Single-cell transcriptomics uncovers cellular architecture and developmental trajectories in hepatoblastoma.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the predominant type of childhood liver cancer. Treatment options for the clinically advanced HB remain limited. We aimed to dissect the cellular and molecular basis underlying HB oncogenesis and heterogeneity at the single-cell level, which could facilitate a better understanding of HB at both the biological and clinical levels. APPROACH AND RESULTS: Single-cell transcriptome profiling of tumor and paired distal liver tissue samples from five patients with HB was performed. Deconvolution analysis was used for integrating the single-cell transcriptomic profiles with the bulk transcriptomes of our HB cohort of post-neoadjuvant chemotherapy tumor samples. A single-cell transcriptomic landscape of early human liver parenchymal development was established for exploring the cellular root and hierarchy of HB oncogenesis. As a result, seven distinct tumor cell subpopulations were annotated, and an effective HB subtyping method was established based on their compositions. A HB tumor cell hierarchy was further revealed to not only fit with the classical cancer stem cell (CSC) model but also mirror the early human liver parenchymal development. Moreover, FACT inhibition, which could disrupt the oncogenic positive feedback loop between MYC and SSRP1 in HB, was identified as a promising epigenetic-targeted therapeutic strategy against the CSC-like HB1-Pro-like1 subpopulation and its related high-risk "Pro-like1" subtype of HB. CONCLUSIONS: Our findings illustrate the cellular architecture and developmental trajectories of HB via integrative bulk and single-cell transcriptome analyses, thus establishing a resourceful framework for the development of targeted diagnostics and therapeutics in the future.

Macrophage Notch1 inhibits TAK1 function and RIPK3-mediated hepatocyte necroptosis through activation of ß-catenin signaling in liver ischemia and reperfusion injury.

BACKGROUND: Notch signaling is highly conserved and critically involved in cell differentiation, immunity, and survival. Activation of the Notch pathway modulates immune cell functions during the inflammatory response. However, it remains unknown whether and how the macrophage Notch1 may control the innate immune signaling TAK1, and RIPK3-mediated hepatocyte necroptosis in liver ischemia and reperfusion injury (IRI). This study investigated the molecular mechanisms of macrophage Notch1 in modulating TAK1-mediated innate immune responses and RIPK3 functions in liver IRI. METHODS: Myeloid-specific Notch1 knockout (Notch1M-KO) and floxed Notch1 (Notch1FL/FL) mice (n = 6/group) were subjected to 90 min partial liver warm ischemia followed by 6 h of reperfusion. In a parallel in vitro study, bone marrow-derived macrophages (BMMs) were isolated from these conditional knockout mice and transfected with CRISPR/Cas9-mediated ß-catenin knockout (KO) vector followed by LPS (100 ng/ml) stimulation. RESULTS: IR stress-induced Notch1 activation evidenced by increased nuclear Notch intracellular domain (NICD) expression in liver macrophages. Myeloid Notch1 deficiency exacerbated IR-induced liver damage, with increased serum ALT levels, macrophage/neutrophil accumulation, and proinflammatory cytokines/chemokines production compared to the Notch1FL/FL controls. Unlike in the Notch1FL/FL controls, Notch1M-KO enhanced TRAF6, TAK1, NF-κB, RIPK3, and MLKL but reduced ß-catenin activation in ischemic livers. However, adoptive transfer of lentivirus ß-catenin-modified macrophages markedly improved liver function with reduced TRAF6, p-TAK1, RIPK3 and p-MLKL in IR-challenged livers. Moreover, disruption of RIPK3 in Notch1M-KO mice with an in vivo mannose-mediated RIPK3 siRNA delivery system diminished IR-triggered hepatocyte death. In vitro studies showed that macrophage NICD and ß-catenin co-localized in the nucleus, whereby ß-catenin interacted with NICD in response to LPS stimulation. Disruption of ß-catenin with a CRISPR/Cas9-mediated ß-catenin KO in Notch1FL/FL macrophage augmented TRAF6 activation leading to enhanced TAK1 function. While CRISPR/Cas9-mediated TRAF6 KO in Notch1M-KO macrophage inhibited RIPK3-mediated hepatocyte necroptosis after co-culture with primary hepatocytes. CONCLUSIONS: Macrophage Notch1 controls TAK1-mediated innate immune responses and RIPK3-mediated hepatocyte necroptosis through activation of ß-catenin. ß-catenin is required for the macrophage Notch1-mediated immune regulation in liver IRI. Our findings demonstrate that the macrophage Notch1-ß-catenin axis is a crucial regulatory mechanism in IR-triggered liver inflammation and provide novel therapeutic potential in organ IRI and transplant recipients. Video abstract.

