Isoporous Membrane Mediated Imprinting Mass Spectrometry Imaging for Spatially-Resolved Metabolomics and Rapid Histopathological Diagnosis.

Surface-assisted laser desorption/ionization (SALDI) mass spectrometry imaging (MSI) holds great value in spatial metabolomics and tumor diagnosis. Tissue imprinting on the SALDI target can avoid laser-induced tissue ablation and simplifies the sample preparation. However, the tissue imprinting process always causes lateral diffusion of biomolecules, thereby losing the fidelity of metabolite distribution on tissue. Herein, a membrane-mediated imprinting mass spectrometry imaging (MMI-MSI) strategy is proposed using isoporous nuclepore track-etched membrane as a mediating imprinting layer to selectively transport metabolites through uniform and vertical pores onto silicon nanowires (SiNWs) array. Compared with conventional direct imprinting technique, MMI-MSI can not only exclude the adsorption of large biomolecules but also avoid the lateral diffusion of metabolites. The whole time for MMI-based sample preparation can be reduced to 2 min, and the lipid peak number can increase from 46 to 113 in kidney tissue detection. Meanwhile, higher resolution of MSI can be achieved due to the confinement effect of the pore channel in the diffusion of metabolites. Based on MMI-MSI, the tumor margins of liver cancer can be clearly discriminated and their different subtypes can be precisely classified. This work demonstrates MMI-MSI is a rapid, highly sensitive, robust and high-resolution technique for spatially-resolved metabolomics and pathological diagnosis.

Risk factor analysis of conversion in laparoscopic liver resection for intrahepatic cholangiocarcinoma.

BACKGROUND: The risk factors of patients with intrahepatic cholangiocarcinoma (ICC) requiring conversion to open surgery have not been adequately studied. This study aimed to determine the risk factors and postoperative outcomes of conversion in patients with ICC. METHODS: From May 2014 to September 2022, Unplanned conversions were compared with successful LLRs. RESULTS: 153 patients with ICC initially underwent LLR, of which 41 (26.8%) required conversion to open surgery. Multivariate analysis for those factors that were statistically significant or confirmed by clinical studies, tumor proximity to the major vessels (OR 6.643, P < 0.001), and previous upper abdominal surgery (OR 3.140, P = 0.040) were independent predictors of unplanned conversions. Compared to successful LLRs, unplanned conversions showed longer operative times (300.0 vs. 225.0 min, P < 0.001), more blood loss (500.0 vs. 200.0 mL, P < 0.001), higher transfusion rates (46.3% vs. 11.6%, P < 0.001), longer length of stays (13.0 vs. 8.0 days, P < 0.001), and higher rates of major morbidity (39.0% vs. 11.6%, P < 0.001). However, there was no statistically significant difference in 30-day or 90-day mortality between the conversion group and the laparoscopic group. CONCLUSION: Conversion during LLR should be anticipated in ICC patients with prior upper abdominal surgery or tumor proximity to major vessels as features.

Activation of IGFBP4 via unconventional mechanism of miRNA attenuates metastasis of intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy. Although its incidence is lower than that of hepatocellular carcinoma (HCC), ICC has a worse prognosis, and it is more prone to recur and metastasize, resulting in a far greater level of malignancy. METHODS: Bioinformatics analysis and qRT-PCR were applied to assess the level of miR-122-5p and IGFBP4. Western blot, transwell assays, wound-healing assays, real-time cellular invasion monitoring, in vivo study were applied to explore the function of miR-122-5p and IGFBP4. Dual luciferase reporter assays and chromatin isolation by RNA purification (ChiRP) were applied to explore the regulation of IGFBP4 by miR-122-5p. RESULTS: Using The Cancer Genome Atlas (TCGA) data set, Sir Run Run Shaw hospital data set and bioinformatics analyses, we identified miR-122-5p as a potential tumor suppressor in ICC and validated its suppressive effect in metastasis and invasion of ICC. Transcriptome sequencing, rescue and complement experiments were used to identify insulin-like growth factor binding protein 4 (IGFBP4) as a target of miR-122-5p. The mechanism by which miR-122-5p regulates IGFBP4 was clarified by chromatin separation RNA purification technology, and dual-luciferase reporter assays. We discovered a rare novel mechanism by which miR-122-5p promotes IGFBP4 mRNA transcription by binding to its promoter region. Furthermore, in mouse orthotopic metastasis model, miR-122-5p inhibited the invasion of ICC. CONCLUSION: In summary, our study revealed a novel mechanism of miR-122-5p and function of the miR-122-5p/IGFBP4 axis in the metastasis of ICC. We also highlighted the clinical value of miR-122-5p and IGFBP4 in inhibiting ICC invasion and metastasis.

cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence.

Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.

Exploration of a screening model for intrahepatic cholangiocarcinoma patients prone to cuproptosis and mechanisms of the susceptibility of CD274-knockdown intrahepatic cholangiocarcinoma cells to cuproptosis.

Intrahepatic cholangiocarcinoma (ICC) is a form of liver cancer with poor long-term survival rates that requires novel therapeutic methods. Our team's previous research found that ICC patients prone to cuproptosis possessed a more satisfactory long-term prognosis and a more sensitive response to copper carrier Elesclomol. Thus, we aimed to identify new diagnostic and treatment strategies for ICC patients prone to cuproptosis and further explore the associated intracellular and extracellular mechanisms of ICC cells prone to cuproptosis. We employed FU-ICC (n = 255) as the training dataset, and validated our findings using SRRSH-ICC (from our center, n = 65), GSE26566 (n = 104), E-MTAB-6389 (n = 78), and scRNA-seq (n = 14) datasets. Single sample gene set enrichment analysis and subsequent unsupervised cluster analysis was conducted on the training dataset for the pan-programmed cell death gene set (including apoptosis, autophagy, ferroptosis, pyroptosis, necroptosis, and cuproptosis) to define and screen ICC patients prone to cuproptosis. We constructed a nomogram model using weighted gene co-expression network analysis and machine learning algorithms to predict ICC patients prone to cuproptosis, then explored its clinical value with multi-center transcriptome profiling. Furthermore, we validated the hub genes with in vitro and animal experiments to define ICC cells prone to cuproptosis. Ultimately, bulk and single-cell transcriptome profiling were utilized to explore the immune microenvironment of ICC cells prone to cuproptosis. Our nomogram model could help predict ICC patients prone to cuproptosis and possessed excellent prediction efficiency and clinical significance via internal and external verification. In vitro experiments demonstrated that ICC cells with siRNA-mediated knockdown of CD274 (PD-L1) and stimulation with elescomol-CuCl2 were prone to cuproptosis, and CD274-negative ICC cells could be defined as ICC cells prone to cuproptosis. The safety and feasibility of lenti-sh CD274+Elesclomol-CuCl2 as a therapeutic approach for ICC were verified using bioinformatics analysis and animal experiments. Bulk and single-cell transcriptome profiling indicated that the interactions between ICC cells prone to cuproptosis and monocytes/macrophages were particularly relevant. In conclusion, this study systematically and comprehensively explored cuproptosis in ICC for the first time. We constructed precise diagnostic and treatment strategies for ICC patients prone to cuproptosis and further explored the intracellular and extracellular mechanisms of ICC cells prone to cuproptosis. Further work with large prospective cohorts will help verify these conclusions.

