Hepatocellular carcinoma (HCC) is a common malignancy and a leading cause of cancer-related mortality. Current guidelines and staging systems provide coarse categories, but often miss within-stage heterogeneity and the clinical context in electronic medical records (EMRs). We present HCC-STAR (Hepatocellular Carcinoma Staging, Treatment And pRognosis), a clinically aligned large language model that reads routine EMR narratives and jointly outputs risk score-based staging, ranked guideline-consistent treatments with evidence-based rationales, and individualized survival estimates. We curated about 30,000 HCC cases from SEER and expanded them into EMR-style narrative training data using a clinician-validated, prompt-based augmentation workflow. On this corpus, we developed a knowledge-aligned reasoning framework optimized with a step-verifiable composite reward, moving beyond text-level memorization of clinical guidelines. In a multi-center cohort of 6,668 patients from 12 hospitals in China, HCC-STAR achieved state-of-the-art performance in treatment recommendation and risk stratification compared with clinical guidelines and competitive models, including GPT-5 and Gemini-2.5 Pro. Hypothetical overall-survival analysis showed a median survival of 51 months under adherence to HCC-STAR recommendations, compared with 29 and 32 months under BCLC and CNLC. In clinician-centric evaluations, blinded hepatobiliary specialists rated HCC-STAR's reasoning and evidence-based justifications as trustworthy. The model surpassed resident and attending physicians in treatment accuracy and helped physicians make more accurate decisions faster when used as an assistant. These findings support HCC-STAR as a reliable and verifiable decision-support system for risk stratification and precision therapy in HCC.

Metabolic syndrome (MetS) was linked to poor cancer outcomes, but its impact on perihilar cholangiocarcinoma (pCCA) survival postresection was unclear. In this study, we investigated the association between MetS and long-term prognosis in patients with pCCA after curative-intent resection. Consecutive patients with pCCA who underwent curative-intent resection at four hospitals (2018–2023) were enrolled and stratified into the MetS and non-MetS groups. Mets was diagnosed when patients met three or more of the following five criteria: (1) body mass index ≥ 25 kg/m2; (2) systolic blood pressure ≥ 130 mmHg or diastolic ≥ 85 mmHg, or prior hypertension treatment; (3) fasting plasma glucose ≥ 6.1 mmol/L or prior diabetes diagnosis; (4) fasting triglycerides ≥ 1.7 mmol/L; and (5) high-density lipoprotein cholesterol < 1.04 mmol/L. non-Mets was defined as meeting fewer than three criteria. Inverse probability of treatment weighting was applied to balance tumor-related confounders. The log-rank test was used to compare overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS). Cox regression was performed to identify independent prognostic factors. Of the 321 included patients, 78 (24.3

This study aimed to investigate the effects of adjuvant chemotherapy versus observation on recurrence and survival in patients treated with curative-intent resection for gallbladder cancer (GBC). We selected consecutive GBC patients treated with curative-intent resection from a multicenter database between 2014 and 2021. The patients were subsequently divided into two groups: an observation group and a chemotherapy group. In the comparison analysis, propensity score matching was employed to adjust for potential confounding factors. The study endpoints were overall survival (OS) and progression-free survival (PFS). Event rates were estimated with Kaplan-Meier curves and compared via the log-rank test. The multivariable Cox regression model was used to identify factors independently associated with OS and PFS. A total of 604 GBC patients treated with curative-intent resection were included in this study, which were 511 in the observation group and 93 in the chemotherapy group. In the comparison between the chemotherapy group and the observation group, after propensity score matching, the 3-year OS rates and PFS rates were significantly higher in the chemotherapy group (n = 73) compared with the observation group (n = 188) after the 6 months. Among the 604 GBC patients, multivariable Cox regression analysis confirmed that chemotherapy was independently associated with better OS and PFS. Adjuvant chemotherapy following curative-intent resection for GBC can reduce the risk of recurrence and prolong survival.