Macrophage Polarization and Liver Ischemia-Reperfusion Injury.

Ischemia-reperfusion injury refers to organ damage caused by the previous insufficient supply of oxygen and nutrients and the involvement of metabolic by-products after blood flow is restored. Liver ischemia-reperfusion injury (IRI) has become a hot research in recent years, because it occurs in many clinical scenarios. After the introduction of liver transplantation and vascular control techniques in liver surgery, liver ischemia-reperfusion injury is considered to be an important factor affecting postoperative mortality and morbidity. As the largest immune organ in the human body, liver contain a lot of immune cells such as resident macrophages (Kupffer cells), dendritic cells, natural killer cells, and natural killer T cells which play a key role in ischemia-reperfusion injury. Among those, macrophage-mediated excessive inflammatory response is considered to be an important factor in liver ischemia-reperfusion injury. The prominent feature of liver injury is an increase in the number of macrophages in liver due to the infiltration of blood monocytes and differentiation into monocyte-derived macrophages. Liver macrophages can be divided into M1 macrophages which can promote inflammation progress and M2 macrophages that inhibit inflammation progress according to their different phenotypes and functions. Both of them can regulate liver aseptic inflammation, and play an important role in triggering, maintaining, and improving liver ischemia-reperfusion injury. This review summarizes studies of macrophage polarization on liver ischemia-reperfusion injury in recent years, to provide potential ideas for translation application in future clinical management.

Tumor-associated lymphangiogenesis predicts unfavorable prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Tumor-associated lymphangiogenesis is considered significant in number of solid malignancies. However, its impact on prognosis of intrahepatic cholangiocarcinoma (ICC) after resection remains further confirmation. Herein, we conducted this study to evaluate prognostic impact of tumor-associated lymphangiogenesis in patients with ICC. METHODS: Extent of tumor-associated lymphangiogenesis of ICC was evaluated by quantifying microlymphatic vessel density (MLVD) from immunohistochemical staining of a lymphatic endothelial-specific antibody (podoplanin). Clinicopathological characteristics were comprehensively analyzed to identify MLVD-associated factors. The patients were stratified into high and low MLVD groups according to the distinctive correlation between the MLVD and overall survival using the Spearman's correlation test. Kaplan-Meier estimation was performed to confirm prognostic impact of MLVD in patients with ICC. Univariate and multivariate analyses were performed using the Cox proportional hazard model. RESULTS: The MLVD between 4 to 12 counts showed inverse proportion to the overall survival (Spearman's r = - 0.66; 95% confidence interval [CI], - 0.82 to - 0.39; p <  0.0001), which was set as a cut-off for the high MLVD group, whereas the MLVD between 13 to 25 showed no correlation to the overall survival (r = - 0.11; 95% CI, - 0.38 to 0.19; p = 0.4791). The high MLVD group showed more frequent lymph node metastasis (p <  0.001) and were more likely to suffer from recurrence of the tumor compared to the low MLVD group (p <  0.001). The high MLVD was found to be independently associated with reduced overall and recurrence-free survival. The 5-year overall survival of the patients with high MLVD was significantly lower compared to those with low MLVD (0% vs 48%). CONCLUSIONS: Our study reveals that tumor-associated lymphangiogenesis is significantly associated with increased lymphatic metastasis, recurrence of the tumor, and reduced overall survival in patients with ICC, thus providing guidance when estimating postresection prognosis.

