatocellular carcinoma (HCC) is one of the most common human malignancies and main cause of cancer mortality worldwide [1] . Conventional treatment for HCC consists of hepatic resection, liver transplantation and radiofrequency ablation [ 2 , 3 ]. Despite improvements in clinical treatment, the 5-year survival rate of advanced HCC patients remains low. The exploration of novel therapeutic targets and the identification of prognostic biomarkers for HCC are vital and essential to improve clinical outcomes. CKLF-like MARVEL transmembrane domaincontaining member 4 ( CMTM4 ), mapped to chromosome 16q22.1, is the most conserved member of the CMTM family. The CMTM family comprises 9 genes: CMTM 1-8 and CKLF . Proteins from CMTM family are involved in the immune system [4] , the male reproductive system [5] , angiogenesis regulation, and tumorigenesis. CMTM4/6 protect programmed death-1 (PD-1) ligand 1 (PD-L1) protein from ubiquitination and suppress tumor specific T cell response via PD-L1 regulation, presenting critical immune checkpoints and potential therapeutic targets for anti-tumor immunity [4] . At the protein level, high CMTM6 expression was associated with worse patient survival in head and neck squamous cell carcinoma (HNSCC) [6] , while the reduced CMTM6 protein predicted poor prognosis for HCC patients [7] . At the transcriptome level, a negative correlation was found between CMTM6 expression and survival time of patients with glioma [8] . The mRNA levels of CMTM family members appears diverse in different tumors [9] . Recently, Bei et al. [10] investigated the clinical significance of the CMTM4 protein in HCC based on 75 pairs of specimens collected from HCC patients. However, the expression and clinical value of CMTM4 mRNA are not well investigated. In this study, we investigate CMTM4 mRNA expression and its role in HCC diagnosis and prognosis using data from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Moreover, we explored the molecular mechanism of CMTM4 in HCC, which may help explain the unfavorable survival of HCC.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 596-601 . [Abstract] ( 64 ) [HTML 1KB] [PDF 0KB] ( 78 )

LETTERS TO THE EDITOR

	602	Shao SY, Wang YL, Feng LM, Zhao Y
		Serum non-high-density lipoprotein cholesterol level is increased in Chinese patients with nonalcoholic fatty liver disease
		Nonalcoholic fatty liver disease (NAFLD) is a growing public health problem globally. Although the primary liver pathology in NAFLD patients is associated with an increased risk of overall mortality, the majority of deaths in NAFLD patients are due to the cardiovascular disease (CVD) [1]. With the change of lifestyle, the prevalence of NAFLD in China is increasing and patients tend to be younger [2] . A relevant epidemiological survey has shown that the prevalence of NAFLD in adults is estimated to be 12%–24% in Asia [3] . Non-high-density lipoprotein cholesterol (non-HDL-C) refers to the sum of all cholesterol subtracts high-density lipoprotein cholesterol (HDL-C), which can more comprehensively reflect the comprehensive metabolic changes of lipoproteins including low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), and very-low-density lipoprotein cholesterol (VLDL-C) [4]. Recently, NAFLD that often coexists with dyslipidemia has been identified as a major modifiable risk factor of CVD, and non-HDL-C has become a new biomarker for assessing and predicting the risk of CVD [4]. Therefore, we used the data from health checkup and examined the relationship between the serum non-HDL-C level and NAFLD.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 602-604 . [Abstract] ( 77 ) [HTML 1KB] [PDF 0KB] ( 75 )

	605	Matias N,Jegatheeswaran S, Nadarajah V, Sheen AJ, Jamdar S, Siriwardena AK
		Non-operative management of pancreatic trauma in adults
		Pancreatic trauma accounts for 0.4% - 2.0% of all trauma-related injuries worldwide [1-3] . The American Association for the Surgery of Trauma (AAST) categorizes pancreatic injury according to the severity [4] . Pancreatic injury involving transection of the gland (grades III to V) typically requires surgical management [4] . However, pancreatic trauma, especially in children and young adults, can be managed without surgery [5] . This study reports the outcome of a policy of preferential non-operative management of pancreatic trauma in adults.
		Hepatobiliary Pancreat Dis Int. 2020; 19(6): 605-606 . [Abstract] ( 68 ) [HTML 1KB] [PDF 0KB] ( 81 )

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