KAT8-catalyzed lactylation promotes eEF1A2-mediated protein synthesis and colorectal carcinogenesis.

Aberrant lysine lactylation (Kla) is associated with various diseases which are caused by excessive glycolysis metabolism. However, the regulatory molecules and downstream protein targets of Kla remain largely unclear. Here, we observed a global Kla abundance profile in colorectal cancer (CRC) that negatively correlates with prognosis. Among lactylated proteins detected in CRC, lactylation of eEF1A2K408 resulted in boosted translation elongation and enhanced protein synthesis which contributed to tumorigenesis. By screening eEF1A2 interacting proteins, we identified that KAT8, a lysine acetyltransferase that acted as a pan-Kla writer, was responsible for installing Kla on many protein substrates involving in diverse biological processes. Deletion of KAT8 inhibited CRC tumor growth, especially in a high-lactic tumor microenvironment. Therefore, the KAT8-eEF1A2 Kla axis is utilized to meet increased translational requirements for oncogenic adaptation. As a lactyltransferase, KAT8 may represent a potential therapeutic target for CRC.

Consensus Guidelines for the Use of Fluorescence Imaging in Hepatobiliary Surgery.

OBJECTIVE: To establish consensus recommendations for the use of fluorescence imaging with indocyanine green (ICG) in hepatobiliary surgery. BACKGROUND: ICG fluorescence imaging has gained popularity in hepatobiliary surgery in recent years. However, there is varied evidence on the use, dosage, and timing of administration of ICG in clinical practice. To standardize the use of this imaging modality in hepatobiliary surgery, a panel of pioneering experts from the Asia-Pacific region sought to establish a set of consensus recommendations by consolidating the available evidence and clinical experiences. METHODS: A total of 13 surgeons experienced in hepatobiliary surgery and/or minimally invasive surgery formed an expert consensus panel in Shanghai, China in October 2018. By the modified Delphi method, they presented the relevant evidence, discussed clinical experiences, and derived consensus statements on the use of ICG in hepatobiliary surgery. Each statement was discussed and modified until a unanimous consensus was achieved. RESULTS: A total of 7 recommendations for the clinical applications of ICG in hepatobiliary surgery were formulated. CONCLUSIONS: The Shanghai consensus recommendations offer practical tips and techniques to augment the safety and technical feasibility of ICG fluorescence-guided hepatobiliary surgery, including laparoscopic cholecystectomy, liver segmentectomy, and liver transplantation.

Laparoscopic anatomical liver resection guided by real-time indocyanine green fluorescence imaging: experience and lessons learned from the initial series in a single center.

BACKGROUND: Anatomical liver resection is an established procedure for primary hepatic tumors. Laparoscopic anatomical hepatectomy has been proven to be technically achievable from S1 to S8 in experienced hands. The indocyanine green (ICG) fluorescence imaging technique offers a novel tool of intraoperative visualization in hepatobiliary surgery. This study aims to investigate the feasibility of laparoscopic anatomical liver resection based on segmental staining using real-time ICG fluorescence. METHODS: From December 2015 to October 2017, 36 patients in our institute underwent lap-ALR using real-time ICG fluorescence mapping of the tumor-bearing portal territory. The procedural and perioperative data were collected and analyzed. RESULTS: In our case series, we successfully performed the fashion of positive staining mostly in segmentectomy or sub-segmentectomy by individually injecting 5-10 ml of ICG (0.025 mg/ml) into its feeding portal branch guided by intraoperative ultrasound, and the negative staining mainly for sectionectomy, hemihepatectomy and multi-segmentectomy by interrupting the Glissonean pedicle serving the tumor-bearing segments and systemically injecting 1 ml of ICG (2.5 mg/ml). Our total successful rate of staining is 53%. No conversion to laparotomy, Clavien III-IV complication or 90-day mortality occurred. Valuable technical feedback, experience and lessons are learned from this initial practice. CONCLUSIONS: Real-time ICG fluorescence imaging adds much precision to laparoscopic anatomical hepatectomy. The success of segmental staining requires a high proficiency of IOUS and skillful interpretation of preoperative 3D simulation. Decision-making on the fashions of positive and negative staining have been initially recommended. Multi-centered practice and technical modification are necessary to standardize its application.