Expression of IL-26 predicts prognosis of patients with hepatocellular carcinoma after surgical resection.

BACKGROUND: There is no data regarding prognostic impact of interleukin (IL)-26 on outcomes of patients with hepatocellular carcinoma (HCC). The present study aimed to evaluate the prognostic impact of IL-26 on HCC patients undergoing liver resection. METHODS: From 2003 to 2008, 122 patients with HCC who received surgical curative resection were enrolled. Patients were stratified into IL-26-upper and -lower groups according to the median expression level from immunohistochemical staining of resected specimens. Prognostic impact of IL-26 was estimated using Kaplan-Meier curves. Univariate and multivariate analyses were performed to evaluate time-dependent prognostic impact and independency of IL-26. Demographic and clinical factors that were associated with IL-26 were comprehensively identified. RESULTS: Prognosis of the patients with high level of IL-26 revealed to be significantly unfavorable in both cumulative recurrence-free survival (P < 0.001) and overall survival (P = 0.002). Upper expression of IL-26 (HR: 1.643; 95% CI: 1.021 to 2.644; P = 0.041) and microvascular invasion (HR: 3.303; 95% CI: 1.255 to 8.696; P = 0.016) were identified as significant independent prognostic factors for overall survival in the multivariable analysis. CONCLUSIONS: IL-26 is a novel prognostic factor for HCC after resection. Evaluation of IL-26 expression may be potentially valuable in clinical therapy when planning individualized follow-up schedule and evaluating candidates for prophylactic adjuvant treatment to prevent recurrence.

Clinical analysis of liver transplantation in autoimmune liver diseases.

BACKGROUND: Autoimmune liver diseases (ALDs) consist of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), IgG4-associated cholangitis and overlap syndromes. Patients with these diseases may gradually progress to end-stage liver diseases and need liver transplantation. The present study aimed to explore the prognosis of patients with ALDs after liver transplantation. METHODS: The clinical data of 80 patients with ALD (24 cases of AIH, 35 of PBC, 15 of PSC and 6 of AIH-PBC overlap syndromes) who underwent liver transplantation in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2004 to September 2016 were collected retrospectively. The causes of death were analyzed and the postoperative cumulative survival rate was estimated by the Kaplan-Meier method. Recurrence and other complications were also analyzed. RESULTS: Of the 80 patients, 18 were males and 62 were females. The average age was 50.5 years and the average Model for End-stage Liver Disease (MELD) score was 14.1. After a median follow-up of 19.8 months, 8 patients died. The 1-, 3- and 5-year cumulative survival rates were all 89.0%. Three cases of recurrent ALDs were diagnosed (3.8%) but they were not totally consistent with primary diseases. Biliary tract complication occurred in 10 patients (12.5%). The new onset of tumor was observed in 1 patient (1.3%). De novo HBV/CMV/EBV infection was found in 3, 8 and 3 patients, respectively. CONCLUSION: Liver transplantation is an effective and safe treatment for end-stage ALD.

Risk stratification system to predict recurrence of intrahepatic cholangiocarcinoma after hepatic resection.

