Prognostic and Immunotherapeutic Predictive Value of CAD Gene in Hepatocellular Carcinoma: Integrated Bioinformatics and Experimental Analysis.

Hepatocellular carcinoma (HCC) is a common type of cancer that ranks first in cancer-associated death worldwide. Carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) are the key components of the pyrimidine pathway, which promotes cancer development. However, the function of CAD in HCC needs to be clarified. In this study, the clinical and transcriptome data of 424 TCGA-derived HCC cases were analyzed. The results demonstrated that high CAD expression was associated with poor prognosis in HCC patients. The effect of CAD on HCC was then investigated comprehensively using GO annotation analysis, KEGG enrichment analysis, Gene Set Enrichment Analysis (GSEA), and CIBERSORT algorithm. The results showed that CAD expression was correlated with immune checkpoint inhibitors and immune cell infiltration. In addition, low CAD levels in HCC patients predicted increased sensitivity to anti-CTLA4 and PD1, while HCC patients with high CAD expression exhibited high sensitivity to chemotherapeutic and molecular-targeted agents, including gemcitabine, paclitaxel, and sorafenib. Finally, the results from clinical sample suggested that CAD expression increased remarkably in HCC compared with non-cancerous tissues. Loss of function experiments demonstrated that CAD knockdown could significantly inhibit HCC cell growth and migration both in vitro and in vivo. Collectively, the results indicated that CAD is a potential oncogene during HCC metastasis and progression. Therefore, CAD is recommended as a candidate marker and target for HCC prediction and treatment.

An inferior vena cava-priority approach in laparoscopic isolated hepatic caudate lobectomy.

PURPOSE: Laparoscopic isolated caudate lobectomy is still a challenging operation for surgeons. The access route of the operation plays a vital role during laparoscopic caudate lobectomy. There are few references regarding this technique. Here, we introduce a preferred inferior vena cava (IVC) approach in laparoscopic caudate lobectomy. METHODS: Twenty-one consecutive patients with caudate hepatic tumours between June 2016 and December 2021 were included in this study. All of them received laparoscopic caudate lobectomy involving an IVC priority approach. The IVC priority approach refers to prioritizing the dissection of the IVC from the liver parenchyma before proceeding with the conventional left or right approach. It emphasizes the importance of the IVC dissection during process. Clinical data, intraoperative parameters and postoperative results were evaluated. Sixteen patients were performed pure IVC priority approach, while 5 patients underwent a combined approach. We subsequently compared the intraoperative and postoperative between the two groups. RESULTS: All 21 patients were treated with laparoscopic technology. The operative time was 190.95 ± 92.65 min. The average estimated blood loss was 251.43 ± 247.45 ml, and four patients needed blood transfusions during the perioperative period. The average duration of hospital stay was 8.43 ± 2.64 (range from 6.0 to 16.0) days. Patients who underwent the pure inferior vena cava (IVC) approach required a shorter hepatic pedicle clamping time (26 vs. 55 min, respectively; P < 0.001) and operation time (150 vs. 380 min, respectively; P = 0.002) than those who underwent the combined approach. Hospitalization (7.0 vs. 9.0 days, respectively; P = 0.006) was shorter in the pure IVC group than in the combined group. CONCLUSIONS: Laparoscopic caudate lobectomy with an IVC priority approach is safe and feasible for patients with caudate hepatic tumours.

Salvage Surgery for Initially Unresectable HCC With PVTT Converted by Locoregional Treatment Plus Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody.

