Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor with a poor prognosis, predominantly CA19-9 positive. High CA19-9 levels correlate with increased aggressiveness and worse outcomes. This study employs multi-omics analysis to reveal molecular features and identify therapeutic targets of CA19-9 positive ICC, aiming to support individualized treatment. Data from seven clinical cohorts, two whole-exome sequencing cohorts, six RNA sequencing/microarray cohorts, one proteomic cohort, 20 single-cell RNA sequencing samples, and one spatial transcriptome sample were analyzed. Key findings were validated on tissue microarrays from 52 ICC samples. CA19-9 positive ICC exhibited poorer OS (median 24.1 v.s. 51.5 months) and RFS (median 11.7 v.s. 28.2 months) compared to negative group (all P < 0.05). Genomic analysis revealed a higher KRAS mutation frequency in the positive group and a greater prevalence of IDH1/2 mutations in the negative group (all P < 0.05). Transcriptomic analysis indicated upregulated glycolysis pathways in CA19-9 positive ICC. Single-cell analysis identified specific glycolysis-related cell subclusters associated with poor prognosis, including Epi_SLC2A1, CAF_VEGFA, and Mph_SPP1. Higher hypoxia in the CA19-9 positive group led to metabolic reprogramming and promoted these cells’ formation. These cells formed interactive communities promoting epithelial-mesenchymal transition (EMT) and angiogenesis. Drug sensitivity analysis identified six potential therapeutic drugs. This study systematically elucidated the clinical, genomic, transcriptomic, and immune features of CA19-9 positive ICC. It reveals glycolysis-associated cellular communities and their cancer-promoting mechanisms, enhancing our understanding of ICC and laying the groundwork for individualized therapeutic strategies.

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct‐type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment.Methods: We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole‐exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single‐cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated.Results: We found that large duct‐type iCCA had worse overall survival and recurrence‐free survival rates than small duct‐type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct‐type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct‐type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct‐type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway.Conclusions: Our findings extend our understanding of large and small duct‐type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct‐type iCCA.

Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality, with liver transplantation (LT) offering curative potential for patients in the early stages. While immune checkpoint inhibitors (ICIs) are effective in managing tumor progression, concerns about graft rejection persist. This study investigates how peri-LT ICIs administration affects rejection rates and survival outcomes in HCC patients. This global study analyzed 386 HCC patients receiving Peri-LT ICIs therapy, integrating data from a systematic literature review and institutional registries. The risk of graft rejection and survival outcomes were assessed using logistic and Cox regression, along with restricted cubic splines modeling dose-response dynamics. Overall graft rejection rates did not significantly differ between Pre-LT (17.5%) and Post-LT (22.1%) ICI users (P = 0.351); however, Post-LT use was associated with higher rates of graft loss/dysfunction (47.1% vs. 25.9%, P < 0.05) and rejection-related mortality (47.1% vs. 18.5%, P < 0.05). In Pre-LT patients, washout periods >30 days (OR = 0.36, 95% CI: 0.18-0.72, P = 0.004) and >1.5 half-life counts (OR = 0.24, 95% CI: 0.12-0.50, P < 0.001) were associated with reduced rejection risk. Post-LT, high PD-L1 expression on graft tissue correlated with increased rejection risk (P < 0.001). Graft rejection following Pre-LT ICIs was linked to poorer overall survival (HR = 5.17, 95% CI: 2.21-12.24, P < 0.001). With careful management, peri-LT ICIs may be considered for HCC patients. Optimizing washout periods and monitoring graft PD-L1 expression may improve transplant outcomes.

Delayed gastric emptying (DGE) is one of the most common complications after pancreaticoduodenectomy (PD). There is currently no widely accepted procedure for PD to reduce the incidence of DGE. Our institution attempts to perform subtotal gastrectomy in patients undergoing PD to reduce DGE. Here we aimed to evaluate the effectiveness and safety of PD with subtotal gastric resection. Patients who underwent PD between January 2014 and December 2021 were reviewed. They were stratified by extent of gastrectomy into a conventional PD group (PD that resected approximately 1/3 of the distal stomach) and a subtotal gastrectomy PD group (PD that resected approximately 3/4 of the distal stomach), which were compared in terms of intraoperative and postoperative parameters. From January 2014 to December 2021, a total of 512 patients underwent PD in the Department of Hepatobiliary Surgery, Peking University People’s Hospital. Nineteen patients were excluded from this study due to benign disease. A total of 493 patients were included, with 378 in the conventional PD group and 115 in the subtotal gastrectomy PD group. Compared with the conventional PD group, the subtotal gastrectomy PD group had a lower incidence of DGE (8.7% vs. 17.7%, p = 0.019), and a shorter hospital stay. Multivariate analysis showed that conventional PD and higher body mass index were independent risk factors for grade B/C DGE. This study showed that, compared with conventional PD, subtotal gastrectomy PD can reduce the incidence of DGE and shorten the length of hospital stay. At the same time, subtotal gastrectomy PD is comparable to conventional PD in terms of surgical safety. Furthermore, high BMI is an independent risk factor for postoperative DGE.

Background: Repeat hepatectomy is an important treatment for patients with repeat recurrent hepatocellular carcinoma (HCC).Methods: This study was a multicenter retrospective analysis of 1,135 patients who underwent primary curative liver resection for HCC. One hundred recurrent patients with second hepatectomy were included to develop a nomogram to predict the risk of post-recurrence survival (PRS). Thirty-eight patients in another institution were used to externally validate the nomogram. Univariate and multivariate Cox regression analyses were used to identify independent risk factors of PRS. Discrimination, calibration, and the Kaplan–Meier curves were used to evaluate the model performance.Results: The nomogram was based on variables associated with PRS after HCC recurrence, including the tumor, node, and metastasis (TNM) stage; albumin and aspartate aminotransferase levels at recurrence; tumor size, site, differentiation of recurrences; and time to recurrence (TTR). The discriminative ability of the nomogram, as indicated by the C statistics (0.758 and 0.811 for training cohort and external validation cohorts, respectively), was shown, which was better than that of the TNM staging system (0.609 and 0.609, respectively). The calibration curves showed ideal agreement between the prediction and the real observations. The area under the curves (AUCs) of the training cohort and external validation cohorts were 0.843 and 0.890, respectively. The Kaplan–Meier curve of the established nomogram also performed better than those of both the TNM and the BCLC staging systems.Conclusions: We constructed a nomogram to predict PRS in patients with repeat hepatectomy (RH) after repeat recurrence of HCC.