Our previous findings demonstrated the promising antitumor activity and manageable safety of sintilimab-lenvatinib conversion therapy. The current study aimed to evaluate long-term survival outcomes in patients with unresectable hepatocellular carcinoma (HCC) who underwent sequential surgical resection after successful conversion therapy. In this prospective, single-arm, expansion, phase II trial, patients with unresectable HCC received lenvatinib plus sintilimab conversion therapy. Hepatectomy was performed in consenting patients after successful conversion therapy. The primary endpoint was the conversion rate; secondary endpoints included median overall survival (OS), 5-year survival rates, and recurrence-free survival (RFS). Successful conversion was achieved in 67 of 120 patients (56%, 67/120). Independent imaging review per mRECIST and RECIST v1.1 criteria demonstrated objective response rates of 58.3% (70/120) and 45.8% (55/120), respectively. With a median follow-up of 41.0 months (95% confidence interval [CI], 39.5-42.5) for the entire cohort, the median OS was 36.0 months (95% CI, 25.0 to not estimable [NE]), with a 5-year OS rate of 42.6% (95% CI, 34.0-53.0). Following multidisciplinary team evaluation and consideration of patient preferences, 60 patients underwent surgical resection, achieving a median RFS of 40.0 months (95% CI, 24.0 to NE) and a 5-year survival rate of 73.9% (95% CI, 62.7-87.1). Grade ≥3 treatment-related adverse events occurred in 37 patients (31%). Approximately half of the patients with unresectable HCC achieved successful conversion after sintilimab plus lenvatinib therapy. Among those who achieved successful conversion, subsequent curative surgery demonstrated not only a favorable safety profile but also significant survival benefits. Trial registration number: ChiCTR1900023914.

PURPOSE:This exploratory study aimed to evaluate the value of PERCIST based on 18F-FDG PET/CT, in conjunction with contrast-enhanced MRI, for assessing pathological response in patients with advanced hepatocellular carcinoma (HCC) treated with neoadjuvant tyrosine kinase inhibitor (TKI) plus anti-PD-1 therapy followed by surgery. METHODS:Patients were prospectively recruited between June 2019 and June 2023 in a clinical trial registered in the Chinese Clinical Trial Registry (ChiCTR1900023914). All patients underwent 18F-FDG PET/CT and contrast-enhanced MRI at baseline and before surgery. PET/CT parameters included tumor size, SUVmax, SUVmean, SULpeak, total lesion glycolysis (TLG), metabolic tumor volume (MTV), and total tumor volume (TTV). Changes in these parameters after treatment were analyzed. Histopathology served as the reference standard. Exploratory diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUC) for PERCIST, mRECIST, and RECIST 1.1. RESULTS:Thirty patients were included. Significant differences between the major pathological response (MPR) and non-MPR groups were observed for ΔSUVmax, ΔTLG, ΔMTV, ΔMTV/TTV, and ΔSULpeak. PERCIST also differed significantly between the two groups. ROC analysis demonstrated that the AUCs were 0.8839 for both PERCIST and ΔMTV/TTV, 0.8170 for mRECIST, and 0.5357 for RECIST 1.1. CONCLUSIONS:PERCIST and ΔMTV/TTV showed promising performance for assessing response to neoadjuvant TKI plus anti-PD-1 therapy in advanced HCC. These preliminary findings suggest that PERCIST may provide complementary information to conventional morphologic criteria.

Portal vein tumor thrombus (PVTT) occurs in more than half of patients with hepatocellular carcinoma (HCC) and is associated with markedly shortened survival and a poor prognosis. Historically, management relied mainly on locoregional therapies or upfront surgical resection, but outcomes remained unsatisfactory. In recent years, immune checkpoint inhibitors (ICIs) combined with antiangiogenic targeted therapy have substantially changed the systemic treatment landscape for advanced HCC and created new opportunities for patients with unresectable or borderline-resectable HCC with PVTT to undergo conversion therapy followed by sequential surgery (CT-S). This review summarizes conventional treatment strategies for HCC with PVTT; the biologic rationale and clinical evidence for the conversion therapy based on the combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic targeted drugs; patient selection and response assessment for CT-S; surgical timing and perioperative management; modified techniques for portal vein management; imaging assessment. Available evidence suggests that CT-S may improve oncologic outcomes in carefully selected patients. However, the evidence is derived predominantly from single-arm studies, retrospective cohorts, and real-world investigations. Multicenter prospective studies are therefore required to define criteria for successful conversion, establish the optimal washout interval, clarify postoperative adjuvant strategies, and determine the generalizability of this approach.