Circ-RAPGEF5 promotes intrahepatic cholangiocarcinoma progression by stabilizing SAE1 to facilitate SUMOylation.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with a poor prognosis. The underlying functions and mechanisms of circular RNA and SUMOylation in the development of ICC remain poorly understood. METHODS: Circular RNA hsa_circ_0001681 (termed Circ-RAPGEF5 hereafter) was identified by circular RNA sequencing from 19 pairs of ICC and adjacent tissue samples. The biological function of Circ-RAPGEF5 in tumor proliferation and metastasis was examined by a series of in vitro assays. A preclinical model was used to validate the therapeutic effect of targeting Circ-RAPGEF5. RNA pull-down and dual-luciferase reporter assays were used to access the RNA interactions. Western blot and Co-IP assays were used to detect SUMOylation levels. RESULTS: Circ-RAPGEF5, which is generated from exons 2 to 6 of the host gene RAPGEF5, was upregulated in ICC. In vitro and in vivo assays showed that Circ-RAPGEF5 promoted ICC tumor proliferation and metastasis, and inhibited apoptosis. Additionally, high Circ-RAPGEF5 expression was significantly correlated with a poor prognosis. Further investigation showed that SAE1, a potential target of Circ-RAPGEF5, was also associated with poor oncological outcomes. RNA pull-down and dual-luciferase reporter assays showed an interaction of miR-3185 with Circ-RAPGEF5 and SAE1. Co-IP and western blot assays showed that Circ-RAPGEF5 is capable of regulating SUMOylation. CONCLUSION: Circ-RAPGEF5 promotes ICC tumor progression and SUMOylation by acting as a sponge for miR-3185 to stabilize SAE1. Targeting Circ-RAPGEF5 or SAE1 might be a novel diagnostic and therapeutic strategy in ICC.

Bulk and single-cell transcriptome profiling reveal extracellular matrix mechanical regulation of lipid metabolism reprograming through YAP/TEAD4/ACADL axis in hepatocellular carcinoma.

Emerging studies have revealed matrix stiffness promotes hepatocellular carcinoma (HCC) development. We studied metabolic dysregulation in HCC using the TCGA-LIHC database (n=374) and GEO datasets (GSE14520). HCC samples were classified into three heterogeneous metabolic pathway subtypes with different metabolic profiles: Cluster 1, an ECM-producing subtype with upregulated glycan metabolism; Cluster 2, a hybrid subtype with partial pathway dysregulation. Cluster 3, a lipogenic subtype with upregulated lipid metabolism; These three subtypes have different prognosis, clinical features and genomic alterations. We identified key enzymes that respond to matrix stiffness and regulate lipid metabolism through bioinformatic analysis. We found long-chain acyl-CoA dehydrogenase (ACADL) is a mechanoreactive enzyme that reprograms HCC cell lipid metabolism in response to extracellular matrix stiffness. ACADL is also regarded as tumor suppressor in HCC. We found that increased extracellular matrix stiffness led to activation of Yes-associated protein (YAP) and the YAP/TEA Domain transcription factor 4 (TEAD4) transcriptional complex was able to directly repress ACADL at the transcriptional level. The ACADL-dependent mechanoresponsive pathway is a potential therapeutic target for HCC treatment.

Safety and feasibility of laparoscopic liver resection for intrahepatic cholangiocarcinoma: a propensity score-matched study.

BACKGROUND: Laparoscopic liver resection (LLR) is controversial in treating intrahepatic cholangiocarcinoma (ICC). Therefore, this study aimed to evaluate the safety and feasibility of LLR for the treatment of ICC and explored the independent factors affecting the long-term prognosis of ICC. METHODS: We included 170 patients undergoing hepatectomy for ICC from December 2010 to December 2021 and divided them into LLR group and open liver resection (OLR) group. We used propensity score matching (PSM) analysis to reduce the impact of data bias and confounding variables and then compared the short-term and long-term prognosis of LLR and OLR in treating ICC; Cox proportional hazards regression model was adopted to explore the independent factors affecting the long-term prognosis of ICC. RESULTS: A total of 105 patients (70 in the LLR group and 35 in the OLR group) were included after 2:1 PSM analysis. There was no difference in demographic characteristics and preoperative indexes between the two groups. The perioperative results of the OLR group were worse than those of the LLR group, that is, the intraoperative blood transfusion rate (24 (68.6) vs 21 (30.0)), blood loss (500 (200-1500) vs 200 (100-525)), and the morbidity of major postoperative complications (9 (25.7) vs 6 (8.5)) in the OLR group were worse than those in LLR group. LLR could enable patients to obtain an equivalent long-term prognosis compared to OLR. The Cox proportional hazards regression model exhibited that no matter before or after PSM, preoperative serum CA12-5 and postoperative hospital stay were independent factors affecting overall survival, while only lymph node metastasis independently influenced recurrence-free survival. CONCLUSIONS: Compared with ICC treated by OLR, the LLR group obtained superior perioperative period outcomes. In the long run, LLR could enable ICC patients to receive an equivalent long-term prognosis compared to OLR. In addition, ICC patients with preoperative abnormal CA12-5, lymph node metastasis, and more extended postoperative hospital stay might suffer from a worse long-term prognosis. However, these conclusions still need multicenter extensive sample prospective research to demonstrate.