BACKGROUND: Previous nomograms for intrahepatic cholangiocarcinoma (ICC) were conducted to predict overall survival, which could be influenced by various factors. Herein, we conducted our nomogram to predict recurrence of the tumor only after hepatic resection. METHODS: The nomogram was established with prognostic factors for the relapse-free survival (RFS) analyzed from our single center cohort and was evaluated by comparing with the American Joint Committee on Cancer (AJCC) staging system for the predictive accuracy. RESULTS: Seropositivity of hepatitis B surface antigen (hazard ratio [HR], 0.505; 95% confidence interval [CI], 0.279 to 0.914; P = 0.024), tumor size of larger than 5 cm (HR, 1.947; 95% CI, 1.177 to 3.219; P = 0.009), Child-Pugh score of B (HR, 3.067; 95% CI, 1.293 to 7.275; P = 0.011), and lymph node metastasis (HR, 2.790; 95% CI, 1.628 to 4.781; P < 0.001) were found to be independent prognostic factors that significantly affected RFS. The calibration curve for the prediction revealed excellent agreement between estimation by our stratification system and actual RFS. The concordance C index of the nomogram (0.71; 95% CI, 0.65 to 0.77) revealed to be significantly higher than the AJCC staging system (0.66; 95% CI, 0.60 to 0.72). In the validation cohort, our risk stratification system (C-index 0.65; 95% CI, 0.59 to 0.71) also revealed more precise prediction than the AJCC staging system (C-index, 0.57; 95% CI, 0.50 to 0.64). CONCLUSIONS: Our nomogram could more accurately predict recurrence of ICC after hepatic resection than the AJCC staging system.

Hypoxia-inducible factor-2α promotes hepatocyte apoptosis during cholestasis.

AIM: Hypoxia-inducible factor-2α (HIF-2α) has been reported to play an important role in a host of pathophysiological processes, including cellular survival. This study explores the role of HIF-2α in cholestasis-mediated hepatocyte apoptosis. METHODS: Hypoxia-inducible factor-2α expression was measured by immunohistochemistry and confocal microscopy. Hepatic apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling. The cholestatic mouse model was treated with bile duct ligation. The c-myc, p53, and Bax protein levels were measured with Western blot analysis. RESULTS: In pediatric and murine cholestatic liver tissues, HIF-2α protein was widely expressed in the nucleus of parenchymal cells as well as in stromal cells. Hepatocyte HIF-2α expression was significantly elevated at the early stage of pediatric cholestasis and decreased at the late stage. In both in vivo and in vitro murine studies, HIF-2α deletion could alleviate cholestasis-mediated hepatocyte apoptosis and regulate the expression of c-myc, p53, and Bax proteins. CONCLUSION: These findings implied the contribution of HIF-2α to cholestasis-mediated hepatocyte apoptosis.

Expression of fibroblast growth factor 21 in patients with biliary atresia.

Fibroblast growth factor 21 is a critical circulating adipokine involving in metabolic disorders and various liver diseases. This study was performed to investigate whether FGF21 is also associated with the pathophysiology of biliary atresia. Serum FGF21 levels were measured in 57 BA patients and 20 age matched healthy controls. We also examined hepatic FGF21 mRNA expression and FGF21 protein levels in liver tissues obtained from 15 BA patients undergoing liver transplantation and 5 cases of pediatric donation after cardiac death donor without liver diseases by RT-PCR and Western blotting. Patients with BA showed significantly higher serum FGF21 levels than those without BA (554.7pg/mL [83-2300] vs. 124.5pg/mL [66-270], P<0.05). Patients with BA also had significantly higher FGF21 mRNA and protein levels in hepatic tissues than control subjects. Serum FGF21 expression increased corresponding to the severity of liver fibrosis. Furthermore, serum FGF21 levels dropped significantly in BA patients within 6months after liver transplantation and approached baseline in healthy controls (P>0.05). In vivo, FXR knockout could significantly abrogate cholestasis induced FGF21 expression. FGF21 levels in serum and liver tissue increased significantly in BA patients. In vivo, cholestasis could induce FGF21 expression in FXR dependent manner.

Health-related quality of life and sleep among Chinese children after living donor liver transplantation.

