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Objective: The timing of laparoscopic cholecystectomy for acute cholecystitis remains controversial. This article reviews the latest evidence for the timing of laparoscopic cholecystectomy in the management of acute cholecystitis. Methodology: Trials comparing early laparoscopic cholecystectomy (ELC; carried out within 1 week of onset of symptoms) versus delayed laparoscopic cholecystectomy (DLC; carried out at least 6 weeks after symptoms settled) for acute cholecystitis were identified from Ovid Medline, Cochrane Library and PubMed database. Only meta-analyses and randomized clinical trials were reviewed. Results: A total of seven prospective randomized trials including 670 patients and four meta-analyses were reviewed. ELC was superior to DLC in terms of a shorter hospital stay without any significant difference in perioperative mortality and morbidity. Conclusions: Current evidence supports ELC as the preferred treatment strategy for acute cholecystitis. It allows a shorter hospital stay, but shares similar operative morbidity, mortality and conversion rate as DLC. [ABSTRACT FROM AUTHOR]

Aim: To review the evidence in using inflow occlusion during liver resection. Other strategies to minimize the untoward effects of inflow occlusion will also be discussed. Methods: Randomized trials evaluating the use of inflow occlusion in hepatectomy and strategies to minimize its associated adverse effects were reviewed in this article. Recent experience showing comparable operative outcomes without the use of portal clamping was also described. Results: Results from randomized trials and meta-analyses were not conclusive on the benefits of routine inflow occlusion during liver resection. Intermittent inflow occlusion and ischaemic preconditioning had been found to be effective in reducing ischaemic-reperfusion injury to remnant liver. With refined operative techniques and better instruments, routine inflow occlusion in liver resection can now be safely avoided. Conclusion: Vascular inflow occlusion is an important armamentarium during liver resection, but it should not be used indiscriminately. With refined techniques and better instruments, hepatectomy can be performed safely without the need for routine inflow occlusion. [ABSTRACT FROM AUTHOR]

Objective: To evaluate any change in the operative and survival outcomes in patients undergoing a right hepatectomy after adoption of the no-clamp technique using a radiofrequency dissecting sealer (TissueLink™) in liver resection. Methods: In all, 58 consecutive patients who underwent a right hepatectomy from July 2003 to December 2007 (Group 1) were compared with 66 consecutive patients who underwent a right hepatectomy from January 1999 to June 2003 (Group 2). In group 1, a liver transection was performed with a cavitron ultrasonic surgical aspirator (CUSA) and TissueLink™ without hilar clamping whereas in group 2, a liver transection was performed with CUSA and diathermy with routine continuous hilar clamping. Results: For the operative outcomes, there was significantly less blood loss (median 450 vs. 900 ml, P < 0.001) in group 1. The complication rate was also significantly lower in group 1 (22.4% vs. 47.0%, P= 0.004). In subgroup analysis for patients with hepatocellular carcinoma (HCC), the overall survival rate was significantly better in group 1; 1-, 3- and 5-year survival rates were 78%, 72% and 57% in group 1 vs. 72%, 44% and 39% in group 2, respectively ( P= 0.048). Conclusions: When compared with the retrospective cohort, a right hepatectomy utilizing TissueLink™ without hilar clamping was feasible with potential benefits in surgical outcomes. [ABSTRACT FROM AUTHOR]

Abstract: FHL2 displays tumor promoting or tumor suppressing activities depending on the types of tumor cells. In this study, we demonstrated that FHL2 overexpression inhibits the proliferation of human HCC cells Hep3B through cell cycle regulation by decreasing cyclin D1 expression while increasing the expressions of p21 and p27. FHL2 overexpression also inhibits migration and invasion of Hep3B cells through the regulation of epithelial–mesenchymal transition. Surprisingly, we also demonstrated an antiapoptotic function for FHL2 overexpression with increased resistance to doxorubicin-induced apoptosis, which indicates the separation of anti-proliferative and anti-apoptotic role of FHL2. Taken together, our results indicate FHL2 could exert anti-apoptotic effect independent of tumor growth suppression. [Copyright &y& Elsevier]

Abstract: A list of diethynylfluorenes and their gold(I) derivatives have been studied for their antitumor activity as a function of their structure–activity relationships. End-capping the fluoren-9-one unit with gold(I) moieties could significantly strengthen the cytotoxic activity in vitro on three human cancer cell lines with induction of reactive oxygen species generation on Hep3B hepatocellular carcinoma cells and exhibit attractive antitumor activity from in vivo nude mice Hep3B xenograft model with limited adverse effects on vital organs including liver and kidney. [Copyright &y& Elsevier]

Pancreatic pseudocyst is an amylase-rich peri-pancreatic fluid collection devoid of epithelial lining. Occasionally, it cannot be differentiated from cystic neoplasm of pancreas and resections are required. We report a case of pancreatic pseudocyst masquerading cystic neoplasm treated with distal pancreatectomy. The investigation strategy and management of cystic lesions of the pancreas are also discussed. [ABSTRACT FROM AUTHOR]

Background: The survival benefit of surveillance for hepatocellular carcinoma (HCC) is controversial. Aim: We aimed to examine the survival benefit of HCC surveillance in chronic viral hepatitis. Methods: Survivals of HCC patients related to chronic viral hepatitis from the Hepatology Clinic (surveillance group) were compared with those referred from other hospitals/clinics (no-surveillance group). Lead-time and length-time biases were adjusted based on tumour volume doubling times. Results: Among 579 patients (91% hepatitis B), 472 (82%) patients had HCC and 79 (17%) of these patients were referred from the surveillance programme. HCC was smaller (4.2 vs. 7.7 cm; P<0.001) and fewer in numbers (2.6 vs. 3.8, P=0.03) in the surveillance group vs. the no-surveillance group. Treatment by surgery (20 vs. 10%, P=0.007) and local ablative therapy (46 vs. 19%, P<0.001) were more frequent in the surveillance group than that in the no-surveillance group. The median survival of the surveillance group (88 weeks) was significantly longer than that of the no-surveillance group (26 weeks) ( P<0.001). The adjusted cumulative survival at 2 years was significantly longer in the surveillance group if the tumour volume doubling time was <90 days ( P=0.0352). Conclusions: HCC surveillance can improve the survival of patients with chronic viral hepatitis B. [ABSTRACT FROM AUTHOR]

Background: Polypoid lesions of the gallbladder encompass a wide variety of pathology. Although most of these lesions are benign, some early carcinomas of the gallbladder do present as polypoid lesions. Problems remain in selecting patients with polypoid lesions of the gallbladder for surgery, the operative approach, and the method of follow-up of those deemed not needing surgery.Data sources: This review was done by Medline search of the English literature by the keywords “polypoid lesions of gallbladder,” “gallbladder polyps,” “carcinoma of gallbladder,” and “benign tumors of gallbladder.”Conclusions: Most small polypoid lesions of the gallbladder are benign and remain static for years. Three- to six-monthly ultrasonography examination is warranted in the initial follow-up period but it is probably unnecessary after 1 or 2 years. Age more than 50 years and size of polyp more than 1 cm are the two most important factors predicting malignancy in polypoid lesions of the gallbladder. Other risk factors include concurrent gallstones, solitary polyp, and symptomatic polyp. Laparoscopic cholecystectomy is the treatment of choice unless the suspicion of malignancy is high, in which case it is advisable to have open exploration, intraoperative frozen section, and preparation for extended resection. [Copyright &y& Elsevier]