Efficacy of laparoscopic repeat hepatectomy compared with open repeat hepatectomy: a single-center, propensity score matching study.

INTRODUCTION: Laparoscopic repeat hepatectomy (LRH) is considered to be a technically challenging procedure which has not been widely applied. This study aimed to assess the accessibility and security of LRH for patients with hepatic tumor recurrence. METHODS: Between January 2010 and October 2020, we performed 48 LRHs and 31 open repeat hepatectomies (ORHs) for recurrent liver cancer. LRHs were matched to ORHs (1:1) using propensity score matching (PSM) created by comparing preoperative factors. The perioperative data of patients were retrospectively analyzed, including baseline data, operative time, intraoperative blood loss, pathology, days of postoperative stay, complication morbidity, and mortality within 30 days. Overall survival and recurrence-free survival rates with appropriate follow-up were obtained to evaluate the long-term outcomes. RESULTS: Compared with the ORH, LRH was related with shorter operative duration (169.9 versus 232.9 ml, p < 0.01), less intraoperative bleeding (100.0 versus 500.0 ml, p < 0.01), lower rate of blood transfusion (8.3% versus 58.1%, p < 0.01), and shorter hospitalization (5.0 versus 11.0 days, p < 0.01). The median follow-up was 31 months. The LRH 1-, 3-, and 5-year overall survival were 77.1%, 61.6%, and 46.2% versus 82.3%, 66.5%, and 29.5% for ORH (p = 0.77). The 1-, 3-, and 5-year disease-free survival rates of the two groups were 73.4%, 62.0%, and 44.3% versus 66.1%, 44.1%, and 14.7%, respectively (p = 0.22). CONCLUSIONS: Laparoscopic repeated hepatectomy is safe and practicable with great short-term results for selected patients.

TAK1 Is a Novel Target in Hepatocellular Carcinoma and Contributes to Sorafenib Resistance.

BACKGROUND & AIMS: Identifying novel and actionable targets in hepatocellular carcinoma (HCC) remains an unmet medical need. TAK1 was originally identified as a transforming growth factor-ß-activated kinase and was further proved to phosphorylate and activate numerous downstream targets and promote cancer progression. However, the role of TAK1 in developed HCC progression and targeted therapy resistance is poorly understood. METHODS: The expression of TAK1 or MTDH in HCC cell lines, tumor tissues, and sorafenib-resistant models was analyzed by in silico analysis, quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. In vivo and in vitro experiments were introduced to examine the function of TAK1 or MTDH in HCC and sorafenib resistance using small interfering RNA and pharmacologic inhibitors in combination with or without sorafenib. Co-immunoprecipitation and RNA immunoprecipitation were carried out to determine the binding between TAK1 and FBXW2 or between MTDH and FBXW2 mRNA. Protein half-life and in vitro ubiquitination experiment was performed to validate whether FBXW2 regulates TAK1 degradation. RESULTS: Our findings unraveled the clinical significance of TAK1 in promoting HCC and sorafenib resistance. We identified a novel E3 ubiquitin ligase, FBXW2, targeting TAK1 for K48-linked polyubiquitylation and subsequent degradation. We also found that MTDH contributes to TAK1 up-regulation in HCC and sorafenib resistance through binding to FBXW2 mRNA and accelerates its degradation. Moreover, combination of TAK1 inhibitor and sorafenib suppressed the growth of sorafenib-resistant HCCLM3 xenograft in mouse models. CONCLUSIONS: These results revealed novel mechanism underlying TAK1 protein degradation and highlighted the therapeutic value of targeting TAK1 in suppressing HCC and overcoming sorafenib resistance.

