Targeting the MCP-GPX4/HMGB1 Axis for Effectively Triggering Immunogenic Ferroptosis in Pancreatic Ductal Adenocarcinoma.

Induction of ferroptosis can inhibit cancer cells in vitro, however, the role of ferroptosis in treatment in vivo is controversial. The immunosuppressive cells activated by the ferroptotic tumor cells can promote the growth of residual tumor cells, hindering the application of ferroptosis stimulation in tumor treatment. In this study, a new strategy is aimed to be identified for effectively triggering immunogenic ferroptosis in pancreatic ductal adenocarcinoma (PDAC) and simultaneously stimulating antitumor immune responses. Toward this, several molecular and biochemical experiments are performed using patient-derived organoid models and a KPC mouse model (LSL-KrasG12D /+, LSL-Trp53R172H/+, Pdx-1-Cre). It is observed that the inhibition of macrophage-capping protein (MCP) suppressed the ubiquitin fold modifier (UFM)ylation of pirin (PIR), a newly identified substrate of UFM1, thereby decreasing the transcription of GPX4, a marker of ferroptosis, and promoting the cytoplasmic transportation of HMGB1, a damage-associated molecular pattern. GPX4 deficiency triggered ferroptosis, and the pre-accumulated cytosolic HMGB1 is released rapidly. This altered release pattern of HMGB1 facilitated the pro-inflammatory M1-like polarization of macrophages. Thus, therapeutic inhibition of MCP yielded dual antitumor effects by stimulating ferroptosis and activating antitumor pro-inflammatory M1-like macrophages. The nanosystem developed for specifically silencing MCP is a promising tool for treating PDAC.

Classification of left-side hepatolithiasis for laparoscopic middle hepatic vein-guided anatomical hemihepatectomy combined with transhepatic duct lithotomy.

BACKGROUND: Laparoscopic middle hepatic vein-guided anatomical hemihepatectomy combined with transhepatic duct lithotomy (MATL) is an approach that can substantially improve stone clearance rates while reducing the rate of postoperative biliary fistula formation, residual stone rates, and rates of recurrence. In this study, we classified left-side hepatolithiasis cases into four subtypes based upon the diseased stone-containing bile duct, the middle hepatic vein, and the right hepatic duct. We then investigated the risk associated with different subtypes and evaluated the safety and efficacy of the MATL procedure. METHODS: In total, 372 patients who underwent left hemihepatectomy for left intrahepatic bile duct stones were enrolled. Based on the distribution of the stones, the cases could be divided into four types. The risk of surgical treatment was compared for the four types and the safety, short-term efficacy, and long-term efficacy of the MATL procedure in the four types of left intrahepatic bile duct stones were studied. RESULTS: Type II was found to be the most likely to cause intraoperative bleeding while type III was likely to cause biliary tract damage and type IV was associated with the highest stone recurrence rate. The MATL procedure did not increase the risk of surgery and was found to reduce the rate of bile leakage, residual stones, and stone recurrence. CONCLUSION: Left-side hepatolithiasis-associated risk classification is feasible and may represent a viable means of improving the safety and feasibility of the MATL procedure.

A novel Laennec's capsule tunnel approach for pure laparoscopic left hemihepatectomy: a propensity score matching study.

Background: With the development of laparoscopic hepatectomy, there are different surgical approaches and pedicle anatomical methods for laparoscopic left hepatectomy. Combined with our practical experience, we proposed a method of transhepatic Laennec membrane tunnel for laparoscopic left hemihepatectomy (LT-LLH) and investigated the feasibility by comparison with the extrahepatic Glissonian approach for laparoscopic left hemihepatectomy (GA-LLH). Patients and methods: The data of patients who underwent laparoscopic left hepatectomy in the Department of Hepatobiliary Pancreatic surgery of Fujian Provincial Hospital from December 2019 to March 2022 were analyzed retrospectively. Among them, 45 cases underwent laparoscopic left hemihepatectomy with an extrahepatic Glissonian approach, and 38 cases underwent laparoscopic left hemihepatectomy via transhepatic Laennec membrane tunnel approach. A 1:1 propensity score matching (PSM) method was performed to compare the perioperative indexes and long-term tumor prognosis between the two groups. Results: After 1:1 PSM, 33 patients in each group were selected for further analysis. Compared with the GA-LLH group, the operation time of the LT-LLH group was shorter. There was no significant difference in the incidence of total complications between the two groups. Moreover, no statistical differences were found in disease-free survival and overall survival between the two groups. Conclusion: It is safe, faster, and convenient for selective appropriate cases to carry out laparoscopic left hemihepatectomy through the hepatic Laennec membrane tunnel, which is suitable for clinical promotion.

