Background:The Institut Mutualiste Montsouris (IMM) 3-level complexity classification has been validated for laparoscopic liver resection (LLR) in several studies with small sample size. However, it has not been well-validated in large studies down to the individual procedure type. Hence, in order to address current limitations in the studies validating the IMM complexity classification, we performed an international multicenter study to validate the IMM complexity classification across its three complexity levels and the categorization of the 11 distinct procedure types. Methods:A retrospective cohort study of 22,252 patients undergoing LLR across 64 centers worldwide between 2005 and 2021 was performed. Baseline characteristics and perioperative outcomes were analyzed across the three difficulty levels and 11 procedure types of the IMM complexity classification. Results:A total of 14,765 patients were included in our final analysis. The main indications for LLR in our study was hepatocellular carcinoma or intrahepatic cholangiocarcinoma (n=7,781, 52.7%) followed by liver metastasectomy (n=3,911, 26.5%). In terms of underlying liver pathology, 5,127 (34.7%) cases had cirrhosis, and 1,214 (8.3%) had portal hypertension. Perioperative outcomes including operative time, open conversion rate, intraoperative blood loss, need for intraoperative blood transfusion, need for Pringle's application, length of stay, postoperative morbidity, major postoperative morbidity and 90-day mortality all demonstrated a significant increasing trend with increasing IMM complexity grades (P<0.001). These trends remained significant following adjustment for baseline characteristics (P<0.001). Notably, when examining the 11 LLR procedure types, all procedures within each IMM complexity grade were individually higher than all procedures in the preceding complexity grade for operative time, blood loss, length of stay, postoperative morbidity and major postoperative morbidity. Conclusions:The three IMM complexity grades were well associated with LLR complexity as determined by key surrogate perioperative measures. Our findings also supported the categorization of the 11 distinct LLR procedures into the three complexity levels.

Across various cancer entities, a wide array of subtypes of B cells that infiltrate tumors can be identified. These subtypes confer these cells with high adaptability in their functions and significant involvement in tumor progression. Tumor-infiltrating B cells act as distinctive microenvironmental mediators that build tertiary lymphoid structures, secrete diverse factors, and generate a wide antibody repertoire, thereby offering a valuable indicator of immunotherapy response. Recent clinical trials have demonstrated that intervening in tumor-infiltrating B cells can be an effective treatment strategy for tumors, including common types such as breast cancer, colorectal carcinoma, and non-small cell lung cancer. These findings suggest that tumor-infiltrating B cells should not be overlooked as therapeutic targets, as they offer significant potential to reduce the incidence of nonresponse, drug resistance, and immune-related adverse effects commonly seen in current treatment techniques. In this review, we explore the historical development of B cells in the context of tumors. We then discuss the various subtypes of tumor-infiltrating B cells, analyzing their diverse roles in tumor development. Additionally, we delve into the signaling pathways of tumor-infiltrating B cells, intercellular crosstalk, and multilevel regulatory mechanisms. Finally, based on immune checkpoints and therapeutic targets on the surface of tumor-infiltrating B cells, we summarize the current understanding which can lead to the development of new intervention methods targeting tumor-infiltrating B cells in the future. This review aims to provide a comprehensive summary of B-cell classification and therapeutic potential, emphasizing their critical role in guiding clinical treatment strategies.

The circadian clock orchestrates many key physiological processes related to anti-tumor immunity, including the cell cycle, energy metabolism, immune infiltration, and cytokine secretion. Increasing evidence suggests that circadian clock disruption is involved in tumorigenesis and tumor progression. Both clinical and basic research indicate that the circadian clock is a central regulator of tumor immunity and an important target for intervention. However, the role of the circadian clock in remodeling tumor immunity, as well as existing and potential intervention strategies, remains largely uncharacterized. To investigate the role of the circadian clock in tumor immunity, we integrated a tumor-related circadian regulatory framework encompassing the central pacemaker, peripheral cell-autonomous clocks, and environmental and behavioral factors such as sleep and feeding. Evidence from epidemiological, clinical, and translational studies reveals that circadian disruption impairs immune surveillance and promotes tumor initiation and progression, contributing to increased cancer risk and poorer outcomes. We further examine the mechanisms by which circadian dysregulation reshapes the tumor immune microenvironment and alters both innate and adaptive antitumor immunity. Finally, we discuss emerging therapeutic approaches that leverage circadian biology to enhance antitumor immune responses, including circadian clock-targeting interventions and chronotherapy, highlighting their potential to improve cancer treatment outcomes. Evidence reviewed here indicates that circadian dysregulation promotes tumor progression through cell-intrinsic clock reprogramming and remodeling of the tumor immune microenvironment. By regulating immune surveillance, metabolic homeostasis, and the function of both immune effector and immunoregulatory cells, the circadian clock plays a central role in antitumor immunity. These findings support the integration of chronotherapy and circadian clock-targeting strategies with immunotherapy to improve the precision and efficacy of cancer treatment.

