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Qingbin Wang,1,2,* Bingkun Wang,1,2,* Xiaowu Ma,1,2 Hongkai Zhuang,1,2 Zhiqin Xie,1,2 Chenwei Tang,1,2 Wenliang Tan,1,2 Lei Yang,1,2 Changzhen Shang,1,2 Yajin Chen1,2 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China; 2Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changzhen Shang; Yajin Chen, Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China, Tel +86 13711279678, Email shangcz_sysu@163.com; chenyaj@mail.sysu.edu.cnPurpose: Ferroptosis has been reported to regulate multiple biological behaviors. However, the prognostic and oncologic values of ferroptosis-related genes (FRGs) have not been comprehensively elucidated in hepatocellular carcinoma (HCC). Here, we aimed to construct FRGs-associated signature for stratification of the prognosis of HCC patients.Methods: A list of FRGs was generated from FerrDb. Public databases were used to extract expression matrices and clinical information. TCGA cohort was randomly divided into a training set and a validation set. Prognostic signature for Overall Survival (OS) was established in training set and validated in internal cohorts (TCGA validation set and entire set) and external cohort (ICGC cohort). Additionally, the role of signature in HCC was well investigated by analysis of mutations, gene set enrichment analysis (GSEA), analysis of immune infiltrates, and analysis of response to immune checkpoint blockade (ICB) treatment. The oncogenic effects of ZFP69B on HCC were also investigated in vitro.Results: We identified 12 FRGs-based signature for OS with LASSO regression. Patients were partitioned into different risk groups based on the signature. Overall, patients in different groups had different prognosis. The signature independently predicted OS in multivariate Cox regression analyses. Anti-tumor immune cells including activated CD8 T cells, cytolytic activity, and Th1 cells were negatively correlated with risk score in both TCGC and ICGC cohorts. Furthermore, low-risk patients responded better to ICB than high-risk patients. In addition, knockdown of ZFP69B reduced proliferation, migration, and invasion, and promoted erastin-induced ferroptosis of HCC cells.Conclusion: We developed a prognostic signature based on FRGs to predict OS of HCC patients. And the signature may facilitate clinicians in identifying those who are likely to benefit from ICIs. The results also indicated that ZFP69B might regulate the process of ferroptosis and could be used as a novel potential target for HCC.Keywords: ferroptosis, hepatocellular carcinoma, immunotherapy, overall survival, signature

Purpose Probing efficacy and safety of lusutrombopag in Chinese chronic liver disease (CLD) and severe thrombocytopenia (PLT 9/L) patients undergoing elective invasive procedures. Methods In this double-blind, parallel-group phase 3 study, 66 patients with CLD and severe thrombocytopenia were randomized 2:1 to lusutrombopag or placebo arm treatment regimens for seven days at 9 centers in China. Responders (PLT ≥ 50 × 109/L that increased to ≥ 20 × 109/L from the baseline and not received rescue therapy for bleeding) on Day 8 (the day after seven-day treatment) were assessed. PLT ≥ 50 × 109/L on or after Day 8 and within 2 days before invasive procedure (alternative criteria for not requiring platelet transfusion) were also analyzed. Adverse events (AEs) were recorded. Results The proportion of responders on Day 8 was evidently higher (p = 0.0011) in the lusutrombopag group (43.2%, 19/44) versus placebo (4.5%, 1/22). And 72.7% (32/44) patients receiving lusutrombopag met the alternative criteria for not requiring platelet transfusion, while 18.2% (4/22) in the placebo group. The median maximum PLT in lusutrombopag group increased to 80.5 × 109/L, and median time to reach maximum was 14.5 days. Compared with placebo, the lusutrombopag group had a lower incidence of bleeding events (6.8% versus 13.6%), and only one patient had thrombotic-related AE. Overall, the incidence of treatment-emergent AEs was comparable between two groups. Conclusions Lusutrombopag was effective in raising PLT, diminishing platelet transfusion requirement, and documented a safety profile like the placebo in CLD and severe thrombocytopenia patients in a Chinese cohort undergoing elective invasive procedures. Chinese clinical trial registration number: CTR20192384.

PDF file - 54K, Sorafenib-resistant HCC specimens exhibit higher p-MET-positive rate compared with sorafenib-sensitive HCC specimens.

PDF file - 52K, Cabozantinib inhibits receptor tyrosine kinases (RTKs) signaling in vivo.

PDF file - 32K, Analysis of cyclin D1 expression and Apoptosis in HCC cells.

Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G1-phase arrest. Cabozantinib inhibited tumor growth in p-MET–positive and p-MET–negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET–positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)–stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker. Clin Cancer Res; 20(11); 2959–70. ©2014 AACR.

PDF file - 100K, Cabozantinib suppress colony-formation in HCC cells.

