Alpha-fetoprotein (AFP) is a well-established diagnostic biomarker for hepatocellular carcinoma (HCC), yet its functional role in tumor progression extends far beyond serological detection. Specifically, its ability to regulate cancer stemness, a key driver of therapy resistance and recurrence, remains largely unexplored. Here, we demonstrate that AFP is a critical functional regulator of cancer stem-like cells (CSC) in HCC. In this study, we employed CRISPR/Cas9-mediated gene editing to generate AFP-knockout models in Huh7 and PLC/PRF/5 cell lines, enabling a systematic investigation of AFP's oncogenic functions. Comparative analyses demonstrated that AFP ablation markedly reduced tumorigenic potential in vivo, accompanied by downregulation of stemness markers (EPCAM and CD44) and inhibition of PI3K/Akt signaling. Mechanistic studies further identified the PI3K/Akt pathway as critical for AFP-mediated maintenance of cancer stem cell properties. Collectively, our findings provide direct evidence that AFP-driven stemness contributes functionally to HCC progression, establishing AFP as a molecular regulator rather than merely a diagnostic marker. This study elucidates a novel AFP-PI3K/Akt-stemness axis in HCC pathogenesis and highlights potential therapeutic targets for stemness-directed interventions in AFP-positive HCC.

BACKGROUND Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare and aggressive primary liver cancer characterized by the presence of both hepatocellular and cholangiocellular differentiation within the same tumor. Its diagnostic complexity and low incidence have resulted in a scarcity of well-established prognostic pathological parameters to guide clinical management. Given the rising global prevalence of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease, and their close association with the occurrence of primary liver cancer, it is plausible that hepatic steatosis influences the prognosis of cHCC-CCA. AIM To investigate the specific clinicopathological role of background hepatic steatosis in patients with cHCC-CCA who underwent curative-intent liver resection. METHODS This multicenter study analyzed 310 patients with cHCC-CCA who underwent curative-intent hepatectomy between 2013 and 2017. Hepatic steatosis in liver tissue was graded pathologically: Grade 0-1 (< 33% hepatocytes) was defined as negligible hepatic steatosis (n = 283, 91.3%), and grade 2-3 (>= 33% hepatocytes) as severe hepatic steatosis (n = 27, 8.7%). Primary endpoints were recurrence-free survival (RFS), overall survival, early (<= 2 years) and late (> 2 years) RFS. RESULTS Patients with severe hepatic steatosis had a significantly prolonged RFS compared to those with negligible steatosis (P = 0.035), with 5-year RFS rates of 28.8% vs 15.7%. This benefit was primarily observed in early RFS (P = 0.024) and was more pronounced in non-cirrhotic patients. In contrast, no statistically significant difference was found in overall survival (P = 0.586) or late RFS (P = 0.931) between the two groups. Multivariate logistic regression analysis showed higher body mass index and lymphocyte count, and lower lactate dehydrogenase were independent predictors for the presence of severe steatosis. Furthermore, multivariate Cox regression analysis confirmed severe hepatic steatosis as an independent protective factor for RFS (hazard ratio = 0.614) and early RFS (hazard ratio = 0.577). CONCLUSION Severe hepatic steatosis is a protective factor associated with RFS and early RFS in patients with cHCC-CCA who underwent hepatectomy, which is especially significant in the absence of liver cirrhosis.

To compare targeted immunotherapy plus adjuvant transarterial chemoembolization (TACE) versus TACE alone in patients with borderline resectable hepatocellular carcinoma (BR-HCC). 297 BR-HCC patients who underwent liver resection were included. Among them, 86 patients received perioperative targeted immunotherapy combined with adjuvant TACE (combination therapy group, which included neoadjuvant therapy and adjuvant therapy), while 211 received adjuvant TACE alone (TACE-only group). After propensity score matching (PSM), the combination therapy group demonstrated significantly improved 1-, 3-, and 5-year OS rates (90.7%, 66.0%, and 58.1%, respectively) compared to the TACE-only group (86.0%, 55.2%, and 35.1%; p = 0.013). Similarly, 1-, 3-, and 5-year RFS rates were higher in the combination therapy group (66.3%, 36.9%, and 31.0%) than in the TACE-only group (55.8%, 23.1%, and 13.8%; p = 0.007). Multivariable analysis confirmed that combination therapy was an independent protective factor for both OS (HR: 0.619, 95% CI: 0.389-0.983) and RFS (0.665, 0.469-0.944). Subgroup analysis showed that in adjuvant therapy and TACE-only, TACE-only was an independent risk factor for OS (1.986, 1.105-3.566) and RFS (1.831, 1.132-2.962) compared with adjuvant therapy (receiving postoperative adjuvant targeted immunotherapy and TACE). Further analysis showed that in the combination therapy subgroup, adjuvant therapy was an independent risk factor for OS (2.701, 1.171-6.230) and RFS (2.051, 1.125-3.739) compared to neoadjuvant therapy (receiving both preoperative neoadjuvant and postoperative adjuvant targeted immunotherapy and TACE). No significant difference in complications/AEs following surgery/TACE was observed between the two groups. Perioperative targeted immunotherapy combined with adjuvant TACE significantly improves OS and RFS in BR-HCC patients without increasing the incidence of complications/AEs following surgery/TACE.