Analyzing molecular typing and clinical application of immunogenic cell death-related genes in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is considered one of the most common cancers, characterized by low early detection and high mortality rates, and is a global health challenge. Immunogenic cell death (ICD) is defined as a specific type of regulated cell death (RCD) capable of reshaping the tumor immune microenvironment by releasing danger signals that trigger immune responses, which would contribute to immunotherapy. METHODS: The ICD gene sets were collected from the literature. We collected expression data and clinical information from public databases for the HCC samples in our study. Data processing and mapping were performed using R software to analyze the differences in biological characteristics between different subgroups. The expression of the ICD representative gene in clinical specimens was assessed by immunohistochemistry, and the role of the representative gene in HCC was evaluated by various in vitro assays, including qRT-PCR, colony formation, and CCK8 assay. Lasso-Cox regression was used to screen prognosis-related genes, and an ICD-related risk model (ICDRM) was constructed. To improve the clinical value of ICDRM, Nomograms and calibration curves were created to predict survival probabilities. Finally, the critical gene of ICDRM was further investigated through pan-cancer analysis and single-cell analysis. RESULTS: We identified two ICD clusters that differed significantly in terms of survival, biological function, and immune infiltration. As well as assessing the immune microenvironment of tumors in HCC patients, we demonstrate that ICDRM can differentiate ICD clusters and predict the prognosis and effectiveness of therapy. High-risk subpopulations are characterized by high TMB, suppressed immunity, and poor survival and response to immunotherapy, whereas the opposite is true for low-risk subpopulations. CONCLUSIONS: This study reveals the potential impact of ICDRM on the tumor microenvironment (TME), immune infiltration, and prognosis of HCC patients, but also a potential tool for predicting prognosis.

Textbook outcomes of hepatocellular carcinoma patients with sarcopenia: A multicenter analysis.

BACKGROUND: The impact of sarcopenia on textbook outcome (TO) after hepatectomy in hepatocellular carcinoma (HCC) patients remains unclear. This study aimed to investigate the association between sarcopenia and TO, to clarify its long and short-term prognostic value, and to develop a nomogram model based on sarcopenia and TO for survival prediction. METHODS: Patients who underwent HCC resection between January 2012 and March 2017 in three large hospitals in Fujian were retrospectively recruited and divided into sarcopenia and non-sarcopenia groups based on skeletal muscle index (SMI) values. TO was defined as no 30-day morality, no 30-day readmission, negative margins, no prolonged hospital stay, and no major complications. Multivariate regression was used to screen for clinical factors associated with TO. Nomograms of overall survival (OS) and recurrence-free survival (RFS) after hepatectomy for HCC were developed. RESULTS: A total of 1172 patients were included in the study. The TO rates were 28.74% (121/421 patients) in the sarcopenia group and 43.4% (326/751 patients) in the non-sarcopenia group. The results showed that sarcopenia was an independent predictor of TO (p < 0.001), TO was an independent predictor of perioperative treatment-related sarcopenia (PTRS)(p = 0.002), and TO was an independent predictor of OS and RFS (p < 0.001). Nomogram models based on sarcopenia and TO were generated and accurately predicted OS and RFS at 1, 3, and 5 years. CONCLUSION: Both sarcopenia and TO are independent predictors of OS and RFS after HCC resection. Sarcopenia was an independent predictor of TO. Sarcopenia influenced long-term survival by affecting short-term postoperative outcomes.

Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy.