Background: Perihilar cholangiocarcinoma (pCCA) is a highly aggressive malignancy that persists even after curative resection. Although serum gamma-glutamyl transferase (GGT) is associated with cancer prognosis, most studies have evaluated its prognostic role only at a single time point. However, the prognostic value of perioperative dynamic trajectories remains unclear. Objectives: To evaluate perioperative GGT trajectories as prognostic markers in patients with pCCA undergoing radical resection. Design: This retrospective multicentre study included 765 patients with pCCA who underwent curative resection at two centres. Methods: Perioperative GGT trajectories were modelled using latent class mixed models. Patients were categorised according to trajectory patterns, and associations with overall survival (OS) were evaluated using multivariate Cox regression with clinical covariates. Model discrimination was assessed using time-dependent receiver operating characteristic analysis. Results: Two distinct perioperative GGT trajectories were identified: flat and V-shaped. The model showed an adequate fit (Bayesian Information Criterion (BIC) = 35818.61) and good classification quality (entropy = 0.69). The two classes accounted for 48.32% and 51.68% of the patients, respectively. Patients in the flat trajectory group had significantly longer OS (HR = 0.603, 95% CI: 0.450–0.808, p < 0.001), independent of other factors. The model yielded AUCs of 0.729 (0.658–0.801) and 0.805 (0.721–0.881) for 3- and 5-year OS, respectively. Conclusion: Perioperative GGT trajectories independently predicted pCCA prognosis. Monitoring GGT dynamics may offer a simple and practical tool for postoperative risk stratification.

Objective The literature on large-scale studies of Chinese patients with adolescent-onset bipolar disorder (adolescent-onset BD) was limited. Based on the analysis of the National Bipolar Mania Pathway Survey (BIPAS) Phase II data, we examined the demographic and clinical characteristics of adults with adolescent-onset BD. Methods Among 899 participants diagnosed with BD from 20 mental health services, demographics and clinical data were collected at screening. Comparisons were made using chi-square (or Fisher's exact) tests and ANOVA. Multivariate logistic regression identified independent factors for adolescent-onset BD, and a CHAID decision tree analysis (SPSS) was constructed to detect risk factors. Results In the sample, 360 (40%) had adolescent-onset BD and 539 (60%) adult-onset BD. Significant differences between the two groups were observed in current age, number of episodes, years of education, gender, age of onset, education level, marital status, occupation, comorbid chronic physical illness, and first episode type. Stratified analysis also revealed significant differences between adolescent-onset BD I and BD II. Multivariate logistic regression identified younger onset age, more frequent episodes, lower education level, marital status, occupation, first episode type, and prior hospitalization as independent factors for adolescent-onset BD. The decision tree model selected current age as the first splitting variable, followed by occupation and marital status as the second, and years of education and prior hospitalization as the third. Conclusions Adolescent-onset BD exhibits distinct demographic and clinical features compared to adult-onset BD. Early recognition and tailored treatment strategies may improve prognosis and outcomes in this population.