UBQLN1 mediates sorafenib resistance through regulating mitochondrial biogenesis and ROS homeostasis by targeting PGC1ß in hepatocellular carcinoma.

The treatment for hepatocellular carcinoma (HCC) is promising in recent years, but still facing critical challenges. The first targeted therapy, sorafenib, prolonged the overall survival by months. However, resistance often occurs, largely limits its efficacy. Sorafenib was found to target the electron transport chain complexes, which results in the generation of reactive oxygen species (ROS). To maintain sorafenib resistance and further facilitate tumor progression, cancer cells develop strategies to overcome excessive ROS production and obtain resistance to oxidative stress-induced cell death. In the present study, we investigated the roles of ROS in sorafenib resistance, and found suppressed ROS levels and reductive redox states in sorafenib-resistant HCC cells. Mitochondria in sorafenib-resistant cells maintained greater functional and morphological integrity under the treatment of sorafenib. However, cellular oxygen consumption rate and mitochondria DNA content analyses revealed fewer numbers of mitochondria in sorafenib-resistant cells. Further investigation attributed this finding to decreased mitochondrial biogenesis, likely caused by the accelerated degradation of peroxisome proliferator-activated receptor γ coactivator 1ß (PGC1ß). Mechanistic dissection showed that upregulated UBQLN1 induced PGC1ß degradation in a ubiquitination-independent manner to attenuate mitochondrial biogenesis and ROS production in sorafenib-resistant cells under sorafenib treatment. Furthermore, clinical investigations further indicated that the patients with higher UBQLN1 levels experienced worse recurrence-free survival. In conclusion, we propose a novel mechanism involving mitochondrial biogenesis and ROS homeostasis in sorafenib resistance, which may offer new therapeutic targets and strategies for HCC patients.

Differentiation and management of hepatobiliary mucinous cystic neoplasms: a single centre experience for 8 years.

BACKGROUND: Hepatobiliary mucinous cystic neoplasms (H-MCNs) are relatively rare cystic neoplasms in the liver. The differential diagnosis of H-MCNs remains big challenging, and the management and prognosis between the hepatic simple cyst (HSC) and H-MCNs are quite different. This study aimed to present our experience in the management of H-MCNs and provide a preoperative H-MCNs risk prediction nomogram to differentiating H-MCNs from liver cystic lesions. METHODS: 29 patients diagnosed with H-MCNs and 75 patients diagnosed with HSC between June 2011 and June 2019 at Zhejiang University School of medicine, Sir Run-Run Shaw Hospital were reviewed in this study. We analyzed the demographic and clinicopathological variables. RESULTS: US, CT, and MRI could accurately diagnose only 3.4%, 46.1%, and 57.1% of H-MCNs, respectively. After univariate analysis and multivariate logistic regression analysis, the variables significantly associated with H-MCNs were enhancement after contrast (p = 0.009), tumour located in the left lobe (p = 0.02) and biliary ductal dilation (p = 0.027). An H-MCNs risk predictive nomogram was constructed, which showed excellent discrimination (areas under the receiver operating characteristic curve were 0.940) and consistent calibration between the predicted probability and actual probability. CONCLUSION: Among patients with H-MCNs, the location of the tumour, enhancement in CT scan, and biliary duct dilation are significantly independent risk factors. The appropriate treatment of H-MCNs is radical resection. Using our Nomogram could facilitate screening and identification of patients with liver cystic lesions.

Laparoscopic anatomical portal territory hepatectomy using Glissonean pedicle approach (Takasaki approach) with indocyanine green fluorescence negative staining: how I do it.

