Eastern Hepatobiliary Surgery Hospital Research Articles

Development and validation of nomograms to predict survival and recurrence after hepatectomy for intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma

BackgroundDespite the Barcelona Clinic Liver Cancer system discouraging hepatectomy for intermediate/advanced hepatocellular carcinoma, the procedure is still performed worldwide, particularly in Asia. This study aimed to develop and validate nomograms for predicting survival and recurrence for these patients. MethodsWe analyzed patients who underwent curative-intent hepatectomy for intermediate/advanced hepatocellular carcinoma between 2010 and 2020 across 3 Chinese hospitals. The Eastern Hepatobiliary Surgery Hospital cohort was used as the training cohort for the nomogram construction, and the Jilin First Hospital and Fujian Mengchao Hepatobiliary Hospital cohorts served as the external validation cohorts. Independent preoperative predictors for survival and recurrence were identified through univariable and multivariable Cox regression analyses. Predictive accuracy was measured using the concordance index and calibration curves. The predictive performance between nomograms and conventional hepatocellular carcinoma staging systems was compared. ResultsA total of 1,328 patients met the inclusion criteria. The nomograms for predicting survival and recurrence were developed using 10 and 6 independent variables, respectively. Nomograms’ concordance indices in the training cohort were 0.777 (95% confidence interval 0.759–0.800) and 0.719 (95% confidence interval 0.697–0.742) for survival and recurrence, outperforming 4 conventional staging systems (P < .001). Nomograms accurately stratified risk into low, intermediate, and high subgroups. These results were validated well by 2 external validation cohorts. ConclusionWe developed and validated nomograms predicting survival and recurrence for patients with intermediate/advanced hepatocellular carcinoma, contradicting Barcelona Clinic Liver Cancer surgical guidelines. These nomograms may facilitate clinicians to formulate personalized surgical decisions, estimate long-term prognosis, and strategize neoadjuvant/adjuvant anti-recurrence therapy.

Sex disparity in clinical characteristics and long-term prognosis after liver resection for patients with intrahepatic cholangiocarcinoma: A propensity score matching analysis

AimTo compare the survival outcomes between male and female patients with intrahepatic cholangiocarcinoma who underwent liver resection. MethodsData from 976 consecutive intrahepatic cholangiocarcinoma patients undergoing liver resection between January 2005 and May 2013 at the Eastern Hepatobiliary Surgery Hospital were prospectively collected and retrospectively reviewed. Patient clinicopathological characteristics, overall survival, and cumulative recurrence rates were compared between male and female patients using propensity score matching. ResultsPropensity score matching generated 313 matched pairs of patients. Among the entire cohort, the 1-, 3-, and 5-year overall survival and recurrence rates of the male and female patients were 60.2 %, 37.3 %, and 27.7 % vs. 65.8 %, 40.4 %, and 31.0 % (P = 0.380) and 50.6 %, 67.4 %, and 74.2 % vs. 44.4 %, 63.5 %, and 69.6 % (P = 0.123), respectively. In the matched cohort, the 1-, 3-, and 5-year overall survival and recurrence rates of the male and female patients were 60.6 %, 35.9 % and 22.4 % vs. 66.4 %, 40.6 % and 31.1 % (P = 0.041) and 51.5 %, 69.3 % and 83.9 % vs. 44.3 %, 63.6 %, and 69.9 % (P = 0.041), respectively. After adjustment for other confounding variables by multivariate Cox regression analysis, male sex was independently associated with worse overall survival (hazard ratio = 1.322, 95 % confidence interval: 1.079–1.621, P = 0.007) and tumor recurrence (hazard ratio = 1.337, 95 % confidence interval: 1.088–1.645, P = 0.006). A subgroup analysis of patients younger than 55 years old after propensity score matching showed that male patients had significantly worse overall survival and higher recurrence rates than female patients after surgery, while no significant difference in long-term overall survival and recurrence was observed between male and female patients older than 55 years old after propensity score matching. ConclusionMale sex was an independent risk factor for overall survival and tumor recurrence in patients after liver resection for intrahepatic cholangiocarcinoma.

Sequential or simultaneous transarterial chemoembolization and radiofrequency ablation for hepatocellular carcinoma within the Milan criteria: A retrospective real‐world study