PDF file - 145K, Supplementary Tables S1. Characteristics of 29 HCC patients. Supplementary Table 2. Effects of cabozantinib on body weight, tumor burden, microvessel density, cell proliferation, and apoptosis of MHCC97 and HepG2 xenografts.

PDF file - 79K, Cabozantinib inhibits phosphorylation of MET in lung tissue and liver metastases.

Xiaowu Ma,1,2,* Hongkai Zhuang,1,2,* Qingbin Wang,1,2 Lei Yang,1,2 Zhiqin Xie,1,2 Ziyu Zhang,1,2 Wenliang Tan,1,2 Chenwei Tang,1,2 Yajin Chen,1,2 Changzhen Shang1,2 1Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yajin Chen; Changzhen Shang, Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China, Tel +86-2034070701, Email cyj0509@126.com; shangcz_sysu@163.comBackground: Solute carrier family 39 member 1 (SLC39A1) has been identified as a zinc ion transport protein that possesses oncogenic properties in various types of cancers. However, its potential function in hepatocellular carcinoma (HCC) remains unknown. This study aimed to investigate the expression profile and potential mechanisms of SLC39A1 in HCC.Methods: SLC39A1 expression was analyzed using multiple databases. The clinical significance and associated biological pathways of SLC39A1 were investigated using bioinformatics analysis. Potential correlations between SLC39A1 expression and tumor immunity in HCC were also evaluated using single-sample gene set enrichment analysis (GSEA). Sixty paired HCC samples were used to verify the expression pattern of SLC39A1. In vitro studies were performed to investigate the oncogenic effects of SLC39A1 in HCC. Western blot analysis was conducted to further investigate the possible involved signaling pathways.Results: The overexpression of SLC39A1 in HCC was determined by bioinformatics analysis and was confirmed in tissues from our center. SLC39A1 overexpression was also significantly correlated with worse prognosis, advanced TNM stage, and histological grade. GSEA analysis demonstrated that SLC39A1 overexpression was involved in various tumor-related pathways, such as the cell cycle and Wnt signaling pathway. SLC39A1 knockdown repressed the proliferation, invasion, and migration abilities of HCC cells. Furthermore, SLC39A1 knockdown decreased the expression of the tumor progression-related proteins (eg, cyclin D1 and MMP2) and Wnt signaling pathway-related proteins (eg, Wnt3A and β-catenin). In addition, SLC39A1 overexpression may be associated with impaired tumor immunity in HCC, as evidenced by the increased infiltration of Th2 cells and reduced infiltration of cytotoxic cells.Conclusion: These findings preliminarily suggested the crucial effect of SLC39A1 overexpression on HCC tumor progression and immunosuppression, suggesting its potential as a novel prognostic and therapeutic target in HCC.Keywords: SLC39A1, hepatocellular carcinoma, prognosis, Wnt signaling pathway, immune infiltration

Although the number of minimally invasive liver resections (MILRs) has been steadily increasing in many institutions, minimally invasive anatomic liver resection (MIALR) remains a complicated procedure that has not been standardized. We present the results of a survey among expert liver surgeons as a benchmark for standardizing MIALR.We administered this survey to 34 expert liver surgeons who routinely perform MIALR. The survey contained questions on personal experience with liver resection, inflow/outflow control methods, and identification techniques of intersegmental/sectional planes (IPs).All 34 participants completed the survey; 24 experts (70%) had more than 11 years of experience with MILR, and over 80% of experts had performed over 100 open resections and MILRs each. Regarding the methods used for laparoscopic or robotic anatomic resection, the Glissonean approach (GA) was a more frequent procedure than the hilar approach (HA). Although hepatic veins were considered essential landmarks, the exposure methods varied. The top three techniques that the experts recommended for identifying IPs were creating a demarcation line, indocyanine green negative staining method, and intraoperative ultrasound.Minimally invasive anatomic liver resection remains a challenging procedure; however, a certain degree of consensus exists among expert liver surgeons.

Laparoscopic hepatectomy (LH) has been widely used in the treatment of hepatocellular carcinoma (HCC). It is generally believed that the long-term outcomes of LH are not inferior to open hepatectomy (OH). However, the quality of evidence is low. The purpose of this study was to reconstruct time-to-event data for meta-analysis based on Kaplan–Meier curves from propensity-score matched studies and compare survival rates following LH and OH for hepatocellular carcinoma. All published propensity-score matched studies reported in English that compared LH and OH for hepatocellular carcinoma with Kaplan–Meier curves were screened. Patients’ survival information was reconstructed with the aid of a computer vision program. Different models (fixed-effects model for two-stage survival analysis and Cox regression for one-stage survival analysis) were performed for sensitivity analysis. In addition to the primary meta-analysis, two specific subgroup analyses were performed on patients by types of resection, cirrhosis status. Time-to-event data were extracted from 45 propensity-score matched studies (N = 8905). According to the time-to-event data and the reconstructed Kaplan–Meier curves, the cumulative overall survival rate was 49.0% and 50.9% in the LH and OH cohorts, respectively, a log-rank test did not demonstrate statistical significance (p > 0.05). The cumulative recurrence-free survival (RFS) probability was both close to 0.0%. The median RFS time was 49.1 (95% CI 46.1 ~ 51.7) and 44.3 (95% CI 41 ~ 46.1) months. The difference in disease status was statistically significant by the Log-rank test (p