Objective: Eradication of Helicobacter pylori is effective in preventing ulcer relapse after simple repair of perforated duodenal ulcers. However, when and how the H. pylori status should be determined remains unclear. The study investigated the role of early endoscopic follow up in managing patients with simple omentopexy for duodenal ulcer perforation. Patients and Method: Patients below the age of 75 years who had simple repair of perforated duodenal ulcer were recruited. They were given a 4-week course of H2 receptor antagonist upon discharge and advised to return for a follow-up endoscopy at 8 weeks after operation. During endoscopic examination, ulcer healing and other gastroduodenal pathology were noted. Random biopsies were taken from the antrum and body of the stomach for determination of H. pylori infection. Results: In a 30-month period, 112 patients were admitted with perforated duodenal ulcers. The perforation was repaired by either laparoscopic (n = 41) or open method ( n = 71). Eleven patients died during hospitalization. Of the 101 patients who recovered, 16 were lost to follow up. Nine patients were considered unfit for endoscopy as a result of medical comorbidities. Among the 76 patients who attended the follow-up endoscopy, 47 were shown to have H. pylori infection (61.8%). Active duodenal ulcers were found in 15 patients, significant erosions in five patients and severe duodenitis in seven patients. Patients infected by H. pylori had a significantly higher proportion of persistent duodenal pathology compared with the uninfected patients (23/47 vs 4/29; P = 0.003). Multivariate analysis revealed that smoking and H. pylori infection were the two independent factors predicting persistent duodenal lesions. Conclusion: Patients treated with simple closure for duodenal ulcer perforation are recommended to have their H. pylori status determined by early follow-up endoscopy, and an eradication regimen should be prescribed to those who are... [ABSTRACT FROM AUTHOR]

The article presents a case study of laparoscopic removal of cystic duct stump stone in a 51-year-old Chinese man who was referred for recurrent right upper pain after cholecystectomy. He underwent endoscopic retrograde cholangiopancreatography (ERCP), which revealed a cystic duct remnant stone compressing onto the bile duct. He then underwent laparascopic surgery to remove the stone following cannulation.

The article presents a case study of a 55-year-old gentleman with duct-type intra-ductal papillary mucinous neoplasm at the pancreatic tail. Topics discussed include diagnosis of a well circumscribed lobulated cystic lesion in the tail of pancreas, use of robot-assisted laparoscopic spleen-preserving distal pancreatectomy, and emphasis on spleen preservation for reducing the lifetime risk of post-splenectomy.

The article presents a case study of 27-year-old man suffering from hepatitis B carrier along with an 8-cm right lobe liver mass that was detected on computed tomography during evaluation of his recurrent pneumothorax. Topics include Castleman's disease, hepatectomy and coexistence of a rare lymphoid disease in a patient with hepatocellular carcinoma.

The article presents a case study of an 80-year-old woman presented with diabetes mellitus, ischaemic heart disease and acute cholangitis. It mentions that computed tomography revealed the presence of Mirizzi syndrome with multiple gallstones and contracted gallbladder. It also mentions that the patient underwent robotic subtotal cholecystectomy and duodenum has been separated from the gallbladder with dissection.

Reactive nodular fibrous pseudotumor ( RNFP) is a rare, benign, reactive lesion to antecedent abdominal surgery or trauma. In the presents study, we report a case of a 54-year-old woman who developed a mass at the hepatic hilum after laparoscopic cholecystectomy. The mass was excised completely in two separate operations, and histopathological examination confirmed RNFP. The clinical significance of the disease is discussed. [ABSTRACT FROM AUTHOR]

Background & Aims: Recent studies demonstrated the importance of fibrosis in promoting an immunosuppressive liver microenvironment and thereby aggressive hepatocellular carcinoma (HCC) growth and resistance to immune checkpoint blockade (ICB), particularly via monocyte-to-monocytic myeloid-derived suppressor cell (M-MDSC) differentiation triggered by hepatic stellate cells (HSCs). We thus aimed to identify druggable targets in these immunosuppressive myeloid cells for HCC therapy., Methods: M-MDSC signature genes were identified by integrated transcriptomic analysis of a human HSC-monocyte culture system and tumor-surrounding fibrotic livers of patients with HCC. Mechanistic and functional studies were conducted using in vitro -generated and patient-derived M-MDSCs. The therapeutic efficacy of a M-MDSC targeting approach was determined in fibrosis-associated HCC mouse models., Results: We uncovered over-expression of protein phosphatase 1 regulatory subunit 15A ( PPP1R15A ), a myeloid cell-enriched endoplasmic reticulum stress modulator, in human M-MDSCs that correlated with poor prognosis and ICB non-responsiveness in patients with HCC. Blocking TGF-β signaling reduced PPP1R15A expression in HSC-induced M-MDSCs, whereas treatment of monocytes by TGF-β upregulated PPP1R15A, which in turn promoted ARG1 and S100A8/9 expression in M-MDSCs and reduced T-cell proliferation. Consistently, lentiviral-mediated knockdown of Ppp1r15a in vivo significantly reduced ARG1 + S100A8/9 + M-MDSCs in fibrotic liver, leading to elevated intratumoral IFN-γ + GZMB + CD8 + T cells and enhanced anti-tumor efficacy of ICB. Notably, pharmacological inhibition of PPP1R15A by Sephin1 reduced the immunosuppressive potential but increased the maturation status of fibrotic HCC patient-derived M-MDSCs., Conclusions: PPP1R15A + M-MDSC cells are involved in immunosuppression in HCC development and represent a novel potential target for therapies., Impact and Implications: Our cross-species analysis has identified PPP1R15A as a therapeutic target governing the anti-T-cell activities of fibrosis-associated M-MDSCs (monocytic myeloid-derived suppressor cells). The results from the preclinical models show that specific inhibition of PPP1R15A can break the immunosuppressive barrier to restrict hepatocellular carcinoma growth and enhance the efficacy of immune checkpoint blockade. PPP1R15A may also function as a prognostic and/or predictive biomarker in patients with hepatocellular carcinoma., (© 2024 The Authors.)

Emergency pancreaticoduodenectomy (EPD) is a rarely performed operation. It is important to know the indications and outcomes of EPD to have a better understanding of its application in clinical practice. A review of eight consecutive cases of EPD was done. Between January 2003 and December 2021, 8 out of 370 patients (2.2%) in a single center received pancreaticoduodenectomy as emergency. There were six males and two females with a median age of 45.5 years. The indications were trauma in three patients, bleeding tumors in two patients, and one patient each in obstructing duodenal tumor, postoperative complication and post-endoscopic retrograde cholangiopancreatography (ERCP) complication. The median operative time and blood loss were 427.5 minutes and 1,825 mL, respectively. There was no operative mortality. Seven patients (87.5%) had postoperative complications. Three patients (37.5%) developed postoperative grade B pancreatic fistula. The median postoperative hospital stay was 23.5 days. Five patients were still alive while three patients survived for 13, 31, and 42 months after the operation. The causes of death were recurrent tumors in two patients, and sepsis in one patient. According to this case series, EPD is associated with increased morbidity and pancreatic fistula, but is still deserved in life-threatening situations and long-term survival is possible after EPD.

