Gut microbiome as a biomarker for predicting early recurrence of HBV-related hepatocellular carcinoma.

To investigate the potential of the gut microbiome as a biomarker for predicting the early recurrence of HBV-related hepatocellular carcinoma (HCC), we enrolled 124 patients diagnosed with HBV-associated HCC and 82 HBV-related hepatitis, and 86 healthy volunteers in our study, collecting 292 stool samples for 16S rRNA sequencing and 35 tumor tissue samples for targeted metabolomics. We performed an integrated bioinformatics analysis of gut microbiome and tissue metabolome data to explore the gut microbial-liver metabolite axis associated with the early recurrence of HCC. We constructed a predictive model based on the gut microbiota and validated its efficacy in the temporal validation cohort. Dialister, Veillonella, the Eubacterium coprostanoligenes group, and Lactobacillus genera, as well as the Streptococcus pneumoniae and Bifidobacterium faecale species, were associated with an early recurrence of HCC. We also found that 23 metabolites, including acetic acid, glutamate, and arachidonic acid, were associated with the early recurrence of HCC. A comprehensive analysis of the gut microbiome and tissue metabolome revealed that the entry of gut microbe-derived acetic acid into the liver to supply energy for tumor growth and proliferation may be a potential mechanism for the recurrence of HCC mediated by gut microbe. We constructed a nomogram to predict early recurrence by combining differential microbial species and clinical indicators, achieving an AUC of 78.0%. Our study suggested that gut microbes may serve as effective biomarkers for predicting early recurrence of HCC, and the gut microbial-tumor metabolite axis may explain the potential mechanism by which gut microbes promote the early recurrence of HCC.

Machine learning radiomics to predict the early recurrence of intrahepatic cholangiocarcinoma after curative resection: A multicentre cohort study.

PURPOSE: Postoperative early recurrence (ER) leads to a poor prognosis for intrahepatic cholangiocarcinoma (ICC). We aimed to develop machine learning (ML) radiomics models to predict ER in ICC after curative resection. METHODS: Patients with ICC undergoing curative surgery from three institutions were retrospectively recruited and assigned to training and external validation cohorts. Preoperative arterial and venous phase contrast-enhanced computed tomography (CECT) images were acquired and segmented. Radiomics features were extracted and ranked through their importance. Univariate and multivariate logistic regression analysis was used to identify clinical characteristics. Various ML algorithms were used to construct radiomics-based models, and the predictive performance was evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis. RESULTS: 127 patients were included for analysis: 90 patients in the training set and 37 patients in the validation set. Ninety-two patients (72.4%) experienced recurrence, including 71 patients exhibiting ER. Male sex, microvascular invasion, TNM stage, and serum CA19-9 were identified as independent risk factors for ER, with the corresponding clinical model having a poor predictive performance (AUC of 0.685). Fifty-seven differential radiomics features were identified, and the 10 most important features were utilized for modelling. Seven ML radiomics models were developed with a mean AUC of 0.87 ± 0.02, higher than the clinical model. Furthermore, the clinical-radiomics models showed similar predictive performance to the radiomics models (AUC of 0.87 ± 0.03). CONCLUSION: ML radiomics models based on CECT are valuable in predicting ER in ICC.

Sarcopenia negatively affects postoperative short-term outcomes of patients with non-cirrhosis liver cancer.