Reports indicate that autophagy is essential for maintaining hepatocyte proliferative capacity during liver regeneration. However, the role of autophagy in fibrotic liver regeneration is incompletely elucidated. We investigated the deregulation of autophagic activities in liver regeneration after partial hepatectomy using a CCl4-induced fibrosis mouse model. The baseline autophagic activity was significantly increased in the fibrotic liver. After 50% partial hepatectomy (PHx), liver regeneration was remarkably decreased, accompanied by increased hepatocyte size and binuclearity ratio. Moreover, the expression of autophagy-related proteins was functionally deregulated and resulted in a reduction in the number of autophagosome and autophagosome-lysosome fusions. We further showed upregulation of autophagy activities through verapamil administration, improved hepatocyte proliferation capacity, and restricted cellular hypertrophy and binuclearity ratio. In conclusion, we demonstrated that the impairment of liver regeneration is associated with aberrant autophagy in fibrotic liver and that enhancing autophagy with verapamil may partially restore the impaired liver regeneration following PHx.

Perioperative management of intrahepatic cholangiocarcinoma patients with hereditary coagulation factor V deficiency: a case report and literature review.

Background: Coagulation factor V (FV) is an essential factor to regulate and participate in the initial coagulation reaction, and it is the most important prothrombin activator in vivo. FV congenital deficiency is a rare hereditary disease, it exposes patients to hemorrhagic risk, with high morbi-mortality. Clinically, laparoscopic major hepatectomy has its own risk of intraoperative hemorrhage, and moreover, coupled with the lack of FV will increase the risk of bleeding even life-threatening. However, several studies have reported the cases of patients with FV deficiency undergoing surgery, there is no report of laparoscopic major hepatectomy in patients with FV deficiency so far. Case Description: Here, we reported one case with no abdominal pain, nausea, vomiting, fever and other discomfort who was diagnosed with intrahepatic cholangiocarcinoma (IHC) complicated with hereditary FV deficiency and then received laparoscopic left hemihepatectomy after conversion therapy. After preoperative sufficient infusion of fresh frozen plasma (FFP) to improve coagulation function, careful intraoperative operation, and strict postoperative monitoring, no obvious complications occurred in the perioperative period. At present, the patient has an overall survival time of 18 months and is still followed up. Conclusions: It is suggested that laparoscopic major hepatectomy is safe and feasible for patients with hereditary FV deficiency under careful perioperative management.

Multiple endocrine neoplasia type 1 involving both the liver and lung: a case report.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant tumor syndrome with a high degree of heterogeneity in clinical phenotypes, generally involving the parathyroid, anterior pituitary, and enteropancreas. In recent years, several new insights into the clinical features of MEN1 have been reported in the literature. However, it is not clear whether MEN1-associated primary tumors can occur in the liver. CASE PRESENTATION: We report the case of a 52-year-old man with multiple endocrine neoplasia type 1 diagnosed by genetic sequencing. After uniportal thoracoscopic right middle lobectomy, laparoscopic radical resection of the liver tumors, and radiofrequency ablation of the parathyroid space, the parathyroid hormone level decreased from 177 pg/ml to a normal level (20 pg/ml). No local tumor recurrence was observed during a follow-up of 5 months. CONCLUSION: We report the first case of MEN1 with simultaneous liver and lung involvement in which the patient underwent radical resection of the tumors, and we propose the possibility that the liver and other nonendocrine organs may also develop diseases associated with MEN1; although, this view needs further verification. Gene detection has crucial clinical significance for guiding diagnosis and treatment.

Verapamil induces autophagy to improve liver regeneration in non-alcoholic fatty liver mice.