BACKGROUND: Laparoscopic anatomical resection (LAR) is a highly challenging procedure. This study aimed to describe our experience of the LAR with an indocyanine green fluorescence negative staining (ICGNS) by the Glissonean pedicle transection (Takasaki) approach. METHODS: From April 2017 to December 2019, 43 consecutive patients underwent LAR with ICGNS strategy in our medical team. The details of the ICGNS strategy were described. The demographic and clinicopathological data of the included patients were retrospectively analyzed. RESULTS: The extent of resections included right hemihepatectomy (n = 12), left hemihepatectom (n = 4), left lateral sectionectomy (n = 3), Right anterior sectionectomy (n = 3), Right posterior sectionectomy (n = 6), central hepatectomy (n = 2), single anterolateral segmentectomy (n = 5), single posterosuperior segmentectomy (n = 6), and bisegmentectomy (n = 2). The mean operation time was 212 ± 53 min, and the median estimated blood loss was 200 (100-300) ml. The overall complication rate was 30.2% (grade I, 14%; grade II, 14%; grade III, 2.3%). The median duration of postoperative hospital stay was 6 (4-7) days. CONCLUSION: ICGNS is a safe and feasible LAR strategy that greatly facilitates selecting the liver transection plane, although its benefits need to be verified by large-sample comparative studies.

Laparoscopic repeat hepatectomy for treating recurrent liver cancer.

BACKGROUND: Laparoscopic repeat hepatectomy (LRH) is a technically challenging procedure, so LRH for recurrent liver cancer has not been widely accepted. The aim of this study was to perform a systematic review of the current literature to identify and evaluate available data of LRH for recurrent hepatocellular carcinoma (rHCC) and metastases tumour of liver, especially of colorectal liver metastases (CRLM), focusing on the safety and feasibility. METHODS: A comprehensive search of the PubMed database was performed for all studies published in English evaluating LRH for rHCC and recurrent metastases tumour of liver from 1st January, 2005 to 1st June, 2019. RESULTS: A total of 15 studies which comprised 444 patients and reported outcomes for the efficacy and safety of LRH in the treatment of rHCC or CRLM were included in the present review. Moreover, nine studies compared the perioperative outcomes of LRH versus open repeat hepatectomy (ORH). LRH was superior to ORH with reduced blood loss, shorter operative time, shorter hospital stay and lower morbidity rates. CONCLUSIONS: LRH can safely performed in rHCC or CRLM patients with cirrhosis, previous open hepatectomy, multiple recurrent lesions and tumours located in difficult posterosuperior segments.

Safety and feasibility of laparoscopic liver resection for hepatocellular carcinoma with clinically significant portal hypertension: a propensity score-matched study.

BACKGROUND: The presence of clinically significant portal hypertension (CSPH) remains a relative contraindication to liver resection for patients with resectable hepatocellular carcinoma (HCC). The goal of this study was to explore whether a laparoscopic approach could extend the indications for hepatectomy to patients with PH. METHOD: Patients who underwent laparoscopic liver resection (LLR) from February 2016 to September 2019 performed by a single medical team were included in this study. We analyzed the surgical and oncological outcomes between groups with and without CSPH before and after propensity score matching (PSM). RESULT: We enrolled 156 patients divided into two groups according to the presence (CSPH, n = 26) or absence (non-CSPH, n = 130) of CSPH. CSPH group was associated with more clinical signs of liver dysfunction (p < 0.05). After PSM (n = 48 patients), the CSPH group tended to have a longer postoperative hospital stay (p = 0.054); however, there was no difference in operation time (p = 0.329), blood loss volume (p = 0.392), transfusion rates (p = 0.701), rate of conversion to open surgery (p = 0.666), surgical margin (p = 0.306), surgical mortality (n = 0), or comprehensive complication index (p = 0.844) between the two groups. The median follow-up time for the entire cohort was 19.6 months (range 0.2-40.6 months). The 3-year overall survival rate was 62.9% in the CSPH group and 84.3% in the non-CSPH group (p = 0.1090), and results were similar after PSM (p = 0.5734). CONCLUSIONS: LLR is safe and feasible for HCC with PH. The introduction of minimally invasive surgery, represented by LLR, can appropriately expand the indications for hepatectomy.

