Chinese Multidisciplinary Expert Consensus on Immune Checkpoint Inhibitor-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition).

Background: Immune checkpoint inhibitor (ICI)-based combination therapy modalities for hepatocellular carcinoma (HCC) have achieved significant efficacy in clinical research and practice and have become the mainstay for the treatment of unresectable HCC. Summary: To better help clinicians use combination immunotherapy drugs and regimens rationally, effectively, and safely, the editorial board facilitated a discussion with multidisciplinary experts in the field, adopted the "Delphi" consensus formation method, and finally revised and completed the "Chinese Multidisciplinary Expert Consensus on the Immune Checkpoint Inhibitors (ICIs)-Based Combination Therapy for Hepatocellular Carcinoma (2023 Edition)" on the basis of the 2021 edition. Key Messages: This consensus primarily focuses on the principles and methods of clinical practice of combination therapy based on ICIs, aiming to summarize the recommendations for clinical application based on the latest research and expert experience and provide application guidance for clinicians.

Case report: Response to tepotinib in Chinese non-small cell lung cancer patients harboring METex14 skipping with varying features.

MET exon 14 (METex14) skipping is the most reported MET mutation in non-small cell lung cancer (NSCLC) and has been confirmed to respond to MET tyrosine kinase inhibitors (TKI) in clinical trials. While MET TKI tepotinib was recently approved for METex14 skipping NSCLC in China, real-world evidence is limited. We report our experience treating NSCLC patients referred from oncology sites across China with tepotinib in the Boao Lecheng Pilot Zone. Four patients have been prescribed the drug with a median age of 67 years (range, 61-71 years). One patient has concomitant BRAF V600E mutation, and another patient had savolitinib as first line of therapy but discontinued due to hepatotoxicity. Till the end of follow-up, four patients were all on tepotinib therapy, with a median duration of therapy of 19 months. One patient achieved partial response and three achieved stable disease. Three patients had peripheral edema, but all were mild. Our experience showed in real clinical setting, tepotinib had robust and durable clinical activity and a favorable toxicity profile in Chinese patients with METex14 skipping NSCLC. It is the first report on the effectiveness of tepotinib in a patient with both METex14 skipping and BRAF V600E mutations and successful MET inhibitor switch after MET inhibitor-induced liver injury.

Collagen in hepatocellular carcinoma: A novel biomarker and therapeutic target.

HCC is globally recognized as a major health threat. Despite significant progress in the development of treatment strategies for liver cancer, recurrence, metastasis, and drug resistance remain key factors leading to a poor prognosis for the majority of liver cancer patients. Thus, there is an urgent need to develop effective biomarkers and therapeutic targets for HCC. Collagen, the most abundant and diverse protein in the tumor microenvironment, is highly expressed in various solid tumors and plays a crucial role in the initiation and progression of tumors. Recent studies have shown that abnormal expression of collagen in the tumor microenvironment is closely related to the occurrence, development, invasion, metastasis, drug resistance, and treatment of liver cancer, making it a potential therapeutic target and a possible diagnostic and prognostic biomarker for HCC. This article provides a comprehensive review of the structure, classification, and origin of collagen, as well as its role in the progression and treatment of HCC and its potential clinical value, offering new insights into the diagnosis, treatment, and prognosis assessment of liver cancer.

Brønsted Acid Catalyzed Asymmetric Synthesis of Cyclopentenones with C4-Quaternary Centers Starting from Vinyl Sulfoxides and Allenyl Ketones or Allenoates.

Starting with chiral vinyl sulfoxides and allenyl ketones or allenoates, a triflic acid-catalyzed asymmetric [3,3]-sigmatropic rearrangement of sulfoniums is reported to have a direct access to highly functionalized C4-chiral cyclopentenones (19 examples, up to 85% yield and >95% enantiomeric excesses). In addition to the use of these chiral compounds as key building blocks in organic synthesis, the antiproliferative activities of sulfoxide substrates and the corresponding cyclopentenones were evaluated, and promising cytotoxicity against the HL-60 human tumor cell line was found.

Association between tissue loss type and amputation risk among Medicare patients with concomitant diabetes and peripheral arterial disease.

