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While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs  in vivo  by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro , NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4 + and CD8 + T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC.

The inducible nitric oxide synthase (iNOS) is associated with more aggressive solid tumors, including hepatocellular carcinoma (HCC). Notch signaling in cancer stem cells promotes cancer progression and requires Notch cleavage by ADAM (a disintegrin and metalloprotease) proteases. We hypothesized that iNOS/NO promotes Notch1 activation through TACE/ADAM17 activation in liver cancer stem cells (LCSCs), leading to a more aggressive cancer phenotype. Expression of the stem cell markers CD24 and CD133 in the tumors of patients with HCC was associated with greater iNOS expression and worse outcomes. The expression of iNOS in CD24⁺CD133⁺ LCSCs, but not CD24⁻CD133⁻ LCSCs, promoted Notch1 signaling and stemness characteristics in vitro and in vivo, as well as accelerating HCC initiation and tumor formation in the mouse xenograft tumor model. iNOS/NO led to Notch1 signaling through a pathway involving the soluble guanylyl cyclase/cGMP/PKG-dependent activation of TACE/ADAM17 and up-regulation of iRhom2 in LCSCs. In patients with HCC, higher TACE/ADAM17 expression and Notch1 activation correlated with poor prognosis. These findings link iNOS to Notch1 signaling in CD24⁺CD133⁺ LCSCs through the activation of TACE/ADAM17 and identify a mechanism for how iNOS contributes to progression of CD24⁺CD133⁺ HCC.

Background Laparoscopic liver resection is rapidly expanding with more than 9500 cases performed worldwide. While initial series reported non-anatomic resection of benign peripheral hepatic lesions, approximately 50–65 % of laparoscopic liver resections are now being done for malignant tumors, primarily hepatocellular carcinoma (HCC) or colorectal cancer liver metastases (mCRC). Methods We performed a literature review of published studies evaluating outcomes of major laparoscopic liver resection, defined as three or more Couinaud segments. Results Initial fears of adverse oncologic outcomes or tumor seeding have not been demonstrated, and dozens of studies have reported comparable 5-year disease-free and overall survival between laparoscopic and open resection of HCC or mCRC in case-cohort and propensity score-matched analyses. Increased experience has led to laparoscopic anatomic liver resections including laparoscopic major hepatectomy. A steep learning curve of 45–60 cases is evident for laparoscopic hepatic resection. Conclusion Laparoscopic major hepatectomy is safe and effective in the treatment of benign and malignant liver tumors when performed in specialized centers with dedicated teams. Comparable to other complex laparoscopic surgeries, laparoscopic major hepatectomy has a learning curve of 45–60 cases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.

Background To assess long-term oncologic outcomes of robotic-assisted liver resection (RLR) for colorectal cancer (CRC) metastases as compared to a propensity-matched cohort of laparoscopic liver resections (LLR). Although safety and short-term outcomes of RLR have been described and previously compared to LLR, long-term and oncologic data are lacking. Methods A retrospective study was performed of all patients who underwent RLR and LLR for CRC metastases at six high-volume centers in the USA and Europe between 2002 and 2017. Propensity matching was used to match baseline characteristics between the two groups. Data were analyzed with a focus on postoperative and oncologic outcomes, as well as long-term recurrence and survival. Results RLR was performed in 115 patients, and 514 patients underwent LLR. Following propensity matching 115 patients in each cohort were compared. Perioperative outcomes including mortality, morbidity, reoperation, readmission, intensive care requirement, length-of-stay and margin status were not statistically different. Both prematching and postmatching analyses demonstrated similar overall survival (OS) and disease-free survival (DFS) between RLR and LLR at 5 years (61 vs. 60% OS, p  = 0.87, and 38 vs. 31% DFS, p  = 0.25, prematching; 61 vs. 60% OS, p  = 0.78, and 38 vs. 44% DFS, p  = 0.62, postmatching). Conclusions Propensity score matching with a large, multicenter database demonstrates that RLR for colorectal metastases is feasible and safe, with perioperative and long-term oncologic outcomes and survival that are largely comparable to LLR.

