The P53-P21-RB1 pathway promotes BRD4 degradation in liver cancer through USP1.

Liver cancer is notoriously refractory to conventional therapeutics. Tumor progression is governed by the interplay between tumor-promoting genes and tumor-suppressor genes. BRD4, an acetyl lysine-binding protein, is overexpressed in many cancer types, which promotes activation of a pro-tumor gene network. But the underlying mechanism for BRD4 overexpression remains incompletely understood. In addition, understanding the regulatory mechanism of BRD4 protein level will shed insight into BRD4-targeting therapeutics. In this study, we investigated the potential relation between BRD4 protein level and P53, the most frequently dysregulated tumor suppressor. By analyzing the TCGA datasets, we first identify a strong negative correlation between protein levels of P53 and BRD4 in liver cancer. Further investigation shows that P53 promotes BRD4 protein degradation. Mechanistically, P53 indirectly represses the transcription of USP1, a deubiquitinase, through the P21-RB1 axis. USP1 itself is also overexpressed in liver cancer and we show USP1 deubiquitinates BRD4 in vivo and in vitro, which increases BRD4 stability. With cell proliferation assays and xenograft model, we show the pro-tumor role of USP1 is partially mediated by BRD4. With functional transcriptomic analysis, we find the USP1-BRD4 axis upholds expression of a group of cancer-related genes. In summary, we identify a functional P53-P21-RB1-USP1-BRD4 axis in liver cancer.

Portal vein velocity predicts portal vein system thrombosis after splenectomy with esophagogastric devascularization.

BACKGROUND: Portal vein system thrombosis (PVST) is a potentially fatal complication after splenectomy with esophagogastric devascularization (SED) in cirrhotic patients with portal hypertension. However, the impact of portal vein velocity (PVV) on PVST after SED remains unclear. Therefore, this study aims to explore this issue. METHODS: Consecutive cirrhotic patients with portal hypertension who underwent SED at Tongji Hospital between January 2010 and June 2022 were enrolled. The patients were divided into two groups based on the presence or absence of PVST, which was assessed using ultrasound or computed tomography after the operation. PVV was measured by duplex Doppler ultrasound within one week before surgery. The independent risk factors for PVST were analyzed using univariate and multivariate logistic regression analysis. A nomogram based on these variables was developed and internally validated using 1000 bootstrap resamples. RESULTS: A total of 562 cirrhotic patients with portal hypertension who underwent SED were included, and PVST occurred in 185 patients (32.9%). Multivariate logistic regression analysis showed that PVV was the strongest independent risk factor for PVST. The incidence of PVST was significantly higher in patients with PVV ≤ 16.5 cm/s than in those with PVV > 16.5 cm/s (76.2% vs. 8.5%, p < 0.0001). The PVV-based nomogram was internally validated and showed good performance (optimism-corrected c-statistic = 0.907). Decision curve and clinical impact curve analyses indicated that the nomogram provided a high clinical benefit. CONCLUSION: A nomogram based on PVV provided an excellent preoperative prediction of PVST after splenectomy with esophagogastric devascularization.

EGR1 knockdown confers protection against ferroptosis and ameliorates intervertebral disc cartilage degeneration by inactivating the MAP3K14/NF-κB axis.

This study explored whether EGR1-MAP3K14-NF-κB axis regulated ferroptosis and IVD cartilage generation. EGR1 and MAP3K14 expression levels were determined in CEP tissues of IVDD patients and intermittent cyclic mechanical tension (ICMT)-treated CEP cells. After EGR1 and MAP3K14 were altered in ICMT-treated CEP cells, the expression levels of degeneration- and ferroptosis-related proteins were measured. Binding relationship between EGR1 and MAP3K14 was evaluated. Additionally, the impacts of EFR1 knockdown on ferroptosis and cartilage degeneration in vivo were analyzed. EGR1 and MAP3K14 were overexpressed in clinical samples and cell models of IVDD. In IVDD cell models, EGR1 knockdown reduced ferroptosis and cartilage degeneration, which was reversed by MAP3K14 overexpression or Erastin treatment. NF-κB pathway inhibition nullified these effects of sh-EGR1 + oe-MAP3K14 treatment. EGR1 knockdown inhibited ferroptosis and relieved CEP degeneration via MAP3K14-NF-κB axis inactivation in vivo. Collectively, our findings highlighted that EGR1 promoted ferroptosis and IVD cartilage degeneration through MAP3K14-NF-κB axis.