BACKGROUND: This study aimed to compare the survival outcomes of patients with initially unresectable hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) who underwent or did not undergo salvage surgery followed by a triple combination conversion treatment consisted of locoregional treatment (LRT), tyrosine kinase inhibitors (TKIs), and anti-PD-1 antibodies. METHODS: The data from 93 consecutive patients with initially unresectable HCC and PVTT across 4 medical centers were retrospectively reviewed. They were converted successfully by the triple combination treatment and underwent or did not undergo salvage resection. The baseline characteristics, conversion schemes, conversion treatment-related adverse events (CTRAEs), overall survival (OS), and progression-free survival (PFS) of the salvage surgery and non-surgery groups were compared. Multivariate Cox regression analysis was performed to identify independent risk factors for OS and PFS. Additionally, subgroup survival analysis was conducted by stratification of degree of tumor response and type of PVTT. RESULTS: Of the 93 patients, 44 underwent salvage surgery, and 49 did not undergo salvage surgery. The OS and PFS of the salvage surgery and non-surgery groups were not significantly different (P = .370 and .334, respectively). The incidence and severity of CTRAEs of the 2 groups were also comparable. Subgroup analyses revealed that for patients with complete response (CR) or types III-IV PVTT, there was a trend toward better survival in patients who did not undergo salvage surgery. Multivariate analysis showed that baseline α-fetoprotein and best tumor response per mRECIST criteria were independent prognostic factors for OS and PFS. CONCLUSIONS: For patients with initially unresectable HCC and PVTT who were successfully converted by the triple combination therapy, salvage liver resection may not be necessary, especially for the patients with CR or types III-IV PVTT.

A new scoring system for predicting the outcome of hepatocellular carcinoma patients without microvascular invasion-a large-scale multicentre study.

BACKGROUND: The prognosis of HCC patients without MVI (so called M0) is highly heterogeneous and the need for adjuvant therapy is still controversial. METHODS: Patients with HCC with M0 who underwent liver resection (LR) or liver transplantation (LT) as an initial therapy were included. The Eastern Hepatobiliary Surgery Hospital (EHBH)-M0 score was developed from a retrospective cohort to form the training cohort. The classification which was developed using multivariate cox regression analysis was externally validated. RESULTS: The score was developed using the following factors: α-fetoprotein level, tumour diameter, liver cirrhosis, total bilirubin, albumin and aspartate aminotransferase. The score differentiated two groups of M0 patients (≤3, >3 points) with distinct long-term prognoses outcomes (median overall survival (OS), 98.0 vs. 46.0 months; p < 0.001). The predictive accuracy of the score was greater than the other commonly used staging systems for HCC. And for M0 patients with a higher score underwent LR. Adjuvant transcatheter arterial chemoembolization (TACE) was effective to prolong OS. CONCLUSIONS: The EHBH M0 scoring system was more accurate in predicting the prognosis of HCC patients with M0 after LR or LT. Adjuvant therapy is recommended for HCC patients who have a higher score.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

Short-term and long-term outcomes after robotic versus open hepatectomy in patients with large hepatocellular carcinoma: a multicenter study.

BACKGROUND: Robotic hepatectomy (RH) is currently widely accepted and it is associated with some benefits when compared to open hepatectomy (OH). However, whether such benefits can still be achieved for patients with large hepatocellular carcinoma (HCC) remain unclear. This study aimed to evaluate the short-term and long-term outcomes of patients undergoing RH or OH. METHODS: Perioperative and survival data from patients with large HCC who underwent RH or OH between January 2010 and December 2020 were collected from eight centres. Propensity score matching (PSM) was performed to minimise potential biases. RESULTS: Using predefined inclusion criteria, 797 patients who underwent OH and 309 patients who underwent RH were enroled in this study. After PSM, 280 patients in the robotic group had shorter operative time (median 181 vs. 201 min, P <0.001), lower estimated blood loss (median 200 vs. 400 ml, P <0.001), and shorter postoperative length of stay (median 6 vs. 9 days, P <0.001) than 465 patients in the open group. There were no significant differences between the two groups in overall survival and recurrence-free survival. Cox analysis showed AFP greater than 400 ng/ml, tumour size greater than 10 cm, and microvascular invasion were independent risk factors for overall survival and recurrence-free survival. After PSM, subgroup analysis showed that patients with a huge HCC (diameter >10 cm) who underwent RH had significantly lower estimated blood loss (median 200.0 vs. 500.0 min, P <0.001), and shorter length of stay (median 7 vs. 10 days, P <0.001) than those who underwent OH. CONCLUSION: Safety and feasibility of RH and OH for patients with large HCC were comparable. RH resulted in similar long-term survival outcomes as OH.