OBJECTIVE: Prior studies have described risk factors associated with amputation in patients with concomitant diabetes and peripheral arterial disease (DM/PAD). However, the association between the severity and extent of tissue loss type and amputation risk remains less well-described. We aimed to quantify the role of different tissue loss types in amputation risk among patients with DM/PAD, in the context of demographic, preventive, and socioeconomic factors. METHODS: Applying International Classification of Diseases (ICD)-9 and ICD-10 codes to Medicare claims data (2007-2019), we identified all patients with continuous fee-for-service Medicare coverage diagnosed with DM/PAD. Eight tissue loss categories were established using ICD-9 and ICD-10 diagnosis codes, ranging from lymphadenitis (least severe) to gangrene (most severe). We created a Cox proportional hazards model to quantify associations between tissue loss type and 1- and 5-year amputation risk, adjusting for age, race/ethnicity, sex, rurality, income, comorbidities, and preventive factors. Regional variation in DM/PAD rates and risk-adjusted amputation rates was examined at the hospital referral region level. RESULTS: We identified 12,257,174 patients with DM/PAD (48% male, 76% White, 10% prior myocardial infarction, 30% chronic kidney disease). Although 2.2 million patients (18%) had some form of tissue loss, 10.0 million patients (82%) did not. The 1-year crude amputation rate (major and minor) was 6.4% in patients with tissue loss, and 0.4% in patients without tissue loss. Among patients with tissue loss, the 1-year any amputation rate varied from 0.89% for patients with lymphadenitis to 26% for patients with gangrene. The 1-year amputation risk varied from two-fold for patients with lymphadenitis (adjusted hazard ratio, 1.96; 95% confidence interval, 1.43-2.69) to 29-fold for patients with gangrene (adjusted hazard ratio, 28.7; 95% confidence interval, 28.1-29.3), compared with patients without tissue loss. No other demographic variable including age, sex, race, or region incurred a hazard ratio for 1- or 5-year amputation risk higher than the least severe tissue loss category. Results were similar across minor and major amputation, and 1- and 5-year amputation outcomes. At a regional level, higher DM/PAD rates were inversely correlated with risk-adjusted 5-year amputation rates (R2 = 0.43). CONCLUSIONS: Among 12 million patients with DM/PAD, the most significant predictor of amputation was the presence and extent of tissue loss, with an association greater in effect size than any other factor studied. Tissue loss could be used in awareness campaigns as a simple marker of high-risk patients. Patients with any type of tissue loss require expedited wound care, revascularization as appropriate, and infection management to avoid amputation. Establishing systems of care to provide these interventions in regions with high amputation rates may prove beneficial for these populations.

An Asymmetric NIR-II Organic Fluorophore with an Ultra-Large Stokes Shift for Imaging-Guided and Targeted Phototherapy.

NIR-II imaging-guided phototherapy is an attractive, yet challenging, tumor treatment strategy. By monitoring the accumulation of phototherapy reagents at the tumor site through imaging and determining the appropriate therapy window, the therapeutic effect could be significantly improved. Probes with NIR-II (1000-1700 nm) fluorescence emission and a large Stokes shift hold great promise for fluorescence imaging with deep penetration, minimized self-quenching, and high spatiotemporal resolution. However, due to the lack of a suitable molecular framework, the design of a simple small-molecule dye with a large Stokes shift and NIR-II fluorescence emission has rarely been reported. Herein, we prepare an asymmetric D-π-A type NIR-II fluorescence probe (TBy). The probe is incapsulated in an amphiphilic polymer and modified with a fibronectin targeting peptide CREKA, which could recognize the fibrin-fibronectin complex overexpressed in multiple malignant tumors. The nanoparticles thus constructed (TByC-NPs) have maximum fluorescence emission at 1037 nm with a large Stokes shift of 426 nm, which is the largest Stokes shift among organic NIR-II fluorescent dyes reported in the literature. The TByC-NPs exhibit a good NIR-II imaging performance, active tumor targeting, and good photothermal and photodynamic capabilities. In vitro and in vivo studies verify that the TByC nanoplatform shows outstanding biocompatibility for NIR-II imaging-guided phototherapy and provides an excellent antitumor effect.