BACKGROUND: Literature review have shown that sarcopenia substantially alters the postoperative outcomes after liver resection for malignant tumors. However, these retrospective studies do not distinguish cirrhotic and non-cirrhotic liver cancer patients, nor combine the assessment of muscle strength in addition to muscle mass. The purpose of this study is to study the relationship between sarcopenia and short-term outcomes after hepatectomy in patients with non-cirrhotic liver cancer. METHODS: From December 2020 to October 2021, 431 consecutive inpatients were prospectively enrolled in this study. Muscle strength and mass were assessed by handgrip strength and the skeletal muscle index (SMI) on preoperative computed tomographic scans, respectively. Based on the SMI and the handgrip strength, patients were divided into four groups: group A (low muscle mass and strength), group B (low muscle mass and normal muscle strength), group C (low muscle strength and normal muscle mass), and group D (normal muscle mass and strength). The main outcome was major complications and the secondary outcome was 90-d Readmission rate. RESULTS: After strictly exclusion, 171 non-cirrhosis patients (median age, 59.00 [IQR, 50.00-67.00] years; 72 females [42.1%]) were selected in the final analysis. Patients in group A had a statistically significantly higher incidence of major postoperative complications (Clavien-Dindo classification ≥ III) (26.1%, p = 0.032), blood transfusion rate (65.2%, p < 0.001), 90-day readmission rate (21.7%, p = 0.037) and hospitalization expenses (60,842.00 [IQR, 35,563.10-87,575.30], p < 0.001) than other groups. Sarcopenia (hazard ratio, 4.21; 95% CI, 1.44-9.48; p = 0.025) and open approach (hazard ratio, 2.56; 95% CI, 1.01-6.49; p = 0.004) were independent risk factors associated with major postoperative complications. CONCLUSIONS: Sarcopenia is closely related to poor short-term postoperative outcomes in non-cirrhosis liver cancer patients and the assessment that combines muscle strength and muscle mass can simply and comprehensively identify it. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT04637048 . (19/11/2020).

Association of gut microbiome and primary liver cancer: A two-sample Mendelian randomization and case-control study.

BACKGROUND AND AIMS: Observational epidemiology studies suggested a relationship between the gut microbiome and primary liver cancer. However, the causal relationship remains unclear because of confounding factors and reverse causality. We aimed to explore the causal role of the gut microbiome in the development of primary liver cancer, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). METHODS: Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies (GWAS) of the gut microbiome and liver cancer, and sequencing data from a case-control study validated the findings. A 5-cohort GWAS study in Germany (N = 8956) served as exposure, whilst the UK biobank GWAS study (N = 456 348) served as an outcome. The case-control study was conducted at the First Affiliated Hospital of Wenzhou Medical University from December 2018 to October 2020 and included 184 HCC patients, 63 ICC patients and 40 healthy controls. RESULTS: A total of 57 features were available for MR analysis, and protective causal associations were identified for Family_Ruminococcaceae (OR = 0.46 [95% CI, 0.26-0.82]; p = .009) and Genus_Porphyromonadaceae (OR = 0.59 [95% CI, 0.42-0.83]; p = .003) with HCC, and for Family_Porphyromonadaceae (OR = 0.36 [95% CI, 0.14-0.94]; p = .036) and Genus_Bacteroidetes (OR = 0.55 [95% CI, 0.34-0.90]; p = .017) with ICC respectively. The case-control study results showed that the healthy controls had a higher relative abundance of Family_Ruminococcaceae (p = .00033), Family_Porphyromonadaceae (p = .0055) and Genus_Bacteroidetes (p = .021) than the liver cancer patients. CONCLUSIONS: This study demonstrates that Ruminococcaceae, Porphyromonadaceae and Bacteroidetes are related to a reduced risk of liver cancer (HCC or ICC), suggesting potential significance for the prevention and control of liver cancer.

Walking activity and emotional distress among breast cancer survivors: the parallel mediating effects of posttraumatic growth and body image.

PURPOSE: Although the antidepressant effects of physical activity have been well established, the underlying psychological mechanisms are understudied among cancer survivors. The present study aims to examine the parallel mediating effects of posttraumatic growth and body image on the association between walking activity and emotional distress (anxiety and depression) among Chinese breast cancer survivors. METHODS: Chinese breast cancer survivors (n = 235) completed a cross-sectional questionnaire that assessed walking activity, anxiety, depression, posttraumatic growth, and body image over the past week. Path analysis was conducted to test the hypothesized mediation model. RESULTS: The hypothesized model was supported: walking activity was positively associated with posttraumatic growth and body image satisfaction, which were then negatively associated with anxiety and depression. After controlling for the mediators, the direct effect of physical activity on depression was still significant, whereas the direct effect of physical activity on anxiety was no longer significant. CONCLUSION: Our findings suggest that posttraumatic growth and body image may be essential psychological pathways underlying the association between walking activity and emotional distress among Chinese breast cancer survivors. Researchers and health practitioners should consider supplementing physical activity interventions with mental health services that facilitate psychological growth and a positive body image to enhance the potential psychological benefits of physical activity.