Discovery of distinct cancer cachexia phenotypes using an unsupervised machine-learning algorithm.

OBJECTIVES: Cancer cachexia is a debilitating condition with widespread negative effects. The heterogeneity of clinical features within patients with cancer cachexia is unclear. The identification and prognostic analysis of diverse phenotypes of cancer cachexia may help develop individualized interventions to improve outcomes for vulnerable populations. The aim of this study was to show that the machine learning-based cancer cachexia classification model generalized well on the external validation cohort. METHODS: This was a nationwide multicenter observational study conducted from October 2012 to April 2021 in China. Unsupervised consensus clustering analysis was applied based on demographic, anthropometric, nutritional, oncological, and quality-of-life data. Key characteristics of each cluster were identified using the standardized mean difference. We used logistic and Cox regression analysis to evaluate 1-, 3-, 5-y, and overall mortality. RESULTS: A consensus clustering algorithm was performed for 4329 patients with cancer cachexia in the discovery cohort, and four clusters with distinct phenotypes were uncovered. From clusters 1 to 4, the clinical characteristics of patients showed a transition from almost unimpaired to mildly, moderately, and severely impaired. Consistently, an increase in mortality from clusters 1 to 4 was observed. The overall mortality rate was 32%, 40%, 54%, and 68%, and the median overall survival time was 21.9, 18, 16.7, and 13.6 mo for patients in clusters 1 to 4, respectively. Our machine learning-based model performed better in predicting mortality than the traditional model. External validation confirmed the above results. CONCLUSIONS: Machine learning is valuable for phenotype classifications of patients with cancer cachexia. Detection of clinically distinct clusters among cachexic patients assists in scheduling personalized treatment strategies and in patient selection for clinical trials.

Surgical outcomes of hepatocellular carcinoma with extrahepatic bile duct tumor thrombus: a multicenter study.

Background: The long-term prognosis after surgery of patients with hepatocellular carcinoma (HCC) and extrahepatic bile duct tumor thrombus (Ex-BDTT) remains unknown. We aimed to identify the surgical outcomes of patients with HCC and Ex-BDTT. Methods: A total of 138 patients with Ex-BDTT who underwent hepatectomy with preservation of the extrahepatic bile duct from five large hospitals in China between January 2009 and December 2017 were included. The Cox proportional hazards model was used to analyze overall survival (OS) and recurrence-free survival (RFS). Results: With a median follow-up of 60 months (range, 1-127.8 months), the median OS and RFS of the patients were 28.6 and 8.9 months, respectively. The 1-, 3-, and 5-year OS rates of HCC patients with Ex-BDTT were 71.7%, 41.2%, and 33.5%, respectively, and the corresponding RFS rates were 43.5%, 21.7%, and 20.0%, respectively. Multivariate analysis identified that major hepatectomy, R0 resection, and major vascular invasion were independent prognostic factors for OS and RFS. In addition, preoperative serum total bilirubin ≥ 4.2 mg/dL was an independent prognostic factor for RFS. Conclusion: Major hepatectomy with preservation of the extrahepatic bile duct can provide favorable long-term survival for HCC patients with Ex-BDTT.

Preoperative and Prognostic Prediction of Microvascular Invasion in Hepatocellular Carcinoma: A Review Based on Artificial Intelligence.