Prognostic implications of preoperative, postoperative, and dynamic changes of alpha-fetoprotein and des-gamma (γ)-carboxy prothrombin expression pattern for hepatocellular carcinoma after hepatic resection: a multicenter observational study.

Background: The utility of pre- and post-operative alpha-fetoprotein (AFP) and des-gamma (γ)-carboxy prothrombin (DCP) expression patterns and their dynamic changes as predictors of the outcome of hepatic resection for hepatocellular carcinoma (HCC) has yet to be well elucidated. Methods: From a multicenter database, AFP and DCP data during the week prior to surgery and the first post-discharge outpatient visit (within 1-2 months after surgery) were collected from patients with HCC who underwent hepatectomy. AFP-DCP expression patterns were categorized according to the number of positive tumor markers (AFP ≥ 20ng/mL, DCP ≥ 40mAU/mL), including double-negative, single-positive, and double-positive. Changes in the AFP-DCP expression patterns were delineated based on variations in the number of positive tumor markers when comparing pre- and post-operative patterns. Results: Preoperatively, 53 patients (8.3%), 337 patients (52.8%), and 248 patients (38.9%) exhibited double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Postoperatively, 463 patients (72.6%), 130 patients (20.4%), and 45 patients (7.0%) showed double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Survival analysis showed a progressive decrease in recurrence-free (RFS) and overall survival (OS) as the number of postoperative positive tumor markers increased (both P < 0.001). Multivariate analysis showed that postoperative AFP-DCP expression pattern, but not preoperative AFP-DCP expression pattern, was an independent risk factor for RFS and OS. Further analysis showed that for patients with positive preoperative markers, prognosis gradually improves as positive markers decrease postoperatively. In particular, when all postoperative markers turned negative, the prognosis was consistent with that of preoperative double-negative patients, regardless of the initial number of positive markers. Conclusions: AFP-DCP expression patterns, particularly postoperative patterns, serve as vital sources of information for prognostic evaluation following hepatectomy for HCC. Moreover, changes in AFP-DCP expression patterns from pre- to post-operation enable dynamic prognostic risk stratification postoperatively, aiding the development of individualized follow-up strategies.

A perylene diimide probe for NIR-II fluorescence imaging guided photothermal and type I/type II photodynamic synergistic therapy.

Phototherapy has garnered significant attention in the past decade. Photothermal and photodynamic synergistic therapy combined with NIR fluorescence imaging has been one of the most attractive treatment options because of the deep tissue penetration, high selectivity and excellent therapeutic effect. Benefiting from the superb photometrics and ease of modification, perylene diimide (PDI) and its derivatives have been employed as sensing probes and therapeutic agents in the biological and biomedical research fields, and exhibiting excellent potential. Herein, we reported the development of a novel organic small-molecule phototherapeutic agent, PDI-TN. The absorption of PDI-TN extends into the NIR region, which provides feasibility for NIR phototherapy. PDI-TN overcomes the traditional Aggregation-Caused Quenching (ACQ) effect and exhibits typical characteristics of Aggregation-Induced Emission (AIE). Subsequently, PDI-TN NPs were obtained by using an amphiphilic triblock copolymer F127 to encapsulate PDI-TN. Interestingly, the PDI-TN NPs not only exhibit satisfactory photothermal effects, but also can generate O2•- and 1O2 through type I and type II pathways, respectively. Additionally, the PDI-TN NPs emit strong fluorescence in the NIR-II region, and show outstanding therapeutic potential for in vivo NIR-II fluorescence imaging. To our knowledge, PDI-TN is the first PDI derivative used for NIR-II fluorescence imaging-guided photodynamic and photothermal synergistic therapy, which suggests excellent potential for future biological/biomedical applications.

Sb3+/Sm3+ Codoped Cs2NaScCl6 All-Inorganic Double Perovskite: Blue Emission of Self-Trapped Excitons and Red-Emission via Energy Transfer.