Summary Background China has a high burden of hepatocellular carcinoma, and hepatitis B virus (HBV) infection is the main causative factor. Patients with hepatocellular carcinoma have a poor prognosis and a substantial unmet clinical need. The phase 2–3 ORIENT-32 study aimed to assess sintilimab (a PD-1 inhibitor) plus IBI305, a bevacizumab biosimilar, versus sorafenib as a first-line treatment for unresectable HBV-associated hepatocellular carcinoma. Methods This randomised, open-label, phase 2–3 study was done at 50 clinical sites in China. Patients aged 18 years or older with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment, and a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. In the phase 2 part of the study, patients received intravenous sintilimab (200 mg every 3 weeks) plus intravenous IBI305 (15 mg/kg every 3 weeks). In the phase 3 part, patients were randomly assigned (2:1) to receive either sintilimab plus IBI305 (sintilimab–bevacizumab biosimilar group) or sorafenib (400 mg orally twice daily; sorafenib group), until disease progression or unacceptable toxicity. Randomisation was done using permuted block randomisation, with a block size of six, via an interactive web response system, and stratified by macrovascular invasion or extrahepatic metastasis, baseline α-fetoprotein, and ECOG performance status. The primary endpoint of the phase 2 part of the study was safety, assessed in all patients who received at least one dose of study drug. The co-primary endpoints of the phase 3 part of the study were overall survival and independent radiological review committee (IRRC)-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population. The study is registered with ClinicalTrials.gov , NCT03794440 . The study is closed to new participants and follow-up is ongoing for long-term outcomes. Findings Between Feb 11, 2019 and Jan 15, 2020, we enrolled 595 patients: 24 were enrolled directly into the phase 2 safety run-in and 571 were randomly assigned to sintilimab–bevacizumab biosimilar (n=380) or sorafenib (n=191). In the phase 2 part of the trial, 24 patients received at least one dose of the study drug, with an objective response rate of 25·0% (95% CI 9·8–46·7). Based on the preliminary safety and activity data of the phase 2 part, in which grade 3 or worse treatment-related adverse events occurred in seven (29%) of 24 patients, the randomised phase 3 part was started. At data cutoff (Aug 15, 2020), the median follow-up was 10·0 months (IQR 8·5–11·7) in the sintilimab–bevacizumab biosimilar group and 10·0 months (8·4–11·7) in the sorafenib group. Patients in the sintilimab–bevacizumab biosimilar group had a significantly longer IRRC-assessed median progression-free survival (4·6 months [95% CI 4·1–5·7]) than did patients in the sorafenib group (2·8 months [2·7–3·2]; stratified hazard ratio [HR] 0·56, 95% CI 0·46–0·70; p Interpretation Sintilimab plus IBI305 showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for Chinese patients with unresectable, HBV-associated hepatocellular carcinoma, with an acceptable safety profile. This combination regimen could provide a novel treatment option for such patients. Funding Innovent Biologics. Translation For the Chinese translation of the abstract see Supplementary Materials section.

Purpose In this systematic review, we aimed to clarify the useful anatomic structures and assess available surgical techniques and strategies required to safely perform minimally invasive anatomic liver resection (MIALR), with a particular focus on the hepatic veins (HVs). Methods A systematic review was conducted using MEDLINE/PubMed for English articles and Ichushi databases for Japanese articles through September 2020. The quality assessment of the articles was performed in accordance with the Scottish Intercollegiate Guidelines Network (SIGN). Results A total of 3,372 studies were obtained, and 59 were selected and reviewed. Due to the limited number of published comparative studies and case series, the degree of evidence from our review was low. Thirty-two articles examined the anatomic landmarks and crucial structures for approaching HVs. Regarding the direction of HV exposure, 32 articles focused on the techniques and advantages of exposing HVs from either the root or the periphery. Ten articles focused on the techniques to perform a segmentectomy 8 in particularly difficult cases of MIALR. In seven articles, bleeding control from HVs was also discussed. Conclusions This review may help experts reach a consensus regarding the best approach to the management of hepatic veins during MIALR.

Low-temperature solid-phase epitaxy is a promising route for the synthesis of thin films of ScAlMgO4, a compound with lattice spacings close to compound semiconductors for which there are no practi...