Anatomical sectionectomy based on Takasaki's segmentation for solitary intrahepatic cholangiocarcinoma: a propensity-matched analysis.

BACKGROUND: Anatomical sectionectomy based on Takasaki's segmentation has shown advantages in hepatocellular carcinoma. However, whether this approach improves the survival of intrahepatic cholangiocarcinoma (ICC) remains unknown. METHODS: A series of 248 consecutive patients with solitary ICCs who underwent hepatectomy were studied retrospectively. The patients were classified into the groups of anatomical sectionectomy based on Takasaki's segmentation (TS group) and non-Takasaki's hepatectomy (NTH group). The bias between the two groups was minimized using propensity score matching (PSM). Recurrence-free survival (RFS) and overall survival (OS) were evaluated with Kaplan-Meier analysis. The Cox proportional hazards model was performed to determine the adverse risk factors associated with survival. RESULTS: After PSM, 67 pairs of patients were compared. Both the RFS and OS rates in the TS group were significantly better than those in the NTH group (23.2 % vs. 16.5 %, and 40.4 % vs. 27.3 %, P = 0.035 and 0.032, respectively). Multivariate analysis showed that NTH was independently associated with worse RFS and OS than TS. The stratified analysis demonstrated that the RFS and OS rates in the TS group with tumor stage I and tumor size ≥3 cm were significantly better than those in the NTH group, while the survival rates for ICC with stage I and tumor size <3 cm or stage II-III showed no significant difference. CONCLUSION: TS was associated with improved RFS and OS in patients with solitary ICC even after PSM. TS may be preferred particularly in patients with tumor stage I and tumor size ≥3 cm.

Lysine demethylase KDM1A promotes cell growth via FKBP8-BCL2 axis in hepatocellular carcinoma.

Advanced hepatocellular carcinoma (HCC) has a dismal prognosis. KDM1A (lysine demethylase 1A), overexpressed in multiple cancer types, is a lysine demethylase that targets both histone and nonhistone proteins. However, it is unclear how KDM1A expression affects HCC etiology. Here, we show that KDM1A can interact with and demethylate FKBP8 (FKBP prolyl isomerase 8), a cytoplasmic protein that regulates cell survival through the antiapoptotic protein BCL2 (B-cell lymphoma-2). We show that demethylation of FKBP8 enhances its ability to stabilize BCL2. Consistently, we observed positive correlation between KDM1A and BCL2 protein levels in liver cancer patients. Functionally, we reveal that FKBP8 demethylation by KDM1A is critical for liver cancer cell growth in vitro and in vivo. We went on to explore the mechanisms that might regulate KDM1A cytoplasmic localization. We found that the cytoplasmic localization and protein stability of KDM1A were promoted by acetylation at lysine-117 by the acetyl transferase KAT8 (lysine acetyltransferase 8). In agreement with this, we show that KDM1A-K117 (lysine 117) acetylation promotes demethylation of FKBP8 and level of BCL2. Finally, it has been shown that the efficacy of sorafenib, a first-line treatment for advanced HCC, is limited by clinical resistance. We show that KDM1A and BCL2 protein levels are increased during acquired sorafenib resistance, whereas inhibiting KDM1A can antagonize sorafenib resistance. Collectively, these results define a functional KDM1A-FKBP8-BCL2 axis in HCC.

Associations among Body Mass Index, Waist-to-Hip Ratio, and Cognitive Impairment Tend to Follow an Opposite Trend and Are Sex Specific: A Population-Based Cross-Sectional Study in a Rural Area of Xi'an, China.