The lead-free halide perovskites possess nontoxicity and excellent chemical stability, whereas relatively weak luminescence intensity limits their potential in practical applications. Therefore, strengthening the luminescence intensity and expanding application fields are urgent tasks for the development of lead-free halide perovskites. In this paper, antimony-doped Cs2NaScCl6 crystals synthesized by a solvothermal method emit bright, deep blue photoluminescence at 447 nm. The photoluminescence (PL), photoluminescence excitation (PLE), and absorption spectra demonstrate that Sb3+ doping effectively activate the intrinsic "dark self-trapped exciton (STE)," leading to an impressive photoluminescence quantum yield (PLQY) value of 78.31% for 1% Sb3+ doping. Furthermore, the luminescence intensity remains above 92% compared with the fresh sample without secondary phases detected even after 90 days under environmental conditions. To expand the emission spectra, rare-earth Sm3+ is further incorporated into Cs2NaScCl6:1% Sb3+ crystals. The results show that Sb ions not only enhance intrinsic STE luminescence but also serve as sensitizers to boost the red-light emission of Sm3+, leading to a significant 500-fold increase in red emission intensity. Finally, the PLQY reaches a stunning 86.78%. These findings provide valuable insights in the design of Sb ion-doped lead-free double perovskites, broadening the application fields in various optoelectronic devices.

IL-17a promotes hepatocellular carcinoma by increasing FAP expression in hepatic stellate cells via activation of the STAT3 signaling pathway.

Studies have shown that hepatic stellate cells (HSCs) and interleukin-17a (IL-17a) play important roles in liver tumorigenesis. In addition, fibroblast activation protein-α (FAP) has been shown to be a key regulator of hepatic stellate cell activation. In this study, in vivo and in vitro experiments were performed to verify the promoting effects of IL-17a administration, IL-17a overexpression, and FAP upregulation in HSCs on liver fibrosis and liver tumorigenesis. The cleavage under targets & release using nuclease (CUT&RUN) technique was used to verify the binding status of STAT3 to the FAP promoter. The in vitro studies showed that IL-17a activated HSCs and promoted HCC development and progression. FAP and IL-17a overexpression also activated HSCs, promoted HCC cell proliferation and migration, and inhibited HCC cell apoptosis. The in vivo studies suggested that IL-17a and FAP overexpression in HSCs facilitated liver tumor development and progression. The CUT&RUN results indicated that FAP expression was regulated by STAT3, which could bind to the FAP promoter region and regulate its transcription status. We concluded that IL-17a promoted HCC by increasing FAP expression in HSCs via activation of the STAT3 signaling pathway.

Development and comprehensive validation of a predictive prognosis model for very early HCC recurrence within one year after curative resection: a multicenter cohort study.

BACKGROUND: The high incidence of early recurrence after liver resection (LR) for hepatocellular carcinoma (HCC) is the main obstacle in achieving good long-term survival outcomes. The aim of the present study is to develop a prognostic model in predicting the risk of very early (1-year) recurrence. MATERIAL AND METHODS: Consecutive patients who underwent LR for HCC with curative intent at multicenters in China were enrolled in this study. The VERM-pre (the Preoperative Very Early Recurrence Model of HCC) with good performance was derived and validated by internal and external cohorts retrospectively and by another two-center cohort prospectively. RESULTS: Seven thousand four hundred one patients were enrolled and divided randomly into three cohorts. Eight variables (tumor diameter, tumor number, macrovascular invasion, satellite nodule, alpha-fetoprotein, level of HBV-DNA, γ-GT, and prothrombin time) were identified as independent risk factors for recurrence-free survival on univariate and multivariate analyses. The VERM-pre model was developed which showed a high capacity of discrimination (C-index: 0.722; AUROC at 1-year: 0.722)) and was validated comprehensively by the internal, external, and prospective cohorts, retrospectively. Calibration plots showed satisfactory fitting of probability of early HCC recurrence in the cohorts. Three risk strata were derived to have significantly different recurrence-free survival rates (low-risk: 80.4-85.4%; intermediate-risk: 59.7-64.8%; high-risk: 32.6-42.6%). In the prospective validation cohort, the swimming plot illustrated consistent outcomes with the beginning predictive score. CONCLUSION: The VERM-pre model accurately predicted the 1-year recurrence rates of HCC after LR with curative intent. The model was retrospectively and prospectively validated and then developed as the online tool.