4001 Background: The combination of C (anti–PD-1 antibody) + R (VEGFR2 tyrosine kinase inhibitor) significantly improved progression-free survival (PFS) and overall survival (OS) vs sorafenib as first-line treatment for advanced HCC, and improved event-free survival vs surgery alone as perioperative treatment for resectable HCC. We conducted a phase 3 trial evaluating C+R with TACE in intermediate-stage HCC and here present data from the protocol-specified PFS interim analysis (IA). Methods: In this multicenter, open-label, phase 3 trial, patients (pts) with TACE-eligible uHCC, Child-Pugh A, ECOG performance status (PS) 0–1 and no extrahepatic spread were randomized 1:1 to receive C (200 mg, iv, Q3W) + R (250 mg, po, QD) + TACE or TACE alone. TACE (cTACE or DEB-TACE) was administered at the investigator (INV)’s discretion; C+R continued until loss of clinical benefits, unacceptable toxicities, or other protocol-specified criteria. The primary endpoint was PFS by BIRC per mRECIST. As of Sep.13, 2025, 214 PFS events occurred and a preplanned IA was performed. Results: 423 pts (ECOG PS 1, 22.9%; AFP ≥400 ng/mL, 26.7%; portal vein invasion [vp1/2], 9.7%) were randomized to C+R+TACE (n=214) or TACE (n=209). As of data cutoff, median follow-up was 16.4 mo. Median PFS by BICR per mRECIST was significantly longer with C+R+TACE vs. TACE (11.1 vs. 8.3 mo; HR 0.73 [95% CI 0.56–0.96]; 1-sided p=0.0127). PFS by BICR per RECIST v1.1 (13.9 vs 9.5 mo; HR 0.67 [95% CI 0.50–0.91]) and by INV per mRECIST (13.8 vs 7.0 mo; HR 0.61 [95% CI 0.47–0.81]) and per REIST v1.1 (15.7 vs 8.4 mo; HR 0.61 [95% CI 0.45–0.81]) showed consistent findings (Table 1). PFS benefits with addition of C+R persisted across most prespecified subgroups. OS was not mature, with an early trend favoring C+R+TACE (HR 0.76 [95% CI 0.46–1.24]); OS was 91.4% vs 85.5% at 12 mo, and 82.0% vs 73.3% at 24 mo. Among treated pts, grade ≥3 TRAEs occurred in 73.7% (157/213) in C+R+TACE arm vs. 28.7% (60/209) in TACE arm; of them, the most common in C+R+TACE arm were increased AST (20.7% vs 12.9%), hypertension (19.7% vs 4.3%), increased ALT (17.8% vs 9.6%), and decreased platelet count (11.3% vs 2.9%). Conclusions: C+R+TACE provided statistically significant and clinically meaningful improvement in PFS vs TACE, with manageable safety, supporting this regimen as a potential new treatment option for TACE-eligible uHCC. Follow-up for OS is ongoing. Clinical trial information: NCT05320692 . PFS outcomes (ITT set). BIRC INV C+R+TACE (n=214) TACE (n=209) C+R+TACE (n=214) TACE (n=209) Per mRECIST Median (95% CI), mo 11.1 (7.8–14.0) 8.3 (6.9–9.5) 13.8 (8.5–17.3) 7.0 (5.7–9.5) HR (95% CI)* 0.73 (0.56–0.96); 1-sided p=0.0127 † 0.61 (0.47–0.81) Per RECIST v1.1 Median (95% CI), mo 13.9 (10.9–19.4) 9.5 (8.1–11.1) 15.7 (10.3–19.6) 8.4 (6.9–10.8) HR (95% CI)* 0.67 (0.50–0.91) 0.61 (0.45–0.81) *Stratified Cox proportional hazard model. †Stratified Log-Rank test.

Background:Patients with perihilar cholangiocarcinoma (pCCA) have high postoperative mortality and a poor prognosis. A reliable preoperative marker is needed to determine whether these patients are likely to benefit from surgical treatment. Objectives:This study aimed to verify the predictive value of preoperative albumin-bilirubin (ALBI) grades for 90-day mortality and long-term outcomes in these patients. Methods and design:This retrospective, multicenter, cohort study included patients with pCCA, surgically treated between January 2012 and December 2023. Patients were divided into ALBI 1-2 and ALBI 3 groups according to preoperative ALBI grade. Logistic and Cox regression analyses evaluated risk factors for 90-day death and overall survival (OS), respectively. Results:Of the 828 included patients, 243 (29.3%) had ALBI grade 3. In total, 744 (89.9%) and 89 (10.1%) patients underwent radical resection and palliative surgery, respectively. The 90-day mortality rate was 8.9% for the entire cohort and 16.5% for patients with ALBI 3, higher than that of ALBI 1-2 (5.8%). Age, extended hemihepatectomy, and ALBI 3 were independent risk factors for 90-day mortality. Patients with ALBI 3 had a higher postoperative intra-abdominal bleeding, bile leakage, and acute organ dysfunction. The median OS of patients with ALBI 3 (21.0 months) was shorter than that of ALBI 1-2 (29.0 months). In the radical resection subgroup, the median OS of ALBI 3 was 23.0 months, poorer than that of ALBI 1-2 (33.0 months). Conclusion:Preoperative ALBI grades can identify patients with pCCA who may benefit from surgical resection. Patients with ALBI 3 had a high risk of postoperative complications, 90-day mortality, and poorer long-term survival, and may benefit only marginally from surgical treatment. Trial registration:ChiCTR2500102958 (Medical Research).