Sepsis, characterized by its complex pathophysiology, presents significant challenges for clinical treatment. An integrative approach combining highly effective antibacterial measures, immunomodulation, and organ protection is urgently needed to enhance the therapeutic efficacy. Here, we construct hybrid cerium-baicalein nanozymes (Ce-BE NZs), which exhibit broad-spectrum non-antibiotic antibacterial and redox enzyme-mimicking activities, effectively scavenging reactive oxygen species and reducing inflammatory mediators in lipopolysaccharide-stimulated macrophages. Ce-BE NZs also correct immune dysregulation, reduce liver injury, and extend survival in both cecal ligation and puncture and "two-hit" sepsis models. Mechanistically, Ce-BE NZs inhibit ferroptosis and mitigate mitochondrial dysfunction by promoting ferritin heavy chain-1 expression, thereby enhancing multi-target sepsis therapy. Additionally, they mitigate ferroptosis and cell damage in a macrophage-incorporating human liver-derived organoid model. Overall, Ce-BE NZs represent a promising multi-target therapy for sepsis and may pave the way for an antibiotic-free and transnational approach to treating other infectious diseases.

Liver transplantation has long been the definitive treatment for end-stage liver diseases, and yet its clinical use remains constrained by donor shortages, surgical risks, and the burden of lifelong immunosuppression. Emerging regenerative strategies, and particularly chemically induced liver progenitors (CLiPs), are reshaping this paradigm by enabling functional restoration rather than organ replacement. CLiP technology utilizes small-molecule-mediated partial reprogramming of mature hepatocytes into proliferative progenitor-like cells, which can be expanded and re-differentiated into functional hepatic lineages. This commentary discusses the conceptual shift from replacement to regeneration, it evaluates the clinical positioning of CLiP-based therapies, and it highlights key translational challenges. Rather than serving as a complete substitute for liver transplantation, such approaches may significantly reduce transplant demand by restoring critical hepatic function in selected patients.

Background: Although emerging evidence has reported the efficacy and safety of sequential surgery following targeted and immunotherapy conversion treatment for patients with initially unresectable hepatocellular carcinoma (HCC), these studies have been limited by small sample sizes and short follow-up periods. Moreover, whether such patients can achieve comparable survival outcomes to those undergoing upfront surgery for early-stage resectable HCC remains unreported. This study aims to compare long-term survival between patients with initially unresectable HCC who underwent sequential surgery after conversion therapy and those with early-stage HCC who received direct surgery. Methods: The retrospective cohort study was conducted from December 2018 through December 2023, with follow-up ending in June 2024. Ninety-nine patients with initially unresectable HCC underwent conversion therapy based on immune checkpoint inhibitors and anti-angiogenic targeted drugs, with a median duration of five cycles, followed by radical hepatectomy. One hundred and eleven patients with Barcelona Clinical Liver Cancer (BCLC) stage A HCC only underwent direct hepatectomy. Clinical characters, surgical features and survival outcomes of the two groups were compared. Results: In this cohort study of 210 patients, the 1-, 3-, and 5-year overall survival (OS) rates of initially unresectable HCC patients who underwent radical hepatectomy after achieving either partial response (PR) or complete response (CR) were comparable to those of early-stage (BCLC-A) HCC patients who received Conclusions: For patients with initially unresectable HCC, radical hepatectomy after effective conversion therapy (defined as achieving either PR or CR by mRECIST) brings a satisfying long-term outcome that is comparable to BCLC-A HCC patients undergoing direct surgery.