A reliable scoring system after major liver resection in mice.

BACKGROUND: Posthepatectomy liver failure and its transplant counterpart, small-for-size syndrome, remain significant limitations for liver resections and segmental liver transplantation. Partial hepatectomy in mice is one of the most commonly used models to study liver regeneration, but blood and tissue sampling necessary to collect data can affect outcomes or even require euthanasia. We therefore developed a quantitative observational system to predict death from hepatectomy during the first 24 postoperative hours. MATERIALS AND METHODS: A total of 100 female, 10 to 12-week-old C57BL/6 mice underwent two-thirds hepatectomy and were monitored for up to 7 d. Our scoring system was based on five categories, each assigned 0-2 points: activity level, body posture, fur condition, respiratory status, and eye appearance. Seventy-five mice were scored 6 h, 12 h, 24 h, 2 d, 3 d, 5 d, and 7 d after surgery. The remaining 25 mice were scored similarly, but underwent, in addition, blood sampling for serum alanine aminotransferase, total bilirubin, interleukin-6, tumor necrosis factor-alpha, or euthanasia with liver sampling for conventional hematoxylin-eosin and Ki-67 staining. RESULTS: Retrospective analysis indicated that body condition scores ≤5 on two consecutive time points within the first 24 postoperative hours accurately predicted eventual death. Animals in the low scoring group also had significantly higher serum alanine aminotransferase, total bilirubin, interleukin-6, tumor necrosis factor-alpha, more hepatocyte necrosis in hematoxylin-eosin, and fewer Ki-67 positive hepatocytes. CONCLUSIONS: Our scoring system accurately predicts survival, hepatocyte damage, liver regeneration, and systemic inflammation in a mouse hepatectomy model, within the first 24 hours of surgery. This could be useful in evaluating posthepatectomy interventions for their effect on survival and liver regeneration.

Robotic radical resection for hilar cholangiocarcinoma: perioperative and long-term outcomes of an initial series.

BACKGROUND: Radical resection for hilar cholangiocarcinoma (HCa) is one of the most challenging abdominal procedures. Robotic-assisted approach is gaining popularity in hepatobiliary surgery but scarcely tried in the management of HCa. We herein report our initial experience of robotic radical resection for HCa. METHODS: Between May 2009 and October 2012, 10 patients underwent fully robotic-assisted radical resection for HCa in a single institute. The perioperative and long-term outcomes were analyzed and compared with a contemporaneous 32 patients undergoing traditional open surgery. RESULTS: The 10 patients presented one of Bismuth-Corlette type II, four of IIIa, one of IIIb and four of IV. There was no significant clinicopathological disparity between the robotic and open groups. The robotic radical resection involves hemihepatectomy plus caudate lobectomy or trisectionectomy, extrahepatic bile duct resection, radical lymphadenectomy and Roux-en-Y hepaticojejunostomy. No conversion to laparotomy occurred. Robotic resection compared unfavorably to traditional open resection in operative time (703 ± 62 vs. 475 ± 121 min, p < 0.001) and morbidity [90 (9/10) vs. 50 %, p = 0.031]. No significant difference was found in blood loss, mortality and postoperative hospital stay. Major complications (≥Clavien-Dindo III) occurred in three patients of robotic group. One patient died of posthepatectomy liver failure on postoperative day 18. The hospital expenditure was much higher in robotic group (USD 27,427 ± 21,316 vs. 15,282 ± 5957, p = 0.018). The tumor recurrence-free survival was inferior in robotic group (p = 0.029). CONCLUSIONS: Fully robotic-assisted radical resection for HCa is technically achievable in experienced hands and should be limited to highly selective patients. Our current results do not support continued practice of robotic surgery for HCa, until significant technical and instrumental refinements are demonstrated.

Living donor liver transplantation using dual grafts: Experience and lessons learned from cases worldwide.

