The rapid progress in cancer immunology and immunotherapy has transformed the paradigm of surgical treatment for hepatobiliary malignancies. Comprehensive treatment strategies based on immunotherapy have been applied for downstaging and conversion treatment, allowing more advanced-stage patients to undergo radical or curative surgery; it has also become a new approach for neoadjuvant and adjuvant therapy. The following points deserve attention: (1) The “dual nature” of surgical treatment：it can “cure” primary malignancies, but also induce perioperative immune suppression through various mechanisms and promote postoperative metastatic recurrence. Minimizing surgical stress is the theoretical basis and advantage of the minimally invasive concept in surgical oncology. (2) Targeting the “surgical immune suppression” is a novel way to combat postoperative metastatic recurrence: the combination of neoadjuvant and adjuvant immunotherapy is a new trend. (3) Traditional lymph node dissection may impair immune responses and immunotherapy outcomes; selective preservation of regional lymph nodes can be a promising approach. For certain subgroups of patients, preoperative therapy leading to complete remission (immunological ablation) raises the possibility of organ-sparing and de-escalation of surgery.

Artificial intelligence (AI) technology is revolutionizing the precision diagnosis and treatment system in digestive system malignancies. In the preoperative stage, deep learning-driven multimodal data can significantly enhance the accuracy of early lesion detection and organ function assessment, while optimizing the prediction of the efficacy neoadjuvant therapy response with radiomics features. During surgery, the automatic surgical phase alorithm and intelligent pathology testing can effectively coordinate the surgical process; the combination of AI with augmented reality navigation system (AR) and mixed reality technology (MR) can improve the accuracy of intraoperative navigation; enhances intraoperative navigation accuracy; and the autonomous surgical robots can improve their ability to perform key tasks during surgery using sophisticated motion control algorithms. In postoperative management, federated learning promotes secure cross-institutional data sharing and alleviates the problem of data silos; and the development of interpretable models can also provide clearer decision-making basis for complication prediction and prognosis management. However, the current clinical translation process still faces three core challenges: (1) Quality control problems: the dual constraints of insufficient model generalization ability and lack of unified evaluation standards; (2) Methodological challenges: the logical opacity of decision-making and the cognitive barriers of the algorithm's causal reasoning process still affect its credibility; (3) Ethical and legal vacuum: the attribution of medical responsibility is unclear, and the legal system has not yet fully adapted to the development of AI applications. Based on this, the future should focus on: (1) Developing transparent AI systems to achieve a paradigm shift from "black box prediction" to "white box deductions"; (2) Establishing systematic AI evaluation standards and ethical and legal regulatory frameworks; (3) Promoting the construction of specialized biorepositories database and causal graph library for digestive oncology. The aim is to help AI upgrade from an auxiliary tool to an intelligent decision-making partner.

Surgical resection remains the primary option for achieving radical cure and long-term survival in the treatment of liver cancer.In recent years,profound changes have taken place in the field of liver surgery:the surgical concept of liver resection for liver cancer has been constantly updated;Significant progress has also been made in many aspects such as liver imaging technology,liver resection techniques and equipment,and perioperative management.Liver resection for liver cancer has gradually developed into a more precise,minimally invasive and safer treatment model.However,liver resection for liver cancer still faces many new challenges up to now:the prevention strategies for recurrence and metastasis are limited;There is a lack of predictive indicators for the efficacy of targeted immunotherapy.Insufficient precision in individualized treatment,etc.

Surgical resection remains the primary option for achieving radical cure and long-term survival in the treatment of liver cancer.In recent years,profound changes have taken place in the field of liver surgery:the surgical concept of liver resection for liver cancer has been constantly updated;Significant progress has also been made in many aspects such as liver imaging technology,liver resection techniques and equipment,and perioperative management.Liver resection for liver cancer has gradually developed into a more precise,minimally invasive and safer treatment model.However,liver resection for liver cancer still faces many new challenges up to now:the prevention strategies for recurrence and metastasis are limited;There is a lack of predictive indicators for the efficacy of targeted immunotherapy.Insufficient precision in individualized treatment,etc.

The rapid progress in cancer immunology and immunotherapy has transformed the paradigm of surgical treatment for hepatobiliary malignancies. Comprehensive treatment strategies based on immunotherapy have been applied for downstaging and conversion treatment, allowing more advanced-stage patients to undergo radical or curative surgery; it has also become a new approach for neoadjuvant and adjuvant therapy. The following points deserve attention: (1) The “dual nature” of surgical treatment：it can “cure” primary malignancies, but also induce perioperative immune suppression through various mechanisms and promote postoperative metastatic recurrence. Minimizing surgical stress is the theoretical basis and advantage of the minimally invasive concept in surgical oncology. (2) Targeting the “surgical immune suppression” is a novel way to combat postoperative metastatic recurrence: the combination of neoadjuvant and adjuvant immunotherapy is a new trend. (3) Traditional lymph node dissection may impair immune responses and immunotherapy outcomes; selective preservation of regional lymph nodes can be a promising approach. For certain subgroups of patients, preoperative therapy leading to complete remission (immunological ablation) raises the possibility of organ-sparing and de-escalation of surgery.