BACKGROUND Intraductal papillary neoplasm of the bile duct (IPNB) is a rare disease of the bile duct. It is characterized by a papillary growth within the bile duct lumen. IPNB was formally recognized as a distinct disease entity in 2010, and its etiology remains unknown. IPNB is a complex disease and generally requires multidisciplinary investigation. CASE SUMMARY We report the case of a 67-year-old patient who was asymptomatic but diagnosed with IPNB during treatment of early gastric cancer due to an obvious elevation of gamma-glutamyl transpeptidase. Computed tomography, magnetic resonance cholangiopancreatography, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography with EyeMax & Ocirc; direct visualization system were crucial for the diagnosis of IPNB. Hepatic surgery was performed, and the patient was discharged without complications. CONCLUSION IPNB is a complicated disease and difficult to diagnose, especially when the patient is asymptomatic. Aggressive surgical resection can achieve adequate clinical outcomes, particularly when IPNB is diagnosed in early stages.

Background Cholangiocarcinoma (CCA) is a highly lethal malignant tumour with increasing incidence. Current therapies exhibit limited benefits, which urgently demand the identification of novel therapeutic targets. Objective We aimed to identify potential therapeutic targets for CCA and broaden current therapies. Design Potential therapeutic targets for CCA were identified by sgRNA library screening and validated in preclinical models. Multi-omics sequencing and various experimental approaches were performed to validate the mechanism by which Aurora kinase B (AURKB) regulates CCA progression and the immune microenvironment, supported by clinical samples from public data sets and Tongji Hospital cohorts. The translational therapy was comprehensively validated in CCA organoid, patient-derived xenograft and preclinical murine models. Results AURKB was identified as a highly expressed and targetable kinase in CCA. Knockout of AURKB significantly inhibited CCA progression, reduced CD8 + T cell exhaustion and enhanced antitumour response. Mechanistically, AURKB promoted the generation of histone H3 lysine 9 tri-methylation (H3K9me3)/serine 10 phosphorylation, leading to a decrease in the enrichment of H3K9me3 at the neutral cholesterol ester hydrolase 1 (NCEH1) promoter, thereby increasing NCEH1 expression and cholesterol levels in tumours. High AURKB expression in clinical samples predicted poorer outcomes in patients with CCA undergoing neoadjuvant chemoimmunotherapy and was associated with cholesterol accumulation within tumours. AURKB inhibitor or simvastatin can suppress CCA progression and significantly enhance sensitivity to chemoimmunotherapy. Conclusions AURKB regulates cholesterol levels and immune microenvironment in tumours, highlighting that targeting AURKB or adopting cholesterol-reducing strategy holds promise for CCA treatment, especially in conjunction with first-line chemoimmunotherapy.

Protein kinases contribute to hepatocellular carcinoma (HCC) development and immune evasion, posing major challenges for HCC management. Here we show STE20/SPS1-related proline/alanine-rich kinase (SPAK) as a candidate immune exhaustion–associated gene identified through a pooled screen of protein kinases. By integrating bioinformatic analyses, data from patient cohorts, and functional studies in mouse models and cell lines, we demonstrate that elevated expression of SPAK promotes HCC progression, enhances stemness, drives immune exhaustion, and contributes to resistance to targeted therapies. Mechanistically, SPAK phosphorylates GSK3β at Ser9, thereby inhibiting proteasome-mediated degradation of c-Jun and PD-L1. Additionally, we find that DNMT3B-dependent intragenic methylation of SPAK contributes to its high expression in HCC. Notably, the SPAK inhibitor exhibits potent inhibitory effects and synergizes with PD-1 blockade to enhance antitumor efficacy. In summary, these findings establish SPAK as a driver of oncogenesis and immune exhaustion in HCC and highlight dual inhibition as a potential therapeutic strategy. Protein kinases contribute to hepatocellular carcinoma progression and immune evasion. This study identifies SPAK as a key driver of oncogenesis and immune exhaustion, showing that SPAK inhibition synergizes with anti-PD-1 therapy to enhance antitumor efficacy.