INTRODUCTION: The relationship between obesity and cognitive impairment (CI) is highly heterogeneous in previous studies, which may be due to insufficient consideration of anthropometric indicators and sex. This study compared the cross-sectional relationships among body mass index (BMI), waist-to-hip ratio (WHR), and CI among people aged ≥40 years, and sex-specific relationships were also considered. METHODS: This was a population-based cross-sectional study with a cluster sampling design. CI was defined as a Mini-Mental State Examination score lower than the cutoff value. Multivariate logistic regression was used. BMI and WHR were fitted as both restricted cubic splines and categorical data. Stratified analysis and interaction analysis were performed to explore the sex-specific relationship. RESULTS: A total of 1,792 subjects (40.5% male) were analyzed, and 230 were confirmed to have CI. The relationships among BMI, WHR, and CI were significant (poverall = 0.023, pnonlinear = 0.097; poverall = 0.017, pnonlinear = 0.078, respectively) but exhibited an opposite trend in the total population in the analyses with BMI and WHR as restricted cubic splines. Further categorical analyses showed that subjects with a BMI <23 kg/m2 tended to have a higher risk of CI than those with BMI ≥23 kg/m2 (16.2% vs. 11.8%, p = 0.017; OR = 1.366 [0.969-1.926], p = 0.075), and subjects with a WHR >0.92 had a significantly higher risk of CI than those with a WHR ≤0.92 (11.7% vs. 16.2%, p = 0.011; OR = 1.619 [1.161-2.258], p = 0.005). In addition, the relationship between a low BMI and CI was more significant in males (p = 0.034), while the relationship between a high WHR and CI was more significant in females (p = 0.002). Further studies are needed to confirm the sex differences because of the marginal significance result in the interaction analysis (p = 0.051 for interaction term BMI × sex; p = 0.056 for interaction term WHR × sex). CONCLUSION: The relationships among BMI, WHR, and CI exhibit an opposite trend. A low BMI or high WHR was positively associated with CI, which was more prominent in males for a low BMI and females for a high WHR.

Liver Collagen Contents Are Closely Associated with the Severity of Cirrhosis and Posthepatectomy Liver Failure in Patients with Hepatocellular Carcinoma and Child-Pugh Grade A Liver Function.

BACKGROUND: Hepatocellular carcinoma (HCC) is usually accompanied by different severities of cirrhosis, which is a risk factor for posthepatectomy liver failure (PHLF). Collagen proportional area (CPA) measurements can quantitatively determine the collagen contents of liver tissue. This study explored the impact of CPA on PHLF, and further investigated the correlation between CPA and a non-invasive method, namely cirrhotic severity scoring (CSS), previously proposed by our team. METHODS: A total of 224 HCC patients with Child-Pugh grade A liver function undergoing hepatectomy between 2017 and 2019 were retrospectively studied. Quantitative digital image analysis of resected liver tissues was used for the CPA measurement. Risk factors for PHLF were subjected to univariate and multivariate analyses, and the correlation between CPA and CSS was analyzed. RESULTS: Overall, 28 (12.5%) patients experienced PHLF. Patients with PHLF had higher CPA values than those without PHLF (p < 0.001). Multivariate analysis showed CPA and extent of hepatectomy to be independent risk factors for PHLF. CPA values were divided into four stages based on their quartiles (C1: < 6.6%; C2: 6.6-10.7%; C3: 10.7-18.0%; C4: ≥ 18.0%). The incidence of PHLF increased with increasing CPA stages (p < 0.001). Furthermore, CSS was significantly correlated with CPA (r = 0.720; p < 0.001). The incidence of PHLF also increased with increasing severity of cirrhosis evaluated by CSS (p < 0.001). CONCLUSIONS: In HCC patients with Child-Pugh grade A liver function, cirrhosis could be staged by liver collagen contents, which significantly influenced PHLF. Furthermore, CSS was useful in the preoperative evaluation of cirrhotic severity.

Use of Direct Liver Stiffness Measurement in Evaluating the Severity of Liver Cirrhosis in Patients with Hepatocellular Carcinoma.