Autophagy is an important factor in liver ischemia-reperfusion injury. In the current study we investigate the function of interferon regulatory factor-1 (IRF1) in regulating autophagy to promote hepatic ischemia reperfusion injury (IR). The high expression of IRF1 during hepatic IR exhibited increased liver damage and was associated with activation of autophagy shown by Western blot markers, as well as immunofluorescent staining for autophagosomes. These effects were diminished by IRF1 deficiency in IRF1 knock out (KO) mice. Moreover, the autophagy inhibitor 3-MA decreased IR-induced liver necrosis and markedly abrogated the rise in liver injury tests (AST/ALT). β-catenin expression decreased during liver IR and was increased in the IRF1 KO mice. Immunoprecipitation assay showed the binding between IRF1 and β-catenin. Overexpression of IRF1 induced autophagy and also inhibited the expression of β-catenin. β-catenin inhibitor increased autophagy while β-catenin agonist suppressed autophagy in primary mouse hepatocytes. These results indicate that IRF1 induced autophagy aggravates hepatic IR injury in part by inhibiting β-catenin and suggests that targeting IRF1 may be an effective strategy in reducing hepatic IR injury.

More than 3,000 laparoscopic liver resections (LLR) are performed worldwide for benign disease, malignancy, and living donor hepatectomy. Minimally invasive hepatic resection approaches include pure laparoscopic, hand-assisted laparoscopic, and a laparoscopic-assisted open “hybrid” approach, where the operation is started laparoscopically to mobilize the liver and begin the dissection, followed by a small laparotomy for completion of the parenchymal transection. Surgeons should have an advanced understanding of hepatic anatomy, extensive experience in open liver surgery, and technical skill to control major vascular and biliary structures laparoscopically before embarking on LLR. Although there is no absolute size criterion, smaller, peripheral lesions (<5 cm) that lie far from major vessels and anticipated transection planes are most amenable to LLR. Although the majority of reported LLR are non-anatomic resections or segmentectomies, several surgical groups are now performing laparoscopic major hepatic resections with excellent safety profiles. Patient benefits from LLR include less operative blood loss, less postoperative pain and narcotic requirement, and a shorter length of hospital stay, with comparable postoperative morbidity and mortality to open liver resection. Comparison studies between LLR and open resection have revealed no differences in width of resection margins for malignant lesions or overall survival after resection for hepatocellular cancer or colorectal cancer liver metastases. Advantages of LLR for HCC in particular include avoidance of collateral vessel ligation, decreased postoperative hepatic insufficiency, and fewer postoperative adhesions, all of which are features that enhance subsequent liver transplantation.

The design of highly defective herpes simplex virus (HSV) vectors for transgene expression in nonneuronal cells in the absence of toxic viral-gene activity has been elusive. Here, we report that elements of the latency locus protect a nonviral promoter against silencing in primary human cells in the absence of any viral-gene expression. We identified a CTCF motif cluster 5′ to the latency promoter and a known long-term regulatory region as important elements for vigorous transgene expression from a vector that is functionally deleted for all five immediate-early genes and the 15-kb internal repeat region. We inserted a 16.5-kb expression cassette for full-length mouse dystrophin and report robust and durable expression in dystrophin-deficient muscle cells in vitro. Given the broad cell tropism of HSV, our design provides a nontoxic vector that can accommodate large transgene constructs for transduction of a wide variety of cells without vector integration, thereby filling an important void in the current arsenal of genetherapy vectors.

Background Laparoscopic liver resection (LLR) has undergone widespread dissemination after the first international consensus conference in 2008, and specialized centers continue to report remarkable achievements. However, little is known about the global adoption of LLR. This study aimed to illuminate geographical variances in the indications and technical aspects of LLR and to delineate the evolution of this approach worldwide. Methods In advance of the Second International Consensus Conference in Morioka, Japan, a web-based, anonymous questionnaire comprising 46 questions, named the International Survey on Technical Aspects of Laparoscopic Liver Resection study, was sent via e-mail to the members of regional and International Hepato-Pancreato-Biliary Association offices. The results of the 13 questions concerning the global diffusion of LLR have been reported previously. Responses to the remaining 33 questions that corresponded to indications and surgical techniques used in LLR were collected and analyzed. Results Survey responses were received from 412 LLR surgeons in 42 countries on five continents. The majority of surgeons in North America had no restrictions on the maximum size or number of tumors to be resected laparoscopically. Likewise, >50 % of surgeons in East Asia and North America performed LLR for the postero-superior ‘difficult’ segments. Major resection was performed in 40 to >60 % of centers in North America, Europe, and East Asia. Donor hepatectomy was performed only in specialized centers. More than 75 % of respondents had adopted a pure laparoscopic approach. A flexible laparoscope was most commonly used in East Asia. Most surgeons used pneumoperitoneal pressure at around 9–16 mmHg. Other techniques and devices were used at the discretion of each surgeon. Conclusions Indications for LLR continue to expand with some regional diversity. Surgical approaches and devices used in LLR are a matter of preference and availability, as in open liver resection.