LDLT is a well-established treatment for most terminal liver diseases in children. Survival rates have improved, yet few studies have considered HRQoL or sleep problems in LDLT recipients. In this cross-sectional study, we enrolled 51 children who had undergone LDLT in Renji Hospital. PedsQL(™) 4.0 Generic Core Scales, PedsQL(™) 3.0 Transplant Module, and Pediatric Sleep Questionnaire were used to assess outcomes. Of all participants, 11.8% (6/51) reported low total HRQoL scores. Participants' scores on most HRQoL subscales were comparable to the scores of healthy children. However, compared with solid organ transplant recipients, LDLT recipients scored significantly lower in About My Medicines II (t = 3.092, p = 0.002) and Worry (t = 2.760, p = 0.006). Sleep problems (41.2%) were common among participants. Hierarchical regression analyses showed that SRBD accounted for significant variance in HRQoL on total generic HRQoL (R(2) = 0.446, p < 0.001), psychosocial health (R(2) = 0.372, p = 0.001), physical health (R(2) = 0.345, p = 0.003), total transplant-specific HRQoL (R(2) = 0.514, p < 0.001), About My Medicines I (R(2) = 0.365, p = 0.013), My Transplant and Others (R(2) = 0.334, p = 0.005), Pain and Hurt (R(2) = 0.544, p < 0.001), Worry (R(2) = 0.401, p = 0.001), Treatment Anxiety (R(2) = 0.526, p < 0.001), How I Look (R(2) = 0.221, p = 0.040), and Communication (R(2) = 0.343, p = 0.012). In conclusion, sleep problems are non-negligible in children after LDLT and predicted significant variance on HRQoL.

CYP3A5 genotypes affect tacrolimus pharmacokinetics and infectious complications in Chinese pediatric liver transplant patients.

Little information is available regarding the impact of cytochrome P450 (CYP) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty-four patients were divided according to CYP3A5 genotype (expression of *1 allele: EX and NEX) for each recipient (R) and donor (D), EX-R/EX-D (n = 21), EX-R/NEX-D (n = 8), NEX-R/EX-D (n = 8) and NEX-R/NEX-D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX-R/EX-D children compared with those who did not express CYP3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p < 0.01). CYP3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX-R/EX-D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP3A5 expression partially explains TAC dose requirement, the effect of CYP3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under- and over-immunosuppression.

Adenosinergic metabolism pathway: an emerging target for improving outcomes of solid organ transplantation.

Extracellular nucleotides are widely recognized as crucial modulators of immune responses in peripheral tissues. Adenosine triphosphate (ATP) and adenosine are key components of extracellular nucleotides, the balance of which contributes to immune homeostasis. Under tissue injury, ATP exerts its pro-inflammatory function, while the adenosinergic pathway rapidly degrades ATP to immunosuppressive adenosine, thus inhibiting excessive and uncontrolled inflammatory responses. Previous reviews have explored the immunoregulatory role of extracellular adenosine in various pathological conditions, especially inflammation and malignancy. However, current knowledge regarding adenosine and adenosinergic metabolism in the context of solid organ transplantation remains fragmented. In this review, we summarize the latest information on adenosine metabolism and the mechanisms by which it suppresses the effector function of immune cells, as well as highlight the protective role of adenosine in all stages of solid organ transplantation, including reducing ischemia reperfusion injury during organ procurement, alleviating rejection, and promoting graft regeneration after transplantation. Finally, we discuss the potential for future clinical translation of adenosinergic pathway in solid organ transplantation.

Programmable Atom-Like Nanoparticle Reporters for High-Precision Urinalysis of In Situ Membrane Proteins.

The expression of disease-specific membrane proteins (MPs) is a crucial indicator for evaluating the onset and progression of diseases. Urinalysis of in situ MPs has the potential for point-of-care disease diagnostics, yet remains challenging due to the lack of molecular reporter to transform the expression information of in situ MPs into the measurable urine composition. Herein, a series of tetrahedral DNA frameworks (TDFs) are employed as the cores of programmable atom-like nanoparticles (PANs) to direct the self-assembly of PAN reporters with defined ligand valence and spatial distribution. With the rational spatial organization of ligands, the interaction between PAN reporters and MPs exhibits superior stability on cell-membrane interface under renal tubule-mimic fluid microenvironment, thus enabling high-fidelity conversion of MPs expression level into binding events and reverse assessment of in situ MP levels via measurement of the renal clearance efficiency of PAN reporters. Such PAN reporter-mediated signal transformation mechanism empowers urinalysis of the onset of acute kidney injury at least 6 h earlier than the existing methods with an area under the curve of 100%. This strategy has the potential for urinalysis of a variety of in situ membrane proteins.