Background:Hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) face a very poor prognosis. And it remains unclear whether sequential surgery following conversion therapy based on immunotherapy combined with targeted therapy can yield long‑term survival benefits. This study aims to evaluate the long-term efficacy and safety of hepatocellular carcinoma patients with portal vein tumor thrombus receiving sequential surgery following conversion therapy with a combination of targeted therapy and immunotherapy, thereby demonstrating the therapeutic potential of this regimen. Methods:Data from 76 HCC patients with PVTT treated with programmed death-1 (PD-1) inhibitors and tyrosine kinase inhibitors (TKIs) followed by surgical treatment at Chinese People's Liberation Army General Hospital (June 2019 to June 2024) were analyzed. Recurrence-free survival (RFS) and overall survival (OS) were primary endpoints. Results:The median RFS was 21 months; the median OS was 62 months. RFS rates at 6 months, 1 year, 2 years, and 3 years were 76.2%, 59.7%, 48.1%, and 42.5%, respectively. OS rates at 6 months, 1 year, 2 years, 3 years, and 5 years were 98.7%, 93.4%, 78.1%, 72.4%, and 45.5%, respectively. Cox regression showed that preoperative alpha-fetoprotein (AFP) ≥20 ng/mL was an independent mortality factor, while non-major-pathological-response (non-mPR) and tumor size >50 mm were independent recurrence factors. Adverse events and surgical complications were evaluated, with no patient deaths resulting from conversion therapy or sequential radical surgery. Conclusions:For HCC patients with PVTT who achieve successful conversion and undergo radical surgery, sequential surgery following conversion therapy based on combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic targeted drugs (AATDs) is associated with favorable RFS and OS, and appears safe and effective. These findings suggest that this regimen may represent a promising option for these patients.

BackgroundImmunotherapy has emerged as a breakthrough in cancer treatment; however, the functional status of B lineage cells within the tumor microenvironment (TME) remains poorly characterized.ObjectiveThis study systematically profiles the heterogeneity and dysfunctional exhausted state of plasma cells in the hepatocellular carcinoma (HCC) TME, and screens molecular signatures correlated with plasma cell exhaustion.MethodsB cell subtypes were identified from a single-cell RNA sequencing (scRNA-seq) dataset comprising 10 untreated patients with primary HCC. Gene expression profiling was performed using transcriptomic data from liver cancer tissues and paired paracancerous tissues. The abundance and distribution of exhausted plasma cells were quantified by immunohistochemistry and multiplex immunofluorescence staining. Furthermore, we analyzed the correlation between plasma cell-specific exhaustion markers and patient prognosis using the TCGA-LIHC cohort.ResultsFTH1 exhibited elevated expression in tumor-infiltrating plasma cells, and its expression level was significantly correlated with the exhausted phenotype of tumor-resident plasma cells. Kaplan-Meier survival analysis revealed that patients with high FTH1 expression had significantly shorter overall survival compared to those with low FTH1 expression (P = 0.0005). Importantly, we observed a significant positive correlation between FTH1 (a molecular signature correlated with plasma cell exhaustion) and the canonical T cell exhaustion marker PD-1 in HCC tumor tissues (P = 0.01).ConclusionThis study systematically profiles the molecular landscape of dysfunctional plasma cells within the HCC TME, confirms a correlation between FTH1 overexpression and plasma cell exhaustion, and provides correlative evidence to support further research on liver cancer immunotherapy targeting plasma cell immunity.

Congenital extrahepatic portosystemic shunts (CEPS) are rare congenital vascular malformations characterized by an abnormal communication between the hepatic portal venous system and the systemic venous system. Type Ⅱ CEPS preserves partial portal venous blood flow and can usually be treated with conventional surgery rather than solely relying on liver transplantation. To determine the optimal surgical methods and complication management strategies for type Ⅱ CEPS patients, we retrospectively analyzed 31 predominantly adult patients with type Ⅱ CEPS, documenting their surgical approaches and the occurrence of postoperative complications. Five surgical approaches were employed: 11 patients underwent shunt occlusion with 5 cases of complications; 5 patients underwent splenic vessels ligation with 2 cases of complications; 5 patients underwent shunt occlusion combined with splenic artery ligation with 4 cases of complications; 8 patients underwent shunt occlusion combined with distal splenorenal shunt with 3 cases of complications; and 2 patients with lower extremity edema underwent inferior vena cava shunt bypass surgery, with no significant complications observed. In conclusion, surgery centering on the shunt occlusion demonstrates promising therapeutic value and remains the mainstay in the treatment of type II CEPS. Meanwhile, postoperative complications remain a concern, necessitating long-term monitoring and management.