In living donor liver transplantation (LDLT), insufficient graft volume could result in small-for-size syndrome in recipients, whereas major liver donation predisposes the donor to a high risk of posthepatectomy liver failure. Dual graft LDLT is therefore introduced to obtain combined graft sufficiency. To date, 367 patients have been reported worldwide. We reviewed all the relevant literature, with a special focus on 43 case reports containing enough data to extract and analyze. A simple decision-making algorithm was developed. Dual graft LDLT is indicated when (1) a single donation is unacceptable due to graft-to-recipient size mismatch; (2) the future liver remnant is insufficient in the single donor after major resection; or (3) there is a significant underlying disorder or anatomical variation within the donor liver. The outcome of dual graft LDLT is reported to be comparable with that of single donor LDLT. Unilateral graft atrophy was found in 7 of the 43 patients, predominantly in the right-sided, heterotopic and initially smaller grafts. Technically, the heterotopic implantation and complex vascular reconstruction are the most demanding. Elaborate surgical planning and modification are needed. Ethical concerns about involving a second living donor need to be addressed. In conclusion, dual graft LDLT should be prudently performed in select cases by surgeons of proven expertise when single donation is unacceptable and a second living donor is available. The decision-making criteria need to be standardized. More surgical modification and clinical research are needed.

[Transient hepatic venous occlusion induced liver hemodynamic change and reperfusion injury in rats].

OBJECTIVE: To observe the hemodynamic change and reperfusion injury cause by transient hepatic venous occlusion and transient hepatic inflow occlusion in rats. METHODS: The rat liver was divided into 3 different areas: the ischemia reperfusion (IR) area: the inflow of the right superior lobe was clamped for half an hour; the non-isolated lobe congestive reperfusion (NIL-CR) area: the outflow of the right median lobe was clamped for half an hour; and the isolated lobe congestive reperfusion (IL-CR) area: the outflow of the left lobe was clamped for half an hour. The flux value and the oxygen saturation of microcirculation were monitored before at clamping for 30 minutes, and on 1 day, 3 days ,and 7 days after reperfusion. The hepatic damage and Suzuki's score were evaluated. RESULTS: After clamping for 30 minutes, the flux value in the IR area was significantly higher than in NIL-CR area (P<0.01) and IL-CR area (P<0.01), the oxygen saturation in the IR area was significantly higher than in NIL-CR area (P<0.01) and IL-CR area (P<0.05). Compared with IR area, both NIL-CR area and IL-CR area were found having more severe liver damage in terms of Suzuki's score in early postoperative period (at clamping for 30 minutes and on 1 day, P<0.01). However, there was no significant difference between NIL-CR area and IL-CR area in flux value, oxygen saturation, and Suzuki's score (P>0.05). CONCLUSIONS: Hepatic venous occlusion can more effectively decrease the blood perfrusion and oxygen saturation; thus, compared to the IR, CR can result in more severe liver damage. The presence of normal liver tissue around the congestion area can not influence liver damage in transient hepatic venous occlusion.

Precision in liver surgery.

Continuous theoretical and technological progress in the face of increasing expectations for quality health care has transformed the surgical paradigm. The authors systematically review these historical trends and propose the novel paradigm of "precision surgery," featuring certainty-based practice to ensure the best result for each patient with multiobjective optimization of therapeutic effectiveness, surgical safety, and minimal invasiveness. The main characteristics of precision surgery may be summarized as determinacy, predictability, controllability, integration, standardization, and individualization. The strategy of precision in liver surgery is to seek a balance of maximizing the removal of the target lesion, while maximizing the functional liver remnant and minimizing surgical invasiveness. In this article, the authors demonstrate the application of precision approaches in specific settings in complex liver surgery. They propose that the concept of precision surgery should be considered for wider application in liver surgery and other fields as a step toward the ultimate goal of perfect surgery.

Hepatitis B Virus Pregenomic RNA Reflecting Viral Replication in Distal Non-tumor Tissues as a Determinant of the Stemness and Recurrence of Hepatocellular Carcinoma.