Massive expansion of immature and suppressive myeloid cells is a common feature of malignant solid tumors. Over-expression of cyclin-dependent kinase 20, also known as cell cycle-related kinase (CCRK), in hepatocellular carcinoma (HCC) correlates with reduced patient survival and low immunotherapy responsiveness. Beyond tumor-intrinsic oncogenicity, here we demonstrated that CCRK is upregulated in myeloid cells in tumor-bearing mice and in patients with HCC. Intratumoral injection of Ccrk -knockdown myeloid-derived suppressor cells (MDSCs) increased tumor-infiltrating CD8 + T cells and suppressed HCC tumorigenicity. Using an indel mutant transgenic model, we showed that Ccrk inactivation in myeloid cells conferred a mature phenotype with elevated IL-12 production, driving Th1 responses and CD8 + T cell cytotoxicity to reduce orthotopic tumor growth and prolong survival. Mechanistically, CCRK activates STAT3/E4BP4 signaling in MDSCs to acquire immunosuppressive activity through transcriptional IL-10 induction and IL-12 suppression. Taken together, our findings unravel mechanistic insights into MDSC-mediated immunosuppression and offer a therapeutic kinase-target for cancer immunotherapy., Competing Interests: The authors declare no competing interests that pertain to this work except the following declaration. J.Z., and A.S.L.C. hold a related US Provisional Patent (Application No: 63/528,199)., (© 2023 The Authors.)

Background & Aims: The hepatic manifestation of the metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), can lead to the development of hepatocellular carcinoma (HCC). Despite a strong causative link, NAFLD-HCC is often underrepresented in systematic genome explorations., Methods: Herein, tumor-normal pairs from 100 patients diagnosed with NAFLD-HCC were subject to next-generation sequencing. Bioinformatic analyses were performed to identify key genomic, epigenomic and transcriptomic events associated with the pathogenesis of NAFLD-HCC. Establishment of primary patient-derived NAFLD-HCC culture was used as a representative human model for downstream in vitro investigations of the underlying CTNNB1 S45P driver mutation. A syngeneic immunocompetent mouse model was used to further test the involvement of CTNNB1 mut and TNFRSF19 in reshaping the tumor microenvironment., Results: Mutational processes operative in the livers of patients with NAFLD inferred susceptibility to tumor formation through defective DNA repair pathways. Dense promoter mutations and dysregulated transcription factors accentuated activated transcriptional regulation in NAFLD-HCC, in particular the enrichment of MAZ-MYC activities. Somatic events common in HCCs arising from NAFLD and viral hepatitis B infection underscore similar driver pathways, although an incidence shift highlights CTNNB1 mut dominance in NAFLD-HCC (33%). Immune exclusion correlated evidently with CTNNB1 mut . Chromatin immunoprecipitation-sequencing integrated with transcriptome and immune profiling revealed a unique transcriptional axis, wherein CTNNB1 mut leads to an upregulation of TNFRSF19 which subsequently represses senescence-associated secretory phenotype-like cytokines (including IL6 and CXCL8). This phenomenon could be reverted by the Wnt-modulator ICG001., Conclusions: The unique mutational processes in the livers of patients with NAFLD and NAFLD-HCC allude to a "field effect" involving a gain-of-function role of CTNNB1 mutations in immune exclusion., Lay Summary: The increasing prevalence of metabolic syndrome in adult populations means that NAFLD is poised to be the major cause of liver cancer in the 21st century. We showed a strong "field effect" in the livers of patients with NAFLD, wherein activated β-catenin was involved in reshaping the tumor-immune microenvironment., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Robotic distal pancreatectomy has been accepted to be safe and effective for pancreatic tail lesion. Whether spleen preservation by preserving the splenic vessels with robot assistance is feasible and beneficial remains controversial. Here we would like to compare the operative outcomes of robotic distal pancreatectomy and splenectomy (DPS) with robotic spleen preserving distal pancreatectomy by means of splenic vessel preservation (SVP)., Methods: Between March 2011 and September 2019, 56 consecutive patients undergoing robotic distal pancreatectomy were identified, with 28 patients in each group. Patient demographics, histopathology findings and operative outcomes were prospectively collected and compared between the two groups. A subgroup analysis was made after excluding malignant and pancreatic lesions >6 cm in the DPS group., Results: The two groups had similar conversion rate, blood loss, morbidity and pancreatic fistula rate. There was no operative mortality. The SVP group had shorter median operative time (245 vs 303.5 min, P = 0.019) and shorter median hospital stay (5 vs 6 days, P = 0.019) than the DPS group. However, all malignant lesions occurred in the DPS group and lesion size in DPS group was significantly larger. After matching, there were 28 SVP and 15 DPS. The histopathology findings and lesion size became comparable. The SVP group still had shorter operative time (245 vs 290 min, P = 0.022) and shorter hospital stay (5 vs 7 days, P = 0.014) than the DPS group., Conclusion: Apart from avoiding risk of overwhelming postsplenectomy sepsis, robotic SVP had additional advantage of shorter operative time and shorter hospital stay than robotic DPS., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Background and Aim: Hepatocellular carcinoma is one of the commonest cancer in the world. Despite curative resection, recurrence remains the largest challenge. Many risk factors were identified for predicting recurrence, including liver fibrosis and cirrhosis. Transient elastography (Fibroscan) is an accurate tool in measuring liver fibrosis. This study aimed to evaluate the use of preoperative liver stiffness measurement (LSM), with Fibroscan in predicting long-term recurrence of hepatocellular carcinoma (HCC) after curative resection., Method: A prospective cohort study was conducted from February 2010 - June 2017 in Prince of Wales hospital. All consecutive patients with HCC undergone hepatectomy were included. Demographic factors, preoperative LSM, tumor characteristics and operative details were assessed. Primary outcome and secondary outcome were overall survival and disease free survival at 1 year, 3 year and 5 year respectively., Results: A total of 401 cases were included. Patients with LSM ≥12kPa had significantly lower 5-year overall survival rate (75.1% vs 57.3%, p < 0.001) and disease free survival rate (45.8% vs. 26.7%, p < 0.001). On multivariate analysis, pre-operative creatinine and vascular invasion of tumor were significant factors in predicting early recurrence (p = 0.012 and p = 0.004). LSM ≥12kPa were the only significant factor in predicting late recurrence (p = 0.048)., Conclusion: Pre-operative liver stiffness measurement could predict the late recurrence of hepatocellular carcinoma after curative resection., Competing Interests: Declaration of competing interest Grace LH Wong has served as a speaker for Echosens. Vincent WS Wong has served as an advisory board member for AbbVie, Gilead and Janssen; a consultant for Merck and NovoMedica; and a speaker for AbbVie, Echosens, Gilead and Roche. Henry LY Chan has served as a consultant and speaker for Abbvie, Bristol-Myers Squibb, F Hoffmann La Roche, Novartis Pharmaceutical, Gilead; a consultant for Janssen, a speaker for Echosens, and have received unrestricted grant for research from Roche. For the remaining authors none were declared., (Copyright © 2021 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Backgrounds/aims: Postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) remains a dreadful complication. Duct-to-mucosa pancreaticojejunostomy (DTMPJ) is a commonly performed anastomosis after PD. This study aims to evaluate whether there is a size limit of pancreatic duct below which POPF rate increases significantly after DTMPJ., Methods: A retrospective study was performed from a database with prospectively collected data on consecutive patients undergoing DTMPJ., Results: Between the years 2003 and 2019, a total of 288 patients with DTMPJ were recruited. POPF occurred in 56.3% of the patients, of which 43.8% were biochemical leak, 8.7% were grade B, and 1.4% were grade C. Overall operative morbidity was 51.4%, of which 19.1% were major complications. Five patients (1.7%) died within 90 days of operation. Patients with grade B/C POPF had significantly soft pancreas ( p < 0.001), smaller duct size ( p = 0.031), and a diagnosis of carcinoma of the pancreas ( p = 0.027). When a clinically significant POPF rate was analysed based on the pancreatic duct diameter, pancreatic duct size ≤ 1 mm had the highest POPF rate (35.7%). There was a significant difference in POPF rate between adjacent ductal diameter ≤ 1 mm and > 1 mm to 2 mm (35.7% vs 13.3%; p = 0.040). Multivariable analysis showed that for the soft pancreas, pancreatic duct diameter ≤ 1 mm was the only significant predictive factor for POPF ( p = 0.027)., Conclusions: DTMPJ can be safely performed for pancreatic duct > 1 mm without significantly increased POPF risk.