Background & aim Shortage of donor hepatocytes limits hepatocyte transplantation for clinical application. Induced hepatic stem cells (iHepSCs) have capacities of self-renewal and bipotential differentiations. Here, we investigated whether iHepSCs could be extensively expanded, and whether they could differentiate into sufficient functional hepatocytes as donors for transplantation therapy after their extensive expansions. Methods Murine extensively expanded iHepSCs (50-55 passages) were induced to differentiate into iHepSC-Heps under a chemically defined condition. iHepSC-Heps were proved for carrying morphological hepatocyte characters and hepatocytic functions including low-density lipoprotein uptake, glycogen storage, CLF secretion, ICG uptake and release, Alb secretion, urea synthesis and metabolism-relative gene expressions respectively. Next, both iHepSCs and iHepSC-Heps were transplanted into Fah-/- mice respectively. Both liver repopulation and alleviation of liver function were compared between two transplantation groups. Results Murine iHepSCs still maintained the capacities of self-renewal and bipotential differentiations after extensive expansion. The efficiency for the functional hepatocyte differentiation from extensively expanded iHepSCs reached to 72.64%. Transplantations of both extensively expanded iHepSCs and iHepSC-Heps resulted in liver engraftment in Fah-/- mice. Survival rate of Fah-/- mice recipients and level of liver repopulation were 50% and 20.32 ± 4.58% respectively in iHepSC-Heps group, while 33% and 10.4 ± 4.3% in iHepSCs group. Conclusions Extensively expanded iHepSCs can efficiently differentiate into hepatocytes in chemical defined medium. Transplantation of iHepSC-Heps was more effective and more efficient than transplantation of iHepSCs in Fah-/- mice. Our results suggested an innovative system to obtain sufficient hepatocytes through hepatic differentiation of iHepSCs generated by lineage reprogramming.

570 Background: ORIENT-32 trial (NCT03794440) assessed sintilimab (anti-PD-1 antibody) plus a bevacizumab biosimilar (anti-VEGF antibody) versus sorafenib (Sor) as first-line treatment for unresectable HCC and demonstrated a significant improvement in both overall survival and progression-free survival. Here we report the updated results of objective response rate (ORR), time to response (TTR), duration of response (DoR) and depth of response (DpR). Methods: 571 eligible patients (pts) with unresectable HCC were enrolled and randomized (2:1) to receive sintilimab (200 mg IV Q3W) plus IBI305 (15 mg/kg IV Q3W) or Sor (400 mg orally, BID) until disease progression or unacceptable toxicity. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)and HCC-modified RECIST (mRECIST). ORR, TTR, DoR, and DpR were analyzed. The DpR was defined as the minimum percentage of (1) sum of longest diameter (SLD) change and (2) longest diameter (LD) change described as mean (standard deviation, SD). Results: At the data cutoff on Dec 30th, 2021, the median follow-up time was 26.7 months. The ORR in sintilimab plus IBI305 and Sor group was 21.0% (77/367) vs 4.7 (8/169) per RECIST 1.1 and 25.1% (92/367) vs 7.7% (13/169) per mRECIST. The median TTR in sintilimab plus IBI305 group was 2.8 (2.4–3.3) months per RECIST 1.1 and 2.6 (1.6–2.9) months per mRECIST. The median DoR in sintilimab plus IBI305gourp was 20.3 (12.3-NE) months per RECIST 1.1. The minimum percentage of SLD change was larger in the sintilimab plus IBI305 arm than in the Sor arm: (−13.4% (35.8) vs 3.2%(26.5) per RECIST 1.1). Similarly, the LD change in the largest liver lesion also favored sintilimab plus IBI305 arm (−27.6% (31.6) vs −11.5% (20.9)), including larger tumors (≥7 cm; −21.2% (30.4) vs −9.9% (23.7)) all per RECIST 1.1. Conclusions: Sintilimab plus IBI305 showed a significant improvement in ORR, TTR, DOR and DpR vs Sor in unresectable HCC. Clinical trial information: NCT03794440 .