AbstractAimsFew studies have investigated differences in sequential transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and simultaneous RFA‐TACE for the treatment of hepatocellular carcinoma (HCC) using the Milan criteria. This study explored the differences in safety and prognosis between sequential TACE‐RFA and simultaneous RFA‐TACE.MethodsThis retrospective real‐world study included 109 patients with HCC within the Milan criteria who underwent sequential TACE‐RFA (n = 75) or simultaneous RFA‐TACE (n = 34) at the Eastern Hepatobiliary Surgery Hospital between January 2017 and 2021. Postoperative complications, length of hospital stay, and long‐term prognosis were compared. The median follow‐up duration of these patients was 39.1 months. Overall survival (OS) and time to tumor recurrence (TTR) curves were plotted using the Kaplan−Meier method and were compared using the logarithmic rank test. Independent risk factors for OS and tumor recurrence (TR) were analyzed using the Cox risk regression model.ResultsMultivariate analysis showed that tumor diameter &gt;3 cm (hazard ratio [HR]: 2.201, 95% confidence interval [CI]: 1.106–4.378, p = 0.025; HR: 2.236, 95% CI: 1.271–3.934, p = 0.005, respectively) and alpha‐fetoprotein (AFP) &gt; 400 μg/L (HR: 2.362, 95% CI: 1.195–4.668, p = 0.013; HR: 1.798, 95% CI: 1.048–3.086, p = 0.033, respectively) were independent risk factors for OS and TTR, whereas the presence of multiple tumors (HR: 2.352, 95% CI: 1.127–4.907, p = 0.023) was an independent risk factor for TTR. Simultaneous RFA‐TACE did not have an effect on OS or TTR. After propensity score‐matched, comparable results were obtained and RFA‐TACE still had no effect on OS or TTR. No significant differences were observed in grade III/IV complications (2/75 [2.7%] vs. 1/34 [2.9%], p = 1.000) between the two groups. However, the RFA‐TACE group had fewer complications than the TACE‐RFA group (24/34 [70.6%] vs. 66/75 [88.0%], p = 0.026). The RFA‐TACE group had a shorter hospital stay and less total cost during hospitalization compared with the TACE‐RFA group (6.0 vs. 10.0 days, p &lt; 0.001; 30,000 vs. 35,000 CNY, p &lt; 0.001).ConclusionsFor HCC within the Milan criteria, there was no significant difference in OS and TTR between RFA‐TACE and TACE‐RFA. However, RFA‐TACE could reduce all‐grade complications and shorten the length of hospital stay compared with TACE‐RFA. Therefore, simultaneous RFA‐TACE may be considered for patients with HCC and good liver function falling within the Milan criteria.

Nomograms to predict long-term survival for patients with gallbladder carcinoma after resection.

Surgical resection remains the primary treatment option for gallbladder carcinoma (GBC). However, there is a pressing demand for prognostic tools that can refine patients' treatment choices and tailor personalized therapies accordingly. The nomograms were constructed using the data of a training cohort (n = 378) of GBC patients at Eastern Hepatobiliary Surgery Hospital (EHBH) between 2008 and 2018. The model's performance was validated in GBC patients (n = 108) at Guangzhou Centre from 2007 to 2018. The 5-year overall survival (OS) rate in the training cohort was 24.4%. Multivariate analyses were performed using preoperative and postoperative data to identify independent predictors of OS. These predictors were then incorporated into preoperative and postoperative nomograms, respectively. The C-index of the preoperative nomogram was 0.661 (95% CI, 0.627 to 0.694) for OS prediction and correctly delineated four subgroups (5-year OS rates: 48.1%, 19.0%, 15.6%, and 8.1%, p < 0.001). The C-index of the postoperative nomogram was 0.778 (95%CI, 0.756 -0.800). Furthermore, this nomogram was superior to the 8th TNM system in both C-index and the net benefit on decision curve analysis. The results were externally validated. The two nomograms showed an optimally prognostic prediction in GBC patients after curative-intent resection.

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

BackgroundThe prognosis of HCC patients without MVI (so called M0) is highly heterogeneous and the need for adjuvant therapy is still controversial. MethodsPatients 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. ResultsThe 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. ConclusionsThe 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.

Perineural invasion confers poorer clinical outcomes in patients with T1/T2 intrahepatic cholangiocarcinoma: a single center, retrospective cohort study.

Intrahepatic cholangiocarcinoma (ICC) poses a significant clinical challenge, demanding a thorough understanding of prognostic indicators for effective patient management. Despite reports suggesting the impact of perineural invasion (PNI) on the prognosis of early-stage ICC patients, there has been a dearth of comprehensive research specifically targeting this subgroup. This study seeks to investigate the influence of PNI on survival outcomes in early-stage ICC patients and aims to enhance the prognostic value of the American Joint Committee on Cancer (AJCC) T category. A cohort of 268 early-stage (T1-T2N0M0) ICC patients, who underwent curative-intent resection (R0) between 2011 and 2015 at the Eastern Hepatobiliary Surgery Hospital, were enrolled in this study. Lasso and Cox regression analyses were employed to explore differences in clinical and prognostic data. Kaplan-Meier curves were generated to illustrate the clinical significance of the combination of PNI and T category. Among the 268 patients, 24.6% exhibited PNI. Patients with PNI demonstrated shorter recurrence-free survival (RFS) [median RFS: 16 months (interquartile range, 9.5-19 months)] and overall survival (OS) [median OS: 16.53 months (interquartile range, 10-25 months)]. PNI emerged as an independent risk factor for both RFS and OS in T1- and T2-stage patients (all P<0.05), whereas tumor size was only an independent risk factor for OS (P=0.004). PNI was associated with all prognostic markers for ICC patients, including gender, jaundice, cholangitis, hepatitis B virus (HBV) infection, cancer antigen 199 (CA199), preoperative serum albumin, and preoperative platelet count (all P<0.05). However, there was no significant difference in RFS (P=0.270) and OS (P=0.360) between T2 patients without PNI and T1 patients with PNI. This study underscores PNI as a robust prognostic factor in early-stage ICC, emphasizing the necessity of incorporating PNI into the AJCC T category for precise risk stratification. Clinically, understanding the impact of PNI on survival outcomes can guide tailored treatment strategies for early ICC patients.