Conversion therapy with a combination of tyrosine kinase inhibitor and anti-programmed death-1 antibody sequential surgery and postoperative adjuvant therapy has shown improved survival benefits in patients with Barcelona C stage (BCLC-C) hepatocellular carcinoma (HCC). We aimed to compare the survival benefits in a retrospective cohort of patients with BCLC-C HCC who underwent surgery after conversion therapy with adjuvant therapy and surgery alone. The conversion therapy group was derived from a prospective clinical study, and from January 2015 to September 2023, we selected patients diagnosed with BCLC-C HCC who underwent liver resection at Chinese PLA General Hospital as the surgical group. The primary endpoint in the comparison of survival benefits between conversion therapy and surgery-alone groups was recurrence-free survival. Propensity score matching was applied to reduce any potential bias in the study. By the end of follow-up, the conversion therapy group mRFS was 37.8 months, with postoperative 1-, 2- and 3-year RFS rates of 66.8%, 54.6%, and 48.3%. In the surgery group, the mRFS was 3.0 months, and postoperative 1- , 2- and 3-year RFS rates of 22.4%, 17.5%, and 15.0%, respectively. On multivariable Cox regression analyses, conversion therapy significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone. For BCLC-C HCC patients, conversion therapy with adjuvant therapy is in relationship with increased survival in comparison with surgery alone.

Immune checkpoint inhibitors (ICIs) combined with anti-angiogenic agents manifest improved survival in advanced hepatocellular carcinoma (HCC), but responses remain heterogeneous. Although high PIVKA-II expression correlates with advanced disease stage, early recurrence, shorter survival, and may predict resistance to anti-PD-1 plus lenvatinib therapy, the tumor microenvironment (TME) and resistance mechanisms in HCC with high PIVKA-II expression remain unclear. Clinical data from 156 resected HCC patients and 104 patients treated with anti-PD-1 plus lenvatinib are analyzed to correlate PIVKA-II expression with clinical features and outcomes. Single-cell RNA sequencing (scRNA-seq) is performed on tumors from 15 untreated and 7 treated patients. Mechanistic findings are validated in vitro and in vivo. High PIVKA-II expression is associated with advanced disease stage, increased microvascular invasion (MVI), early recurrence, and poor response to therapy. ScRNA-seq revealed an immunosuppressive TME enriched with regulatory T cells (Tregs), exhausted CD8⁺ T cells, and SPP1⁺ tumor-associated macrophages (TAMs). Mechanistically, tumors with high PIVKA-II expression upregulated NQO1, which stabilized p65 by inhibiting ubiquitination, activating the NF-κB/CXCL12 axis, and recruiting Tregs. This pathway mediated therapeutic resistance. Plerixafor, a CXCL12 inhibitor, disrupted this axis and significantly enhanced anti-tumor efficacy when combined with anti-PD-1 plus lenvatinib in vivo. PIVKA-II is a potentially effective biomarker for predicting resistance to anti-PD-1 plus lenvatinib therapy. Its high expression denotes an immunosuppressive TME. Targeting the NQO1/CXCL12/Tregs axis with Plerixafor may restore sensitivity and improve outcomes.

Background: A significant portion of primary liver cancer patients in China are diagnosed at intermediate-to-advanced stages, often making them ineligible for curative surgery. Furthermore, high postoperative recurrence rates, reaching up to 70%, pose a major challenge for long-term survival. The emergence of novel systemic treatments, such as immune checkpoint inhibitor combinations, and advancements in locoregional therapies have created new opportunities for conversion and perioperative strategies. This updated consensus aims to standardize the clinical application of these therapies based on the latest evidence, with the objective of improving patient prognosis. Methods: A multidisciplinary committee of 97 experts was convened to revise previous guidelines. The process involved a comprehensive search of medical databases and conference proceedings, with evidence graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Consensus statements were finalized through a formal electronic voting process, requiring at least 80% agreement for approval, resulting in 18 updated statements. Results: The consensus provides refined definitions for conversion and perioperative therapy. It recommends various strategies for oncological conversion, including systemic therapy with anti-angiogenic drugs plus immunotherapy, and locoregional approaches like precision transarterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC). The document strongly affirms surgical resection as a crucial step for achieving long-term survival after successful conversion and offers guidance on surgical timing and adjuvant therapy. For resectable patients with high-risk features, neoadjuvant and adjuvant treatments are outlined to mitigate recurrence. The consensus also advocates for using dynamic enhanced magnetic resonance imaging ( MRI) and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria for efficacy assessment and underscores the essential role of a multidisciplinary team in management. Conclusions: This updated consensus offers standardized, evidence-based guidance for clinicians on implementing conversion and perioperative strategies to optimize patient-centered care and highlights the need for continued research to further refine these promising approaches.