Background: The differences in the prognostic value of microvascular invasion (MVI) and satellite nodules (S) for patients with hepatocellular carcinoma (HCC) remain unclear. We aimed to evaluate the effect of MVI and/or S on recurrence patterns and long-term prognosis of patients with HCC after hepatectomy. Methods: Patients with HCC who underwent hepatectomy in 23 cancer centers in China between 2012 and 2022 were included in this study. Patients were divided into four groups based on the histopathological diagnosis of MVI and/or S. Data were analyzed retrospectively. Results: The 3,145 enrolled patients were divided into four groups: No MVI or S, MVI-only, S-only, and MVI and S groups, comprising 1,495, 806, 245, and 599 patients, respectively. Patients in the S-only group exhibited a higher early recurrence (ER) rate compared to those in the MVI-only group (P=0.03). Patients in the MVI and S group had shorter median overall survival (OS) (30.2 vs. 72.5 vs. 53.8 vs. 47.8 months, P<0.001) and recurrence-free survival (RFS) (8.4 vs. 63.0 vs. 28.4 vs. 25.0 months, P<0.001) compared to those in the No MVI or S, MVI-only, and S-only groups, respectively. Multivariate analyses showed that MVI and S were both independent risk factors for OS, RFS, aggressive recurrence (AR), ER, and early aggressive recurrence (EAR). Conclusions: MVI and S were both independently associated with AR, ER, EAR, and poor long-term prognosis in patients with HCC after hepatectomy. Distinguishing between MVI and S is necessary for postoperative prognostic stratification and management in patients with HCC after hepatectomy.

Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited therapeutic options. While the prevalence of overweight/obese (OW/OB) women continues to rise, the impact of obesity on molecular features of TNBC remains incompletely understood. We investigated clinicopathological and molecular data (including genomic, transcriptomic, proteomic and metabolomic profiling) using our original multi-omics database of TNBC (N = 465) for associations with patient body mass index (BMI). Multi-omics profiling revealed that OW/OB patients exhibited worse survival as well as elevated inflammation of tumor microenvironment, higher expression of immune checkpoints, and dysregulated lipid metabolism. Our in vivo experiments demonstrated that tumors in obese mice displayed faster growth rates, a higher proportion of PD-1+CD8+ T cells and enhanced responsiveness to anti-PD-1 treatment. In addition, we analyzed data from four independent clinical trials and discovered that OW/OB patients demonstrated higher pathological complete response rates and longer progression-free survival following anti-PD-1-based immunotherapy. In conclusion, our study systematically revealed that obesity is associated with coordinated immune-metabolic remodeling in TNBC, characterized by checkpoint enrichment and lipid dysregulation, which may help explain the enhanced anti-PD-1 responsiveness and should be taken into account in the field of precision medicine.

Innervation is critical in tumor progression. However, the involvement of sensory neurons in the ecosystem of triple-negative breast cancer (TNBC) remains poorly elucidated. Here, we decipher that sensory neurons, the dominant neuron type in the TNBC ecosystem, drive the immune-excluded tumor microenvironment (TME) by stimulating a dense extracellular matrix. Mechanistically, a high concentration of nerve growth factor (NGF) in TME triggers sensory neurons to secrete the neuropeptide calcitonin gene-related peptide (CGRP), thereby activating cancer-associated fibroblasts (CAFs) to secrete collagen. Specifically, CGRP binds to its receptor RAMP1 (receptor activity modifying protein 1), which is expressed mainly on CAFs, and subsequently activates cyclic AMP (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein 1 (CREB1) signaling to increase collagen deposition. Clinically, targeting sensory neurons remodels the disordered TME and synergizes with anti-programmed cell death protein 1 (PD-1) immunotherapy in TNBC. Collectively, our findings reveal a connection between sensory neurons and CAFs that obstructs antitumor immunity in TNBC. The CGRP antagonist rimegepant thus has clinical translational potential as an immuno-sensitizer to augment tumor immunotherapy.