Tenofovir vs Entecavir Among Patients With HBV-Related HCC After Resection

Tenofovir disoproxil and entecavir are both commonly used first-line antiviral treatments, but their comparative recurrence and overall survival (OS) benefits remain unclear. To explore differences of tenofovir disoproxil vs entecavir in recurrence-free survival (RFS) and OS after liver resection with curative intent in patients with hepatocellular cancer (HCC) related to hepatitis B virus (HBV). This retrospective cohort study was conducted at Eastern Hepatobiliary Surgery Hospital, a tertiary referral hospital in Shanghai, China, between January 4, 2015, and April 1, 2023. Participants included patients with HBV-related HCC who underwent liver resection with curative intent from January 2015 to December 2018. Patients who received tenofovir disoproxil were matched with patients who received entecavir in a 1:1 ratio using propensity score matching. Data were analyzed from April 3 to May 31, 2023. Receiving tenofovir disoproxil or entecavir as antiviral treatment for HBV. Primary end points were RFS and OS rates. Among 4451 patients (mean [SD] age, 58.1 [10.0] years; 3764 male [84.6%]; median [range] follow-up, of 51 [3 to 91] months), 989 patients in each of the groups were selected in propensity score matching. Baseline characteristics were comparable. In propensity score-matched groups, OS rates were 92.2% at 1 year, 70.9% at 3 years, and 54.2% at 5 years in the entecavir group, compared with 90.9% at 1 year, 75.2% at 3 years, and 64.0% at 5 years in the tenofovir disoproxil group. RFS rates were 83.9% at 1 year, 50.0% at 3 years, and 43.3% at 5 years in the entecavir group, compared with 85.3% at 1 year, 55.6% at 3 years, and 51.4% at 5 years in the tenofovir disoproxil group. Patients in the tenofovir disoproxil group had better OS (hazard ratio, 0.82; 95% CI, 0.72 to 0.94; P = .004) and RFS rates (hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = .001) compared with the entecavir group. Restricted mean survival time differences of entecavir vs tenofovir disoproxil groups were -0.05 (95% CI, -0.18 to 0.08) months at 1 year (P = .45), 0.20 (95% CI, -0.62 to 1.03) months at 3 years (P = .63), and 1.82 (95% CI, 0.14 to 3.51) months at 5 years (P = .03). These findings suggest that in patients undergoing curative liver resection for HBV-related HCC, tenofovir disoproxil was associated with better long-term OS and RFS rates compared with entecavir, providing insights for antiviral treatment.

Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies.

Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma (ICC) patients. In this study, we developed a methylation signature that precisely predicts overall survival (OS) after surgery. An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing (WGBS) was conducted for two independent cohorts (discovery cohort, n=164; validation cohort, n=170) from three hepatobiliary centers in China. By referring to differentially methylated regions (DMRs), we proposed the concept of prognostically methylated regions (PMRs), which were composed of consecutive prognostically methylated CpGs (PMCs). Using machine learning strategies (Random Forest and the least absolute shrinkage and selector regression), a prognostic methylation score (PMS) was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort. The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74, respectively. In the whole cohort, the PMS was an independent predictor of OS [hazard ratio (HR) =8.12; 95% confidence interval (CI): 5.48-12.04; P<0.001], and the C-index (0.78) of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine (JHUSM) nomogram (0.69, P<0.001), the Eastern Hepatobiliary Surgery Hospital (EHBSH) nomogram (0.67, P<0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system (0.61, P<0.001), and MEGNA prognostic score (0.60, P<0.001). The patients in quartile 4 of PMS could benefit from adjuvant therapy (AT) (HR =0.54; 95% CI: 0.32-0.91; log-rank P=0.043), whereas those in the quartiles 1-3 could not. However, other nomograms and staging system failed to do so. Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors, pathway activation, and immune microenvironment. The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients, and might facilitate decisions in treatment of ICC patients.

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

BackgroundImmune-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.MethodsPatients 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.ResultsBaseline 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.ConclusionThe 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.