Microvascular invasion of hepatocellular carcinoma is an important factor affecting tumor recurrence after liver resection and liver transplantation. There are many ways to classify microvascular invasion, however, an international consensus is urgently needed. Recently, artificial intelligence has emerged as an important tool for improving the clinical management of hepatocellular carcinoma. Many studies about microvascular invasion currently focus on preoperative and prognosis prediction of microvascular invasion using artificial intelligence. In this paper, we review the definition and staging of microvascular invasion, especially the diagnosis of it by using artificial intelligence. In preoperative prediction, deep learning based on multimodal data modeling of radiomics-screened features, clinical features, and medical images is currently the most effective means. In prognostic prediction, pathology is the gold standard, and the techniques used should more effectively utilize the global features of the pathology images.

Overall survival of patients with hepatocellular carcinoma treated with sintilimab and disease outcome after treatment discontinuation.

BACKGROUND: The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. METHODS: This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). RESULTS: Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). CONCLUSIONS: In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab.

Postoperative adjuvant aspirin for patients with hepatitis B virus-related hepatocellular carcinoma and portal vein tumor thrombus: An open-label, randomized controlled trial.

Purpose: To compare the survival outcomes of postoperative adjuvant aspirin with surgery alone in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). Methods: From June 2013 to July 2015, an open-label, randomized controlled study was conducted in patients with resectable HBV-related HCC and PVTT. Patients were randomly assigned to undergo surgical resection and postoperative adjuvant aspirin (n = 40) or hepatectomy alone (n = 40). The primary end point was overall survival (OS). The secondary end points were time to recurrence of primary tumor (t-TTR) and time to recurrence of PVTT (p-TTR). The expression levels of COX1 and COX2 in surgical specimens of the aspirin group were correlated with patients' survival. Results: The median OS were 16.2 and 13.4 months for the adjuvant aspirin and surgery alone groups, respectively. The median t-TTR were 5.3 and 3.2 months for the adjuvant aspirin and surgery alone groups, respectively. There was no significant difference in the OS and t-TTR between the two groups of patients (P = 0.078 and 0.336, respectively). The median p-TTR were 12.0 months and 5.4 months for the adjuvant aspirin group and the surgery alone group, respectively. Patients in the adjuvant aspirin group had markedly longer p-TTR (P = 0.001). Increased expressions of COX1 or COX2 in tumor tissues denoted better prognosis for patients receiving adjuvant aspirin. Conclusion: For patients with resectable HBV-related HCC and PVTT, postoperative adjuvant aspirin significantly prolonged time to recurrence of PVTT than surgery alone. Expression of COX1 or COX2 may predict survival in these patients.

S1PR1 regulates ovarian cancer cell senescence through the PDK1-LATS1/2-YAP pathway.

Cell senescence deters the activation of various oncogenes. Induction of senescence is, therefore, a potentially effective strategy to interfere with vital processes in tumor cells. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in various cancer types, including ovarian cancer. The mechanism by which S1PR1 regulates ovarian cancer cell senescence is currently elusive. In this study, we demonstrate that S1PR1 was highly expressed in human ovarian cancer tissues and cell lines. S1PR1 deletion inhibited the proliferation and migration of ovarian cancer cells. S1PR1 deletion promoted ovarian cancer cell senescence and sensitized ovarian cancer cells to cisplatin chemotherapy. Exposure of ovarian cancer cells to sphingosine-1-phosphate (S1P) increased the expression of 3-phosphatidylinositol-dependent protein kinase 1 (PDK1), decreased the expression of large tumor suppressor 1/2 (LATS1/2), and induced phosphorylation of Yes-associated protein (p-YAP). Opposite results were obtained in S1PR1 knockout cells following pharmacological inhibition. After silencing LATS1/2 in S1PR1-deficient ovarian cancer cells, senescence was suppressed and S1PR1 expression was increased concomitantly with YAP expression. Transcriptional regulation of S1PR1 by YAP was confirmed by chromatin immunoprecipitation. Accordingly, the S1PR1-PDK1-LATS1/2-YAP pathway regulates ovarian cancer cell senescence and does so through a YAP-mediated feedback loop. S1PR1 constitutes a druggable target for the induction of senescence in ovarian cancer cells. Pharmacological intervention in the S1PR1-PDK1-LATS1/2-YAP signaling axis may augment the efficacy of standard chemotherapy.

Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC). However, long-term survival outcomes and treatment response of HCC patients undergoing immunotherapy is unpredictable. The study aimed to evaluate the role of alpha-fetoprotein (AFP) combined with neutrophil-to-lymphocyte ratio (NLR) to predict the prognosis and treatment response of HCC patients receiving ICIs. METHODS: Patients with unresectable HCC who received ICI treatment were included. The HCC immunotherapy score was developed from a retrospective cohort at the Eastern Hepatobiliary Surgery Hospital to form the training cohort. The clinical variables independently associated with overall survival (OS) were identified using univariate and multivariate Cox regression analysis. Based on multivariate analysis of OS, a predictive score based on AFP and NLR was constructed, and patients were stratified into three risk groups according to this score. The clinical utility of this score to predict progression-free survival (PFS) and differentiate objective response rate (ORR) and disease control rate (DCR) was also performed. This score was validated in an independent external validation cohort at the First Affiliated Hospital of Wenzhou Medical University. RESULTS: Baseline AFP ≤ 400 ng/ml (hazard ratio [HR] 0.48; 95% CI, 0.24-0.97; P = 0.039) and NLR ≤ 2.77 (HR 0.11; 95% CI, 0.03-0.37; P<0.001) were found to be independent risk factors of OS. The two labolatory values were used to develop the score to predict survival outcomes and treatment response in HCC patients receiving immunotherapy, which assigned 1 point for AFP > 400 ng/ml and 3 points for NLR > 2.77. Patients with 0 point were classified as the low-risk group. Patients with 1-3 points were categorized as the intermediate-risk group. Patients with 4 points were classified as the high-risk group. In the training cohort, the median OS of the low-risk group was not reached. The median OS of the intermediate-risk group and high-risk group were 29.0 (95% CI 20.8-37.3) months and 16.0 (95% CI 10.8-21.2) months, respectively (P < 0.001). The median PFS of the low-risk group was not reached. The median PFS of the intermediate-risk group and high-risk group were 14.6 (95% CI 11.3-17.8) months and 7.6 (95% CI 3.6-11.7) months, respectively (P < 0.001). The ORR and DCR were highest in the low-risk group, followed by the intermediate-risk group and the high-risk group (P < 0.001, P = 0.007, respectively). This score also had good predictive power using the validation cohort. CONCLUSION: The HCC immunotherapy score based on AFP and NLR can predict survival outcomes and treatment response in patients receiving ICI treatments, suggesting that this score could serve as a useful tool for identification of HCC patients likely to benefit from immunotherapy.

Gemcitabine and cisplatin or oxaliplatin chemotherapy combined with atezolizumab plus bevacizumab for advanced biliary tract cancers: a single-arm trial.

Advanced biliary tract cancer (BTC) has a poor prognosis, even after combined chemotherapy of gemcitabine and oxaliplatin (GEMOX). To investigate the efficacy and safety of GEMOX chemotherapy combining atezolizumab and bevacizumab in advanced BTC, the authors designed an open-label, single-arm, phase II clinical trial and will enroll patients with stage IV BTC. The participants will receive GEMOX chemotherapy combined with atezolizumab plus bevacizumab. The primary end point is objective response rate; the secondary end points are overall survival, disease control rate, progression-free survival, time to progression, duration of response and safety. The results of this trial are expected to provide novel, safe and effective treatment options for patients with advanced BTC, which could further improve their prognosis. Clinical Trial Registration: ChiCTR2100049830 (ChiCTR.org).

Camrelizumab plus gemcitabine and oxaliplatin for the treatment of advanced intrahepatic cholangiocarcinoma: a bi-centric observational retrospective study.