Long-term risk of colorectal cancer after removal of adenomas during screening colonoscopies in a large community-based population in China.

Patients with conventional adenoma removal are recommended to undergo colonoscopy surveillance to prevent colorectal cancer (CRC). However, evidence supporting the guidelines of colonoscopy surveillance is limited, especially among the Chinese population. We investigated the association between colonoscopy adenoma findings and CRC risk among individuals aged 40 to 74 years who underwent baseline colonoscopy from 2007 to 2016 in Jiashan and Haining, Zhejiang, China; 34 382 participants were categorized into advanced adenoma, nonadvanced adenoma and no adenoma based on adenoma findings. A multivariable Cox regression model was used to estimate the hazard ratio (HR) of CRC incidence with adjustment for potential confounding factors. After a median follow-up time of 7.7 years, 113 incident cases of CRC were identified (18 occurred in 1632 participants with advanced adenoma, 16 in 3973 participants with nonadvanced adenoma and 79 in 28 777 participants with no adenoma). Compared to no adenoma group, the adjusted HR for CRC in advanced adenoma group was 4.01 (95% CI, 2.37-6.77). For nonadvanced adenomas, individuals with ≥3 adenomas showed an increased risk of CRC (HR, 3.65; 95% CI, 1.43-9.31), but no significantly increased risk of CRC was found for 1 to 2 nonadvanced adenomas, compared to those with no adenoma. Our study suggested that the risk of subsequent CRC increased in individuals with high-risk adenoma (at least one advanced adenoma or ≥3 nonadvanced adenomas), but not in those with 1 to 2 nonadvanced adenomas. These results provide the first evidence from the Chinese population for the current surveillance guidelines.

Noncoding RNA-mediated molecular bases of chemotherapy resistance in hepatocellular carcinoma.

Despite the significant progress in decreasing the occurrence and mortality of hepatocellular carcinoma (HCC), it remains a public health issue worldwide on the basis of its late presentation and tumor recurrence. To date, apart from surgical interventions, such as surgical resection, liver transplantation and locoregional ablation, current standard antitumor protocols include conventional cytotoxic chemotherapy. However, due to the high chemoresistance nature, most current therapeutic agents show dismal outcomes for this refractory malignancy, leading to disease relapse. Nevertheless, the molecular mechanisms involved in chemotherapy resistance remain systematically ambiguous. Herein, HCC is hierarchically characterized by the formation of primitive cancer stem cells (CSCs), progression of epithelial-mesenchymal transition (EMT), unbalanced autophagy, delivery of extracellular vesicles (EVs), escape of immune surveillance, disruption of ferroptosis, alteration of the tumor microenvironment and multidrug resistance-related signaling pathways that mediate the multiplicity and complexity of chemoresistance. Of note, anecdotal evidence has corroborated that noncoding RNAs (ncRNAs) extensively participate in the critical physiological processes mentioned above. Therefore, understanding the detailed regulatory bases that underlie ncRNA-mediated chemoresistance is expected to yield novel insights into HCC treatment. In the present review, a comprehensive summary of the latest progress in the investigation of chemotherapy resistance concerning ncRNAs will be elucidated to promote tailored individual treatment for HCC patients.

Laparoscopic versus open surgery for hilar cholangiocarcinoma: a retrospective cohort study on short-term and long-term outcomes.