Immune checkpoint inhibitor plus tyrosine kinase inhibitor with or without transarterial chemoembolization for unresectable hepatocellular carcinoma.

e16123 Background: Transcatheter arterial chemoembolization (TACE) has been combined with immune checkpoint inhibitor (ICI)-based systematic therapies for unresectable HCC (uHCC) with promising efficacy. However, whether the addition of TACE to the combination of ICI and tyrosine kinase inhibitor (TKI) (ICI+TKI+TACE) is superior to ICI+TKI combination therapy is still not clear. Thus, this study compares the efficacy of ICI+TKI+TACE triple therapy and ICI+TKI doublet therapy in patients with uHCC. Methods: uHCC patients treated with either ICI+TKI+TACE triple therapy or ICI+TKI doublet therapy were retrospectively recruited between January 2016 and December 2021 at Eastern Hepatobiliary Surgery Hospital. The patients from ICI+TKI+TACE group and ICI+TKI group were further subjected to propensity score matching based on the baseline characteristics. The primary outcome was progression-free survival (PFS) in matched patients. The secondary outcomes were overall survival (OS) and objective response rate (ORR). Post-progression survival (PPS) as well as treatment-related adverse events (TRAEs) were also assessed. Results: A total of 120 patients were matched. The median PFS was 8.4 months in ICI+TKI+TACE triple therapy group versus 6.6 months in ICI+TKI doublet therapy group (HR 0.72, 95%CI 0.48-1.08; p=0.115). Similar results were obtained in term of OS (26.9 versus 24.2 months, HR 0.88, 95% CI 0.51-1.52; p=0.670). The ORR in the triple therapy group was comparable with that in the doublet therapy group (16.6% versus 21.6%, p=0.487). Further subgroup analysis for PFS illustrated that patients without previous locoregional treatment (preLRT) (10.5 versus 3.7 months, HR 0.35 [0.16-0.76]; p=0.009), without previous treatment (10.5 versus 3.5 months, HR 0.34 [0.14-0.81]; p=0.015) or treated with lenvatinib (14.8 versus 6.9 months, HR 0.52 [0.31-0.87]; p=0.013) can significantly benefit from triple therapy compared with doublet therapy. A remarkable interaction between treatment and preLRT ( p=0.049) or TKIs-combined ( p=0.005) was also detected in term of PFS. Kaplan-Meier analysis of PPS revealed that patients with post progression treatment displayed significant improved survival in both ICI+TKI+TACE and ICI+TKI groups. The incidence of TRAEs was comparable between two groups. Conclusions: In selected uHCC patients (without preLRT or treated with lenvatinib as combination), the addition of TACE to ICI+TKI combination therapy can remarkably improve PFS.

Efficacy and predictors of immune checkpoint inhibitors in patients with gallbladder cancer.

e16124 Background: Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) has shown promising efficacy in multiple cancers including biliary tract cancers (BTCs). However, the data focusing on the efficacy of ICIs in patients with gallbladder cancer (GBC) is still limited. This study aims to assess the efficacy of ICIs in GBC and explore the clinicopathological and molecular markers of ICI benefit. Methods: This was a single center, retrospective study, including 80 GBC patients who had received ICI (anti-PD-1 monoclonal antibody) therapy at Eastern Hepatobiliary Surgery Hospital (Shanghai, China) between January 2016 and December 2020. Tumor samples from 31 of these patients who had previously underwent surgical resection before ICI therapy were obtained and conducted for whole exome sequencing and immunohistochemical analysis. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR) and disease control rate (DCR). The associations between efficacy with clinicopathological factors, genetic variations and PD-L1/CD8 expression were further explored. Results: Of 80 patients with GBC, 36 were male, the median age was 61 years (range, 30-79). The median PFS and OS was 4.5 months (95% CI, 2.99-5.95) and 8.7 months (95% CI, 7.07-10.26) respectively. Multivariate analysis indicated that alcohol intake history (HR, 2.66; 95% CI, 1.31-5.40; p=0.007), extrahepatic metastasis (HR, 2.03; 95% CI, 1.15-3.59; p=0.015), carcinoma embryonic antigen (CEA) level ≥100U/mL (HR, 3.58; 95% CI, 1.65-7.74; p=0.001) and immune-related adverse events (irAEs) (HR, 0.24; 95% CI, 0.10-0.57; p=0.001) were independent prognostic factors for PFS. Extrahepatic metastasis (HR, 2.42; 95% CI, 1.37-4.31; p=0.003), CEA level ≥100U/mL (HR, 2.82; 95% CI, 1.33-5.95; p=0.007) and irAEs (HR, 0.32; 95% CI, 0.14-0.72; p=0.006) were independent prognostic factors for OS. ORR and DCR were 13.75% and 37.5%, respectively. Patients with irAEs (85.7%, OR, 16.00; 95% CI, 3.26-78.61; p&lt;0.001), high CD8+ T-cells-infiltrated GBCs (87.5%, OR, 19.83; 95% CI, 2.00-196.38; p=0.011), immune inflamed phenotype (66.7%, OR, 5.60; 95% CI, 1.16-27.08; p=0.032) had higher DCR, while patients with high level of total bilirubin (TBIL&gt;34.2μmol/L) (8.3%, OR, 0.12; 95% CI, 0.01-0.97; p=0.048) had lower DCR. Patients with high CD8+ T-cells-infiltrated or immune inflamed GBCs also had a notably improved PFS and OS. Conclusions: ICIs were effective in patients with GBC. Alcohol intake history, extrahepatic metastasis, CEA level ≥100U/mL, irAEs, high positivity of CD8+ T-cells and immune inflamed phenotype may be useful for predicting the efficacy of ICIs in GBC.