Background: Immune checkpoint inhibitor (ICI), coupled with systemic chemotherapy, may enhance the clinical benefit of cancer by potentiating antitumor immunity, but its efficacy and safety are not clear in advanced intrahepatic cholangiocarcinoma (ICC). This study aims to assess the efficacy and safety of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) for the treatment of advanced ICC in the real world. Methods: Advanced ICC patients receiving at least one session of camrelizumab plus GEMOX combination treatment from March 2020 to February 2022 at two high-volume centers were considered eligible. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The primary endpoint was objective response rate (ORR), disease control rate (DCR), time to response (TTR), and duration of response (DOR). The secondary end points included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs). Results: 30 eligible ICC patients were enrolled and analyzed in this observational retrospective study. The median follow-up time was 24.0 (21.5-26.5) months. The ORR and DCR were 40% and 73.3%, respectively. The median TTR was 2.4 months and the median DOR was 5.0 months. The median PFS and OS were 7.5 months and 17.0 months, respectively. The most common TRAEs were fever (83.3%), fatigue (73.3%), and nausea (70%). Of all TRAEs, thrombocytopenia, and neutropenia were the most frequent severe AE (both 10%). Conclusion: The combination of camrelizumab and GEMOX is a potentially efficacious and safe treatment modality for advanced ICC patients. Potential biomarkers are needed to identify patients who might benefit from this treatment option.

Efficacy and safety of a triple combination of atezolizumab, bevacizumab plus GEMOX for advanced biliary tract cancer: a multicenter, single-arm, retrospective study.

Background: Anti-programmed cell death ligand 1/vascular endothelial growth factor inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit, but it has not been investigated in advanced biliary tract cancer (BTC). Objectives: We investigated the efficacy and safety of atezolizumab, bevacizumab, and gemcitabine plus oxaliplatin (GEMOX) in advanced BTC and explore the potential biomarkers related to the response. Design: Multicenter, single-arm, retrospective study. Methods: Advanced BTC patients, who received a triple combination therapy at three medical centers between 18 March 2020 and 1 September 2021, were included. Treatment response was evaluated via mRECIST and RECIST v1.1. Endpoints included the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The whole exome sequencing of pathological tissues was conducted for bioinformatic analysis. Results: In all, 30 patients were enrolled. The best ORR was 76.7% and the DCR was 90.0%. The median PFS was 12.0 months, and the median OS was not reached. During the treatment, 10.0% (3/30) of patients suffered from ⩾grade 3 treatment-related adverse events (TRAEs). Furthermore, fever (73.3%), neutropenia (63.3%), increased aspartate transaminase and alanine aminotransferase levels (50.0% and 43.3%, respectively) are the most common TRAEs. Bioinformatics analysis revealed patients with altered ALS2CL had a higher ORR. Conclusion: The triple combination of atezolizumab, bevacizumab, and GEMOX may be efficacious and safe for patients with advanced BTC. ALS2CL may be a potential predictive biomarker for the efficacy of triple combination therapy.

Laparoscopic and open liver resection for hepatocellular carcinoma with type 2 diabetes mellitus: multicenter propensity score-matched study.

PURPOSE: This study aimed at analyzing and comparing the perioperative results and long-term oncological outcomes of hepatocellular carcinoma (HCC) patients with type 2 diabetes mellitus (T2DM) treated with laparoscopic (LLR) versus open liver resection (OLR). METHODS: Clinicopathological data of HCC patients with T2DM who underwent LLR or OLR as initial treatment from four medical centers were retrospectively reviewed. The survival outcomes of patients who underwent laparoscopic liver resection (LLR) were compared with those of patients who underwent open liver resection (OLR). Using the Kaplan-Meier method, survival curves for the two groups of patients were generated, and the log-rank test was used to compare survival differences. Propensity score matching (PSM) analysis was used to match patients of the LLR and OLR groups in a 1:1 ratio. RESULTS: 230 HCC patients with T2DM were enrolled, including 101 patients in the LLR group and 129 patients in the OLR group. After PSM, 90 patients were matched in each of the study group. Compared with the OLR group, the LLR group had less blood loss, a shorter hospitalization and fewer postoperative complications. The LLR group had a significantly better overall survival (OS) and recurrence-free survival (RFS) than the OLR group before and after PSM. Subgroup analysis demonstrated that HCC patients with T2DM had survival benefits from LLR regardless of the course of T2DM. CONCLUSIONS: Laparoscopic liver resection for HCC patients with T2DM can be safely performed with favorable perioperative and long-term oncological outcomes at high-volume liver cancer centers, regardless of the course of T2DM.