BACKGROUND: Severity of liver cirrhosis plays an important role in determining the safe extents of hepatectomy in patients with hepatocellular carcinoma (HCC). The aim of this study was to investigate whether direct liver stiffness measurement can help surgeons to evaluate the severity of liver cirrhosis in HCC patients. METHODS: Overall, 119 HCC patients who underwent open hepatectomy were retrospectively studied. The severity of liver cirrhosis was histologically staged using the Laennec staging system. Direct liver stiffness measurement was performed during operation using a sclerometer device named LX-C Shaw hardmeter, and its efficacy in assessing the severity of liver cirrhosis was compared with that of transient elastography (TE) and cirrhotic severity scoring (CSS) previously proposed by our team. RESULTS: Liver stiffness measured by LX-C Shaw hardmeter was significantly correlated with the severity of liver cirrhosis. Spearman correlation coefficients for the correlation between the severity of liver cirrhosis and direct liver stiffness measurement, TE, and CSS were 0.751, 0.454, and 0.705, respectively (all P < 0.001). The areas under the receiver operating characteristic curves (AUCs) of direct liver stiffness measurement were 0.891 for moderate cirrhosis and 0.944 for severe cirrhosis and superior to those of TE (0.735 and 0.776, respectively) and CSS (0.888 and 0.905, respectively). CONCLUSIONS: Direct liver stiffness measurement is a useful method in evaluating the severity of liver cirrhosis in HCC patients.

Effectiveness comparison of indocyanine green retention test with the cirrhotic severity scoring in evaluating the pathological severity of liver cirrhosis in patients with hepatocellular carcinoma and Child-Pugh grade A liver function.

BACKGROUND: Evaluating cirrhotic severity is essential for individualizing surgical modalities for patients with hepatocellular carcinoma (HCC). Our previous study proposed a non-invasive method named cirrhotic severity scoring (CSS) to stage liver cirrhosis. Indocyanine green retention rate at 15 min (ICG-R15) has been widely used for the preoperative evaluation of hepatic functional reserve; however, whether ICG-R15 is well correlated with cirrhotic severity, and especially whether comparable with CSS in predicting cirrhotic severity in HCC patients with Child-Pugh grade A liver function remains unknown. METHODS: Overall, 510 HCC patients with Child-Pugh grade A liver function undergoing hepatectomy between January 2011 and December 2014 were retrospectively studied. Cirrhotic severity was pathologically assessed using the Laennec staging system. The correlations between ICG-R15, CSS, and cirrhotic severity were analyzed. Furthermore, the performance of ICG-R15 and CSS in predicting posthepatectomy liver failure (PHLF) and 90-day mortality was compared. RESULTS: Patients with no, mild, moderate, and severe cirrhosis accounted for 15.9%, 29.2%, 35.9%, and 19.0%, respectively, in the entire cohort. ICG-R15 was found to be less than 10% in 100%, 93.3%, 86.3%, and 70.1% of the patients with no, mild, moderate, and severe cirrhosis, respectively. There was only a weak correlation between ICG-R15 and the pathological severity of liver cirrhosis (r = 0.325; P < 0.001). However, CSS showed a strong correlation with the pathological severity of liver cirrhosis (r = 0.788; P < 0.001). For those with ICG-R15 in the normal range, the accuracy of CSS in diagnosing no/mild, moderate, and severe cirrhosis was 89.1%, 72.8%, and 72.1%, respectively. In addition, CSS was superior to ICG-R15 in predicting PHLF and 90-day mortality. CONCLUSIONS: CSS was more useful than ICG-R15 in the preoperative assessment of cirrhotic severity in HCC patients with Child-Pugh grade A liver function. More studies are needed to further validate CSS in patients with different Child-Pugh grades.

Predicting the severity of liver cirrhosis through clinical parameters.