Background Long noncoding RNAs (lncRNAs) are reported to play important roles in tumorigenesis of various malignant tumors. However, the clinical significance of aberrant lncRNA expression in hepatocellular carcinoma (HCC) is still elusive. Methods Firstly, a differentially expressed lncRNA CTC‐297N7.9 in HCC was detected by analyzing the data from The Cancer Genome Atlas (TCGA). Secondly, the expression level of CTC‐297N7.9 was examined in four HCC cell lines and 60 pairs of HCC tissues by polymerase chain reaction (PCR) assay at our center. Thirdly, receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic value of CTC‐297N7.9 for HCC. Correlation and survival analysis of HCC patients from the TCGA and our center were also carried out to assess the predictive value of CTC‐297N7.9. Finally, survival prognostic models were established combining lncRNA expression and other clinical parameters. Results The expression of CTC‐297N7.9 was downregulated in HCC cell lines and HCC tissues. ROC curve revealed its significant diagnostic value in HCC. CTC‐297N7.9 expression correlated with serum alpha‐fetal protein (AFP), tumor stage, and tumor differentiation. Survival analysis indicated that overall survival (OS) and disease‐free survival (DFS) are all positively associated with CTC‐297N7.9 expression, especially in patients without viral hepatitis or cirrhosis. Cox regression analysis showed that CTC‐297N7.9 expression level is an independent prognostic factor for both OS and DFS in HCC patients. Based on the model, CTC‐297N7.9 was observed to be negatively correlated to risk score, indicating its role as a protective factor for HCC. Conclusion Our study demonstrated that the low expression of CTC‐297N7.9 is associated with poor prognosis in HCC patients, suggesting its possible role as a potential prognostic marker for HCC., Our study demonstrated a novel long noncoding RNA CTC‐297N7.9, which expression was negatively correlated with the prognosis of hepatocellular carcinoma (HCC) patients, using bioinformatics analysis method and tissue specimen. CTC‐297N7.9 was proved to have potential to be a prognostic biomarker for HCC.

Background and Aims: Cholecystectomy is the “gold standard” for treating diseases of the gallbladder. In addition, non-alcoholic fatty liver disease (NAFLD), liver fibrosis or cirrhosis, are major causes of morbidity and mortality across the world. However, the association between cholecystectomy and these diseases is still unclear. We assessed the association among US adults and examined the possible risk factors.Methods: This cross-sectional study used data from 2017 to 2018 National Health and Nutrition Examination Survey, a population-based nationally representative sample of US. Liver fibrosis and cirrhosis were defined by median stiffness, which was assessed by transient elastography. Furthermore, patients who had undergone cholecystectomy were identified based on the questionnaire. In addition, Propensity Score Matching (PSM, 1:1) was performed based on gender, age, body mass index (BMI) and diabetes.Results: Of the 4,497 included participants, cholecystectomy was associated with 60.0% higher risk of liver fibrosis (OR:1.600;95% CI:1.278–2.002), and 73.3% higher risk of liver cirrhosis (OR:1.733, 95% CI:1.076–2.792). After PSM based on age, gender, BMI group and history of diabetes, cholecystectomy was associated with 139.3% higher risk of liver fibrosis (OR: 2.393;95% CI: 1.738–3.297), and 228.7% higher risk of liver cirrhosis (OR: 3.287, 95% CI: 1.496–7.218).Conclusions: The present study showed that cholecystectomy is positively associated with liver fibrosis and cirrhosis in US adults. The discovery of these risk factors therefore provides new insights on the prevention of NAFLD, liver fibrosis, and cirrhosis.

The Brisbane 2000 Terminology for Liver Anatomy and Resections, based on Couinaud's segments, did not address how to identify segmental borders and anatomic territories of less than one segment. Smaller anatomic resections including segmentectomies and subsegmentectomies, have not been well defined. The advent of minimally invasive liver resection has enhanced the possibilities of more precise resection due to a magnified view and reduced bleeding, and minimally invasive anatomic liver resection (MIALR) is becoming popular gradually. Therefore, there is a need for updating the Brisbane 2000 system, including anatomic segmentectomy or less. An online "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was hosted on February 23, 2021.The Steering Committee invited 34 international experts from around the world. The Expert Committee (EC) selected 12 questions and two future research topics in the terminology session. The EC created seven tentative definitions and five recommendations based on the experts' opinions and the literature review performed by the Research Committee. Two Delphi Rounds finalized those definitions and recommendations.This paper presents seven definitions and five recommendations regarding anatomic segmentectomy or less. In addition, two future research topics are discussed.The PAM-HBP Surgery Consensus has presented the Tokyo 2020 Terminology for Liver Anatomy and Resections. The terminology has added definitions of liver anatomy and resections that were not defined in the Brisbane 2000 system.

Reconfiguration of amorphous complex oxides provides a readily controllable source of stress that can be leveraged in nanoscale assembly to access a broad range of 3D geometries and hybrid materials. An amorphous SrTiO3 layer on a Si:B/Si1-x Gex :B heterostructure is reconfigured at the atomic scale upon heating, exhibiting a change in volume of ≈2% and accompanying biaxial stress. The Si:B/Si1-x Gex :B bilayer is fabricated by molecular beam epitaxy, followed by sputter deposition of SrTiO3 at room temperature. The processes yield a hybrid oxide/semiconductor nanomembrane. Upon release from the substrate, the nanomembrane rolls up and has a curvature determined by the stress in the epitaxially grown Si:B/Si1-x Gex :B heterostructure. Heating to 600 °C leads to a decrease of the radius of curvature consistent with the development of a large compressive biaxial stress during the reconfiguration of SrTiO3 . The control of stresses via post-deposition processing provides a new route to the assembly of complex-oxide-based heterostructures in 3D geometry. The reconfiguration of metastable mechanical stressors enables i) synthesis of various types of strained superlattice structures that cannot be fabricated by direct growth and ii) technologies based on strain engineering of complex oxides via highly scalable lithographic processes and on large-area semiconductor substrates.