Lymph node metastasis (LNM) is a crucial prognostic indicator in perihilar cholangiocarcinoma (pCCA); however, preoperative tools for assessing LNM risk and determining the optimal extent of lymph node (LN) dissection remain limited. This study aimed to identify preoperative LNM predictors to guide regional LN dissections. This multi-institutional retrospective study included 364 patients who underwent curative-intent pCCA resection (2020–2024). Multivariate logistic regression was used to identify independent predictors of preoperative LNM. Eventually, 148 (40.7

Objective To investigate the impact of propofol-based total intravenous anesthesia(TIVA)versus sevoflurane-propofol intravenous-inhalation combined anesthesia(IICA)on 5-year postoperative survival rates in patients undergoing radical hepatectomy for hepatocellular carcinoma(HCC).Methods A retrospective cohort study was conducted on the clinical and follow-up data from 504 patients undergoing radical HCC surgery in our hospital between January 2015 and December 2017.According to different anesthesia techniques,the patients were divided into a IICA groups(n=176)and a TIVA group(n=328).The 5-year postoperative survival rates were compared between the 2 groups of patients.Stratified analyses were carried out by age,tumor size and number,Child-Pugh class and model for end-stage liver disease(MELD)score,presence of portal vein tumor thrombus(PVTT),intraoperative transfusion,hepatitis B surface antigen status,alpha-fetoprotein(AFP),tumor node metastasis(TNM)stage,and Barcelona clinic liver cancer(BCLC)stage to compare the impact of the 2 anesthesia methods on postoperative survival rates in subgroups.Results Among the cohort,the median 5-year survival was 33.00(14.25 to 60.00)months in the TIVA group with 212 deaths(64.60%),and 27.00(11.00 to 60.00)months in the IICA group with 125 deaths(71.00%).There was no statistically significant difference in 5-year survival rate between groups(HR=1.27,95%CI:0.96 to 1.67,P>0.05).Stratified analysis revealed significant increased 5-year mortality risk with CIVA in subgroups with MELD score>7.24(HR=1.61,95%CI:1.11 to 2.32,P=0.011),BCLC stage B(HR=1.74,95%CI:1.11 to 2.71,P=0.015),absence of PVTT(HR=1.35,95%CI:1.04 to 1.74,P=0.026),and no intraoperative transfusion(HR=1.34,95%CI:1.02 to 1.75,P=0.034).Conclusion Among patients undergoing radical hepatectomy for HCC,there is no difference in 5-year overall survival between propofol-based TIVA and sevoflurane-propofol IICA.However,IICA is associated with significantly increased 5-year mortality risk in specific subgroups:MELD score>7.24,absence of PVTT,BCLC stage B,and no intraoperative transfusion.

Background:While curative-intent resection for gallbladder cancer (GBC) is being increasingly performed in elderly patients, perioperative morbidity and long-term oncological outcomes in this population remain unclear. Methods:Consecutive patients with GBC who underwent curative-intent resection (2016-2020) were identified from a multicentre database and stratified as elderly (>70 years) or younger (≤70 years). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to minimise selection bias. The outcomes compared included overall survival (OS), cancer-specific survival (CSS) and short-term outcomes. Logistic regression was used to identify risk factors for major morbidity and Cox regression was used for CSS, with the Fine-Gray competing risk model further applied to account for non-cancer-related death in the analysis of CSS. Results:Among the 575 patients enrolled, 432 were younger and 143 were elderly. After 1:1 PSM and IPTW, elderly patients had significantly higher 90-day major morbidity rates than younger patients (p=0.029 and p=0.010, respectively), but also demonstrated better CSS in both cohorts (p=0.038 and p<0.001, respectively). OS was significantly longer in elderly patients only after PSM (p<0.001), with no significant difference after IPTW (p=0.684). Multi-adjusted analysis confirmed that advanced age was an independent risk factor for major morbidities (original cohort: OR 1.71 (95% CI 1.12 to 2.59); PSM: OR 1.88 (95% CI 1.08 to 3.30); IPTW: OR 1.83 (95% CI 1.17 to 2.82)) but was associated with longer CSS (original cohort: HR 0.65 (95% CI 0.44 to 0.97); PSM: HR 0.29 (95% CI 0.18 to 0.45); IPTW: HR 0.62 (95% CI 0.42 to 0.90); Fine-Gray model: HR 0.34 (95% CI 0.30 to 0.39)). Conclusion:Despite a higher risk of major postoperative morbidity, advanced age itself might not be considered a contraindication for curative-intent resection. Selected elderly patients with GBC may achieve superior CSS compared to their younger counterparts.