Hundreds of millions of people worldwide endure continuous suffering and significant economic burdens due to inflammatory diseases. Various acute and chronic inflammatory diseases and the natural aging of the human body are common causes of organ damage. Therefore, how to reasonably regulate inflammation, tissue repair and regeneration after organ damage has been of great concern, especially the pathological repair caused by inflammation will lead to the destruction of the original structure and function of tissues and organs. Low-intensity pulsed ultrasound (LIPUS) is a promising non-invasive physical therapy that can produce different biological effects on organs, tissues and cells. Certain clinical trials have demonstrated the outstanding capacity of LIPUS in anti-inflammation and repair. Many in vivo and in vitro basic studies have also reported the molecular effect mechanisms by which LIPUS exerts capacity of anti-inflammation and repair. This review focuses on the molecular mechanism of LIPUS anti-inflammation and repair and emphasizes the crucial role of LIPUS in various diseases. In addition, we compile clinical trials to provide readers with a more thorough understanding of the current potential of LIPUS in inflammation control and organ function restoration.

Background: Presently, evidence on the volume-outcome relationship for minimally-invasive liver resections (MILR) remains heterogeneous. This study aimed to investigate the volume-outcome relationships in expert centers which had already mounted the initial learning curve of MILR and had a case volume of >20 MILR/annum. Methods: This was an international multicenter retrospective analysis of 22,210 patients undergoing MILR between 2015 and 2022 at 64 centers. Centers were stratified into medium volume (MV), high volume (HV) and very high volume (VHV) defined as 20-50/51-80 and >80 MLR/annum. Difficulty of resections was graded according to the Iwate score and Institute Mutualiste Montsouris (IMM) system. Results: A total of 19,691 MILR met study criteria and were included. Of the 19,961 patients, 4,747 (2 5.6%), 4,222 (23.8%) and 10,243 (50.7%) were performed in 28 MV, 15 HV and 17 VHV centers, respectively. In the overall IMM I and IMM III cohorts, open conversion rates were consistently significantly higher in MV centers. Significantly, in the subgroup analysis of IMM 3 MILR, the VHV cohort had less blood loss [>500 mL: 443.7 (19.6%) vs. 221.6 (22.1%) (MV) vs. 296.9 (26.0%) (HV), P=0.001], shorter operative times [292 vs. 362.7 (MV) vs. 372.9 (HV) min, P<0.001] and shorter postoperative stay [7.8 vs. 8.3 (MV) and 10 (HV) days, P<0.001]. However, the HV cohort had the lower rates of open conversion [79.4 (7.0%) vs. 174.3(7.7%) (VHV) vs. 103.2 (10.3%) (MV); P=0.03]. Conclusions: Center volume-outcome relationship beyond 20 MILR/annum was not clear and results were heterogenous suggesting that factors other than center volume alone had a more significant impact on perioperative outcomes of MILR in these expert centers.

The bidirectional communication between the liver and bone profoundly influences the development and progression of both liver and bone diseases and significantly affects systemic homeostasis. Through the metabolic and immune crosstalk mediated by hepatokines, osteokines, extracellular vesicles, gut microbiota, and neuroendocrine factors, the liver-bone axis not only affects the progression from chronic liver disease to liver cancer but also modulates the balance of bone formation and resorption as well as bone marrow homeostasis. Furthermore, a dysfunctional liver-bone axis can lead to systemic complications characterized by dyslipidemia and hyperglycemia. In this review, we discuss the pathophysiological changes induced by the dysregulated liver-bone axis and elucidate the specific mediating factors and mechanisms involved. We also summarize the current efforts in translating the liver-bone axis into clinical applications, aiming to provide potential therapeutic strategies for liver and bone diseases.

BACKGROUND:Laparoscopic right hepatectomy (L-RH) is a technically complex procedure, characterized by diverse tumor presentations and anatomical variations. While the Iwate Difficulty Scoring System (I-DSS) is widely utilized to assess technical difficulty in laparoscopic liver resections, its predictive value for surgical outcomes in L-RH remains unclear. This study aimed to evaluate the clinical utility of the I-DSS specifically in the context of L-RH. METHODS:This international, multicenter study included 1732 patients who underwent L-RH at 78 centers between 2005 and 2023. Baseline clinicopathological characteristics and surgical outcomes were collected and analyzed based on I-DSS grades. Multivariable analyses were performed to adjust for potential confounders. RESULTS:Patients were categorized into three I-DSS grades: intermediate (n = 13), advanced (n = 355), and expert (n = 1364). Unadjusted analysis showed that higher I-DSS grades were associated with shorter operation time and increased morbidity. However, after adjustment for baseline factors, no significant differences were observed across I-DSS grades in terms of intra- and postoperative outcomes, including operation time, blood loss, transfusion, morbidity, mortality, and surgical margin positivity. CONCLUSIONS:The I-DSS has limited ability to stratify technical difficulty in L-RH. Future studies should be undertaken to develop a new difficulty classification system tailored specifically to specific procedures such as L-RH.