Insufficient T cell infiltration into noninflamed tumors, such as hepatocellular carcinoma (HCC), restricts the effectiveness of immune-checkpoint blockade (ICB) for a subset of patients. Epigenetic therapy provides further opportunities to rewire cancer-associated transcriptional programs, but whether and how selective epigenetic inhibition counteracts the immune-excluded phenotype remain incompletely defined. Here, we showed that pharmacological inhibition of histone deacetylase 8 (HDAC8), a histone H3 lysine 27 (H3K27)-specific isozyme overexpressed in a variety of human cancers, thwarts HCC tumorigenicity in a T cell-dependent manner. The tumor-suppressive effect of selective HDAC8 inhibition was abrogated by CD8 + T cell depletion or regulatory T cell adoptive transfer. Chromatin profiling of human HDAC8-expressing HCCs revealed genome-wide H3K27 deacetylation in 1251 silenced enhancer-target gene pairs that are enriched in metabolic and immune regulators. Mechanistically, down-regulation of HDAC8 increased global and enhancer acetylation of H3K27 to reactivate production of T cell-trafficking chemokines by HCC cells, thus relieving T cell exclusion in both immunodeficient and humanized mouse models. In an HCC preclinical model, selective HDAC8 inhibition increased tumor-infiltrating CD8 + T cells and potentiated eradication of established hepatomas by anti-PD-L1 therapy without evidence of toxicity. Mice treated with HDAC8 and PD-L1 coblockade were protected against subsequent tumor rechallenge as a result of the induction of memory T cells and remained tumor-free for greater than 15 months. Collectively, our study demonstrates that selective HDAC8 inhibition elicits effective and durable responses to ICB by co-opting adaptive immunity through enhancer reprogramming., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types. Although a role for cancer cell invasion programs has been well characterized, whether and how liver-intrinsic factors drive metastatic spread is incompletely understood. Here, we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase (CCRK) signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment. Using an inducible liver-specific transgenic model, we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer (CRC) metastasis to the liver, which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs) and lacking natural killer T (NKT) cells. Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7% (metastatic tumor weights) in the melanoma and CRC models, respectively. Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) signaling to increase the PMN-MDSC-trafficking chemokine C-X-C motif ligand 1 (CXCL1), which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice. Accordingly, CRC liver metastasis patients exhibited hyperactivation of hepatic CCRK/NF-κB/CXCL1 signaling, which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors. In summary, this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance. Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

Sorafenib resistance has become the main obstacle in the effective treatment of advanced hepatocellular carcinoma (HCC) patients. Activation of nuclear factor kappa B (NF-κB) is a newly identified mechanism that contributes to desensitized sorafenib. Cytochrome P450 1A2 (CYP1A2) functions as a tumor suppressor in HCC and its expression is negatively associated with NF-κB in the liver. This study aimed to study whether CYP1A2 could overcome sorafenib resistance. To investigate whether CYP1A2 and NF-κB p65 played roles in sorafenib desensitization, we established sorafenib-resistant (SR) HCC cells. SR cells decreased the expression of CYP1A2 along with the upregulation of NF-κB p65. CYP1A2 overexpression attenuated SR cell proliferation, increased sorafenib sensitivity, and inhibited the NF-κB pathway, whereas CYP1A2 silence showed opposite effects. Sorafenib, in combination with omeprazole, a CYP1A2 inducer, significantly hindered the growth and invasion of SR cells in vitro as well as decreased the tumor growth in vivo. The combination treatment markedly increased CYP1A2 expression and inhibited the sorafenib-induced NF-κB signaling. In addition, the overexpression of NF-κB p65 stimulated the SR cell growth and desensitized sorafenib in SR cells, where CYP1A2 overexpression reversed the phenomenon. Lastly, the majority of HCC tissue samples displayed decreased CYP1A2 but increased NF-κB p65 protein expression. Collectively, CYP1A2 can sensitize SR cells to sorafenib via inhibiting NF-κB p65 axis. Omeprazole in combination with sorafenib exerts a synergistic effect in alleviating acquired sorafenib resistance.

Rationale: Hyperactivation of HGF/MET signaling pathway is a critical driver in liver tumorigenesis. Cytochrome P450 1A2 (CYP1A2) was significantly down-regulated in hepatocellular carcinoma (HCC). However, little is explored about its tumor suppressive role in HCC. In this study, we examined the functional mechanisms and clinical implication of CYP1A2 in HCC. Methods: The clinical impact of CYP1A2 was evaluated in HCC patients in Hong Kong cohort. The biological functions of CYP1A2 were investigated in vitro and in vivo . A series of biochemical experiments including Western blot assay, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and Co-immunoprecipitation assay were conducted. Results: CYP1A2 expression was prominently silenced in HCC tumor tissues and the high expression of CYP1A2 was significantly correlated with lower AFP level, less vascular invasion, and better tumor-free survival in local cohort of HCC patients. The overexpression of CYP1A2 inhibited HCC cell viability and clonogenicity, reduced cell migration and invasion abilities in vitro , and suppressed tumorigenicity in vivo , whereas CYP1A2 knockdown exhibited the opposite effects. CYP1A2 significantly hindered HGF/MET signaling and Matrix metalloproteinases (MMPs) expression in HCC cells. Mechanically, CYP1A2 decreased HGF level and diminished HIF-1α expression, both of which are recognized as key regulators of MET activation. As the transcriptional activator of MET, HIF-1α was identified as a binding partner of CYP1A2. Direct binding of CYP1A2 with HIF-1α induced ubiquitin-mediated degradation of HIF-1α, inhibiting HIF-1α-mediated transcriptions. Conclusions: In conclusion, our results have identified CYP1A2 as a novel antagonist of HGF/MET signaling, and CYP1A2 may serve as an independent new biomarker for the prognosis of HCC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD)., Methods: This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection., Results: In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity., Discussion: Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.