Comparison on the efficacy and prognosis of different strategies for intrahepatic recurrent hepatocellular carcinoma: A systematic review and Bayesian network meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) has a high rate of recurrence. This network meta-analysis aimed to compare the oncological prognosis of the conventional treatments for intrahepatic recurrent hepatocellular carcinoma (rHCC) and identify the optimal strategy. METHODS: We conducted a literature search of online database, published between January 2009 and October 2019. Relevant studies analyzing the outcomes of the different interventions for rHCC were included. We synthesized the results using R software and the "gemtc" package. RESULTS: A total of 21 studies involving 2818 patients were ultimately enrolled to be analyzed. We assessed five related therapeutic interventions and two oncological outcomes. The benefits orders of overall survival (OS) from largest to least were salvage liver transplantation (SLT), repeat hepatectomy (RH), radiofrequency ablation (RFA), stereotactic body radiation therapy (SBRT), and transarterial chemoembolization (TACE). For the benefits of recurrence-free survival (RFS), SLT and RH remained the top two treatments. Subgroup analysis of smaller (≤3 cm) and larger (>3 cm) tumour reached similar results. Consistency and heterogeneity analysis did not show significant inconsistency and heterogeneity. DISCUSSION: Our findings demonstrated that SLT and RH were the best two treatments for rHCC. Nevertheless, the selection of strategies should also depend on tumour characteristics and basic health situation.

Robot-Assisted Partial Splenectomy for Splenic Epidermoid Cyst.

The splenic cyst is a rare disease with unknown etiology. The inner wall of the cyst has lining epithelium. The cyst can be unilocular or multilocular. According to pathology, it can be divided into four types: epidermoid cyst, dermoid cyst, cystic lymphangioma, and cystic hemangioma. Ultrasound examination is often the first choice for splenic cysts because of its nonradiation, low cost, and convenient examination. The images are mostly cystic masses with clear borders and dark areas without echoes, after the detection of splenic space-occupying lesions by ultrasonography, CT, and MRI. Here, we report robot-assisted partial splenectomy for a splenic cyst. Imaging diagnosis of abdominal CT enhancement: the cystic space-occupying of the spleen is considered. We should improve the preoperative examination and exclude operative contraindications. During the operation, there was about 8 cm of the upper pole of the spleen, and the boundary was clear. There was no obvious abnormality in the exploration of the abdominal viscera. The operation was successful. The operative time was 115 minutes, and the blood loss was 20 ml. On the first day after the operation, the patient took a liquid diet. The time of first anal exhaust was on the second day after operation. The patient was discharged at the fourth day. Postoperative pathology revealed epidermoid cyst. The therapy strategy of the splenic cyst is ambiguous. Better understanding of the splenic segmental anatomy and surgical skills has made minimally invasive partial splenectomy a preferred treatment for splenic cysts. In this paper, we report a case of splenic epidermoid cyst managed successfully by robot-assisted partial splenectomy.

LXR activation potentiates sorafenib sensitivity in HCC by activating microRNA-378a transcription.