IMPDH2 suppression impedes cell proliferation by instigating cell cycle arrest and stimulates apoptosis in pediatric hepatoblastoma.

BACKGROUND: Hepatoblastoma (HB) is the most common pediatric liver tumor, presenting significant therapeutic challenges due to its high rates of recurrence and metastasis. While Inosine Monophosphate Dehydrogenase 2(IMPDH2) has been associated with cancer progression, its specific role and clinical implications in HB have not been fully elucidated. METHODS: This study utilized Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and Tissue Microarray (TMA) for validation. Following this, IMPDH2 was suppressed, and a series of in vitro assays were conducted. Flow cytometry was employed to assess apoptosis and cell cycle arrest. Additionally, the study explored the synergistic therapeutic effects of mycophenolate mofetil (MMF) and doxorubicin (DOX) on HB cell lines. RESULTS: The study identified a marked overexpression of IMPDH2 in HB tissues, which was strongly correlated with reduced Overall Survival (OS) and Event-Free Survival (EFS). IMPDH2 upregulation was also found to be associated with key clinical-pathological features, including pre-chemotherapy alpha-fetoprotein (AFP) levels, presence of preoperative metastasis, and the pre-treatment extent of tumor (PRETEXT) staging system. Knockdown of IMPDH2 significantly inhibited HB cell proliferation and tumorigenicity, inducing cell cycle arrest at the G0/G1 phase. Notably, the combination of MMF, identified as a specific IMPDH2 inhibitor, with DOX, substantially enhanced the therapeutic response. CONCLUSION: The overexpression of IMPDH2 was closely linked to adverse outcomes in HB patients and appeared to accelerate cell cycle progression. These findings suggest that IMPDH2 may serve as a valuable prognostic indicator and a potential therapeutic target for HB. IMPACT: The present study unveiled a significant overexpression of inosine monophosphate dehydrogenase 2 (IMPDH2) in hepatoblastoma (HB) tissues, particularly in association with metastasis and recurrence of the disease. The pronounced upregulation of IMPDH2 was found to be intimately correlated with adverse outcomes in HB patients. This overexpression appears to accelerate the progression of the cell cycle, suggesting that IMPDH2 may serve as a promising candidate for both a prognostic marker and a therapeutic target in the context of HB.

Development of a deep learning model for predicting recurrence of hepatocellular carcinoma after liver transplantation.

Background: Liver transplantation (LT) is one of the main curative treatments for hepatocellular carcinoma (HCC). Milan criteria has long been applied to candidate LT patients with HCC. However, the application of Milan criteria failed to precisely predict patients at risk of recurrence. As a result, we aimed to establish and validate a deep learning model comparing with Milan criteria and better guide post-LT treatment. Methods: A total of 356 HCC patients who received LT with complete follow-up data were evaluated. The entire cohort was randomly divided into training set (n = 286) and validation set (n = 70). Multi-layer-perceptron model provided by pycox library was first used to construct the recurrence prediction model. Then tabular neural network (TabNet) that combines elements of deep learning and tabular data processing techniques was utilized to compare with Milan criteria and verify the performance of the model we proposed. Results: Patients with larger tumor size over 7 cm, poorer differentiation of tumor grade and multiple tumor numbers were first classified as high risk of recurrence. We trained a classification model with TabNet and our proposed model performed better than the Milan criteria in terms of accuracy (0.95 vs. 0.86, p < 0.05). In addition, our model showed better performance results with improved AUC, NRI and hazard ratio, proving the robustness of the model. Conclusion: A prognostic model had been proposed based on the use of TabNet on various parameters from HCC patients. The model performed well in post-LT recurrence prediction and the identification of high-risk subgroups.