Background The concept of Minimally invasive anatomic liver resection (MIALR) is gaining popularity. However, specific technical skills need to be acquired to safely perform MIALR. The "Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (PAM-HBP Surgery Consensus)" was developed as a special program during the 32nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS). Methods Thirty-four international experts gathered online for the consensus. A Research Committee performed a comprehensive literature review, classifying studies according to the Scottish Intercollegiate Guidelines Network (SIGN) method. Based on the literature review and experts' opinions, tentative recommendations were drafted and circulated among experts using online Delphi Rounds. Finally, formulated recommendations were presented online in the Expert Consensus Meeting of the JSHBPS on February 23rd, 2021. The final recommendations were validated and finalized by the 2nd Delphi Round in May 2021. Results Seven Clinical Questions (CQs) were selected, and 22 recommendations were formulated. All recommendations reached more than 85% consensus among experts at the final Delphi Round. Conclusions The Expert Consensus Meeting for safely performing MIALR has presented a set of clinical guidelines based on available literature and experts' opinions. We expect these guidelines to have a favorable effect on the safe implementation and development of MIALR.

Background This study aimed to investigate the work status of clinicians in China and their management strategy alteration for patients with hepatocellular carcinoma (HCC) during the COVID-19 pandemic. Methods A nationwide online questionnaire survey was conducted in 42 class-A tertiary hospitals across China. Experienced clinicians of HCC-related specialties responded with their work status and management suggestions for HCC patients during the pandemic. Results 716 doctors responded effectively with a response rate of 60.1%, and 664 were included in the final analysis. Overall, 51.4% (341/664) of clinicians reported more than a 60% reduction of the regular workload and surgeons declared the highest proportion of workload reduction. 92.5% (614/664) of the respondents have been using online medical consultation to substitute for the “face-to-face” visits. Adaptive adjustment for the treatment strategy for HCC was made, including the recommendations of noninvasive and minimally invasive treatments such as transcatheter arterial chemoembolization for early and intermediate stage. Targeted therapy has been the mainstay for advanced stage and also as a bridge therapy for resectable HCC. Discussion During the COVID-19 pandemic, online medical consultation is recommended to avoid social contact. Targeted therapy as a bridge therapy is recommended for resectable HCC considering the possibility of delayed surgery.

An atomic layer deposition (ALD) process is reported for the growth of nanoscale PrAlO3 thin films for two-dimensional electronics and memory device applications using tris(isopropylcyclopentadieny...

The objective of this meta-analysis was to evaluate the effectiveness and safety of lymph node dissection (LND) in patients with intrahepatic cholangiocarcinoma (ICC).A literature search with a date range of January 2000 to January 2018 was performed to identify studies comparing lymph node dissection (LND+) with non-lymph node dissection (LND-) for patients with ICC. The LND + group was further divided into positive (LND + N+) and negative (LND + N-) lymph node status groups based on pathological analysis.13 studies including 1377 patients were eligible. There were no significant differences in overall survival (OS) (HR 1.13, 95% CI 0.94-1.36; P = 0.20), disease-free survival (DFS) (HR 1.23, 95% CI 0.94-1.60; P = 0.13), or recurrence (OR 1.39, 95% CI 0.90-2.15; P = 0.14) between LND + group and LND-group. Postoperative morbidity was significantly higher in the LND + group (OR 2.67, 95% CI 1.74-4.10; P 0.001). A subset analysis showed that OS was similar between LND + N- and LND-groups (HR 1.13, 95% CI 0.82-1.56; P = 0.450). However when comparing, OS of the LND-group to the LND+N+ group there was a significant increase in OS for the LND-group (HR 3.26, 95% CI 1.85-5.76; P 0.001).LND does not seem to positively affect overall survival and is associated with increased post-operative morbidity.