Sorafenib resistance is a major obstacle to the treatment of advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are multifunctional regulators of gene expression with profound impact for human disease. Therefore, better understanding of the biological mechanisms of abnormally expressed miRNAs is critical to discovering novel, promising therapeutic targets for HCC treatment. This study aimed to investigate the role of miR-378a-3p in the sorafenib resistance of HCC and elucidate the underlying molecular mechanisms. Methods: A novel hub miR-378a-3p was identified based on miRNA microarray and bioinformatics analysis. The abnormal expression of miR-378-3p was validated in different HCC patient cohorts and sorafenib-resistant (SR) HCC cell lines. The functional role of miR-378a-3p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. Interactions among miR-378a-3p, LXRα, and IGF1R were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-378a-3p and its targets were evaluated in HCC samples. HCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of LXRα and its downstream miR-378a-3p. Results: miR-378a-3p expression was frequently reduced in established sorafenib-resistant HCC cell lines. The decreased miR-378a-3p levels correlated with poor overall survival of HCC patients following sorafenib treatment. miR-378a-3p overexpression induced apoptosis in SR HCC cells, whereas miR-378a-3p silencing exerted the opposite effects. IGF1R was identified as a novel target of miR-378a-3p. Furthermore, the primary miR-378 level was not consistent with its precursor miRNA level in SR HCC cells, which was attributed to the downregulation of exportin5 (XPO5) and subsequently reduced nuclear export of precursor miR-378 and restrained maturation of miR-378-3p. In this context, we combined an agonist GW3965 of liver X receptor alpha (LXRα), which functioned as a transcription activator of miRNA-378a, and its activation re-sensitized sorafenib-resistant cells to sorafenib treatment in vitro and in vivo. Conclusions: Our finding suggested decreased expression of XPO5 prevents maturation of miR-378a-3p, which leaded to the overexpression of IGF-1R and counteracted the effects of sorafenib-induced apoptosis. LXRα was able to activate miRNA-378a-3p transcription in HCC cells and could be a potential combinable treatment strategy with sorafenib to suppress HCC progression.

Laparoscopic Anatomical Portal Territory Hepatectomy with Cirrhosis by Takasaki's Approach and Indocyanine Green Fluorescence Navigation (with Video).

BACKGROUND: Anatomical liver resection has shown advantages in the treatment of hepatocellular carcinoma (HCC).1 Pure laparoscopic hepatectomy for some deep lesions remains challenging, especially for anatomical resection.2 Because of many kinds of hepatic venous variations, resection along the hepatic vein may not be a "real" anatomical resection. We used a three-dimensional visualization technique to construct a portal territory model which represented the patient-specific anatomy. During the operation, the territory was visualized by indocyanine green (ICG) navigation. PATIENT: A 48-year-old man was admitted to our institution with a single hepatic mass of 4.5 cm in segment 7. The patient suffered hepatitis B related cirrhosis and portal hypertension. METHODS: A resection plan was put forward by 3-D visualization technique in advance (Fig. 1a). The patient was placed in a supine position with pillows underneath the upper right semi-lateral body. The position of the trocar is shown in Fig. 1b. After removal of the gallbladder and overhang of the G6, the G7 was dissected and ligated by Takasaki's Glissonean pedicle approach (Fig. 1c).3 The ischemic line appeared and was consistent with the demarcation line of portal territory (Fig. 1d). A parenchyma transection was performed along the boundary of the unstained side of the ICG fluorescence. Fig. 1 Some important images from the video. a The trocar position of this laparoscopic surgery. Operator-1 or -2: the first and the second trocar for the operator; assistant: the trocar for the assistant; operator/assistant: the trocar can be used by operator and assistant interchangeably; scope: the trocar for the laparoscope. b The transection plan constructed by preoperative 3-D visualization technique. The blue area was the tumor-bearing portal territory and targeted part of the liver that should be removed. c The intrahepatic anterior and posterior Glissonean pedicle of G6 and G7. G6: glissonean pedicle of segment 6; G7: glissonean pedicle of segment 7. d The ischemic line, the demarcation line of portal territory staining by ICG and the target territory constructed by 3-D visualization technique before the operation RESULT: The operation time was 205 min, the estimated blood loss was 150 ml. With no postoperative complications, the patient was discharged on the fourth day. Hepatocellular carcinoma was confirmed in histopathology. The resection margin was free of tumor involvement. CONCLUSION: A preoperative 3-D visualization technique combined with intraoperative ICG fluorescence navigation could facilitate a precise and safe laparoscopic anatomical hepatectomy.

Correction to: Laparoscopic Anatomical Portal Territory Hepatectomy with Cirrhosis by Takasaki's Approach and Indocyanine Green Fluorescence Navigation (with Video).

In the original version of the article all of the authors' first and last names were transposed. The original article has been updated.