Introduction: Upper gastrointestinal bleeding (UGIB) in patients suffering from hepatocellular carcinoma (HCC) is usually due to oesophageal or gastric varices secondary to portal hypertension. Very rarely, HCC can directly invade into the stomach or duodenum resulting in UGIB., Presentation of Case: A 62-year-old man presented to the emergency department for haematemesis and tarry stool. He was a hepatitis B carrier and had received open radiofrequency ablation and wedge resection for HCC previously. Urgent endoscopy and contrast computed tomography confirmed recurrent HCC invading into the duodenum. The patient received radical resection and remained disease free for 7 years after the operation., Discussion: Direct invasion into gastrointestinal tract by HCC is rare. Different modalities of treatment have been reported in the literature with variable success. En-bloc resection should be considered if surgically feasible in order to achieve good haemostasis and possible long term survival., Conclusion: Upper gastrointestinal bleeding is a rare presentation of hepatocellular carcinoma and long term survival can be achieved by curative surgery., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In this study, the neuro-modulation effect of topical mesenchymal stem cells (MSCs) was tested in a rodent middle carotid artery occlusion (MCAO) model. Twenty-four hours after MCAO, craniotomy was made and 0.8 × 10 6 GFP-MSCs were topically applied to the exposed parietal cortex. The MSCs were fixed in position by a thin layer of fibrin glue (N = 30). In the control group, saline were topically applied to the ipsilateral parietal cortex (N = 30). Three days after topical application, few GFP-positive cells were found in the ischemic penumbra. They expressed GFAP and NeuN. Topical MSCs triggered microglial activation, astrocytosis and cellular proliferation at day 3. The recovery of neurological functions were significantly enhanced as determined in Rotarod test and Morris Water Maze test with smaller infarct volume. PCR array showed that expressions of ten genes of neurogenesis were altered in the penumbra region (fold change > 1.25, p < 0.05) in MSCs group: Apoe, Ascl1, Efnb1, Mef2c, Nog, A100a6 and B2m were up-regulated; Pax2, Pax3 and Th were down-regulated. In conclusion, topical application provided a direct and effective transplant method for the delivery of MSCs to the surface of ipsilateral cerebral cortex and the topical MSCs could improve the neurological function from cerebral ischemia resulting from a major cerebral artery occlusion in a rodent experimental model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The advantages of radiofrequency ablation (RFA) over hepatectomy as a treatment for early-stage hepatocellular carcinoma (HCC) include reduced morbidity and more rapid recovery. Although minimally invasive surgery provides similar benefits, few studies have compared the long-term oncological outcomes of these techniques. This study aimed to compare the outcomes of minimally invasive hepatectomy (MIH) and RFA., Methods: Patients who underwent MIH or RFA for HCC between January 2005 and January 2015 were included in a propensity score matching analysis. Only patients who underwent minimally invasive procedures for small HCC were included. Baseline clinical and laboratory parameters were retrieved from the hospital database and analyzed., Results: Two hundred and twenty-five patients underwent MIH or RFA for HCC during the study period. Propensity score matching yielded 59 patient-pairs. The complication rates did not differ statistically between the 2 groups (p = 0.309). However, MIH provided significantly better overall (p = 0.005) and disease-free survival outcomes (p < 0.001) than RFA., Conclusions: Compared with RFA, MIH provided better long-term survival outcomes in patients with early-stage HCC, with no increase in the incidence of complications. When feasible, MIH should be considered a first-line treatment for this patient population., (© 2019 S. Karger AG, Basel.)

Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28-8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells [tumor proportion score] together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28-8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28-8 and SP263 assays. In conclusion, the 22C3, 28-8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.

Long noncoding RNAs (lncRNA) play critical roles in the development of cancer, including hepatocellular carcinoma (HCC). However, the mechanisms underlying their deregulation remain largely unexplored. In this study, we report that two lncRNAs frequently downregulated in HCC function as tumor suppressors and are epigenetically silenced by histone methyltransferase EZH2. lncRNAs TCAM1P-004 and RP11-598D14.1 were inhibited by EZH-mediated trimethylation of H3K27me3 at their promoters. Downregulation of TCAM1P-004 and RP11-598D14.1 was frequently observed in HCC tumors compared with adjacent normal tissues. Both lncRNAs inhibited cell growth, cell survival, and transformation in HCC cells in vitro as well as tumor formation in vivo . Using RNA pull-down and mass spectrometry, we demonstrated that TCAM1P-004 bound IGF2BP1 and HIST1H1C, whereas RP11-598D14.1 bound IGF2BP1 and STAU1. These lncRNA-protein interactions were critical in regulating p53, MAPK, and HIF1α pathways that promoted cell proliferation in HCC. Overexpression of EZH2 was critical in repressing TCAM1P-004 and RP11-598D14.1, and EZH2-TCAM1P-004/RP11-598D14.1-regulated pathways were prevalent in human HCC. Aberrant suppression of TCAM1P-004 and RP11-598D14.1 led to loss of their tumor-suppressive effects by disrupting the interaction with IGF2BP1, HIST1H1C, and STAU1, which in turn promoted HCC development and progression. Collectively, these findings demonstrate the role of TCAMP1P-004 and RP11-598D14.1 in suppressing tumor growth and suggest that EZH2 may serve as a therapeutic target in HCC. SIGNIFICANCE: EZH2-mediated loss of lncRNAs TCAM1P-004 and RP11-598D14.1 hinders the formation of tumor suppressor lncRNA-protein complexes and subsequently promotes HCC growth., (©2019 American Association for Cancer Research.)

Background: Transarterial chemoembolization (TACE) is the most commonly used adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Responses to TACE are variable due to tumor and patient heterogeneity. We had previously demonstrated that expression of Granulin-epithelin precursor (GEP) and ATP-dependent binding cassette (ABC)B5 in liver cancer stem cells was associated with chemoresistance. The present study aimed to evaluate the association between GEP/ABCB5 expression and response to adjuvant TACE after curative resection for HCC., Methods: Patients received adjuvant TACE after curative resection for HCC and patients received curative resection alone were identified from a prospectively collected database. Clinical samples were retrieved for biomarker analysis. Patients were categorized into 3 risk groups according to their GEP/ABCB5 status for survival analysis: low (GEP-/ABCB5-), intermediate (either GEP+/ABCB5- or GEP-/ABCB5+) and high (GEP+/ABCB5+). Early recurrence (recurrence within 2 years after resection) and disease-free survival were analyzed., Results: Clinical samples from 44 patients who had followed-up for more than 2 years were retrieved for further biomarker analysis. Among them, 18 received adjuvant TACE and 26 received surgery alone. Patients with adjuvant TACE in the intermediate risk group was associated with significantly better overall survival and 2-year disease-free survival than those who had surgery alone (P = 0.036 and P = 0.011, respectively). Adjuvant TACE did not offer any significant differences in the early recurrence rate, 2-year disease-free survival and overall survival for patients in low and high risk groups., Conclusions: Adjuvant TACE can only provide survival benefits for patients in the intermediate risk group (either GEP+/ABCB5- or GEP-/ABCB5+). A larger clinical study is warranted to confirm its role in patient selection for adjuvant TACE., (Copyright © 2018. Published by Elsevier B.V.)