BACKGROUND: Severity of liver cirrhosis plays a vital role in determining an appropriate surgical strategy for HCC treatment. However, preoperative evaluation of the severity of cirrhosis has not been established in a surgical setting. This study aims to develop a model to predict the severity of cirrhosis. METHODS: Overall, 604 patients with hepatocellular carcinoma (HCC) and hepatitis B virus-related cirrhosis undergoing liver resection from Jan 2005 to Jun 2013 were randomly divided into either the model building group (n = 304) or the test group (n = 300). The severity of cirrhosis of the resected specimens was pathologically staged according to the Laennec scoring system, which sub-classified cirrhosis into either stage F4A, F4B, or F4C. RESULTS: A logistic regression analysis showed that varicosity, portal vein diameter, spleen thickness, and platelet count were significantly associated with the histologic sub-classification of cirrhosis in the model building group. Based on these four parameters, a scoring model for predicting the severity of cirrhosis was established. The model was then verified in the test group, the areas under the ROC (AUROC) for predicting mild (F4A), moderate (F4B), and severe cirrhosis (F4C) were 0.861 (95% confidence interval [CI], 0.810-0.911), 0.860 (95% CI, 0.819-0.901), and 0.968 (95% CI, 0.951-0.985), respectively. The accuracy of this model in predicting mild, moderate, and severe cirrhosis is 79.3%, 81.0%, and 85.3%, respectively. CONCLUSIONS: By using this model, the severity of cirrhosis can be reliably staged preoperatively, which will provide more information on cirrhotic livers in surgical settings for the treatment of hepatitis B virus-related HCC.

Morphologic severity of cirrhosis determines the extent of liver resection in patients with hepatocellular carcinoma and Child-Pugh grade A cirrhosis.

BACKGROUND: Liver resection is the mainstay of treatment for patients with hepatocellular carcinoma and compensated cirrhosis. We investigated the relationship between the morphologic severity of cirrhosis and post-hepatectomy liver failure (PHLF) and evaluated the role of cirrhosis staging in determination of the extent limit for liver resection. METHODS: The clinicopathologic data of 672 consecutive patients with Child-Pugh grade A liver function who underwent curative liver resection for hepatocellular carcinoma in Tongji Hospital from 2009 to 2013 were retrospectively reviewed. Severity of cirrhosis was staged morphologically and histologically. Risk factors for histologic cirrhosis and PHLF were analyzed. The extent limit of liver resection with reference to morphologic staging was studied. RESULTS: Morphologic and histologic stages were significantly correlated (τ = 0.809, P < 0.001). Multivariate analysis showed that morphologic staging was the most crucial factor for histologic cirrhosis (odds ratio = 26.99, 95% confidence interval = 16.88-43.14, P < 0.001) and PHLF (odds ratio = 11.48, 95% confidence interval = 6.04-21.82, P < 0.001). The incidence of PHLF was high in patients with mild cirrhosis after resection of four or more liver segments (13.6%), those with moderate cirrhosis after major resection (38.1%), and those with severe cirrhosis or severe portal hypertension after resection of two or more liver segments (63.2% and 50.0%, respectively). CONCLUSIONS: Morphologic severity of cirrhosis is an independent predictor of PHLF. Resection of fewer than four liver segments is justified in patients with mild cirrhosis. Major resection is not recommended in patients with moderate cirrhosis. In patients with severe cirrhosis or severe portal hypertension, only resection of fewer than two liver segments can be safely performed.

Severity of liver cirrhosis: a key role in the selection of surgical modality for Child-Pugh A hepatocellular carcinoma.

Hepatocellular carcinoma is the third leading cause of cancer-related death in the world, and cirrhosis is the main cause of hepatocellular carcinoma and adversely affects surgical outcomes. Liver resection, liver transplantation, and local ablation are potentially curative therapies for early hepatocellular carcinoma (HCC). There exists an obvious histological variability of severity within cirrhosis which has different clinical stages. For patients with Child-Pugh B cirrhosis and/or portal hypertension and HCC within Milan criteria, consensus guidelines suggest that liver transplantation is the best treatment of choice; liver resection is widely accepted as first-line treatment for patients with early-stage HCC and preserved liver function; and local ablation is the treatment of choice in patients with small tumors who are not candidates for surgery or can be used as a temporary treatment during the waiting period for transplantation. For patients with compensated cirrhosis or Child A cirrhosis, the selection of surgical modality based on subclassification of cirrhosis remains unclear. This review examines the current status of the selection of surgical modality for hepatocellular carcinoma treatment in cirrhotic patients and aims to emphasize the effects of the severity of cirrhosis on the selection of surgical modality for the treatment of hepatocellular carcinoma.