A Protective Role of Canonical Wnt/ß-Catenin Pathway in Pathogenic Bacteria-Induced Inflammatory Responses.

Inflammation is a complex host defensive response against various disease-associated pathogens. A baseline extent of inflammation is supposed to be tightly associated with a sequence of immune-modulated processes, resulting in the protection of the host organism against pathogen invasion; however, as a matter of fact is that an uncontrolled inflammatory cascade is the main factor responsible for the host damage, accordingly suggesting a significant and indispensable involvement of negative feedback mechanism in modulation of inflammation. Evidence accumulated so far has supported a repressive effect of the canonical Wnt/ß-catenin pathway on microbial-triggered inflammation via diverse mechanisms, although that consequence is dependent on the cellular context, types of stimuli, and cytokine environment. It is of particular interest and importance to comprehend the precise way in which the Wnt/ß-catenin pathway is activated, due to its essential anti-inflammatory properties. It is assumed that an inflammatory milieu is necessary for initiating and activating this signaling, implying that Wnt activity is responsible for shielding tissues from overwhelming inflammation, thus sustaining a balanced physiological condition against bacterial infection. This review gathers the recent efforts to elucidate the mechanistic details through how Wnt/ß-catenin signaling modulates anti-inflammatory responses in response to bacterial infection and its interactions with other inflammatory signals, which warrants further study for the development of specific interventions for the treatment of inflammatory diseases. Further clinical trials from different disease settings are required.

Impact of three-dimensional reconstruction visualization technology on short-term and long-term outcomes after hepatectomy in patients with hepatocellular carcinoma: a propensity-score-matched and inverse probability of treatment-weighted multicenter study.

BACKGROUND: Three-dimensional reconstruction visualization technology (3D-RVT) is an important tool in the preoperative assessment of patients undergoing liver resection. However, it is not clear whether this technique can improve short-term and long-term outcomes in patients with hepatocellular carcinoma (HCC) compared with two-dimensional (2D) imaging. METHOD: A total of 3402 patients from five centers were consecutively enrolled from January 2016 to December 2020, and grouped based on the use of 3D-RVT or 2D imaging for preoperative assessment. Baseline characteristics were balanced using propensity score matching (PSM, 1:1) and stabilized inverse probability of treatment-weighting (IPTW) to reduce potential selection bias. The perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) were compared between the two groups. Cox-regression analysis was used to identify the risk factors associated with RFS. RESULTS: A total of 1681 patients underwent 3D-RVT assessment before hepatectomy (3D group), while 1721 patients used 2D assessment (2D group). The PSM cohort included 892 patient pairs. In the IPTW cohort, there were 1608.3 patients in the 3D group and 1777.9 patients in the 2D group. In both cohorts, the 3D group had shorter operation times, lower morbidity and liver failure rates, as well as shorter postoperative hospital stays. The 3D group had more margins ≥10 mm and better RFS than the 2D group. The presence of tumors with a diameter ≥5 cm, intraoperative blood transfusion and multiple tumors were identified as independent risk factors for RFS, while 3D assessment and anatomical resection were independent protective factors. CONCLUSION: In this multicenter study, perioperative outcomes and RFS of HCC patients following 3D-RVT assessment were significantly different from those following 2D imaging assessment. Thus, 3D-RVT may be a feasible alternative assessment method before hepatectomy for these patients.

Balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution in postoperative liver regeneration.