Nonalcoholic fatty liver disease (NAFLD)-induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world; however, mechanisms that contribute to its formation are largely unknown, and targeted therapy is currently not available. Our RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase ( SQLE ) as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. Hepatocyte-specific Sqle transgenic expression in mice accelerated the development of high-fat, high-cholesterol diet-induced HCC. SQLE exerts its oncogenic effect via its metabolites, cholesteryl ester and nicotinamide adenine dinucleotide phosphate (NADP + ). Increased SQLE expression promotes the biosynthesis of cholesteryl ester, which induces NAFLD-HCC cell growth. SQLE increased the NADP + /NADPH (reduced form of NADP + ) ratio, which triggered a cascade of events involving oxidative stress-induced DNA methyltransferase 3A (DNMT3A) expression, DNMT3A-mediated epigenetic silencing of PTEN, and activation of AKT-mTOR (mammalian target of rapamycin). In human NAFLD-HCC and HCC, SQLE is overexpressed and its expression is associated with poor patient outcomes. Terbinafine, a U.S. Food and Drug Administration-approved antifungal drug targeting SQLE , markedly inhibited SQLE -induced NAFLD-HCC cell growth in NAFLD-HCC and HCC cells and attenuated tumor development in xenograft models and in Sqle transgenic mice. Suppression of tumor growth by terbinafine is associated with decreased cholesteryl ester concentrations, restoration of PTEN expression, and inhibition of AKT-mTOR, consistent with blockade of SQLE function. Collectively, we established SQLE as an oncogene in NAFLD-HCC and propose that repurposing SQLE inhibitors may be a promising approach for the prevention and treatment of NAFLD-HCC., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background and Aims: The role of electroacupuncture (EA) in reducing sedative and analgesic requirements during EUS is uncertain. The aim of this study was to investigate the efficacy of EA in reducing procedure-related pain and discomfort during EUS., Methods: This was a double-blinded randomized controlled study conducted between March 2014 and July 2016. Consecutive patients who were scheduled for diagnostic EUS were recruited and randomized to receive EA or sham-electroacupuncture (SA). The primary outcome was the dosage of propofol used. Other outcome measurements included pain scores, anxiety scores, satisfaction scores, patients' willingness to repeat the procedure, total procedure time, and adverse events., Results: A total of 128 patients were recruited to the study. The patients who received EA had significantly fewer requirements for patient-controlled sedation and analgesia (PCA). The median (interquartile range) number of demands for PCA (2 [1-5] vs 16.5 [8.5-33.8]; P < .001), the number of successful demands (2 [1-4] vs 9 [5.3-13]; P < .001), and the total dose of propofol (0.15 [0.08-0.34] vs 0.77 [0.38-1.09]; P < .001) and alfentanil (0.38 [0.20-0.86] vs 1.92 [0.94-2.72]; P < .001) were all significantly less. Patients who received EA also had significantly lower procedural pain scores and anxiety scores (P < .001), and higher satisfaction scores (P < .001), and they were more willing to repeat the procedure (P < .001). Being in the SA group and the procedure time were significant predictors of increased PCA demands (P < .001 and P = .009, respectively)., Conclusions: In conclusion, the use of EA reduced sedative and analgesia demands, improved patient experience, and was associated with a low risk of adverse events during diagnostic EUS. (Clinical trial registration number: NCT02066194.)., (Copyright © 2018 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objectives: The project is aimed to compare the tissue sampling rate and the diagnostic accuracy rate of EUS-FNA using 22G nitinol and reverse bevel-tipped needles., Subjects and Methods: This was a prospective, randomized, crossover study in a tertiary academic hospital. All consecutive adult patients undergoing EUS-guided FNA for lesions > 2 cm were recruited. Patients fulfilling the inclusion and exclusion criteria underwent EUS-guided FNA using both needles in sequence. They were randomized on a 1:1 basis to determine whether EUS-FNA would be performed first using the 22G reverse bevel-tipped (ProCore) needle followed by the nitinol needle or vice versa. The patients and the pathologists were blinded to the type of needle used., Results: Forty patients with suspected malignant neoplasms were recruited to the study. No significant differences were found in the diagnostic yield (76.9% vs. 84.6%, P = 0.389), accuracy (71.8% vs. 84.6%, P = 0.170), sensitivity (77.8% vs. 86.1%, P = 0.358), specificity (100% vs. 100%, P = 1), positive predictive value (100% vs. 100%, P = 1), and negative predictive value (20.0% vs. 28.6%, P = 1). The percentage of obtained tissue for histological assessment was also similar (41.0% vs. 46.2%, P = 0.648). In terms of the quantity of tissue obtained with the needles, a larger proportion of patients in the nitinol group obtained more tissue for assessment (P = 0.003)., Conclusion: The tissue-sampling rate and the diagnostic accuracy of the new 22G ProCore needle were comparable to the conventional 22G FNA needle in the absence of an on-site cytopathologist., Competing Interests: There are no conflicts of interest.

Background: Both microwave ablation (MWA) and radiofrequency ablation (RFA) are commonly employed local ablation techniques for malignant liver tumors. However, comparative data on long-term results between these two techniques is scarce in the literature., Methods: This is a retrospective comparative study between MWA and RFA for hepatocellular carcinoma (HCC) using surgical approach., Results: The MWA group consisted of 26 patients while the RFA group consisted of 47 case-matched patients. The two groups were comparable, except patients were older and their platelet count was lower in the MWA group. The median follow-up period was 47.5 months in MWA group and 52.9 months in RFA group (p = 0.322). There was no difference in 5-year overall survival (MWA 73.1%, RFA 46.3%, p = 0.082) and 5-year disease free survival (MWA 13.8%, RFA 14.6%, p = 0.736). When a subgroup analysis of tumors ≥ 3.5 cm was performed, there were 16 patients in the MWA group and 21 patients in the RFA group, the 5-year overall and disease-free survival were MWA 75.0%, RFA 28.6% (p = 0.022) and MWA 25.0%, RFA 4.8% (p = 0.207), respectively., Conclusion: MWA is comparable to RFA for HCC in terms of long-term outcomes. For tumors ≥ 3.5 cm, MWA is associated with a better overall 5-year survival., (Copyright © 2016. Published by Elsevier Taiwan.)

Background: Ischemia-reperfusion injury (IRI) is commonly encountered after liver surgery. This study evaluated the hepatoprotective effects of topically applied adipose-derived mesenchymal stromal cells (ADMSCs) on hepatic IRI in a rat model., Methods: ADMSCs from transgenic green fluorescent protein Sprague-Dawley rats were topically applied to the liver surface of Sprague-Dawley rats after hepatic IRI and fixed in position by fibrin glue (group A, n = 24). An equivalent amount of ADMSCs were administered through the portal (group B, n = 24) or tail vein (group C, n = 24). In the control group (group D, n = 20), no treatment was given to the IRI liver., Results: All the rats in group A and group D survived. Within 2 days after hepatic IRI, only 50% of rats survived in group B, and ADMSCs were detected in thromboemboli within large vessels. 62.5% of the rats died in group C because most of the ADMSCs were trapped in the lungs. ADMSCs migrated across the liver capsule and homed to the injured liver parenchyma 3 days after topical application in group A. The homed ADMSCs expressed hepatocyte nuclear factor-4α and hepatocyte nuclear factor-1. Compared with group D, the rate of hepatic regeneration in group A was enhanced with less inflammation, smaller necrotic areas, and improved liver function. Proinflammatory cytokines IL-6, IL-21, and CD70 were significantly downregulated in group A by 6.3-, 2.7-, and 12.7-fold, respectively ( P < 0.05). The neurogenic locus NOTCH homolog protein pathway was activated in the topical ADMSCs., Conclusions: Topically applied adipose-derived mesenchymal stromal cells demonstrated hepatoprotective effects on hepatic IRI in an animal model., Competing Interests: The authors declare no funding or conflicts of interest.