The predictive value of next generation sequencing for matching advanced hepatocellular carcinoma patients to targeted and immunotherapy.

Background: Targeted and Immunotherapy has emerged as a new first-line treatment for advanced hepatocellular carcinoma (aHCC). To identify the appropriate targeted and immunotherapy, we implemented next generation sequencing (NGS) to provide predictive and prognostic values for aHCC patients. Methods: Pretreatment samples from 127 HCC patients were examined for genomic changes using 680-gene NGS, and PD-L1 expression was detected by immunohistochemistry. Demographic and treatment data were included for analyses of links among treatment outcomes, drug responses, and genetic profiles. A prognostic index model for predicting benefit from treatment was constructed, taking into account of biomarkers, including TP53, TERT, PD-L1, and tumor mutation burden (TMB) as possible independent prognostic factors. Results: The multivariate Cox regression analyses showed that PD-L1≥1% (HR 25.07, 95%CI 1.56 - 403.29, p=0.023), TMB≥5Mb (HR 86.67, 95% CI 4.00 - 1876.48, p=0.004), TERT MU (HR 84.09, 95% CI 5.23 - 1352.70, p=0.002) and TP53 WT (HR 0.01, 95%CI 0.00 - 0.47, p=0.022) were independent risk factors for overall survival (OS), even after adjusting for various confounders. A prognostic nomogram for OS was developed, with an area under the ROC curve of 0.91, 0.85, and 0.98 at 1-, 2-, and 3- year, respectively, and a prognostic index cutoff of 1.2. According to the cutoff value, the patients were divided into the high-risk group (n=29) and low-risk group (n=98). The benefit of targeted and immunotherapy in the low-risk group was not distinguishable according to types of agents. However, treatment of Atezolizumab and Bevacizumab appeared to provide longer OS in the high-risk group (12 months vs 9.2, 9, or 5 months for other treatments, p<0.001). Conclusion: The prognostic model constructed by PD-L1, TMB, TERT, and TP53 can identify aHCC patients who would benefit from targeted and immunotherapy, providing insights for the personalized treatment of HCC.

Nomograms confirm serum IL-6 and CRP as predictors of immune checkpoint inhibitor efficacy in unresectable hepatocellular carcinoma.

Background: Immunotherapy based on immune checkpoint inhibitors (ICIs) has become the first-line treatment for unresectable hepatocellular carcinoma (uHCC). However, only a small portion of patients are responsive to ICIs. It is important to identify the patients who are likely to benefit from ICIs in clinical practice. We aimed to examine the significance of serum IL-6 and CRP levels in predicting the effectiveness of ICIs for uHCC. Methods: We retrospectively recruited 222 uHCC patients who received ICIs treatment (training cohort: 124 patients, validation cohort: 98 patients). In the training cohort, patients are categorized into the response group (R) and no-response group (NR). The levels of serum IL-6 and CRP were compared between the two groups. Internal validation was performed in the validation cohort. Survival analysis was carried out using the Kaplan-Meier method and Cox proportional hazard regression model. The nomograms were developed and assessed using the consistency index (C-index) and calibration curve. Results: Serum levels of IL-6 and CRP were significantly lower in the R group than in the NR group (9.94 vs. 36.85 pg/ml, p< 0.001; 9.90 vs. 24.50 mg/L, p< 0.001, respectively). An ROC curve was employed to identify the optimal cut-off values for IL-6 and CRP in both groups, resulting in values of 19.82 pg/ml and 15.50 mg/L, respectively. Multivariate Cox regression analysis revealed that MVI (HR 1.751, 95%CI 1.059-2.894, p=0.029; HR 1.530, 95%CI 0.955-2.451, p=0.077), elevated IL-6 (HR 1.624, 95%CI 1.016-2.596, p=0.043; HR 2.146, 95%CI 1.361-3.383, p =0.001) and high CRP (HR 1.709, 95%CI 1.041-2.807, p=0.034; HR 1.846, 95%CI 1.128-3.022, p = 0.015) were independent risk factors for PFS and OS, even after various confounders adjustments. Nomograms are well-structured and validated prognostic maps constructed from three variables, as MVI, IL6 and CRP. Conclusion: Low levels of IL-6 and CRP have a positive correlation with efficacy for uHCC patients receiving ICIs.