With the global incidence of hepatocellular carcinoma (HCC) on the rise, precise staging has become critical for guiding treatment decisions and improving long-term outcomes. The Barcelona Clinic Liver Cancer (BCLC) staging system, widely used for HCC classification, incorporates factors such as Child–Pugh A or B liver function, tumor size and number, absence of cancer-related symptoms, and lack of vascular invasion or extrahepatic metastasis. For intermediate-stage HCC, transarterial chemoembolization (TACE) remains the globally recommended standard. However, the substantial heterogeneity in tumor burden and liver function among patients means that not all individuals benefit equally from TACE. As a result, a uniform treatment approach is insufficient. Preserving liver function is now recognized as equally important as achieving high objective response rates, with the ultimate goal of prolonging overall survival. In response, researchers have proposed advanced stratification methods for stage B HCC to optimize therapeutic outcomes. While these stratification criteria remain under debate, there is a growing shift from TACE-centric strategies toward personalized targeted therapies for specific subpopulations. This review explores advanced stratification concepts, evaluates corresponding treatment strategies, analyzes ongoing clinical trials, and assesses their potential to transform the management of intermediate-stage HCC—while also outlining future directions for its treatment.

Hepatocellular carcinoma stands as one of the foremost contributors to cancer-associated fatalities globally, and the limitations of traditional treatment methods have prompted researchers to explore new therapeutic options. Recently, cell therapy has emerged as a promising approach for HCC, showing significant potential in improving patient outcomes. This review article explores the use of cell therapy for HCC, covering different types, the mechanisms behind their effectiveness, recent advancements in clinical trials, and ongoing challenges. This article aims to provide insightful perspectives for future research and clinical applications in treating HCC by synthesizing current knowledge.

Intrahepatic bile duct stone disease has a high morbidity in China, with a high rate of additional surgery, a high rate of cancer development, and a high disease burden. Activation of the MAPK pathway leading to up-regulation of MUC5AC expression is an important factor in the formation of intrahepatic bile duct stones. Exosomes or extracellular vesicles (EVs) can be used as therapeutic vectors to encapsulate and carry drugs into diseased cells to achieve a therapeutic effect. The current study alleviated intrahepatic bile duct stone disease by preparing EVs carrying miR-141-3p. First, the researchers loaded mesenchymal stem cell (ESC)-derived EVs with miR-141-3p (miR-141-3p-EVs) and verified the phenotypes and characteristics of miR-141-3p-EVs. miR-141- 3p-EVs successfully reduced the inflammatory level of human biliary epithelial cells (HIBEC) and lowered, via the MAPK pathway, MUC5AC expression. In an experiment involving an animal model of intrahepatic bile duct stones, miR-141-3p-EVs effectively alleviated stone formation, and the intrinsic mechanism was associated with the decreased level of MAPK pathway expression. In conclusion, results suggested that the EV-based strategy of miR- 141-3p delivery to intrahepatic bile duct epithelial cells has value and provides a new approach for the treatment of intrahepatic biliary stone disease.