Efficacy and safety of donafenib combined with transcatheter arterial chemoembolization (TACE) and anti-PD1 antibody for the treatment of unresectable hepatocellular carcinoma (uHCC): A retrospective study.

e16120 Background: For unresectable hepatocellular carcinoma (uHCC), the efficacy of TACE monotherapy is not satisfactory. It has recently been reported that molecular targeted drugs combined with anti-PD1 antibody and TACE exhibit improved anti-tumor efficacy compared with monotherapy. Donafenib is a new generation of multi-kinase inhibitor which is approved as the first-line treatment for uHCC. This study aimed to explore the efficacy and safety of the combination therapy of donafenib, anti-PD1 monoclonal antibody and TACE in patients with uHCC. Methods: This was a single-center retrospective study, and involved patients with uHCC who received donafenib (200 mg po bid) combined with TACE and anti-PD1 monoclonal antibody or donafenib (200 mg po bid) combined with TACE at Shanghai Eastern Hepatobiliary Surgery Hospital from September 2021 to September 2022. All patients had at least one measurable lesion defined by mRECIST criteria. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) data of patients were collected and analyzed. Results: A total of 34 patients with uHCC were included and had a median age of 56 years (32–81 years). Of these patients, 3 (9%) were classed as BCLC stage B, 31 (91%) were BCLC stage C. All 34 patients were complicated with HBV infection. First-line treatment was administered to 24 patients (71%), among which 21 patients received donafenib combined with TACE and anti-PD1 antibody. 3 patients were treated with donafenib combined with TACE. The remaining 10 patients (19%) received second-line treatment, among which 7 patients were treated with donafenib combined with TACE and anti-PD1 antibody. 3 patients received donafenib combined with TACE. There were 14 patients (41%) with baseline AFP ≥400 ng/mL. At data cut-off, the median follow-up time was 5 months [95% CI: 3.42-6.58]. The best overall response rate (BOR) was complete response in 5 patients (14.7%), partial response in 13 patients (38.2%), stable disease in 10 patients (29.4%), and progressive disease in 6 patients (17.6%). The ORR was 52.9% (95%CI: 36.7–68.6%) and DCR was 82.4% (95%CI: 66.5–91.7%). The median PFS and median OS were not reached, the one-year PFS rate was 61.6% (95%CI: 38–78.7%), and the one-year OS rate was 83.1% (95%CI: 56.1–95.2%). The ORR (58%) and DCR (87.5%) of patients receiving first-line treatment were better compared with those of patients receiving second-line treatment (40% and 70%, respectively). Treatment-related adverse events (TRAE) were reported by 30 patients (88.2%), of which 7 patients (20.6%) had grade 3 TRAE. No grade 4 or 5 TRAE was reported. Conclusions: Donafenib combined with TACE and anti-PD-1 antibody exhibited encouraging efficacy and favorable safety profile in patients with uHCC.

Dynamic monitoring of ctDNA to predict response to immunotherapy plus chemotherapy in BTC.

e14550 Background: The survival of advanced BTC patients, especially those who received palliative surgery was unfavorable and the treatment options for these patients were limited. Immune checkpoint inhibitors （ICIs） were approved for the treatment for patients with BTC. However, only a subset of patients benefits from this treatment and the clinical performance was not well evaluated. Therefore, there is a need for a method that can promptly and dynamically evaluate the efficacy of patients receiving immunotherapy. Previous studies have shown that ctDNA can detect relapse and monitor therapeutic efficacy in diverse cancer. We performed a retrospective observational study examining whether ctDNA could serve as a biomarker to track treatment responses in BTC. Methods: Patients diagnosed with advanced BTC and who received ICI were screened and enrolled between January 2020 and October 2022 at Shanghai Eastern Hepatobiliary Surgery Hospital. The key inclusion criteria for patients were as follows: a recent diagnosis of gallbladder/intrahepatic cholangiocarcinoma; received immunotherapy (or plus target therapy); received ctDNA NGS monitoring. Patients were excluded based on the following criteria: patients with multiple primary cancers, or had history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation, or HIV infected person, or severe infections with poor clinical control. Blood samples were collected for ctDNA analysis at the beginning, after 3 and 6 months of ICI treatment. Results: The median age was 66 (42-79), and 12 (44.4%) were male. The ECOG score was mostly 1 (23 cases, 85.2%). Most of the patients were stage IV (21, 77.8%), and there were 5 (18.5%) stage III patients, 1 (3.7%) stage II and 0 (0%) stage I patients. The BTC patients were mostly histologically diagnosed with gallbladder cancer (GBC, 11, 40.7%) and intrahepatic cholangiocarcinoma (8 cases, 29.63%). There were 55% patients received palliative surgery. Among all mutations detected in ctDNA, the mutation status of KRSA at baseline was detected to be related to patient survival, and the KRAS-mut group had a significantly lower probability of overall survival compared to the KRAS-WT group (p=0.014). Patients with more than 3 new mutations during treatment presented a significantly unfavorable OS (p=0.025) and a trend of unfavorable PFS (p=0.062). Besides, patients with increasing amounts of total ctDNA during dynamic monitoring showed significantly worse overall survival probability (p=0.023). Conclusions: Mutation of KRAS in tissues at baseline might be a predictive marker of response to immunotherapy and survival prognosis. ctDNA as a compose biomarker can monitor treatment responses and predict overall survival. Considering the small size and the relatively short follow-up time of our cohort, further prospective and randomized controlled studies are indispensable.