Criteria and prognostic models for patients with hepatocellular carcinoma undergoing liver transplantation.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated death globally. Liver transplantation (LT) has emerged as a key treatment for patients with HCC, and the Milan criteria have been adopted as the cornerstone of the selection policy. To allow more patients to benefit from LT, a number of expanded criteria have been proposed, many of which use radiologic morphological characteristics with larger and more tumors as surrogates to predict outcomes. Other groups developed indices incorporating biological variables and dynamic markers of response to locoregional treatment. These expanded selection criteria achieved satisfactory results with limited liver supplies. In addition, a number of prognostic models have been developed using clinicopathological characteristics, imaging radiomics features, genetic data, and advanced techniques such as artificial intelligence. These models could improve prognostic estimation, establish surveillance strategies, and bolster long-term outcomes in patients with HCC. In this study, we reviewed the latest findings and achievements regarding the selection criteria and post-transplant prognostic models for LT in patients with HCC.

Increased Platelet Aggregation in Adults After Orthotopic Liver Transplantation Indicates Higher Probability of Early Postoperative Survival.

BACKGROUND Studies have shown that increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death, but studies on the association between platelet aggregation function and early postoperative survival in orthotopic liver transplantation (OLT) patients are rare. We conducted a retrospective study to investigate whole-blood platelet aggregation during the perioperative period of OLT patients and its association with clinical outcomes. MATERIAL AND METHODS Adult patients who underwent OLT between January 1 and April 30, 2021 were retrospectively reviewed. Laboratory test results indicating primary hemostasis were analyzed. The generalized linear model was used to investigate the association between primary hemostasis parameters and survival. RESULTS A total of 256 patients were enrolled. The median platelet count (PLT) was 61.5 (39.5-106.3)×109/L before transplantation. The median MA value was 43.1 (34.5-56.2) mm. From the 1st to the 3rd day after transplantation, PLT and MA both indicated a significant decrease. Two weeks after transplantation, PLT rose to 143.0 (85.0-209.0)×109/L, and the MA value rose to 56.7 (52.2-62.7) mm. On multivariate analysis, PLT at 1 week after transplantation (OR: 1.07; P=0.006) and MA value (OR: 1.12; P=0.003) were independently associated with outcome. The AUROC of the model combined with MA value, MELD score, and age was 0.945 (95% CI: 0.911-0.978). CONCLUSIONS The change in primary hemostasis during the early postoperative period of adult OLT is mainly characterized by the increase of platelet count and function 14 days after transplantation. Higher PLT was associated with higher survival at 14 days after transplantation, while a higher PLT ratio was associated with survival at 3 months after transplantation. Based on comprehensive consideration, the model combined with MA value, MELD score, and age more reliably indicated the associated with early survival after transplantation.

Patient-derived models facilitate precision medicine in liver cancer by remodeling cell-matrix interaction.

Liver cancer is an aggressive tumor originating in the liver with a dismal prognosis. Current evidence suggests that liver cancer is the fifth most prevalent cancer worldwide and the second most deadly type of malignancy. Tumor heterogeneity accounts for the differences in drug responses among patients, emphasizing the importance of precision medicine. Patient-derived models of cancer are widely used preclinical models to study precision medicine since they preserve tumor heterogeneity ex vivo in the study of many cancers. Patient-derived models preserving cell-cell and cell-matrix interactions better recapitulate in vivo conditions, including patient-derived xenografts (PDXs), induced pluripotent stem cells (iPSCs), precision-cut liver slices (PCLSs), patient-derived organoids (PDOs), and patient-derived tumor spheroids (PDTSs). In this review, we provide a comprehensive overview of the different modalities used to establish preclinical models for precision medicine in liver cancer.