Abstract There are several staging systems for hepatocellular carcinoma (HCC); however, the best prognostic system for Chinese patients has not been established. The aim of this study was to evaluate nine staging systems and identify the best prognostic staging system for Chinese patients with HCC. This retrospective study included 1,495 patients with HCC from 2012 to 2022 in 17 hospitals in China. The predictive ability of nine HCC staging systems was evaluated based on homogeneity, monotonicity of gradients, Akaike’s information criterion, and area under the receiver operating characteristic curve. Overall survival at 1, 3 and 5 years was 59.90%, 40.34%, and 34.83%, respectively. Multivariable Cox analysis identified older age, multiple tumor nodules, maximum tumor size > 5 cm, macrovascular invasion, distant metastases, treatment modalities, worse performance status, low protein, high bilirubin, and high alpha-fetoprotein as independent prognostic factors. The Hong Kong Liver Cancer (HKLC) system showed the highest predictive accuracy for Chinese patients in hepatitis B virus-infected populations and in those undergoing non-curative treatment. The Cancer of the Liver Italian Program showed the best predictive ability in patients with hepatitis C virus infection or in the curative treatment subgroup. HKLC may be the most consistent and reliable prognostic model for patients with HCC in the Chinese population.

BACKGROUND:Although several PD-1 or PD-L1 inhibitors combined with antiangiogenic agents have been approved as first-line treatment of advanced hepatocellular carcinoma, treatment needs remain unmet given the high incidence and mortality of hepatocellular carcinoma and due to factors such as regional approval status, medical insurance restrictions, and cost considerations. In this phase 3 HEPATORCH study, we aimed to compare the efficacy and safety of toripalimab plus bevacizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. METHODS:We did a randomised, open-label, phase 3 study in 57 hospitals across mainland China, Taiwan, and Singapore. Using a central interactive web response system, eligible patients aged 18-75 years with unresectable or metastatic hepatocellular carcinoma were randomly assigned (1:1) through a stratified block randomisation method to receive 240 mg toripalimab (intravenously, once every 3 weeks) plus 15 mg/kg bevacizumab (intravenously, once every 3 weeks) or 400 mg sorafenib (oral, twice daily). Randomisation was stratified by macrovascular invasion or extrahepatic spread (presence vs absence), ECOG performance status score (0 vs 1), and history of locoregional therapy (yes vs no). The co-primary endpoints were progression-free survival (assessed by the Independent Review Committee per Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. Efficacy analysis was performed in the intention-to-treat population (ie, all patients randomly assigned to a treatment group). Safety was assessed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT04723004, and is completed. FINDINGS:Between Nov 23, 2020, and Jan 21, 2022, 545 patients were screened for study inclusion, of whom 219 did not meet the screening criteria. 326 patients were randomly assigned to receive an intervention: 162 patients were assigned to the toripalimab plus bevacizumab group and 164 were assigned to the sorafenib group, with median age 58·0 years (IQR 50·0-66·0) and 56·0 years (49·0-61·0) years, respectively. All 326 patients were included in the intention-to-treat population and the safety population. 282 (87%) patients were male and 44 (14%) were female. At the primary analysis of progression-free survival (data cutoff Aug 10, 2022), median follow-up was 9·4 months (IQR 7·0-12·0). Toripalimab plus bevacizumab significantly prolonged progression-free survival compared with sorafenib (median 5·8 months [95% CI 4·6-7·2] vs 4·0 months [2·8-4·2]; hazard ratio [HR] 0·69 [95% CI 0·53-0·91; p=0·0086). At the final analysis of overall survival (May 31, 2024), median follow-up was 16·4 months (IQR 7·1-29·5). Toripalimab plus bevacizumab significantly improved overall survival compared with sorafenib (median 20·0 months [95% CI 15·3-23·4] vs 14·5 months [11·4-18·8]; HR 0·76 [95% CI 0·58-0·99; p=0·039). Grade 3 or higher adverse events occurred in 102 (63%) patients in the toripalimab plus bevacizumab group compared with 100 (61%) in the sorafenib group, and led to discontinuation of treatment in 21 (13·0%) participants in the toripalimab plus bevacizumab group and 20 (12%) participants in the sorafenib group. The incidence of treatment-related fatal adverse events (two [1%] vs one [1%]) was similar between the toripalimab plus bevacizumab and sorafenib groups. The most common (incidence ≥5% in the toripalimab plus bevacizumab group) grade 3-4 adverse events were hypertension (26 [16%] in the toripalimab plus bevacizumab group vs 19 [12%] in the sorafenib group), thrombocytopenia (16 [10%] vs four [2%]), upper gastrointestinal haemorrhage (ten [6%] vs one [1%]), anaemia (nine [6%] vs seven [4%]), and abnormal hepatic function (nine [6%] vs five [3%]). The most common (incidence ≥2% in the toripalimab plus bevacizumab group) serious adverse events were upper gastrointestinal haemorrhage (12 [7%] vs one [1%]), abnormal hepatic function (eight [5%] vs five [3%]), ascites (six [4%] vs three [2%]), and gastrointestinal haemorrhage (four [2%] vs three [2%]). INTERPRETATION:Among patients with previously untreated advanced hepatocellular carcinoma, toripalimab plus bevacizumab resulted in significantly longer progression-free survival and overall survival than did sorafenib, with an acceptable safety profile. Based on these results, the regimen has been approved for use in China by the National Medical Products Administration. FUNDING:Shanghai Junshi Biosciences. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