BACKGROUND: Laparoscopic surgery (LS) for hilar cholangiocarcinoma (HCCa) remains under development, and its feasibility and safety remain controversial. This study therefore evaluated the outcomes of this technique and compared them to those of open surgery (OS). METHODS: In total, 149 patients underwent surgical resection for HCCa at our center between February 2017 and September 2020. After screening and propensity score matching, 47 OS group patients and 20 LS group patients remained, and their baseline characteristics, pathologic findings, surgical outcomes, and long-term outcomes were compared. RESULT: The baseline characteristics and pathologic findings were comparable between the two groups. The mean incision length was longer in the OS group than in the LS group (21.0 cm vs. 13.2 cm, P < 0.001). No significant differences were observed in the other surgical outcomes between the two groups. Regarding long-term outcomes, the overall survival rate and disease-free survival rate of the OS group were significantly higher than those of the LS group (P = 0.0057, P = 0.043). However, the two groups had significantly different follow-up times (19.2 months vs. 14.7 months, P = 0.041). CONCLUSION: LS for HCCa is technically achievable, and our study revealed that it is equivalent to OS in terms of short-term outcomes but was poorer in terms of long-term outcomes.

Comprehensive Analysis of Transcriptional Expression of hsa-mir-21 Predicted Target Genes and Immune Characteristics in Kidney Renal Clear Cell Carcinoma.

Background: To uncover advanced prognosis biomarkers in patient with kidney renal clear cell carcinoma (KIRC), our study was the first to make a comprehensive analysis of hsa-mir-21 predicted target genes and explore the immune characteristics in KIRC. Methods: In this study, the comprehensive analysis of hsa-mir-21 predicted target genes and immune characteristics in KIRC were analyzed via TIMER2.0, UALCAN, Metascape, Kaplan-Meier plotter, Human Protein Atlas, CancerSEA, JASPAR, GEPIA, R package: GSVA package (version 1.34.0) & immune infiltration algorithm (ssGSEA) and R package: RMS package (version 6.2-0) & SURVIVAL package (version 3.2-10). Results: Up-transcriptional expressions of RP2, NFIA, SPRY1 were significantly associated with favorable prognosis in KIRC, whereas that of TGFBI was markedly significantly to unfavorable prognosis. Additionally, RP2, NFIA, SPRY1 and TGFBI were significantly relevant to the immune infiltration in KIRC. Finally, ZNF263 was a common predicted transcription factor of RP2, NFIA, SPRY1 and TGFBI, which can as an independent indicator for prognosis in KIRC patients. Conclusions: Hsa-mir-21 predicted target genes (RP2, NFIA, SPRY1 and TGFBI) and the common transcription factor ZNF263 could be the advanced prognosis biomarkers in KIRC patients.

Berberine inhibits proliferation and migration of colorectal cancer cells by downregulation of GRP78.

Human colorectal cancer (CRC), a highly malignant and metastatic carcinoma, is resistant to many present anticancer therapies. The inhibition of tumor survival and growth through receptor suppression is a promising way to treat CRC. The study aimed to investigate the effect of a natural plant triterpenoid, berberine (BBR), on SW480 cells and whether its role is mediated by Glucose-regulated protein 78 (GRP78). MTT assay, wound healing assay, and Annexin V-FITC assay were used to measure the effect of BBR on the proliferation, migration, and apoptosis of SW480 cells, respectively. Immunofluorescence and western blotting were used to evaluate both the downregulation of BBR on GRP78 and the role of GRP78 in the effect of BBR on SW480 cells. Our results revealed that BBR inhibited the proliferation and migration, as well as induced the apoptosis of SW480 cells, in a dose-dependent manner. BBR induced the dose-dependent inhibition of cell proliferation in HT-29 cells. BBR inhibited the expression of GRP78 and its localization on the cell surface. Moreover, BBR inhibited the expression of Bax, Bcl-2, c-Myc, and Vimentin and up-regulated the cytokeratin expression in SW480 cells. In addition, we found that the effects of BBR on cell proliferation, migration, and apoptosis in SW480 cells were reversed by the overexpression of GRP78. Our findings demonstrated that BBR inhibited the proliferation and migration and induced the apoptosis of SW480 cells by downregulating the expression of GRP78, and targeting GRP78 might be a potential way to develop the effective anticancer therapy.