Background: The existence of hepatic cancer stem cells (CSCs) contributes to chemotherapy resistance and cancer recurrence after treatment or surgery. However, very little is known about the hepatitis B virus (HBV) replication and its relationship with the stemness of hepatocellular carcinoma (HCC) in HBV-related HCC patients. Methods: We collected tumor tissues (T), matched adjacent non-tumor tissues (NT), and distal non-tumor tissues (FNT) from 55 HCC patients for analysis. Results: We found HBV DNA levels were higher in T samples than NT and FNT samples, but HBV pgRNA and total RNA expressed lower in T samples. HBV pgRNA and total RNA correlate to HBV DNA among the T, NT, and FNT samples. Further evidence for HBV replication in T samples was provided by HBV S, reverse transcriptase, and X genes sequencing, showing that HBV sequences and genotypes differed between T and matched NT and FNT samples. HBV pgRNA and total RNA showed more frequent significant correlations with CSC markers in NT samples in HBsAg-positive patients. The markers CD133 and OCT4 expressed higher in FNT samples, and HBV replication marker of pgRNA levels was significantly positively correlated to these two markers only in FNT samples. The detection of pgRNA and OCT4 in FNT was correlated to the recurrence of HCC in the resection of HCC patients. Analysis of HBV receptor, sodium taurocholate co-transporting polypeptide (NTCP), showed that NTCP was correlated negatively to CSC markers in T samples, except for the CD44. Conclusion: HBV replication may present in HCC with a weak transcriptomic signature. Moreover, the expression level of HBV pgRNA in distal non-tumor tissues is a sensitive marker for HBV replication and prognosis, which is associated with CSC-related markers especially with OCT4 in distal non-tumor tissues and recurrence of HCC in HBV-related HCC patients.

Surgery After Conversion Therapy With PD-1 Inhibitors Plus Tyrosine Kinase Inhibitors Are Effective and Safe for Advanced Hepatocellular Carcinoma: A Pilot Study of Ten Patients.

BACKGROUND AND AIMS: Immunotherapy with PD-1 inhibitors combined with tyrosine kinase inhibitors (TKIs) has been proven to be effective against advanced hepatocellular carcinoma (HCC). The aim of this study was to identify the feasibility and safety of subsequent salvage surgery after this combination therapy. METHODS AND PATIENTS: A retrospective analysis was performed on patients with primary HCC with major vascular invasion between 2018 and 2019. All cases were treated with a combination of a PD-1 inhibitor and TKI agents and subsequent surgery. RESULTS: A total of 10 HCC cases with major vascular invasion met the successful conversion criteria after the combination therapy, and eight patients underwent subsequent salvage surgery after both radiology and 3D quantitative oncological assessment. Partial response (PR) was recorded in 7 of 10 patients and complete response (CR) in 3 of 10 patients before salvage surgery. Salvage surgery included right hepatectomy, left hepatectomy, and anatomic segmental hepatectomy. The mean intraoperative blood loss was 1,650 ml (50-3,000 ml). No complications beyond Clavien-Dindo level III or postoperative mortality were observed. The viable tumor cell rate of the PR cases (modified response evaluation criteria in solid tumors, mRECIST) varied from 1.5% to 100%, and only one patient had pathology-proven pathological complete response (pCR). The postoperative median follow-up time was 19.7 months (9.1-24.9 months). The 12-month recurrence-free survival rate of all cases who underwent salvage surgery was 75%. CONCLUSION: Salvage surgery was effective and safe after conversion therapy with PD-1 inhibitors plus TKIs and may increase the long-term oncological benefit for patients with unresectable HCC.

GOLM1 restricts colitis and colon tumorigenesis by ensuring Notch signaling equilibrium in intestinal homeostasis.

Intestinal epithelium serves as the first barrier against the infections and injuries that mediate colonic inflammation. Colorectal cancer is often accompanied with chronic inflammation. Differed from its well-known oncogenic role in many malignancies, we present here that Golgi membrane protein 1 (GOLM1, also referred to as GP73) suppresses colorectal tumorigenesis via maintenance of intestinal epithelial barrier. GOLM1 deficiency in mice conferred susceptibility to mucosal inflammation and colitis-induced epithelial damage, which consequently promoted colon cancer. Mechanistically, depletion of GOLM1 in intestinal epithelial cells (IECs) led to aberrant Notch activation that interfered with IEC differentiation, maturation, and lineage commitment in mice. Pharmacological inhibition of Notch pathway alleviated epithelial lesions and restrained pro-tumorigenic inflammation in GOLM1-deficient mice. Therefore, GOLM1 maintains IEC homeostasis and protects against colitis and colon tumorigenesis by modulating the equilibrium of Notch signaling pathway.