PPDPF suppresses the development of hepatocellular carcinoma through TRIM21-mediated ubiquitination of RIPK1.

Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.

A reasonable identification of the early recurrence time based on microvascular invasion for hepatocellular carcinoma after R0 resection: A multicenter retrospective study.

BACKGROUND: Early and late recurrence of hepatocellular carcinoma (HCC) have different clinical outcomes, especially for those accompanied by microvascular invasion (MVI), but the definition of early recurrence remains controversial. Therefore, a reasonable identification of the early recurrence time for HCC is urgently needed. METHODS: Resected recurrence patients were enrolled and divided into two cohorts, one for identification of the early recurrence time and another for verification of the accuracy of the point. Univariable and multivariable Cox regression analyses were adopted to identify the prognostic factors of recurrence HCC (rHCC) and Kaplan-Meier method was applied to analyze the overall survival (OS). The appropriate cutoff value was determined by the exhaustive method using different recurrence intervals from 1 to 24 months in turn. RESULTS: In total, 292 resected rHCC patients were analyzed to calculate the early recurrence interval, and another 421 resected rHCC patients with MVI were enrolled to verify the efficacy of adjuvant transarterial chemoembolization (TACE) in this recurrence interval. MVI was identified as an independent risk factor by multivariable analysis. The OS of rHCC patients without MVI is better than that of patients with MVI when the recurrence time was within 13 months, while not beyond 13 months. The verification cohort demonstrated that adjuvant TACE provided longer survival for rHCC with MVI when the recurrence time was within 13 months, while not beyond 13 months. CONCLUSION: For HCC patients with MVI who underwent R0 resection, 13 months may be a reasonable early recurrence time point, and within this interval, postoperative adjuvant TACE may result in longer survival compared with surgery alone.

Network pharmacology-based analysis of Resinacein S against non-alcoholic fatty liver disease by modulating lipid metabolism.

Background: Ganoderma lucidum is reportedly the best source of traditional natural bioactive constituents. Ganoderma triterpenoids (GTs) have been verified as an alternative adjuvant for treating leukemia, cancer, hepatitis and diabetes. One of the major triterpenoids, Resinacein S, has been found to regulate lipid metabolism and mitochondrial biogenesis. Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that has become a major public health problem. Given the regulatory effects on lipid metabolism of Resinacein S, we sought to explore potential protective effects against NAFLD. Methods: Resinacein S was extracted and isolated from G. lucidum. And mice were fed with high fat diet with or without Resinacein S to detect hepatic steatosis. According to Network Pharmacology and RNA-seq, we analyzed the hub genes of Resinacein S against NAFLD disease. Results: Our results can be summarized as follows: (1) The structure of Resinacein S was elucidated using NMR and MS methods. (2) Resinacein S treatment could significantly attenuate high-fat diet (HFD)-induced hepatic steatosis and hepatic lipid accumulation in mouse. (3) GO terms, KEGG pathways and the PPI network of Resinacein S induced Differentially Expressed Genes (DEGs) demonstrated the key target genes of Resinacein S against NAFLD. (4) The hub proteins in PPI network analysis could be used for NAFLD diagnosis and treatment as drug targets. Conclusion: Resinacein S can significantly change the lipid metabolism in liver cells and yield a protective effect against steatosis and liver injury. Intersected proteins between NAFLD related genes and Resinacein S-induced DEGs, especially the hub protein in PPI network analysis, can be used to characterize targets of Resinacein S against NAFLD.