Background:Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer lacking personalized pathological parameters. Microscopic tumor focus (MTF), a microscopic intrahepatic metastatic pattern, remains poorly characterized, with unclear prognostic and therapeutic relevance in cHCC-CCA. In this study, the detailed significance of MTF in cHCC-CCA was investigated. Methods:A multicenter study included 310 cHCC-CCA patients who underwent curative-intent hepatectomy. MTF was further graded by its number/distribution (MTF 0: absence of MTF; MTF 1: 1-5 proximal MTFs; MTF 2: >5 proximal MTFs/≥1 distal MTFs) and subclassified by its histology (HCC-type MTF; CCA-type MTF; HCC + CCA-type MTF). Results:MTF was detected in 48.1% (149/310) of patients (MTF 1: 43.2%, MTF 2: 4.8%; HCC-type MTF: 17.7%; CCA-type MTF: 20.6%; HCC + CCA type MTF: 9.7%). MTF positivity correlated with poorer recurrence-free survival (RFS) (median time: 0.23 and 0.89 years), early RFS, and overall survival (OS) (median time: 1.53 and 2.95 years, all P<0.001), with MTF 2 and HCC + CCA-type MTF predicting the worst prognosis. For MTF-positive patients, surgical margin >0.1 cm improved RFS, early RFS, and OS, while surgical margin had no effect on MTF-negative patients. Age, tumor diameter, microvascular invasion and perineural invasion independently predicted MTF (area under the curve =0.704); MTF histology was an independent prognostic factor for RFS, early RFS, and OS (all Harrell's concordance index >0.7). Conclusions:This study standardized the definition of MTF and confirmed its prognostic value in cHCC-CCA. MTF stratification based on its number/distribution and histology enables more precise prognostic assessment. The presence of MTF could guide individualized selection of surgical margin.

BACKGROUND:The pathological diagnostic purpose of the tumor component proportion of combined hepatocellular-cholangiocarcinoma (CHC) remains a perplexing issue, hindering clinicians from characterizing its biological behavior and formulating intervention strategies. METHODS:A multicenter database of patients with CHC who underwent therapeutic hepatectomy was analyzed. Based on a > 70% hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA) component, the patients were stratified into three groups: CHCHCC-dominant, CHCbalanced, and CHCCCA-dominant. Survival outcomes were assessed using Kaplan-Meier analysis. Tumor markers and recurrence patterns were compared via Chi-square test, and prognostic factors were identified through Cox regression analysis. Postoperative adjuvant transarterial chemoembolization (PA-TACE) benefits were further evaluated. RESULTS:Among 19 641 patients with primary liver cancer, 306 with CHC were classified: 93 (30.4%) in the CHCHCC-dominant group, 101 (33.0%) in the CHCbalanced group, and 112 (36.6%) in the CHCCCA-dominant group. The best and the worst prognoses were observed in the CHCHCC-dominant group and CHCCCA-dominant group, respectively (median RFS time: CHCHCC-dominant group 1.02 years, CHCbalanced group 0.36 years, CHCCCA-dominant group 0.30 years; median OS time: CHCHCC-dominant group 3.16 years, CHCbalanced group 1.93 years, CHCCCA-dominant group 1.86 years). The highest ratios of elevated alpha-fetoprotein and carbohydrate antigen 19-9 were recorded in the CHCHCC-dominant group and the CHCCCA-dominant group, respectively. CHCHCC-dominant and CHCCCA-dominant patients showed the most frequent intrahepatic and extrahepatic recurrences, respectively. PA-TACE improved early RFS (< 2 years) only in CHCHCC-dominant patients. Multivariate analysis confirmed that tumor component proportion was an independent prognostic factor for all survival endpoints. CONCLUSIONS:Predominant HCC or CCA components (> 70% tumor composition) critically shape CHC biology and prognosis. Tumor component proportion emerges as a novel parameter for therapeutic decision-making. We proposed a comprehensive flow chart integrating pathological sampling, histological component evaluation, clinical data mapping, and postoperative intervention strategies for CHC.