Artificial intelligence (AI) technology is revolutionizing the precision diagnosis and treatment system in digestive system malignancies. In the preoperative stage, deep learning-driven multimodal data can significantly enhance the accuracy of early lesion detection and organ function assessment, while optimizing the prediction of the efficacy neoadjuvant therapy response with radiomics features. During surgery, the automatic surgical phase alorithm and intelligent pathology testing can effectively coordinate the surgical process; the combination of AI with augmented reality navigation system (AR) and mixed reality technology (MR) can improve the accuracy of intraoperative navigation; enhances intraoperative navigation accuracy; and the autonomous surgical robots can improve their ability to perform key tasks during surgery using sophisticated motion control algorithms. In postoperative management, federated learning promotes secure cross-institutional data sharing and alleviates the problem of data silos; and the development of interpretable models can also provide clearer decision-making basis for complication prediction and prognosis management. However, the current clinical translation process still faces three core challenges: (1) Quality control problems: the dual constraints of insufficient model generalization ability and lack of unified evaluation standards; (2) Methodological challenges: the logical opacity of decision-making and the cognitive barriers of the algorithm's causal reasoning process still affect its credibility; (3) Ethical and legal vacuum: the attribution of medical responsibility is unclear, and the legal system has not yet fully adapted to the development of AI applications. Based on this, the future should focus on: (1) Developing transparent AI systems to achieve a paradigm shift from "black box prediction" to "white box deductions"; (2) Establishing systematic AI evaluation standards and ethical and legal regulatory frameworks; (3) Promoting the construction of specialized biorepositories database and causal graph library for digestive oncology. The aim is to help AI upgrade from an auxiliary tool to an intelligent decision-making partner.

Surgery is still the first choice for patients with hepatocellular carcinoma(HCC).However,about 70%of HCC patients in China are first diagnosed in the advanced stage and have lost the opportunity for surgery.Recently,the rapid development of systematic therapy has brought new hope for patients with advanced HCC.The combination of molecular targeted therapy and immunotherapy with or without local therapy significantly improves the survival of advanced HCC and alters the landscape of surgical treatment in advanced HCC.In addition,systemic therapy also brings new opportunities for perioperative treatment of HCC patients.Conversion therapy,neoadjuvant therapy,and postoperative adjuvant therapy can increase the chances of surgical treatment,reduce the risk of postoperative metastasis and recurrence,and prolong the overall survival of HCC patients.Systematic therapy based on molecular targeted therapy and immunotherapy has been applied through the whole process of HCC surgical treatment,and has completely altered the surgery paradigm of HCC.However,further research is needed to determine the optimal combination protocol,screen the sensitive populations,address drug resistance,and reduce systemic adverse events.

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.
Anilides/pharmacology* ; Animals ; Carcinoma, Hepatocellular/drug therapy* ; Cell Line, Tumor ; Cell Proliferation ; Endothelial Cells/metabolism* ; Humans ; Liver Neoplasms/drug therapy* ; Pyridines/pharmacology* ; Sirolimus/pharmacology* ; Xenograft Model Antitumor Assays

Objective:To compare the prognoses of salvage liver transplantation fulfilling the Criteria of Milan, University of California San Francisco(UCSF)and Hangzhou.Methods:Clinical data were retrospectively reviewed for 256 patients with recurrent hepatocellular carcinoma(HCC)undergoing donation after citizen death(DCD)liver transplantation(LT)from January 2015 to October 2019.They were divided into two groups of primary(PLT, n=175)and salvage(SLT, n=81). General profiles, tumor pathological characteristics and postoperative complications of two groups were compared by T-test, rank-sum or χ2 test.Kaplan-Meier method and Log rank test were employed for comparing overall survival rate(OS)and recurrence-free survival rate(RFS)between two groups.In SLT group, 31 cases fulfilled Milan criteria, 45 cases UCSF criteria and 69 cases Hangzhou criteria.OS/RFS of three groups were compared.According to there was downstaging or bridging treatment pre-LT, SLT group was divided into downstaging group(n=32)and non-downstaging group(n=49). OS/RFS of two groups were compared.According to the Rescit1.1 criteria, downstaging group were divided into remission group(n=14)and non-remission group(n=18)and OS/RFS of two groups were compared. Results:The operative durations of PLT and SLT groups were(439.5±74.9)and(475.1±83.4)min respectively.There was significant inter-group difference( P<0.05); However, no significant inter-group difference existed in amount of intraoperative bleeding, blood transfusion, postoperative hospital stay or incidence of postoperative complications(all P>0.05). No significant difference existed in OS/RFS between PLT and SLT groups( P>0.05). No significant difference existed in OS at 1/3/5 years post-SLT among Milan, UCSF and Hangzhou criteria groups(all P>0.05); However, RFS in Milan criteria group at 1/3/5 years post-SLT were 93.5%, 81.7% and 81.7% respectively.They were significantly higher than 68.9%, 59.7% and 59.7% in UCSF criteria group and 78.3%, 58.8% and 55.5% in Hangzhou criteria group(all P<0.05). For patients on downstaging therapy, OS in the Remission group at 1, 3 and 5 years post-SLT were 100%, 73% and 73% respectively, which was significantly higher than 83.3%, 49.4% and 0 in non-Remission group( P=0.042). RFS in the Remission group at 1, 3 and 5 years post-SLT were 100%, 62.5% and 46.9% respectively, which was significantly higher than 52.9%, 0 and 0 in no-Remission group( P=0.001). Conclusions:The survival outcome of SLT recipients is similar to that of PLT recipients.The overall survival of SLT recipients shows no significant difference between Milan, UCSF and Hangzhou criteria.However, SLT recipients fulfilling Milan criteria have the longest recurrence-free time.The prognosis of patients with remission after preoperative descending treatment is superior to that of patients without remission.