Alopecia areata (AA) is a common and recurrent type of hair loss. Despite oral administration of baricitinib exerts a good effect on refractory AA, the long-term administration of baricitinib carries significant side effects, poor compliance, and the efficacy is difficult to maintain after drug withdrawal. Therefore, the exploration of a safe and effective local administration of baricitinib to treat AA is of great clinical importance. However, baricitinib has a large molecular weight and is barely soluble in water, while the hair follicle lies deep, thus conventional topical dosage forms are ineffective. This study investigated the efficacy of local injection of baricitinib-loaded mesenchymal stem cell exosomes (EVs) in the treatment of AA. First, we constructed baricitinib loaded EVs (EV-B) and established AA mouse model by intravenously injection with murine INF-gamma according to previous literature reports. The therapeutic effects of EV-B on hair regrowth were recorded and the underlying mechanism was also analyzed by Luminex protein biochip test and western-blot. Compared to control group, the baricitinib, EV and EV-B groups exhibited improved hair coverage in the AA mouse model. Besides, EV-B group achieved the optimal effect. The underlying mechanism might be attributed to the improvement of drug delivery efficiency as well as the synergistic effect of EVs, leading to better inhibition of JAK-STAT pathway and upregulation of the Wnt/beta-catenin pathway. Our findings proved the effectiveness of EV-B on the treatment of AA, and might provide a new therapeutic approach for AA in future clinical application.

Objectives: Pancreas transplant is currently the most effective method for maintaining physiological blood sugar levels and reversing small blood vessel injuries. Our team developed a model of whole pancreas transplant based on microsurgical techniques following the investigation of more than 300 mice. Materials and Methods: A mouse pancreatic transplant model is required to investigate the pathophysiological process of pancreas transplant and pancreatic preservation technologies. Recently, the segment-neck pancreas transplant has been the most utilized mouse pancreatic transplant model. The innovative mouse pancreatic transplant model that we developed in this study uses the whole pancreas and returns heart blood flow into the liver via the portal vein. Results: With our mouse pancreatic transplant model, the survival rate of mice after transplant was >80%, and the success rate of pancreatic transplant was >90%. Conclusions: The segment-neck and the whole pancreas model can guarantee that the transplanted pancreas functions effectively, and both have excellent postoperative outcomes, survival rates and pancreatic active rates.

Aim. The study aims to explore the expression levels and clinicopathological significance of BRAF V600E and mucin 6 in intrahepatic cholangiocarcinoma. Method. Immunohistochemistry for BRAF V600E and mucin 6 was performed in 110 patients with intrahepatic cholangiocarcinoma. Subsequently, a comprehensive review of medical records and clinicopathological analysis was undertaken. Results. BRAF V600E expression was detected in 11 patients (10%); mucin 6 expression was observed in 19 intrahepatic cholangiocarcinoma specimens (17%). Thereafter, Cox regression models indicated that positive expression of either MUC6 positive (hazard ratio = 0.091, 95% confidence interval = 0.034-0.247, P < .001) and BRAF V600E positive (hazard ratio =0.150, 95% confidence interval = 0.058-0.388, P < .001) was significantly linked with longer overall survival for intrahepatic cholangiocarcinoma patients. Conclusion. The study concludes that positive expression of BRAF V600E and mucin 6 could potentially implied significant survival benefits for patients diagnosed with intrahepatic cholangiocarcinoma.

Up to half of hepatocellular carcinoma (HCC) cases are diagnosed at an advanced stage, for which effective treatment options are lacking, resulting in a poor prognosis. Over the past few years, the combination of immune checkpoint inhibitors and anti-angiogenic targeted therapy has proven highly efficacious in treating advanced HCC, significantly extending patients' survival and providing a potential for sequential curative surgery. After sequential curative hepatectomy or liver transplantation following conversion therapy, patients can receive long-term survival benefits. In order to improve the long-term survival rate of the overall population with liver cancer and achieve the goal of a 15% increase in the overall 5-year survival rate outlined in the Healthy China 2030 blueprint, the Professional Committee for Prevention and Control of Hepatobiliary and Pancreatic Diseases of Chinese Preventive Medicine Association, Chinese Society of Liver Cancer, and the Liver Study Group of Surgery Committee of Beijing Medical Association organized in-depth discussions among relevant domestic experts in the field. These discussions focused on the latest progress since the release of the Chinese expert consensus on conversion therapy of immune checkpoint inhibitors combined antiangiogenic targeted drugs for advanced hepatocellular carcinoma (2021 Edition) and resulted in a new consensus on the modifications and supplements to related key points. This consensus aims to further guide clinical practice, standardize medical care, and promote the development of the discipline.