BACKGROUND:The prognostic role of perineural invasion (PNI) in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains undefined. This multicenter study assessed the incidence, patterns, and clinical significance of PNI in cHCC-CCA. METHODS:This study included 307 patients with cHCC-CCA undergoing hepatectomy with curative intent. Three independent pathologists conducted histopathological assessments of the frequency (single/multiple), involved tumor components (HCC/CCA/intermediate cell carcinoma), and spatial distribution (intratumoral/intratumoral + peritumoral/peritumoral) of PNI. The impact of postoperative adjuvant transarterial chemoembolization (PA-TACE) on the prognosis was further evaluated. Survival outcomes (recurrence-free survival [RFS], overall survival [OS], and early [≤2 years] and late [>2 years] RFS) were analyzed using Kaplan-Meier and Cox regression. Logistic regression identified the predictors of PNI. RESULTS:Among 307 patients (median age, 52.7 years; 87.6% male), the prevalence of PNI was 16.0% (49 of 307). PNI-positive patients had significantly worse median RFS (0.21 vs 0.54 years; hazard ratio [HR], 2.003; P <.001) and OS (1.18 vs 2.56 years; HR, 2.213; P <.001) than PNI-negative patients. Early RFS differed significantly (P <.001), but late RFS did not (P =.443). Subgroup analysis showed that the worst RFS and early RFS were noted in patients with HCC-component PNI (P =.025; P =.024) and purely intratumoral PNI (P =.025; P =.024). PA-TACE improved the early RFS only in PNI-negative patients (P =.031). Elevated alkaline phosphatase (odds ratio [OR], 1.005; P =.029), macrovascular invasion (OR, 2.873; P =.003), microvascular invasion (OR, 2.291; P =.033), and absent tumor capsule (OR, 2.539; P =.014) independently predicted PNI. Multivariable analysis confirmed PNI as an independent risk factor for RFS (HR, 1.700; P =.002), OS (HR, 1.760; P =.001), and early RFS (HR, 1.749; P =.001). CONCLUSION:PNI is a noteworthy pathological feature in cHCC-CCA, independently associated with early recurrence, inferior survival, and increased therapeutic challenge. Standardized pathological reporting of PNI status may improve prognostic stratification for patients with cHCC-CCA.

Introduction:Since the release of the World Health Organization (WHO) Classification of Tumours-Digestive System Tumours in 2019, the pathology of intrahepatic cholangiocarcinoma (iCCA) has entered an era of integrated diagnosis, encompassing gross classification, histological subtyping, as well as drug molecular target screening. Substantial evidence indicates that the histological subtypes of iCCA are significantly associated with the detection frequency of molecular targets relevant to the targeted therapy and immunotherapy. Through rational immunohistochemistry profiling, patients with iCCA can be precisely diagnosed and individually managed. Methods:A thorough literature search was conducted using terms pertinent to the pathological diagnosis, histological subtyping, targeted therapy, and immunotherapy of iCCA. The content related to immunohistochemistry was summarized. Results:In the first part, we summarize the immunohistochemical markers for the histological subtype of iCCA (e.g., large duct type iCCA, small duct type iCCA), with a particular emphasis on their percentage of positive cases, expression location, and association with prognosis. Subsequently, a summary of the immunohistochemical markers for targeted therapy and immunotherapy of iCCA is performed, focusing on the consistency between immunohistochemistry and molecular detection, optimal clone, and prognostic significance. Conclusions:This review summarizes the critical role of immunohistochemistry in the pathological diagnosis of iCCA. It is noted that any diagnosis must be made by integrating comprehensive information. A pathological diagnosis merely based on immunohistochemical results is unreasonable. The development of subtype-specific and drug-targeted antibodies holds promise for refining iCCA precise diagnosis and therapeutic stratification.