Introduction Minimally invasive liver resections(MILR) is increasingly performed even in patients with cirrhosis and clinically significant portal hypertension(CSPH). However, the benefits of robotic liver resection(RLR) over laparoscopic liver resection(LLR) in patients with cirrhosis and CSPH remain unclear. Methods We conducted a posthoc international, multicenter study including 2,328 patients with cirrhosis and CSPH who underwent MILR(2,004 LLR and 324 RLR). Propensity score matching(PSM) was performed in 1:1 and 2:1 ratios to compare perioperative outcomes between the two approaches. A mixed-effects logistic regression model with centre as a random effect was additionally applied to the full unmatched cohort as a complementary analysis to account for centre-level clustering Results After 1:1 PSM(n=287 per group), RLR was associated with significantly shorter operative time(180 vs. 210 minutes, p=0.002), reduced estimated blood loss(100 vs. 200 mL, p<0.001), lower open conversion rate(3.8% vs 9.2%, p=0.012), lower postoperative morbidity rate(15% vs 26.5%, p=0.002) and shorter postoperative stay(5 vs. 6 days, p<0.001). However, mixed-effects logistic regression on the entire unmatched cohort demonstrated that RLR was only associated with a significantly lower postoperative morbidity at the expense of a longer operation time. Conclusions Both RLR and LLR can be performed safely in selected patients with cirrhosis and CSPH. RLR was associated with lower postoperative morbidity.

The overall response rate to immunotherapy is modest in hepatocellular carcinoma (HCC), and immunotherapy resistance mechanisms are incompletely understood. We report that the E3 ubiquitin ligase Riplet is universally silenced by promoter hypermethylation in HCC. Loss of Riplet modulates fatty acid metabolism to promote terminal exhaustion of CD8 T cells. Riplet loss impedes K48-linked polyubiquitination of fatty acid synthase (FASN), consequently accelerating fatty acid production in HCC. Tumor cell-derived free fatty acids, especially palmitic acid (PA/C16:0), activate STAT3 (signal transducers and activators of transcription 3) by enhancing its palmitoylation in T cells, consequently triggering terminal CD8 T cell exhaustion. HCC cells with Riplet deficiency are resistant to anti-PD-1 therapy, and treatment with an FASN inhibitor overcomes resistance. Our study shows how Riplet can alter lipid metabolism and induce CD8 T cell exhaustion and anti-PD-1 resistance, thus suggesting avenues for combined therapies for treating patients with Riplet-deficient HCC.

OBJECTIVE:This study aimed to establish global benchmark outcomes indicators for robotic liver resections (R-LR). BACKGROUND:In recent years, minimally invasive liver resections and in particular R-LR has seen an increase in uptake in recent years. Although, benchmark outcomes have been recently established for laparoscopic (L) -LR, this has not been established for R-LR. METHODS:This is a post hoc analysis of a multicenter database of 5,213 patients undergoing R-LR in 51 international centers between 2016 and 2022. Benchmark cutoffs for 16 outcome indicators of low-risk R-LR were established. The 75 th percentile of individual center medians for a given outcome indicator was set as the benchmark cutoff. Four procedures were selected for benchmarking: left lateral sectionectomy(LLS)/H23, left hepatectomy(LH)/H234±1, right hepatectomy(RH)/H5678±1 and right posterior sectionectomy/H67 (RPS). RESULTS:There were 1,654 R-LR cases (528 LLS/H23, 432 LH/H234±1, 408 RH/H5678±1, 286 RPS/H67) performed in 24 expert centers, of which 518 (31.3%) R-LR cases qualified as low risk benchmark cases. Benchmark outcomes were established for R-LLS/H23, R-LH/ H234±1, R-RH/ H5678±1 and R-RPS/H67 for operation time (190, 323, 474, 413) min, open conversion rate (0.0, 0.0, 1.3, 0.0)%, estimated blood loss (100, 250, 600, 550) mls, blood transfusion rate (0.0 ,0.0, 20.0, 29.2)%, postoperative major morbidity (0.0 ,0.0, 20.9, 16.7)%, 90-day mortality (0.0, 0.0,0.0, 0.0)% and textbook outcome (12.5,24.3,0,0)%. CONCLUSIONS:The present study established the first global benchmark values for R-LR. It provided an up-to-date reference of best achievable outcomes for auditing and benchmarking.