There is a high prevalence of suicidal ideation (SI), suicide attempts (SA), and non-suicidal self-injury (NSSI) in bipolar disorder (BD). Understanding the nature of suicidality and NSSI in BD is an important way to inform optimal intervention for reducing suicide risk. We aimed to investigate the prevalence and correlates of SI, SA, and NSSI in patients with BD using data from a national survey. We used network analysis to explore the associations among suicidality, NSSI, addictive features of NSSI, and symptoms of BD. Participants with BD were recruited from 20 research centers in China. Suicidality, NSSI, addictive features, and symptoms of BD were measured via a standardized electronic case report form. We used logistic regression and network analysis for data analysis. Of the 1,055 participants recruited, over 50

To investigate the effect of an enhanced rehabilitation program on upper limb function in patients with abdominal pedicle flap surgery, we retrospectively analyzed 70 patients who received abdominal pedicled flap surgery between 2017 and 2022. Patients were categorized into the traditional rehabilitation group (rehabilitation initiated after the stage II pedicle dissection of the abdominal pedicle flap) and the enhanced rehabilitation group (rehabilitation initiated on the first day following the stage II abdominal pedicle flap surgery). All the patients received identical rehabilitation protocols. Passive Range of Motion (PROM), activities of daily living (ADL), Functional Independence Measure (FIM), and Manual Muscle Testing (MMT) were assessed at 5 days and 1 month following the stage II surgery. The main causes of injury were electrical burns in both groups. The hospital stay of patients in the enhanced group was significantly shorter than the traditional group. One month assessment indicated both groups showed significant improvements in the PROM of shoulder flexion, abduction, and elbow extension compared to the 5 days assessment. Notably, at 5 days assessment, the enhanced group had significantly higher PROM in shoulder abduction and elbow extension compared to the traditional group. Furthermore, the enhanced group continued to exhibit higher PROM in shoulder flexion and abduction than the traditional group at one month assessment. At one month assessment, a significant increase was observed in the ADL, FIM, and MMT of both groups compared to the 5 days. The study indicated the enhanced rehabilitation program immediately following the stage I surgery can effectively improve the PROM of the shoulder and elbow and reduce the length of hospital stay for patients.

Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy with an immunosuppressive microenvironment and a limited immunotherapy response. Cholesterol is necessary for rapid growth of cancer cells, and cholesterol metabolism reprogramming is a hallmark of PAAD. How PAAD cells initiate cholesterol reprogramming to sustain their growth demand and suppressive immunomicroenvironment remains elusive. In this study, we for the first time revealed that PAAD cells overcome cholesterol shortage and immune surveillance via ectopically overexpressing NPC1L1, a cholesterol transporter, but function as a two-pronged checkpoint, which not only directly suppresses TCR activation of CD8+T cells but also hijacks the intracellular cholesterol from CD8+T cells. In vivo, we showed that ezetimibe, an NPC1L1 inhibitor usually for hypercholesterolemia, efficiently prevented PAAD cells from depriving cholesterol of CD8+T cells, and improved the anti-tumor immunity of PAAD to synergize with PD-1 blockade, suggesting NPC1L1 as a promising target to rescue the anti-tumor activity in PAAD.