Objective:To investigate the imaging anatomical features of donor liver blood vessels in laparoscopic left lateral donor liver acquisition and their clinical significance.Methods:The retrospective and descriptive study was conducted. The clinical data of 39 living donor liver transplantation (LDLT) donors who were admitted to Huashan Hospital Affiliated to Fudan University between October 2016 and December 2018 were collected. There were 10 males and 29 females, aged (31±7)years. The clinical data of 39 LDLT recipients were collected. There were 26 males and 13 females, aged 8 months (range, 4-68 months). Abdominal enhanced computed tomography and three-dimensional vascular reconstruction were performed on donors to evaluate the anatomical characteristics of hepatic vessels. All the donors underwent laparoscopic left lateral donor liver acquisition. Observation indicators: (1) three-dimensional vascular reconstruction of preoperative imaging; (2) surgical conditions; (3) follow-up. Follow-up was performed using outpatient examination to detect complications of recipients after LDLT up to October 2019. Measurement data with normal distribution were expressed as Mean± SD, and comparison between groups was analyzed by the t test. Measurement data with skewed distribution were represented as M (range). Count data were expressed as absolute numbers or percentages. Results:(1) Three-dimensional vascular reconstruction of preoperative imaging: the anatomical characteristics of hepatic artery and hepatic vein revealed by three-dimensional vascular reconstruction of preoperative imaging of 39 donors included ① middle hepatic artery was present in 11 donors, among which 5 started from the right hepatic artery, 3 from the confluence of the right and left hepatic artery, and 3 from the left hepatic artery. Two donors had anatomical variation in the left hepatic artery which was presentation of left accessory hepatic artery originated from the left gastric artery. The other 26 donors had no middle hepatic artery or anatomical variation in the left hepatic artery. ② The left hepatic vein and the middle hepatic vein of 9 donors were respectively drained into the inferior vena cava. Seven donors had the left upper branch of the left hepatic vein, and 23 donors had a joint trunk of the left hepatic vein and the middle hepatic vein which drained into the inferior vena cava. (2) Surgical conditions: ① all the 39 donors successfully underwent laparoscopic left lateral donor liver acquisition. The operation time and volume of intraoperative blood loss were (160±32)minutes and (142±74)mL. ② Of 11 donors with middle hepatic artery, left hepatic artery was the dominant artery in 8 donors and was used for hepatic artery anastomosis and reconstruction in liver transplantation, middle hepatic artery started from left hepatic artery in 3 donors and the joint trunk of left and middle hepatic artery was used for hepatic artery anastomosis and reconstruction in liver transplantation. Of 2 donors with anatomical variation in the left hepatic artery, one had left accessory hepatic artery as the dominant artery and the other had left hepatic artery as the dominant artery. Left accessory hepatic artery and left hepatic artery were respectively used for hepatic artery anastomosis and reconstruction in liver transplantation. The other 26 donors had left hepatic artery for hepatic artery anastomosis and reconstruction in liver transplantation. ③ Among the 39 donors, 11 received intraoperative left hepatic vein preferred approach and 28 received intraoperative non-left hepatic vein preferred approach. The operation time and volume of intraoperative blood loss of donors with left hepatic vein preferred approach were (147±22)minutes and (110±44)mL, respectively, versus (169±33)minutes and (154±81)mL of donors with non-left hepatic vein preferred approach, showing significant differences in the above indicators between the two groups ( t=4.19, 2.81, P<0.05). (3) Follow-up: 39 donors were followed up for 10 months. During the follow-up, there was no hepatic artery anastomotic bleeding, stenosis, ischemic bile duct injury and biliary stenosis caused by poor hepatic arterial blood supply, or any complications related to hepatic venous outflow tract stenosis. Conclusions:Three-dimensional vascular reconstruction before laparoscopic left lateral donor liver acquisition can reveal the anatomical variation of middle hepatic artery and left hepatic artery, which can guide the selection of surgical approach. The left hepatic vein preferred approach is recommended for the qualified donor in the laparoscopic left lateral donor liver acquisition, which can shorten the operation time and reduce the volume of intraoperative blood loss.