A retrospective study of the efficacy and safety of donafenib combined with TACE as adjuvant therapy in patients with high-risk recurrence factors after hepatocellular carcinoma surgery.

e16121 Background: Surgical resection is the most important treatment for patients with hepatocellular carcinoma (HCC) to obtain long-term survival. However, the 5-year recurrence rate after hepatectomy is as high as 40%-60% and above. Reducing the postoperative recurrence rate is the key to improve the overall efficacy of HCC. This study aimed to evaluate the efficacy and safety of donafenib combined with TACE as adjuvant therapy in HCC patients with high-risk recurrence factors after surgical resection. Methods: This single-center retrospective study enrolled primary HCC patients with high-risk recurrence factors who underwent surgical resection at Shanghai Eastern Hepatobiliary Surgery Hospital from April 2021 to October 2022. High-risk recurrence factors included: the number of tumors ≥ 3, tumor diameter ≥ 5 cm, portal vein tumor thrombus, microvascular invasion (MVI) and satellite lesions. Patients received adjuvant therapy of donafenib combined with TACE after surgery. Patients’ demographic characteristics, etiological characteristics, 1-year recurrence-free survival rate (RFSR), recurrence-free survival (RFS), overall survival (OS), and treatment-related safety were analyzed. Results: A total of 40 patients were enrolled with a median age of 55.5 years (21-78), 39 patients (97.5%) in BCLC stage B and 1 patient (2.5%) in BCLC stage C. 33 patients (82.5%) were co-infected with HBV. All 40 patients had ECOG PS scores of 0 and Child-Pugh scores of A. A total of 34 patients (85%) with MVI were pathologically reported after surgery, 23 patients (57.5%) with tumor diameter ≥5cm, 9 patients (22.5%) with portal vein cancer thrombus, and 6 patients (15%) with satellite lesions. All patients received at least one TACE treatment after surgery, 31 patients (77.5%) received the TACE treatment one month after surgery, and 9 patients (22.5%) received the TACE treatment within one month after surgery. The initial dose of donafenib was 200mg/day. As of the cut-off date of data collection, the median follow-up time was 9 months (95%CI: 7.73-10.27), 4 patients relapsed and 2 patients died. The median RFS was 18 months (95% CI: 13.673-22.327), the one-year RFSR was 83.3% (95% CI: 61.9%-93.8%), and the one-year OS rate was 95.8% (95% CI: 75.2%-99.6%). 21 patients (52.5%) had combined treatment-related adverse events (TRAE), of which 4 patients (10%) had Grade 3 TRAE and no grade 4 or 5 TRAE were reported. Common adverse events included hand-foot skin reaction (9 patients, 22.5%), diarrhea (9 patients, 22.5%), rash (5 patients, 12.5%), hypertension, and gastrointestinal reactions (2 patients each, 5%). Conclusions: Donafenib combined with TACE was used for adjuvant therapy in patients with high-risk recurrence of HCC, which has a high one-year recurrence-free survival rate and was well tolerated.

Adjuvant TACE may not improve recurrence-free or overall survival in HCC patients with low risk of recurrence after hepatectomy.