Introduction Major hepatectomy is the mainstay of curative-intent resection for perihilar cholangiocarcinoma (pCCA) patients. Textbook Outcomes in Liver Surgery (TOLS) are a new composite parameter for evaluating the short-term outcomes of surgery; however, their association with overall survival (OS) is unknown. Therefore, this study aimed to investigate the association between TOLS and OS in pCCA patients following major hepatectomy. Methods Consecutive pCCA patients who underwent major hepatectomy between 2014 and 2020 at 5 hospitals were included in this analysis. TOLS were defined as no intraoperative grade ≥ 2 incidents, no postoperative grade B/C bile leakage, no postoperative grade B/C liver failure, no postoperative major morbidity, no readmission within 90 days due to surgery-related major morbidity, no mortality within 90 days after hospital discharge, and R0 resection. The Kaplan‒Meier method was used to compare OS rates between patients who achieved TOLS and those who did not. Cox regression analysis was used to identify independent risk factors for poor OS. Results In total, 399 patients were included in this study, 214 (53.6%) of whom achieved TOLS. After excluding patients who died within 90 days, the 5-year OS rate of patients who achieved TOLS were significantly greater than that of patients who did not achieve TOLS (5-year OS rate: 26.2% vs. 17.3%, P=0.001). TOLS were independently associated with OS for pCCA patients following major hepatectomy. Conclusions TOLS were achieved in approximately half of the pCCA patients following major hepatectomy, and the patients who achieved TOLS had better survival.

OBJECTIVE:We collected maintenance treatment medication information from Chinese multicenter bipolar disorder patients, exploring the characteristics of medication use and related factors. We analyzed medication guideline adherence and compared trends in medication use with a study from 2014. METHODS:323 patients receiving maintenance therapy for bipolar disorder across 20 hospitals have been recruited. Their prescription information was collected to compare with the recommended drug protocols outlined by CANMAT to assess consistency. Additionally, descriptive statistics were conducted to document the quantities and percentages of different classes of medications used. Regression analysis was employed to explore factors influencing medication choices. RESULT:The rate of medication inconsistency in this study was 12.38 %, characterized by inappropriate use of antidepressants and mood stabilizers. The rate of using additional drugs was 67.80 %, with antipsychotics being the most common adjunctive treatment in the Bipolar I group and antidepressants in the Bipolar II group. Factors influencing the occurrence of adjunctive therapy included previous hospitalization, most recent episode type, and gender. The rate of polypharmacy was 47.10 %, with previous hospitalization and most recent episode type being the main influencing factors. CONCLUSION:There has been a noticeable improvement in guideline concordance in medication use compared to 2014; however, improper use of antidepressants remains a significant clinical issue. The increasing prevalence of adjunctive medication use underscores the need for more personalized medication recommendations in clinical guidelines.

Macrophages hold a critical position in maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. TIM3 is a promising protector in MCD-induced steatohepatitis in acute liver injury. However, we recently find TIM3 as a driver of fibrosis in MCD/HFD-induced chronic liver injury. This study aims to explore how macrophage TIM3 drivers NAFLD-associated chronic liver injury as well as identify a subtype of fibrotic patients suitable for anti-TIM3 immunotherapy. Here, we found that TIM3 was highly expressed in liver macrophages in a long-term MCD- or HFD-fed mice with fibrotic NASH. Elevated β-TrCP in macrophages promoted TIM3 polyubiquitination and membrane translocation. The ubiquitinated TIM3 then bound with PI3K and followed by inhibition of mTOR and activation of macrophage M2 polarization and TGF-β release, leading to HSC activation and liver fibrosis. Furthermore, elevated TIM3 was attributed to the transcriptional TBP upregulation and miR-4524a-5p downregulation. Targeting of TIM3 significantly attenuated liver fibrosis in mice. In clinical NASH patients, elevated macrophage TIM3 is positively correlated with TBP expression and negatively associated with miR-4524a-5p. Decreased miR-4524a-5p in plasma was a biomarker for the NASH fibrosis patients suitable for anti-TIM3 therapy. In conclusion, this study reveals that miR-4524a-5p/TBP promotes β-TrCP/TIM3 complex activation in macrophages and aggravates chronic NASH fibrosis, providing miR-4524a-5p as an effective blood biomarker for a subtype of chronic NASH patients with fibrosis suitable for anti-TIM3 treatment.