Background Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) lacks standardized pathological diagnostic paradigm. The significance of tumor necrosis in cHCC-CCA remains undefined. This study aimed to decipher its role and develop a practical grading system. Methods A multicenter analysis was conducted on 307 cHCC-CCA patients. Tumor necrosis was pathologically graded as: TN1 (no necrosis, N = 35), TN2 (focal necrosis; maximum diameter of a single focus ≤0.55 cm/one low-power field, N = 129), and TN3 (extensive necrosis; >0.55 cm, N = 143). Associations between tumor necrosis and clinicopathological features, recurrence-free survival (RFS), overall survival (OS), early RFS (≤2 years), and late RFS (>2 years) were assessed. The impact of postoperative adjuvant transarterial chemoembolization (PA-TACE) was also evaluated. Results Higher necrosis grades (TN2/TN3) were significantly associated with aggressive tumor characteristics, including larger tumor size, vascular invasion, and lymph node metastasis. TN3 patients had the worst median RFS (0.28 years) and OS (1.36 years), compared to TN2 (RFS: 0.68 years; OS: 2.64 years) and TN1 (RFS: 1.46 years; OS: not reached). The grading system was an independent prognostic factor for RFS, OS, and early RFS in multivariate analysis. PA-TACE significantly improved early RFS in the TN2/TN3 groups and RFS in the TN3 group specifically, but not in the TN1 group. Conclusions Tumor necrosis in cHCC-CCA indicates aggressive tumor biology and poorer outcomes. The proposed three-tier grading system provides robust prognostic stratification. PA-TACE benefits patients with significant necrosis (TN2/TN3), particularly in preventing early recurrence. Standardized assessment of tumor necrosis is recommended to optimize risk stratification and guide adjuvant therapy decisions for cHCC-CCA patients.

Metabolites play a critical role in regulating cell signaling by interacting with proteins either noncovalently or covalently,with spontaneous modifications being less understood.In a recent Cell Research study,Zhao et al.report that the accumulation of S-D-lactoylglutathione upon NF-κB activation induces spontaneous lysine o-lactylation,a process essential for maintaining immune homeostasis and appropriate host defense.

The tumor microenvironment (TME) is a complex and dynamic ecosystem crucial for cancer development and progression. Within this intricate milieu, T-cells constitute a heterogeneous population and serve as a cornerstone of antitumor immunity. Notably, T-cells can rapidly transition across a wide spectrum of phenotypic and functional states within the disrupted TME. Despite the crucial role of T-cells in cancer immunity, a comprehensive understanding of their plasticity within the TME remains limited. In this review, we delve into the functional plasticity and spatial distribution of T-cells in response to diverse microenvironmental conditions. Additionally, we review the plasticity of T-cell functional states during conventional therapies, highlighting their potential to enhance or limit therapeutic outcomes. Finally, we propose innovative therapeutic approaches that leverage T-cell plasticity to enhance clinical efficacy by regulating the immune response within the TME. By providing insights into the dynamics of T-cell behavior, this review highlights the promising potential of targeting T-cell plasticity as an immuno-sensitizer to refine therapeutic strategies and overcome current challenges in cancer treatment.

Purpose:Tertiary lymphoid structure (TLS) has been well-established across multiple tumor types for predicting efficacy of immunotherapy and prognostic evaluation. However, its role in combined hepatocellular-cholangiocarcinoma (cHCC-CCA) remains unclear. Refinement of TLS pathological assessment could potentially optimize postoperative management in these patients. This study aimed to develop a practical histopathological grading system of intratumoral TLS to improve prognostic stratification of cHCC-CCA patients. Patients and Methods:A cohort of 310 cHCC-CCA patients undergoing hepatectomy with curative intent was analyzed. Three pathologists re-evaluated pathological slides to establish a four-tier TLS grading system: TLS 0 (absent), TLS 1 (immature TLS only), TLS 2a [single mature TLS (mTLS)], and TLS 2b (multiple mTLS). Associations with recurrence-free survival (RFS), overall survival (OS), early RFS (≤1 year), late RFS (>1 year), and recurrence patterns were assessed. Predictive factors for TLS were also investigated. Results:Patients were stratified into TLS 0 (29.4%), TLS 1 (51.6%), TLS 2a (6.8%), and TLS 2b (12.3%). Survival outcomes significantly correlated with TLS presence and maturation. Median RFS increased stepwise: 0.24 years (TLS 0), 0.49 years (TLS 1), 1.13 years (TLS 2a), and 1.16 years (TLS 2b) (P<0.001). Median OS also improved progressively: 1.32 years (TLS 0), 2.20 years (TLS 1), 3.24 years (TLS 2a), and 10.04 years (TLS 2b) (P<0.001). TLS presence was associated with increased extrahepatic recurrence. The TLS grading system emerged as an independent prognostic factor for RFS, OS, and early RFS. Smaller tumor diameter was the sole significant predictive factor for both TLS and mTLS. Conclusion:This novel TLS grading system effectively stratifies prognosis in cHCC-CCA, with increasing intratumoral mTLS indicating better outcomes. This practical method can be integrated into routine pathological reporting to aid clinical decision-making.