BACKGROUND & AIMS: Post-hepatectomy liver failure (PHLF) leads to poor prognosis in patients undergoing hepatectomy, with hepatic vascular reconstitution playing a critical role. However, the regulators of hepatic vascular reconstitution remain unclear. In this study, we aimed to investigate the regulatory mechanisms of hepatic vascular reconstitution and identify biomarkers predicting PHLF in patients undergoing hepatectomy. METHODS: Candidate genes that were associated with hepatic vascular reconstitution were screened using adeno-associated virus vectors in Alb-Cre-CRISPR/Cas9 mice subjected to partial hepatectomy. The biological activities of candidate genes were estimated using endothelial precursor transfusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) models. The level of candidates was detected in biopsies from patients undergoing ALPPS. Risk factors for PHLF were also screened using retrospective data. RESULTS: Downregulation of Gata3 and upregulation of Ramp2 in hepatocytes promoted the proliferation of liver sinusoidal endothelial cells and hepatic revascularization. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor A (VEGFA) played opposite roles in regulating the migration of endothelial precursors from bone marrow and the formation of new sinusoids after hepatectomy. Gata3 restricted endothelial cell function in patient-derived hepatic organoids, which was abrogated by a Gata3 inhibitor. Moreover, overexpression of Gata3 led to higher mortality in ALPPS mice, which was improved by a PEDF-neutralizing antibody. The expression of Gata3/RAMP and PEDF/VEGFA tended to have a negative correlation in patients undergoing ALPPS. A nomogram incorporating multiple factors, such as serum PEDF/VEGF index, was constructed and could efficiently predict the risk of PHLF. CONCLUSIONS: The balance of Gata3 and Ramp2 in hepatocytes regulates the proliferation of liver sinusoidal endothelial cells and hepatic revascularization via changes in the expression of PEDF and VEGFA, revealing potential targets for the prevention and treatment of PHLF. IMPACT AND IMPLICATIONS: In this study, we show that the balance of Gata3 and Ramp2 in hepatocytes regulates hepatic vascular reconstitution by promoting a shift from pigment epithelium-derived factor (PEDF) to vascular endothelial growth factor A (VEGFA) expression during hepatectomy- or ALLPS (associating liver partition and portal vein ligation for staged hepatectomy)-induced liver regeneration. We also identified serum PEDF/VEGFA index as a potential predictor of post-hepatectomy liver failure in patients who underwent hepatectomy. This study improves our understanding of how hepatocytes contribute to liver regeneration and provides new targets for the prevention and treatment of post-hepatectomy liver failure.

A multicenter propensity score analysis of significance of hepatic resection type for early-stage hepatocellular carcinoma.

BACKGROUND: The impact of hepatic resection type on long-term oncological prognosis of patients with early-stage hepatocellular carcinoma (HCC) has not been systematically investigated. We sought to determine risk factors, recurrence patterns, and survival outcomes after anatomical resection (AR) versus non-anatomical resection (NAR) for early-stage HCC. METHODS: From a prospectively collected multicenter database, consecutive patients undergoing curative hepatectomy for early-stage HCC were identified. Recurrence patterns, overall survival (OS), recurrence-free survival (RFS), and risk factors were investigated in patients undergoing AR versus NAR using propensity score matching (PSM), subgroup analysis, and COX regression analysis. RESULTS: A total of 3585 patients with early-stage HCC were enrolled, including 1287 and 2298 in the AR and NAR groups, respectively. After PSM, the OS and RFS of patients in the AR group were 58.8% and 42.7%, which were higher than those in the NAR group (52.2% and 30.6%, both p < 0.01). The benefits of AR were consistent across most subgroup analyses of OS and RFS. Multivariable COX regression analysis showed that AR was independently associated with better OS and RFS. Notably, although recurrence patterns were comparable, the risk factors for recurrence were not identical for AR versus NAR. Microvascular invasion and narrow resection margin were only associated with a higher recurrence rate after NAR. CONCLUSIONS: This study demonstrated that AR decreases the risk of tumor recurrence and improves OS and RFS in patients with early-stage HCC. AR should be adopted as long as such a surgical maneuver is feasible for initial treatment of early-stage HCC.

Spatial multimodal analysis revealed tertiary lymphoid structures as a risk stratification indicator in combined hepatocellular-cholangiocarcinoma.

The microenvironment created by tertiary lymphoid structures (TLSs) can support and regulate immune responses, affecting the prognosis and immune treatment of patients. Nevertheless, the actual importance of TLSs for predicting the prognosis of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) patients remains unclear. Herein, using spatial transcriptomic analysis, we revealed that a gene signature of TLSs specific to cHCC-CCA was associated with high-intensity immune infiltration. Then, a novel scoring system was developed to evaluate the distribution and frequency of TLSs in intra-tumoral and extra-tumoral regions (iTLS and eTLS scores) in 146 cHCC-CCA patients. iTLS score was positively associated with promising prognosis, likely due to the decreased frequency of suppressive immune cell like Tregs, and the ratio of CD163+ macrophages to macrophages in intra-tumoral TLSs via imaging mass cytometry, while improved prognosis is not necessarily indicated by a higher eTLS score. Overall, this study highlights the potential of TLSs as a prognostic factor and an indicator of immune therapy in cHCC-CCA.

Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients.

BACKGROUND: Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). METHODS: Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. RESULTS: Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages. CONCLUSION: The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.

Prognosis value of microscopic bile duct invasion in hepatocellular carcinoma: A multicenter study.

OBJECTIVE: To evaluate the prognostic significance of microscopic bile duct invasion (MiBDI) in hepatocellular carcinoma (HCC) following R0 resection. PATIENTS AND METHODS: Patients who underwent R0 resection for HCC at nine medical centers were stratified into five groups: neither bile duct nor vascular invasion (MiBDI-MVI-), microscopic bile duct invasion alone (MiBDI+MVI-), both microscopic bile duct and vascular invasion (MiBDI+MVI+), microscopic vascular invasion alone (MiBDI-MVI+), and macroscopic bile duct invasion (MaBDI). Overall survival (OS) was assessed using Kaplan-Meier analysis, and independent risk factors of OS were determined using Cox proportional hazards models. RESULTS: A total of 377 HCC cases were analyzed. The OS for MiBDI+MVI- was similar to that of MiBDI-MVI- (p > 0.05) but better than MiBDI+MVI+, MiBDI-MVI+, and MaBDI (all p < 0.05). Multivariate analysis indicated that MiBDI was not an independent risk factor for OS, while MVI and MaBDI were. CONCLUSIONS: Overall survival (OS) in patients with MiBDI was superior to those with MVI and MaBDI. Isolated MiBDI did not influence OS in patients with HCC after R0 resection.

Circular RNA cFAM210A, degradable by HBx, inhibits HCC tumorigenesis by suppressing YBX1 transactivation.

Hepatitis B protein x (HBx) has been reported to promote tumorigenesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the mechanism awaits further investigation. In this study, we found that cFAM210A (a circular RNA derived from the third exon of transcript NM_001098801 of the FAM210A gene; CircBase ID: hsa_circ_0003979) can be silenced by HBx. cFAM210A expression was downregulated and negatively correlated with tumorigenesis in patients with HBV-related HCC. Furthermore, cFAM210A reduced the proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, HBx increased the N6-methyladenosine (m6A) level of cFAM210A by promoting the expression of RBM15 (an m6A methyltransferase), thus inducing the degradation of cFAM210A via the YTHDF2-HRSP12-RNase P/MRP pathway. cFAM210A bound to YBX1 and inhibited its phosphorylation, suppressing its transactivation function toward MET. These findings suggest the important role of circular RNAs in HBx-induced hepatocarcinogenesis and identify cFAM210A a potential target in the prevention and treatment of HBV-related HCC.

Preoperative Three-Dimensional Morphological Tumor Features Predict Microvascular Invasion in Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: The study was designed to evaluate microvascular invasion (MVI) using three-dimensional (3D) morphological indicators prior to surgery. MATERIALS AND METHODS: This retrospective study included 156 patients with hepatocellular carcinoma (HCC) at our hospital from 2017 to 2018. Through thin-layer CT scanning and 3D reconstruction, the tumor surface inclination angles can be quantitatively analyzed to determine the surface irregularity rate (SIR), which serves as a comprehensive assessment method for tumor irregularity based on preoperative 3D morphological evaluation. Univariate and multivariate logistic regression analyses were employed to investigate the correlation with MVI. RESULTS: The SIR was related to MVI (OR: 10.667, P < 0.001). Multivariate logistic regression analysis showed that the SIR was an independent risk factor for MVI. The area under the receiver operating characteristic curve (ROC) of prediction model composed of the morphological indicator SIR was 0.831 (95% confidence interval: 0.759-0.895). CONCLUSION: The preoperative 3D morphological indicator SIR of a tumor is an accurate predictor of MVI, providing a valuable tool in clinical decision-making.