Background: Sorafenib appears to increase the survival rate of hepatocellular carcinoma (HCC) patients, but its response rate is seriously limited due to drug resistance. Molecular mechanisms underlying sorafenib resistance are still unknown. Herein, we explored the possible role of miR-1226-3p in sorafenib resistance of HCC. Methods: The miR-1226-3p expression level in HCC cell lines was evaluated by qRT-PCR. Cell viabilities to sorafenib were measured by CCK-8 assay. Cell apoptosis and proliferation were detected by flow cytometry and EdU proliferation assay. A luciferase reporter of DUSP4 3'-UTR was used for validation as a target gene of miR-1226-3p. Finally, the effects of in vivo antitumor efficacy of miR-1226-3p combined with sorafenib were evaluated by HCC tumor xenografts in nude mice. Results: Bioinformatics analysis from Gene Expression Omnibus (GEO) datasets GSE56059 suggested that miR-1226-3p expression was downregulated in HCC patients who showed progressive disease (PD) after sorafenib treatment. SK-HEP-1 cells expressed lower levels of miR-1226-3p than HepG2 cells. We confirmed that SK-HEP-1 cells were more resistant to sorafenib compared to HepG2 cells. In addition, miR-1226-3p mimic increased cell apoptosis of SK-HEP-1 cells, whereas miR-1226-3p inhibitor significantly impaired cell apoptosis of HepG2 cells after sorafenib treatment. Moreover, we validated that miR-1226-3p directly targeted dual specificity phosphatase 4 (DUSP4), and further demonstrated that knockdown of DUSP4 reduced sorafenib resistance by regulating the JNK-Bcl-2 axis. Conclusions: miR-1226-3p promotes sorafenib sensitivity of HCC through downregulation of DUSP4 expression, and targeting miR-1226-3p may be a novel therapeutic strategy for overcoming sorafenib resistance.

Crystallization from an amorphous precursor presents a new route to control the properties of complex oxides by selecting their nanoscale morphology. A key challenge in crystal growth from the amor...

Background The role of tumor necrosis factor alpha (TNF-α) in targeted therapy for hepatocellular carcinoma (HCC) remains largely unknown. The current study aimed to clarify the mechanistic effects of targeting TNF-α to overcome sorafenib resistance in HCC. Methods A correlation of TNF-α expression with the prognosis was analyzed in 62 HCC patients who underwent surgical resection and subsequent received adjuvant sorafenib treatment. The relation of TNF-α expression and sorafenib sensitivity was determined in different HCC cell lines. The combined therapeutic effects of sorafenib and ulinastatin, which could inhibit TNF-α expression, on HCC were examined in vitro and in vivo. Findings High TNF-α expression was correlated with poor outcomes in HCC patients who received adjuvant sorafenib after surgery. In vitro experiments showed that TNF-α promotes HCC cell resistant to sorafenib through inducing epithelial-mesenchymal transition (EMT). Notably, the current study revealed that sorafenib has no significant influence on the expression and secretion of TNF-α, and sorafenib had limited effectiveness on reversing EMT in HCC cells with high TNF-α expression. Inhibiting the expression of TNF-α with ulinastatin significantly enhanced the anti-tumor effect of sorafenib on HCC cells with high expression of TNF-α in vitro and in vivo. Interpretation: Our findings indicate that TNF-α may serve as a novel predictor of sorafenib sensitivity in HCC patients. Sorafenib combined with ulinastatin may improve the effectiveness of treatment of HCC in patients with high expression of TNF-α. Fund This work was supported by grants from the National Natural Science Foundation of China (no.81572398; no.81672419), the Science and Technology Planning Project of Guangdong Province (no. 2017A010105003; no.2015A050502023; no.2016A020216010), and the Natural Science Foundation of Guangdong Province (no.2014A030313061; no. 2013B021800101).

e16181 Background: The effect of checkpoint inhibitor therapy on HBV infection is uncertain. TIS, an anti-PD-1 antibody, was clinically active and well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). Objective response rate by independent committee review (IRC) in pts with a history of HBV infection was consistent with the overall population (12.5% vs 13.3%, respectively). We explored whether TIS treatment was associated with increased HBV DNA and the clinical significance of HBV DNA elevations. Methods: Pts with ≥ 1 prior systemic therapy for advanced HCC received TIS 200 mg IV Q3W. Pts with inactive, chronic, or active HBV were eligible if HBV DNA levels were < 500 IU/mL at screening (pts with detectable hepatitis B surface antigen [HBsAg] or detectable HBV DNA were required to be managed per treatment guidelines). HBV DNA testing was conducted every 4 cycles if HBV DNA was detectable at screening, or when clinically indicated. Results: Among 249 enrolled pts, 128 had a history of HBV infection. Of these pts, 114 were HBsAg positive at baseline (BL), 36 had detectable HBV DNA at BL, and 32 had detectable HBV DNA and HBsAg at BL. Clinically significant increases in HBV DNA levels from BL were reported in 7 pts, with no pattern relative to the time of TIS initiation (Table). All 7 pts were HBsAg positive at BL and had been receiving antiviral treatment for ≥ 3 months before the first dose of TIS. Six out of the 7 pts had increases in alanine transaminase (ALT) from BL during the study (Table), 4 of whom had ≥ 3-fold increases in ALT which were observed concurrently or soon after HBV DNA increases. IRC-assessed best overall response (BOR) was partial response (PR) for 1 pt with increased HBV DNA and progressive disease for the remaining 6. HBV-related treatment-emergent adverse events (TEAEs) were reported in 6 of the 7 pts (2 pts had a Grade 3 TEAE of hepatitis B; 2 pts had a Grade 2 TEAE of HBV reactivation; 2 pts had a TEAE of increased HBV DNA, with one Grade 1 and one Grade 3 event). All HBV-related TEAEs were non-serious and did not result in discontinuation of TIS. Conclusions: Clinically significant increases in HBV DNA from BL were reported in a small number of pts, which does not suggest that TIS is associated with increased HBV DNA. Tumor responses in these pts were consistent with the overall population and HBV-related TEAEs were manageable and did not require discontinuation of TIS, demonstrating that HBV DNA increases did not impact treatment. The effects of TIS in pts with HBV infection will be further investigated in an ongoing Phase 3 trial (NCT03412773). Clinical trial information: NCT03419897. [Table: see text]