Objective:Recurrence continues to be a pivotal challenge among hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers. In the international consensus guidelines, HR+/HER2- breast cancer relapse patterns are divided into three distinct types: primary resistant, secondary resistant, and endocrine sensitive. However, owing to the lack of cohorts with treatment and follow-up data, the heterogeneity among different recurrence patterns remains uncharted. Current treatments still lack precision. Methods:This analysis included data from a large-scale multiomics study of a HR+/HER2- breast cancer cohort (n=314). Through the analysis of transcriptomics (n=312), proteomics (n=124), whole-exome sequencing (n=290), metabolomics (n=217), and digital pathology (n=228) data, we explored distinctive molecular features and identified putative therapeutic targets for patients experiencing recurrence. Results:We explored distinct clinicopathological characteristics, biological heterogeneity, and potential therapeutic strategies for recurrence. Based on a shared relapse signature, we stratified patients into high- and low-recurrence-risk groups. Patients with different relapse patterns presented unique molecular features in primary tumors. Specifically, receptor tyrosine kinase (RTK) pathway activation in the primary resistant group suggested the utility of RTK inhibitors, whereas mammalian target of rapamycin (mTOR) and cell cycle pathway activation in the secondary resistant group highlighted the potential of mTOR and CDK4/6 inhibitors. Interestingly, the endocrine-sensitive group displayed a quiescent state and high genomic instability, suggesting that targeting quiescent cells and using poly-ADP-ribose polymerase (PARP) inhibitors could be effective strategies. Conclusions:These findings illuminate the clinicopathological and molecular landscape of HR+/HER2- breast cancer patients with distinct recurrence patterns, highlighting potential targeted therapies.

Cell proliferation requires anabolic supports. How the cell cycle integrates anabolism remains poorly understood. Herein, it is identified that G1-phase regulator cell division cycle 20-like protein 1 (CDH1) coordinates anabolic events to ensure cell cycle initiation. CDH1 degrades Von Hippel-Lindau (VHL), concomitantly activates hypoxia-inducible factor 1α (HIF1α), which enhances angiogenesis and glucose metabolism, and activates mitochondrial lactyltransferase alanyl tRNA synthetase (AARS2), which lactylates and inactivates pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), thereby conserving anabolites. Among the CDH1-accumulated anabolites, ribose-5-phosphate (R5P) binds to transketolase-like-1 (TKTL1) to bridge CDH1 to cyclin-dependent kinase 2 (CDK2) and Skp1-Cullin-F-box and β-transducin repeat-containing protein (SCFβ -TRCP) complex, thereby facilitating CDH1 phosphorylation and degradation to promote cell cycle initiation. This CDH1-VHL-HIF1α/AARS2-R5P/TKTL1 circuit is supported by the observation that low R5P levels and high CDH1 expression correlate with proliferating cancer cells and tissues. Moreover, it is demonstrated that an artificial R5P signal, generated by ribose-5-sulfate (R5S), sensitizes cancer cells to apoptosis by initiating the cell cycle in the absence of sufficient anabolite supply. These suggest that cancer signatures, including the Warburg effect and angiogenesis, are intrinsically driven by CDH1.