Purpose: To evaluate survival, tumor response, and treatment toxicity of transarterial ethanol ablation (TEA) in patients with unresectable hepatocellular carcinoma (HCC)., Materials and Methods: This prospective study involved 186 patients (146 men and 40 women; median age, 65 y [interquartile range, 57-72.3 y]). Of 186 patients, 146 (78.5%) were hepatitis B virus carriers, 18 (9.7%) were hepatitis C virus carriers, 82 (44.1%) had tumors ≥ 5 cm, and 43 (23.1%) had multifocal tumors. Overall survival (OS), complete response (CR) by European Association for the Study of the Liver criteria, time to progression (TTP), progression-free survival (PFS), and treatment toxicities were evaluated. Univariate and multivariate analyses for prognostic factors of OS were performed., Results: Median OS was 25.7 months (95% confidence interval [CI], 20.9-30.5) and varied significantly between Child-Pugh A and B (28.7 mo vs 13.4 mo, P < .001), and Barcelona Clinic Liver Cancer A and B or C (37.1 mo vs 17.7 mo, P = .001). Prognostic factors for longer OS were solitary tumor, tumor size < 5 cm, > 1 treatments, and CR of all tumors at 6 months. TTP was 9.1 months (95% CI, 6.9-11.3). PFS was 8.4 months (95% CI, 7.1-9.7). CR occurred in 69.1% (159/230) of lesions and 48.9% (88/180) of patients at 6 months. Any one symptom of the postembolization syndrome of grade 2 severity occurred in < 22% (41/186) of patients. No treatment-related hepatitis or death occurred within 30 days. Transient respiratory decompensation occurred in three patients (1.6% [3/186]), and alcoholic intoxication occurred in one patient (0.5% [1/186])., Conclusions: TEA appears to be safe and effective for local control of HCC., (Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.)

Promyelocytic leukemia zinc finger (PLZF) acts as a tumor-suppressor gene in a series of cancers including prostate, melanoma, colon cancer and leukemia. However, its role in hepatocellular carcinoma (HCC) has not yet been illustrated. The present study aimed to investigate the expression and epigenetic regulation of PLZF as well as its clinical significance in HCC. We found that the expression of PLZF was significantly downregulated in HCC samples at both the RNA level (P<0.001) and protein level compared with these levels in adjacent normal tissues. The relative expression level of PLZF was also positively correlated with the ALP level (P=0.026) noted in the HCC patients. However, hypermethylation was only detected in one out of 5 paired HCC samples, indicating that methylation of the selected promoter region (from -1702 to -1388) may not be the major regulatory mechanism for the downregulation of PLZF in HCC. A receiver operating characteristic (ROC) curve was created to evaluate the diagnostic value for differentiating between HCC and benign diseases. The area under the ROC curve (AUC) for indicating the value of PLZF as an HCC biomarker was 0.794 (95% CI, 0.697-0.892; P<0.001). Taken together, our results suggest that PLZF may play an important role in HCC development and may be a potential biomarker for the diagnosis of HCC.

Abuse of ketamine leads to liver injury. We investigated the histopathologic and radiologic features of ketamine abusers with significant liver injury in a cross-sectional survey of 297 consecutive chronic abusers of ketamine with urinary tract dysfunction. Liver biopsy and magnetic resonance cholangiopancreatography were performed in patients with liver injury (concentrations of bilirubin, alkaline phosphatase, and/or alanine aminotransferase >2-fold the upper limit of normal). The prevalence of liver injury was 9.8% (all cases cholestatic). Bile duct injury was observed in all 7 patients assessed by liver biopsy. Two patients had bridging fibrosis despite their young age. Three of 6 patients who underwent magnetic resonance cholangiopancreatography examination were found to have prominent or dilated common bile ducts without obstructions or extrinsic compressions. Ketamine abuse therefore appears to lead to common bile duct dilatation, microscopic bile duct injury, and even significant liver fibrosis., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined the risk factors associated with failure of enhanced recovery protocol after major hepatobiliary and pancreatic (HBP) surgery., Setting and Participants: A retrospective cohort of 194 adult patients undergoing major HBP surgery at a university hospital in Hong Kong was followed up for 30 days. The patients were from a larger cohort study of 736 consecutive adults with preoperative urinary cotinine concentration to examine the association between passive smoking and risk of perioperative respiratory complications and postoperative morbidities., Outcome Measures: The primary outcome was failure of enhanced recovery protocol. This was defined as a composite measure of the following events: intensive care unit (ICU) stay more than 24 h after surgery, unplanned admission to ICU within 30 days after surgery, hospital readmission, reoperation and mortality., Results: There were 25 failures of enhanced recovery after HBP surgery (12.9%, 95% CI 8.5% to 18.4%). After adjusting for elective ICU admission, smokers (relative risk (RR ) 2.21, 95% CI 1.10 to 4.46), high preoperative alanine transaminase/glutamic-pyruvic transaminase (RR 3.55,95% CI 1.68 to 7.49) and postoperative morbidities (RR 2.69, 95% CI 1.30 to 5.56) were associated with failures of enhanced recovery in the generalised estimating equation risk model. Compared with those managed successfully, failures stayed longer in ICU (median 19 vs 25 h, p<0.001) and in hospital for postoperative care (median 7 vs 13 days, p=0.003)., Conclusions: Smokers and patients having high preoperative alanine transaminase/glutamic-pyruvic transaminase concentration or have a high risk of postoperative morbidities are likely to fail enhanced recovery protocol in HBP surgery programmes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The outcome after curative resection for hepatocellular carcinoma (HCC) remains unsatisfactory due to the high recurrence rate after surgery. In patients with hepatitis B virus (HBV)-related HCC, which is the majority of patients with HCC in Asia, a high viral load is a strong risk factor for HCC recurrence. It is logical to believe that antiviral therapy may improve the post-operative outcome by promoting viral clearance and hepatocyte regeneration, as well as improving residual liver volume in HCC patients with hepatitis B. However, the effect of antiviral therapy on clinical outcomes after liver resection in patients with HBV-related HCC remains to be established. There are two main groups of antiviral treatment for HBV-oral nucleos(t)ide analogues and interferon. Interferon treatment reduces the overall incidence of HBV-related HCC in sustained responders. However, side effects may limit its long-term clinical application. Nucleos(t)ide analogues carry fewer side effects and are potent in terms of viral suppression when compared to interferon and are typically implemented for patients with more advanced liver diseases. They may also improve the outcome after curative resection for HBV-related HCC. There are increasing evidence to suggest that antiviral therapy could suppress HBV, decrease the perioperative reactivation of viral replication, reduce liver injury, preserve the liver function before and after operation, and may lower the risk of HCC recurrence. After all, antiviral therapy may improve the survival after liver resection by reducing recurrence and delaying the liver damage by the virus, resulting in a higher chance of receiving aggressive salvage therapy during HCC recurrence.