To identify whether adjuvant transarterial chemoembolization (TACE) can improve prognosis in HCC patients with a low risk of recurrence (tumor size ≤ 5 cm, single nodule, no satellites, and no microvascular or macrovascular invasions) after hepatectomy. The data of 489 HCC patients with a low risk of recurrence after hepatectomy from Shanghai Cancer Center (SHCC) and Eastern Hepatobiliary Surgery Hospital (EHBH) were retrospectively reviewed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier curves and Cox proportional hazards regression models. The effects of selection bias and confounding factors were balanced using propensity score matching (PSM). In the SHCC cohort, 40 patients (19.9%, 40/201) received adjuvant TACE, and in the EHBH cohort, 113 patients (46.2%, 133/288) received adjuvant TACE. Compared to the patients without adjuvant TACE after hepatectomy, patients receiving adjuvant TACE had significantly shorter RFS (P=0.022; P=0.014) in both cohorts before PSM. However, no significant difference existed in OS (P=0.568; P=0.082). Multivariate analysis revealed that serum alkaline phosphatase and adjuvant TACE were independent prognostic factors for recurrence in both cohorts. Furthermore, significant differences existed in tumor size between the adjuvant TACE and non-adjuvant TACE groups in the SHCC cohort. There were differences in transfusion, Barcelona Clinic Liver Cancer stage and tumor-node-metastasis stage in the EHBH cohort. These factors were balanced by PSM. After PSM, patients with adjuvant TACE after hepatectomy still had significantly shorter RFS than those without (P=0.035; P=0.035) in both cohorts, but there was no difference in OS (P=0.638; P=0.159). Adjuvant TACE was the only independent prognostic factor for recurrence in multivariate analysis, with hazard ratios of 1.95 and 1.57. Adjuvant TACE may not improve long-term survival and might promote postoperative recurrence in HCC patients with a low risk of recurrence after hepatectomy.

Development of preoperative and postoperative machine learning models to predict the recurrence of huge hepatocellular carcinoma following surgical resection.

Resection has been commonly utilized for treating huge hepatocellular carcinoma (HCC) with a diameter of ≥10 cm; however, a high rate of mortality is reported due to recurrence. The present study was designed to predict the recurrence following resection based on preoperative and postoperative machine learning models. In total, 1,082 patients with HCC who underwent liver resection in the Eastern Hepatobiliary Surgery Hospital cohort between January 2008 and December 2016 were divided into a training cohort and an internal validation cohort. In addition, 164 patients from Mengchao Hepatobiliary Hospital cohort between January 2014 and December 2016 served as an external validation cohort. The demographic information, and serological, MRI, and pathological data were obtained from each patient prior to and following surgery, followed by evaluating the model performance using the concordance index, time-dependent receiver operating characteristic curves, prediction error cures, and a calibration curve. A preoperative random survival forest (RSF) model and a postoperative RSF model were constructed based on the training set, which outperformed the conventional models, such as the Barcelona Clinic Liver Cancer (BCLC), the 8th edition of the American Joint Committee on Cancer (AJCC 8th) staging systems, and the Chinese stage systems. In addition, the preoperative and postoperative RSF models could also re-stratify patients with BCLC stage A/B/C or AJCC 8th stage IB/II/IIIA/IIIB or Chinese stage IB/IIA/IIB/IIIA into low-risk, intermediate-risk, and high-risk groups in the training and the two validation cohorts. The preoperative and postoperative RSF models were effective for predicting recurrence in patients with huge HCC following hepatectomy.

Development and validation of prognostic dynamic nomograms for hepatitis B Virus-related hepatocellular carcinoma with microvascular invasion after curative resection.

The prediction models of postoperative survival for hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) with microvascular invasion (MVI) have not been well established. The study objective was the development of nomograms to predict disease recurrence and overall survival (OS) in these patients. Data were obtained from 1046 HBV-related MVI-positive HCC patients who had undergone curative resection from January 2014 to December 2017. The study was approved by the Eastern Hepatobiliary Surgery Hospital and Jinling Hospital ethics committee, and patients provided informed consent for the use of their data. Nomograms for recurrence and OS were created by Cox regression model in the training cohort (n=530). The modes were verified in an internal validation cohort (n= 265) and an external validation cohort (n= 251). The nomograms of recurrence and OS based on preoperative serological indicators (HBV-DNA, neutrophil-lymphocyte ratio, a-fetoprotein), tumor clinicopathologic features (diameter, number), surgical margin and postoperative adjuvant TACE achieved high C-indexes of 0.722 (95% confidence interval [CI], 0.711-0.732) and 0.759 (95% CI, 0.747-0.771) in the training cohort, respectively, which were significantly higher than conventional HCC staging systems (BCLC, CNLC, HKLC).The nomograms were validated in the internal validation cohort (0.747 for recurrence, 0.758 for OS) and external validation cohort(0.719 for recurrence, 0.714 for OS) had well-fitted calibration curves. Our nomograms accurately stratified patients with HBV-HCC with MVI into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. Prediction models for recurrence-free survival (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-RFS/) and OS (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-OS/) were constructed. The two nomograms showed good predictive performance and accurately distinguished different recurrence and OS by the nomograms scores for HBV-HCC patients with MVI after resection.

A surgical nursing perspective analysis of glucose variability in BCLC stage B-C hepatocellular carcinoma patients with and without T2D within 1 year of hepatectomy: a retrospective cohort study from 2016 to 2020.