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs from young APCs effectively inhibit M1 macrophage polarization. Accordingly, targeted liposomes are designed to deliver miR-145-5p mimics to ATMs, which effectively prevent the obesity in middle-aged mice. Collectively, our findings highlight the role of APC-derived EVs in midlife obesity and propose miR-145-5pas a promising therapeutic target for clinical applications. Middle-aged individuals are more susceptible to obesity, but the mechanisms are unclear. Here, the authors show that extracellular vesicles from adipose progenitor cells in middle-aged individuals lack miR-145-5p, driving inflammation, and that restoring miR-145-5p could prevent midlife obesity.

Background: Intrahepatic and perihepatic abscess (IPHA) is a severe yet understudied complication that can occur after hepatectomy. This multicenter study aimed to elucidate the clinical features, risk factors, and outcomes of IPHA after hepatectomy for hepatocellular carcinoma (HCC), and to develop a novel prediction model for personalized risk assessment. Methods: This was a multicenter cohort study of HCC patients who underwent curative-intent hepatectomy. IPHA was defined as an imaging-confirmed abscess located in the hepatic or perihepatic space within 30 days after surgery. A nomogram-based prediction model was developed using preoperative and intraoperative variables, and its performance was evaluated by the concordance index (C-index). Results: Among the 4621 patients identified, 154 (3.3 %) developed IPHA. IPHA was associated with significantly prolonged hospital stays (median: 16 vs. 11 days, P < 0.001), increased 30-day readmission rates (33.0 % vs. 3.1 %, P < 0.001), and higher 90-day mortality (11.7 % vs. 2.8 %, P < 0.001). Multivariate analysis identified obesity, diabetes mellitus, portal hypertension, major hepatectomy, open surgery, and intraoperative diaphragmatic incision as independent risk factors. The prediction model demonstrated robust discrimination (C-index: 0.747) and calibration. Conclusions: IPHA significantly impacts postoperative outcomes following HCC resection. The novel prediction model aids in preoperative risk assessment to improve patient outcomes.

Alterations in fibroblast growth factor receptor 2 (FGFR2) represent potential therapeutic targets in intrahepatic cholangiocarcinoma (ICC), yet they occur in only about 10% of patients. In this study, patients with advanced ICC are tested for FGFR2 alterations via pre-enrollment biopsy; those with alterations are excluded. Eligible patients receive locoregional gemcitabine combined with camrelizumab and surufatinib until disease progression or intolerable adverse events (AEs). Between July 2022 and June 2024, 23 eligible patients are enrolled. Twelve patients achieve partial response, resulting in an objective response rate of 52.2%. The median progression-free survival is 11.3 months, and the median overall survival is 20.3 months. Eighteen patients experience at least one AE, including one grade 3 event. Exploratory analysis indicates that responders show significantly higher tumor PD-L1 expression than non-responders do, with median tumor proportion scores of 8% and 2%, respectively. The study is registered at ClinicalTrials.gov (NCT05236699).

Lung metastasis is the most common site of extrahepatic spread in hepatocellular carcinoma (HCC) and is associated with significantly poorer outcomes. Current guidelines classify these patients as Barcelona Clinic Liver Cancer (BCLC) stage C, recommending systemic therapy alone. However, this one-size-fits-all approach may overlook potential benefits in selected patients. In this multicenter cohort study of 1203 HCC patients-including 119 with lung metastases-we evaluated prognostic factors and treatment outcomes. Lung metastasis significantly reduced overall survival, both before and after propensity score matching. However, among patients with early-stage intrahepatic tumors, curative locoregional treatments such as hepatectomy or radiofrequency ablation improved survival and led to outcomes comparable to those without metastasis. Systemic therapies including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) prolonged survival, and combination regimens yielding the greatest benefit. Interestingly, lung metastases impaired intrahepatic response to systemic monotherapy, but this effect was mitigated by combining TKIs with ICIs. These findings suggest that a subset of HCC patients with lung metastases may benefit from individualized, multimodal treatment strategies, challenging the current staging framework and supporting a more refined, personalized therapeutic approach in this population.