Background Sorafenib can prolong the survival of patients with advanced hepatocellular carcinoma (HCC). However, drug resistance remains the main obstacle to improving its efficiency. This study aimed to explore the likely molecular mechanism of sorafenib resistance. Methods Differentially expressed microRNAs (miRNAs) related to sorafenib response were analyzed with the Limma package in R software. The expression levels of miR-126-3p and sprouty-related EVH1 domain-containing protein 1 (SPRED1) in HCC cells were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell viability and proliferation were detected with Cell Counting Kit-8 (CCK-8), EdU proliferation, and clone formation assays. Transwell assays were performed to measure cell migration and invasion. TargetScan, MicroRNA Target Prediction Database (miRDB), and StarBase v2.0 were used to predict the targets of miR-126-3p. SPRED1 was confirmed as a target gene of miR-126-3p by dual-luciferase reporter assay and Western blotting. Finally, the in vivo anti-tumor effect of LV-miR-126-3p inhibitor combined with sorafenib was evaluated via subcutaneous tumor models. Results HCC cells with high expression of miR-126-3p exhibited increased resistance to sorafenib. The results of bioinformatics analysis and the dual-luciferase reporter assay showed that miR-126-3p directly targeted SPRED1. The sensitivity of HCC cells to sorafenib was markedly enhanced by SPRED1 upregulation. Gain- and loss-of function experiments verified that miR-126-3p induced sorafenib resistance in HCC through downregulating SPRED1. Furthermore, the inhibition of miR-126-3p markedly increased the effectiveness of sorafenib against HCC in vivo. Mechanistically, our results suggested that miR-126-3p promoted sorafenib resistance via targeting SPRED1 and activating the ERK signaling pathway. Conclusions Our study demonstrates that regulating the miR-126-3p/SPRED1 axis might be a promising strategy for enhancing the antitumor effect of sorafenib in the treatment of HCC.

4072 Background: Tislelizumab, an anti-PD-1 monoclonal antibody, demonstrated clinical activity and was well tolerated in pts with previously treated advanced HCC in the Phase 2 RATIONALE-208 study (NCT03419897). At the time of this study, SOR and LEN were recommended first-line treatments for pts with advanced HCC and continue to have an important role in the first-line treatment of HCC despite the recent approval of new immuno-oncology-based combinations (atezolizumab and bevacizumab) in some regions. We report the clinical outcomes of pts with advanced HCC who were previously treated with SOR/LEN. Methods: Pts who had received ≥ 1 prior line of systemic therapy for advanced HCC received tislelizumab 200 mg intravenously once every three weeks. Objective response rate (ORR) by independent review committee (IRC) (ORRIRC), duration of response by IRC (DORIRC), progression-free survival by IRC (PFSIRC), overall survival (OS), and safety were evaluated in pts who had been previously treated with SOR/LEN. Results: As of February 2020, 249 pts were enrolled and 235 pts had received prior treatment with SOR/LEN, of whom 126 and 109 pts had received 1 or ≥ 2 prior lines of systemic therapy, respectively. At study entry, 211 (89.8%) pts had BCLC stage C and 187 (79.6%) pts had extrahepatic spread. Median follow-up duration for pts previously treated with SOR/LEN was 12.5 months and ORRIRC was 13.6% (95% CI: 9.5, 18.7), including 2 complete responses and 30 partial responses. Median DORIRC was not reached. Median PFSIRC and OS of pts previously treated with SOR/LEN was 2.7 months (95% CI: 1.6, 2.8) and 13.5 months (95% CI: 10.9, 15.8), respectively. Tislelizumab was generally well tolerated in pts previously treated with SOR/LEN (Table), and the most common treatment-emergent adverse events were increased aspartate aminotransferase (n=70; 28.1%) and alanine aminotransferase (n=52; 20.9%). Conclusions: Tislelizumab was investigated beyond the first-line setting, as effective second- and third-line treatment options are limited for pts with advanced HCC and there is an unmet medical need. This analysis indicates that tislelizumab is clinically active and well tolerated in pts with advanced HCC who have received prior systemic treatment with SOR/LEN. Clinical trial information: NCT03419897. [Table: see text]