Mesenchymal stem cells (MSCs) have been shown in various animal models to be capable of neurorepair and neuroprotection. To carry out a therapeutic function, MSCs must be delivered to the target organ. MSCs are administered to patients via systemic infusion, which has many drawbacks, including a low engraftment rate and the migration of MSCs to non-target organs. However, other approaches such as direct intracerebral injection of MSCs might cause cerebral bleeding. In this study, a traumatic brain injury (TBI) was induced over the right parietal cerebral cortex in Sprague Dawley rats, and green fluorescent protein (GFP)-expressing MSCs (GFP-MSCs), together with a thin layer of fibrin, were applied to the external surface of the contralateral side 2 days later. Within 5 days of topical application, the GFP-MSCs had migrated from the site of application on the cortical surface, through the white matter, and had emerged at the cortical surface of the TBI site on the contralateral cerebral hemisphere, apparently following axons along the corpus callosum. In sham-injured control animals, the topically applied GFP-MSCs proliferated superficially on the cortex at the site of application, and no GFP-MSCs were found at the contralateral cortical surface. In all instances, GFP-MSCs were not detected in other organs of either the test or the control animals. Our study demonstrated that MSCs topically applied to the brain surface can migrate to a TBI site., (Copyright © 2012. Published by Elsevier Ltd.)

Backgrounds and Purpose: To determine the predictors for recurrence in patients receiving curative hepatectomy for hepatocellular carcinoma (HCC)., Methods: From January 2001 to July 2007, all patients having hepatectomy for first occurrence HCC with curative intent were identified from a prospectively collected database. Prognostic factors for recurrence and survival after resection were analyzed., Results: A total of 235 patients were included. With a median follow-up of 50.2 (0.07-125.1) months, the recurrence rate was 57.0%. The 1-, 3-, and 5-year overall survival rates were 83.9%, 66.0%, and 58.1% respectively. Multivariate analysis demonstrated that multi-focal lesions (HR: 2.93, P < 0.001), alpha-fetoprotein (AFP) level greater than 100 ng/ml (HR: 1.74, P = 0.002) and history of tumor rupture (HR: 2.84, P = 0.003) were independent risk factors for recurrence of HCC after hepatectomy., Conclusions: Predictors for HCC recurrence can be identified before operation. These important parameters should be considered before and after contemplating curative resection for HCC patients and for risk stratification in future clinical trials for neoadjuvant or post-resection adjuvant therapy. The possible use of neoadjuvant or adjuvant treatment to improve survival should be addressed by further trials., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Recent studies revealed an unexpected role of the neurotrophin receptor pathway, BDNF/TrkB signaling, in cancer metastasis and anoikis (i.e. detachment-induced cell death). Survival of cancer cells in detached state (known as anoikis-resistance) is known to be pre-requisite for metastasis. Nasopharyngeal carcinoma (NPC), an endemic head and neck cancer in Southeast Asia, is highly invasive, metastatic, and etiologically associated with Epstein-Barr virus (EBV, an oncovirus) infection. Mechanistic studies on the invasive/metastatic nature of NPC can facilitate the development of anti-metastatic therapy in NPC. Thus far, the role of BDNF/TrkB signaling in virus-associated human cancer is unclear. Here, using multiple cell line models of NPC with EBV-association (HONE-1-EBV, HK1-LMP1 and C666-1), we investigated the potential involvement of BDNF/TrkB signaling in cellular migration and anoikis-resistant characteristics of NPC. We found that all three EBV-associated NPC cell lines tested were intrinsically anoikis-resistant (i.e. survived in detached state) and expressed both BDNF and TrkB. BDNF stimulation induced cellular migration, but not proliferation of these cells. Further, we examined if pharmacologic targeting of anoikis-resistance of NPC cells can be achievable by a proof-of-concept Trk inhibitor, K252a, in these EBV-associated NPC models. Our results demonstrated that K252a, was able to attenuate BDNF-induced migration and proliferation of NPC cells. More importantly, we demonstrated for the first time that K252a harbored potent anoikis-sensitization activity (i.e. sensitizing cancer cells to detachment-induced cell death) against EBV-associated human cancer cells, namely NPC cells. This proof-of-concept study demonstrated that K252a, a Trk inhibitor, can potentially be used as an anoikis-sensitizing agent in NPC.

We have investigated the potential in vivo anti-tumour activity of corilagin using the Hep3B hepatocellular carcinoma cell line and an athymic nude mice xenograft model. The purity of corilagin was confirmed by high performance liquid chromatographic analysis. Corilagin was administrated intraperitoneally for a continuous period of 7 days at a concentration of 15 mg/kg of body weight per day. A significant inhibition of tumour growth was observed when treated mice are compared with control groups. Furthermore, analysis of enzymes markers of liver function, including alanine aminotransferase and asparate aminotransferase, suggested that current therapeutic dosage of corilagin did not exert adverse effect on liver. Our observations support the view that corilagin is considerably effective to retard the in vivo growth of xenografted Hep3B hepatocellular carcinoma., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Aim: Recently, we have demonstrated that silymarin has a comparable pharmaceutical activity as Phyllanthus urinaria extract when used to rescue mice from acetaminophen-induced acute liver injury. In the present study, we further compared the therapeutic action of silymarin with N-acetyl cysteine (commonly used in clinical practice for emergency treatments) as a rescuer in mice after administering a lethal dose of acetaminophen for 24 h., Methods: Acute liver injury was induced in the treatment groups by intraperitoneally administered acetaminophen at a dose of 550 mg/kg body weight on day 1. The control group received an equal volume of physiological saline intraperitoneally. From day 2 to 4, the treatment groups received various doses of silymarin or N-acetyl cysteine orally once daily, while the control group and the acetaminophen group received an equal volume of water orally. The mortality rate was recorded in all groups. On day 5, all mice were sacrificed for examination., Results: Silymarin greatly improved the counteracting effects on mortality rate as compared to N-acetyl cysteine., Conclusion: Silymarin should be further considered as an antidote for patients with acetaminopheninduced acute hepatic injury and delayed treatment., (Copyright © 2010 S. Karger AG, Basel.)

We report a rare case of spontaneous liver rupture in a patient with hypereosinophilic syndrome (HES), of which the diagnosis was delayed, resulting in a fatal outcome. The diagnostic criteria and treatment of HES with hepatic involvement were reviewed. The possible cause of spontaneous liver rupture in HES and its management were also discussed. To our knowledge, this is the first case report of spontaneous liver rupture in HES. We emphasized the need of a high index of suspicion in diagnosing HES, so that early treatment could be initiated.

Objective: To compare the survival between patients with synchronous and metachronous colorectal liver metastases after hepatectomy with new generation of peri-operative chemotherapy., Methods: From October 2002 to January 2008, patients receiving hepatectomy for synchronous or metachronous colorectal liver metastasis were studied retrospectively., Results: Fifty-five patients (synchronous group=35, metachronous group=20) underwent hepatectomy for colorectal liver metastases. Besides younger age with male predominance, patients in the synchronous group had more tumour multinodularity and bilobe liver involvement. They had received less hepatic curative hepatectomy (81.1% vs. 100%) with a higher rate of peri-operative chemotherapy (91.4% vs. 50%) and postoperative morbidity (25.7% vs. 0%). However both groups had no statistical significant difference in median overall survival (OS) and disease free survival (DFS). Inferior OS and DFS were observed in the synchronous group for patients who had no peri-operative chemotherapy or those showing poor response to chemotherapy. The most favourable OS is observed in both groups after performing globally curative hepatectomy., Conclusion: Synchronous colorectal liver metastasis is not a poor prognostic factor for survival when compared with the metachronous metastasis. Globally curative hepatectomy in combination of new generation of chemotherapy is recommended for the management of resectable colorectal liver metastasis.