BACKGROUND AND AIMS:Liver fibrosis, a progressive condition driven by chronic liver injury and excessive scar tissue formation, can lead to cirrhosis, a life-threatening disease. Activation of hepatic stellate cells (HSCs) is central to fibrosis progression, yet current therapies fail to halt or reverse this process. This study evaluated a combination therapy targeting HSCs to ameliorate fibrosis and promote liver repair. METHODS:A small molecule cocktail, SBCH (SB431542, a TGF-β inhibitor, and CHIR99021, a GSK-3 inhibitor), was tested in three fibrosis models: CCl4-induced, bile duct ligation (BDL) and non-alcoholic steatohepatitis (NASH) with diethylnitrosamine (DEN). Therapeutic effects were assessed using phenotypic analyses, in vivo tracing and single-cell RNA sequencing to uncover mechanisms. RESULTS:SBCH significantly reduced fibrosis in all models by inhibiting HSC activation and fibrogenic activity. The suppression of PI3K/Akt pathway and EMT cascade contribute to the fibrosis-ameliorating effect of SBCH treatment. Furthermore, in vivo tracing and single-cell RNA sequencing revealed that SBCH induced the conversion of activated HSCs into hepatocyte-like cells (ciHeps), which integrated into liver tissue, repaired liver damage and restored liver integrity and function. CONCLUSIONS:SBCH mitigates liver fibrosis through multifaceted mechanisms, including the inhibition of HSC activation, suppression of fibrogenic activity and regulation of key signalling pathways such as PI3K/Akt and EMT. In addition, SBCH induces the trans-differentiation of activated HSCs into hepatocyte-like cells (ciHeps), effectively reducing pathogenic HSCs while increasing functional ciHeps. This dual-target approach not only facilitates liver tissue repair but also restores liver function, offering a promising therapeutic strategy for liver fibrosis and cirrhosis, with potential applications in conditions arising from various aetiologies of liver injury.

Background and Objective: Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC.Methods: We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023.Key Content and Findings: Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, Wnt/ beta-catenin, microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI.Conclusions: The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a unique type of liver tumor that contains both hepatocellu-lar carcinoma and cholangiocarcinoma components within a single tumor. The fifth edition of the World Health Organiza-tion classification provides a definition and diagnostic criteria for cHCC-CCA. However, the heterogeneous histomorphology and presentation resulting from variation of the proportion of each component poses challenges for clinical diagnosis and treatment. A diagnosis of cHCC-CCA may be suggested by the synchronous elevation of serum tumor markers for hepa-tocellular carcinoma and cholangiocarcinoma, a mixed en-hancement pattern on imaging, and a discrepancy between the elevation of tumor marker and the imaging enhancement pattern. Histopathological examination using hematoxylin and eosin staining is considered the gold standard for diag-nosing cHCC-CCA, and comprehensive examination of resec-tion or biopsy specimens is crucial for an accurate diagnosis. Currently, there is no standard treatment for cHCC-CCA, and surgery is the mainstay. Anatomic hepatectomy with lym-phadenectomy is among the recommended surgical proce-dures. The role of liver transplantation in the management of cHCC-CCA is still uncertain. Transarterial chemoembolization may be effective for unresectable cHCC-CCA, particularly for hypervascular tumors. However, the available evidence does not support systemic therapy for advanced cHCC-CCA. The prognosis of cHCC-CCA is generally poor, and there is no es-tablished staging system. Further research is needed to bet -ter understand the histogenesis and clinical management of cHCC-CCA. This review provides an overview of the current literature on cHCC-CCA with a focus on its clinical character-istics, pathological diagnosis, and management.

Background:Microvascular invasion (MVI) is closely correlated with poor clinical outcomes in patients with hepatocellular carcinoma (HCC). A grading system of MVI is needed to assist in the management of HCC patient. Methods:Multicenter data of HCC patients who underwent liver resection with curative intent was analyzed. This grading system was established by detected number and distance from tumor boundary of MVI. Survival outcomes were compared among patients in each group. This system was verified by time-receiver operating characteristic curve, time-area under the curve, calibration curve, and decision curve analyses. Cox regression analysis was performed to study the associated factors of prognosis. Logistic analysis was used to study the predictive factors of MVI. Results:All patients were classified into 4 groups: M0: no MVI; M1: 1~5 proximal MVIs (≤1 cm from tumor boundary); M2a: >5 proximal MVIs (≤1 cm from tumor boundary); M2b: ≥1 distal MVIs (>1 cm from tumor boundary). The recurrence-free survival (RFS), overall survival (OS), and early RFS rates among all the individual groups were significantly different. Based on the number of proximal MVI (0~5 vs >5), patients in the M2b group were further divided into two subgroups which also showed different prognosis. Multiple methods showed this grading system to be significantly better than the MVI two-tiered system in prognostic evaluation. Four multivariate models for RFS, OS, early RFS, late RFS, and a predictive model of MVI were then established and were shown to satisfactorily evaluate prognosis and have a great discriminatory power, respectively. Conclusion:This MVI grading system could precisely evaluate prognosis of HCC patients after liver resection with curative intent and it could be employed in routine pathological reports. The severity of MVI from both adjacent and distant from tumor boundary should be stated. A hypothesis about two occurrence modes of distal MVI was proposed.