Indocyanine green fluorescence image-guided total laparoscopic living donor right hepatectomy: The first case report from Mainland China.

INTRODUCTION: Total laparoscopic living donor right hepatectomy (TLDRH) is sporadically reported worldwide. Liver transection margin used to be determined by ischemic demarcation or intraoperative ultrasonography. To identify the site of bile duct division relied on preoperative MRCP and intraoperative cholangiography, which is experience demanding. PRESENTATION OF CASE: A 34-year-old man volunteered for living donation to his brother who suffered decompensated HBV-related cirrhosis. Right lobe donation without MHV fulfilled the volumetric criteria. After hilum dissection, ICG was injected into the right portal branch. Right lobe was transected tracing the real-time fluorescence-enhanced borderline and the course of MHV. The right bile duct was transected above the bifurcation that was fluorescently visualized within the parenchyma. The liver graft was retrieved from a pre-made suprapubic incision after simple vascular clamping. The warm ischemia time was 6 min. The recipient procedure was successful with back-table graft venoplasty using cryopreserved iliac artery allografts. The donor recovered uneventfully and was discharged from hospital on POD 7. DISCUSSION: The operative time, blood loss and postoperative course of donor is comparable to those undergoing ordinary laparoscopic right hepatectomy in our institute. ICG fluorescence can real-timely visualize the surgical margin and biliary branches of right lobe, which helps preserve every last bit of functional liver volume for the donor and avoid the complicated traditional intraoperative cholangiography. CONCLUSION: TLDRH proves to be achievable in surgical teams confortable with both laparoscopic hepatectomy and LDLT. ICG fluorescence navigation could make the procedure simplified, safer and more accurate. More practice and technical modification are necessary.

Prognostic significance of neutrophil-to-lymphocyte ratio in biliary tract cancers: a systematic review and meta-analysis.

BACKGROUND: Inflammation was considered to perform crucial roles in the development and metastasis of malignancies. A heightened neutrophil-lymphocyte ratio has been described to be associated with detrimental survivals in different malignancies. Debate remains over the impact of heightened neutrophil-lymphocyte ratio on survivals in biliary tract cancer. The review evaluated the prognostic value of neutrophil-lymphocyte ratio in biliary tract cancer. METHODS: MEDLINE, the Cochrane Library, EMBASE, and the Chinese SinoMed were systematically searched for relevant articles. Associations between neutrophil-lymphocyte ratio and long-term outcomes were expressed as the hazard ratios and 95% confidence intervals. The odds ratio was utilized to assess the association between neutrophil-lymphocyte ratio and clinicopathological parameters. RESULTS: Fourteen studies consisting of 3217 patients were analyzed: 1278 (39.73%) in the high pretreatment neutrophil-lymphocyte ratio group and 1939 (60.27%) in the low pretreatment neutrophil-lymphocyte ratio one. The results proved that heightened pretreatment neutrophil-lymphocyte ratio was significantly associated with detrimental overall survival and relapse free survival for biliary tract cancer patients. In addition, elevated neutrophil-lymphocyte ratio was positively correlated with higher carbohydrate antigen 19-9 levels, advanced TNM staging and greater lymph node involvement. CONCLUSION: This meta-analysis marked that an increased pretreatment neutrophil-lymphocyte ratio was significantly linked with detrimental long-term outcomes and clinicopathological parameters for patients with biliary tract cancer.

Efficacy of transarterial chemoembolization for hepatocellular carcinoma with portal vein thrombosis: a meta-analysis.