Previous research has reported that variability in glucose levels is associated with a variety of patient characteristics in colon cancer. However, relevant research is still lacking in relation to hepatocellular carcinoma (HCC). A total of 95 HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage B-C who underwent liver resection at the Eastern Hepatobiliary Surgery Hospital and Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were included in this study. The patients were divided into 2 groups with type 2 diabetes (T2D) and without T2D. The primary outcome variable was blood glucose variability at 1 month and within 1 year of HCC surgery. In this study, the age of patients with T2D was greater than that of patients without T2D (mean age: 70.3±8.45 vs. 60.4±11.27 years, P=0.031). Compared to the patients without T2D, those with T2D had higher blood glucose measurements within 1 month (33 vs. 7) and 1 year (46.5 vs. 22.5, P<0.001) of surgery. The T2D patients and non-T2D patients did not differ in terms of chemotherapy medication or other characteristics. Among the 95 patients with BCLC stage B-C HCC, those with T2D had higher variability in glucose levels (P<0.001) than those without T2D within 1 month of surgery [standard deviation (SD) =46.43 mg/dL, coefficient of variation (CV) =23.5% vs. SD =21.56 mg/dL, CV =13.21%], and within 1 year of surgery (SD =42.49 mg/dL, CV =26.14% vs. SD =20.45 mg/dL, CV =17.36%). A correlation was found between a lower body mass index and higher variability in glucose levels within 1 month of surgery among patients with T2D [SD (r=-0.431, P<0.05) and CV (r=-0.464, P<0.01)]. A higher preoperative blood glucose level in T2D patients was correlated with a higher blood glucose variability within 1 year of surgery (r=0.435, P<0.01). Variability in glucose levels was weakly correlated with the demographic and clinical characteristics of patients who do not have T2D. HCC patients with T2D in BCLC stage B-C showed greater variability in glucose levels within 1 month and 1 year of surgery. Preoperative hyperglycemia, insulin use, and a lower cumulative dose of steroids were clinical features correlated with a higher variability in glucose levels in T2D patients.

Development and validation of a nomogram to predict overall survival in patients with incidental gallbladder cancer: A retrospective cohort study.

The aim of this study was to develop and validate a nomogram to predict the overall survival of incidental gallbladder cancer. A total of 383 eligible patients with incidental gallbladder cancer diagnosed in Shanghai Eastern Hepatobiliary Surgery Hospital from 2011 to 2021 were retrospectively included. They were randomly divided into a training cohort (70%) and a validation cohort (30%). Univariate and multivariate analyses and the Akaike information criterion were used to identify variables independently associated with overall survival. A Cox proportional hazards model was used to construct the nomogram. The C-index, area under time-dependent receiver operating characteristic curves and calibration curves were used to evaluate the discrimination and calibration of the nomogram. T stage, N metastasis, peritoneal metastasis, reresection and histology were independent prognostic factors for overall survival. Based on these predictors, a nomogram was successfully established. The C-index of the nomogram in the training cohort and validation cohort was 0.76 and 0.814, respectively. The AUCs of the nomogram in the training cohort were 0.8, 0.819 and 0.815 for predicting OS at 1, 3 and 5 years, respectively, while the AUCs of the nomogram in the validation cohort were 0.846, 0.845 and 0.902 for predicting OS at 1, 3 and 5 years, respectively. Compared with the 8th AJCC staging system, the AUCs of the nomogram in the present study showed a better discriminative ability. Calibration curves for the training and validation cohorts showed excellent agreement between the predicted and observed outcomes at 1, 3 and 5 years. The nomogram in this study showed excellent discrimination and calibration in predicting overall survival in patients with incidental gallbladder cancer. It is useful for physicians to obtain accurate long-term survival information and to help them make optimal treatment and follow-up decisions.

Novel models for early prediction and prevention of acute respiratory distress syndrome in patients following hepatectomy: A clinical translational study based on 1,032 patients.

Acute respiratory distress syndrome (ARDS) is a serious organ failure and postoperative complication. However, the incidence rate, early prediction and prevention of postoperative ARDS in patients undergoing hepatectomy remain unidentified. A total of 1,032 patients undergoing hepatectomy between 2019 and 2020, at the Eastern Hepatobiliary Surgery Hospital were included. Patients in 2019 and 2020 were used as the development and validation cohorts, respectively. The incidence rate of ARDS was assessed. A logistic regression model and a least absolute shrinkage and selection operator (LASSO) regression model were used for constructing ARDS prediction models. The incidence of ARDS was 8.8% (43/490) in the development cohort and 5.7% (31/542) in the validation cohort. Operation time, postoperative aspartate aminotransferase (AST), and postoperative hemoglobin (Hb) were all critical predictors identified by the logistic regression model, with an area under the curve (AUC) of 0.804 in the development cohort and 0.752 in the validation cohort. Additionally, nine predictors were identified by the LASSO regression model, with an AUC of 0.848 in the development cohort and 0.786 in the validation cohort. We reported the incidence of ARDS in patients undergoing hepatectomy and developed two simple and practical prediction models for early predicting postoperative ARDS in patients undergoing hepatectomy. These tools may improve clinicians' ability to early estimate the risk of postoperative ARDS and timely prevent its emergence.