Verapamil can restore intracellular calcium homeostasis, increase the fusion of autophagosomes and lysosomes, reduce lipid droplet accumulation and inhibit inflammation and insulin resistance in high-fat-fed mice. The present study aimed to investigate verapamil's effect and its underlying liver regeneration mechanism in mice with non-alcoholic fatty liver. After 50% hepatectomy was performed, the changes of autophagy and liver regeneration were evaluated by detecting cell proliferation and autophagy at each time point. Then, 25mg/kg verapamil was injected intraperitoneally for 10 d before an operation in the mild to moderate fatty liver and severe fatty liver groups. The control group and mild to moderate fatty liver group reached the peak of proliferation at 24-48h after operation, and the mice with severe fatty liver and steatohepatitis reached the peak at 48-72h. Autophagy in the normal group and mild to moderate fatty liver group reached the peak 48 hours after operation. Verapamil injection can enhance autophagy, reduce the weight of fatty liver mice, improve liver function and liver regeneration. Verapamil can induce autophagy, improve hepatocyte function and promote hepatocyte regeneration through the mTOR independent signaling pathway, thus improving the process of liver regeneration after partial hepatectomy.

A Prognostic Scoring System for Predicting Overall Survival of Patients with the TNM 8th Edition Stage I and II Hepatocellular Carcinoma After Surgery: A Population-Based Study.

PURPOSE: Postoperative prognosis prediction models for patients with stage Ⅰ and Ⅱ hepatocellular carcinoma (HCC) according to the 8th edition of the Tumor-Node-Metastasis staging system after surgery are rare. This study aimed to build a prognostic score to predict survival outcomes and stratify these patients into different prognostic strata. PATIENTS AND METHODS: We developed a web-based nomogram that incorporated four selected risk factors based on the multivariate Cox regression, using a training set (n=3567) from the Surveillance, Epidemiology, and End Results (SEER) database. It was validated with an independent internal set from the SEER database (n=1783) and an external validation set of 516 Chinese patients. The predictive performance and discrimination ability of our model were further evaluated and compared with those of the conventional HCC staging systems. RESULTS: Our nomogram consistently outperformed the conventional staging systems in the training, internal validation set, and external validation set. We quantified the nomogram model into a numerical SNIG (an abbreviation of the incorporated variables - size, number, MVI, and grade) score by summing the points assigned to each incorporated variable, leading to the optimal cut-off values of 6 and 10, which could stratify patients into 3 categories (SNIG score <6, 6-10, ≥10). This yielded significantly different median overall survivals (interquartile ranges) of 42.0 (20.0-72.0) and 37.0 (17.0-67.0); 28.0 (12.0-60.0) and 42.0 (21.75-82.0); 40.0 (18.0-70.0) and 29.0 (11.5-61.0) months for the 3 categories in the entire SEER and external validation sets, respectively. CONCLUSION: We developed a web-based SNIG model to graphically and numerically predict the overall survival of stage Ⅰ and Ⅱ HCC. This scoring system may shed light on risk stratification for these patients in clinical practice and clinical trials.

Immunohistochemical Signature Add Prognostic Value in Patients With Early and Intermediate Hepatocellular Carcinoma Underwent Curative Liver Resection.

Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide; however, accurate prognostic tools are still lacking. We aimed to identify immunohistochemistry (IHC)-based signature as a prognostic classifier to predict recurrence and survival in patients with HCC at Barcelona Clinic Liver Cancer (BCLC) early- and immediate-stage. In total, 567 patients who underwent curative liver resection at two independent centers were enrolled. The least absolute shrinkage and selection operator regression model was used to identify significant IHC features, and penalized Cox regression was used to further narrow down the features in the training cohort (n = 201). The candidate IHC features were validated in internal (n = 101) and external validation cohorts (n = 265). Three IHC features, hepatocyte paraffin antigen 1, CD34, and Ki-67, were identified as candidate predictors for recurrence-free survival (RFS), and were used to categorize patients into low- and high-risk recurrence groups in the training cohort (P < 0.001). The discriminative performance of the 3-IHC_based classifier was validated using internal and external cohorts (P < 0.001). Furthermore, we developed a 3-IHC_based nomogram integrating the BCLC stage, microvascular invasion, and 3-IHC_based classifier to predict 2- and 5-year RFS in the training cohort; this nomogram exhibited acceptable area under the curve values for the training, internal validation, and external validation cohorts (2-year: 0.817, 0.787, and 0.810; 5-year: 0.726, 0.662, and 0.715; respectively). The newly developed 3-IHC_based classifier can effectively predict recurrence and survival in patients with early- and intermediate-stage HCC after curative liver resection.