BACKGROUND: Transarterial chemoembolization (TACE) is commonly used to treat advanced hepatocellular carcinoma (HCC), but less is known regarding safety and efficacy of TACE in patients with HCC and portal vein tumour thrombosis (PVTT). The objective of this study was to evaluate the effect of TACE treatment on 1-year survival in patients with HCC and PVTT. METHODS: Medline, EMBASE, CENTRAL databases (until July 2013) were searched for studies that evaluated the efficacy of TACE with regard to survival in patients with HCC and PVTT. One-year survival rate, the primary end point, was compared between patients who received TACE and those who received control treatment. RESULTS: Five prospective studies were identified that assessed the efficacy of TACE on survival. These studies included 600 patients: 335 received TACE therapy and 226 received control treatments. Three of the five studies reported 1-year survival data and were used in the meta-analysis. The combined odds ratio (3.079, 95% confidence interval = 1.094-8.662) indicated that patients who received TACE had a significantly better 1-year survival rate compared with patients in the control group (P = 0.033). CONCLUSIONS: There are several limitations to this analysis that should be considered when interpreting the findings. The studies used different treatment regimens as controls or with TACE. These differences across the studies may have altered the 1-year survival outcomes in each study and confounded our analysis. This meta-analysis showed that TACE improves the 1-year survival of patients with HCC and PVTT. However, additional prospective controlled trials are required to further substantiate these findings.

Perioperative and long-term outcomes of liver resection for hepatitis B virus-related hepatocellular carcinoma without versus with hepatic inflow occlusion: study protocol for a prospective randomized controlled trial.

BACKGROUND: The high prevalence of hepatitis B virus (HBV) imposes a huge burden of hepatocellular carcinoma (HCC) in Asia. Surgical resection remains an important therapeutic strategy for HCC. Hepatic inflow occlusion, known as the Pringle maneuver, is the most commonly used method of reducing blood loss during liver parenchymal transection. A major issue with this maneuver is ischemia-reperfusion injury to the remnant liver, and the hemodynamic disturbance it induces in the tumor-bearing liver raises an oncological concern. Given the technical advances in living donor liver transplantation, vascular occlusion in liver resection can be avoided in experienced hands. The aim of this study is to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with hepatic inflow occlusion. METHODS/DESIGN: This study will include eligible patients with HBV-related HCC elected for liver resection. Fifty-seven patients will be enrolled in each randomization arm to detect a 20 % difference in the serum level of total bilirubin on postoperative day 5 (80 % power and α = 0.05). The secondary endpoints include procedural parameters, perioperative liver function and inflammatory response, postoperative morbidity and mortality, and long-term outcomes. Patients will be followed for up to 5 years. Data will be statistically analyzed on an intention-to-treat basis. DISCUSSION: This prospective randomized controlled trial is designed to compare the perioperative and long-term outcomes of liver resection for HBV-related HCC without versus with vascular occlusion. The clinical implications of these outcomes may change current surgical practice and fill the oncological gaps therein. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02563158 . Registered on 28 September 2015.

STAT3 regulates the migration and invasion of a stem­like subpopulation through microRNA­21 and multiple targets in hepatocellular carcinoma.

Despite advances in the detection and treatment of hepatocellular carcinoma (HCC), the prognosis remains poor partly due to recurrence or extra/intrahepatic metastasis. Stem­like cancer cells are considered the source of malignant phenotypes including metastasis in various types of cancer. HCC side population (SP), considered as stem­like cancer cells, plays an important role in the migration and invasion in HCC, while the mechanisms involved remain unknown. In the present study, high levels of STAT3 and phospho­STAT3 were observed in MHCC97H SP cells compared with the main population (MP) cells. Inhibition of phospho­STAT3 led to a reduction of miR­21 expression, an increase of PTEN, RECK, and programmed cell death 4 (PDCD4) expression as well as the migration and invasion of SP cells. A set of rescue experiments was performed using different combinations of STAT3 inhibitor, miR­21 mimics and siRNAs to observe the expression of miR­21 targets, cell migration and invasion alterations. Data indicated that the alterations induced by STAT3 inhibition were partly reversed by the upregulation of miR­21. Additionally, the cells migration and invasion when silencing the targets of miR­21 were also reversed by STAT3 inhibition. In conclusion, the present study revealed the aberrant expression of STAT3 and miR­21 in HCC SP cells. Targeting STAT3 may limit HCC migration and invasion, which is likely to involve the regulation of miR­21 and its targets PTEN, RECK and PDCD4. Strategies directed towards STAT3 may therefore be a novel approach for the treatment of HCC.