Comprehensive evaluation of the mechanism of human adipose mesenchymal stem cells ameliorating liver fibrosis by transcriptomics and metabolomics analysis.

Liver fibrosis is a chronic liver disease with progressive wound healing reaction caused by liver injury. Currently, there is no FDA approved drugs for liver fibrosis. Human adipose mesenchymal stem cells (hADSCs) have shown remarkable therapeutic effects in liver diseases. However, few studies have evaluated the therapeutic role of hADSCs in liver fibrosis, and the detailed mechanism of action is unknown. Here, we investigated the in vitro and in vivo anti-fibrosis efficacy of hADSCs and identified important metabolic changes and detailed mechanisms through transcriptomic and metabolomic analyses. We found that hADSCs could inhibit the proliferation of activated hepatic stellate cells (HSCs), promote their apoptosis, and effectively inhibit the expression of pro-fibrotic protein. It can significantly reduce collagen deposition and liver injury, improve liver function and alleviate liver inflammation in cirrhotic mouse models. In addition, transcriptome analysis revealed that the key mechanism of hADSCs against liver fibrosis is the regulation of AGE-RAGE signaling pathway. Metabolic analysis showed that hADSCs influenced changes of metabolites in lipid metabolism. Therefore, our study shows that hADSCs could reduce the activation of hepatic stellate cells and inhibit the progression of liver fibrosis, which has important potential in the treatment of liver fibrosis as well as other refractory chronic liver diseases.

Liver resection versus microwave ablation for solitary and small (≤ 3 cm) HCC with early recurrence in different stages of liver cirrhosis: A propensity score matching study.

BACKGROUND: This study aimed to compare the effectiveness of liver resection (LR) and microwave ablation (MWA) in hepatocellular carcinoma (HCC) patients with early recurrence and varying stages of cirrhosis. METHOD: This study analyzed patients with HCC who underwent hepatectomy and experienced early tumor recurrence (≤3 cm) between December 2002 and December 2020 at the Tongji Hospital. Treatment effectiveness was assessed using a propensity score matching (PSM) analysis. RESULTS: This study included 295 patients (106, LR; 189, MWA), 86 patients in each of the 2 groups were chosen for further comparison, after PSM. After PSM, both LR and MWA demonstrated similar recurrence-free survival (RFS) and overall survival (OS) rates (p = 0.060 and p = 0.118, respectively). However, the LR group had more treatment-related complications. In patients with moderate or severe cirrhosis, no significant differences in RFS or OS rates were found between the LR and MWA groups (p = 0.779 and p = 0.772, respectively). In patients without cirrhosis or with mild cirrhosis, LR showed better RFS and OS rates than MWA (p = 0.024 and p = 0.047, respectively). Multivariate analysis after PSM identified moderate or severe cirrhosis and recurrence intervals ≤12 months as independent predictors of poor RFS and OS in patients with early recurrence of HCC. CONCLUSION: LR is more effective than MWA for early recurrence of HCC in patients without cirrhosis or with mild cirrhosis, showing improved RFS and OS rates. In patients with moderate or severe cirrhosis, the OS and RFS were statistically equal between the two therapies. However, MWA may be preferred owing to its low complication rate.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Conversion therapy for advanced hepatocellular carcinoma with vascular invasion: a comprehensive review.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and has a high mortality rate worldwide. The percentage of HCC patients with vascular invasion at the time of initial HCC diagnosis is 10%-40%. According to most guidelines, HCC with vascular invasion is classified as advanced stage, and resection is only suggested for a minority of such patients. Recently, advances in systemic and locoregional treatments for such patients have resulted in amazing response rates. Therefore, a "conversion therapy" strategy including systemic and locoregional treatments is proposed to select patients from an initially unresectable state to eventually undergo R0 resection. Recently, many studies have proven that conversion therapy followed by subsequent surgery is achievable in well-selected advanced HCC patients and can provide prolonged long-term outcomes. Based on published research, this review has summarized the clinical experience and evidence of conversion treatment in HCC patients with vascular invasion.