Oxidative stress-related DNA damage and homologous recombination repairing induced by N,N-dimethylformamide.

The intensified anthropogenic release of N,N-dimethylformamide (DMF) has been proven to have hepatotoxic effects. However, the potential mechanism for DMF-induced toxicity has rarely been investigated. Our research implicated that DMF induced a significantly dose-dependent increase in reactive oxygen species (ROS) in HL-7702 human liver cells. Moreover, oxidative stress-related DNA damage, marked as 8-hydroxy-2'-deoxyguanosine, was increased 1.5-fold at 100 mmol l(-1) . The most severe DNA lesion (double-strand break, DSB), measured as the formation of γH2AX foci, was increased at/above 6.4 mmol l(-1) , and approximately 50% of cells underwent DSB at the peak induction. Subsequently, the DNA repair system triggered by molecules of RAD50 and MRE11A induced the homologous recombination (HR) pathway by upregulation of both gene and protein levels of RAD50, RAD51, XRCC2 and XRCC3 at 16 mmol l(-1) and was attenuated at 40 mmol l(-1) . Consequently, cellular death observed at 40 mmol l(-1) was exaggerated compared with exposure at 16 mmol l(-1) . Although the exact mechanism relying on the DMF-induced hepatotoxicity needs further clarification, oxidative stress and DNA damage involved in DSBs partially explain the reason for DMF-induced liver injury. Oxidative stress-induced DNA damage should be first considered during risk assessment on liver-targeted chemicals. Copyright © 2015 John Wiley & Sons, Ltd.

Impact of sarcopenia on the short-term and long-term outcomes of intrahepatic cholangiocarcinoma undergoing hepatectomy: A multi-center study.

BACKGROUND: Sarcopenia is associated with adverse prognosis of intrahepatic cholangiocarcinoma (iCCA) after surgery. METHODS: 321 patients with iCCA undergoing surgery were retrospectively recruited and assigned to training and validation cohort. Skeletal muscle index (SMI) was assessed to define sarcopenia. Logistic regression and cox regression analysis were used to identify risk factors. A novel sarcopenia-based nomogram was constructed and validated by ROC curves, calibration curves, and DCA curves. RESULTS: 260 patients were included for analysis. The median age was 63.0 years and 161 patients (61.9%) were diagnosed with sarcopenia. Patients with sarcopenia exhibited a higher rate of postoperative complications, a worse OS and RFS than patients without sarcopenia. Sarcopenia, low albumin and intraoperative blood transfusion were independent risk factors of postoperative complications, while sarcopenia and low albumin were risk factors of high CCI≥26.2. Sarcopenia, high PS score, low-undifferentiated differentiation, perineural invasion, TNM stage III-IV were risk factors of OS, and a novel nomogram based on these five factors was built to predict the 12-, 24-, and 36-months OS, with the mean AUC > 0.6. CONCLUSION: Sarcopenia is negatively associated with both postoperative complications and survival prognosis of iCCA undergoing hepatectomy.

The Mediation/Moderation Effects of Gut Microbiota on Sleep Quality and Primary Liver Cancer: A Mendelian Randomization and Case-Control Study.

Background: Primary liver cancer (PLC) is a fatal malignancy, sleep quality and gut microbiota were shown to be associated with PLC. However, the mechanism of how sleep quality affects PLC is unclear. This study aims to investigate the mediation/moderation effects of gut microbiota on sleep quality and the occurrence of PLC. Methods: The causality of sleep quality and the occurrence of PLC was detected through the Mendelian randomization (MR) analysis based on the data including 305,359 individuals (Finland Database) and 456,348 participants (UK Biobank). The primary method used for MR analysis was inverse-variance weighted analysis. Gut microbiota' mediation/moderation effects were uncovered in the case-control study including 254 patients with PLC and 193 people with benign liver diseases through the mediation/moderation effect analyses. People's sleep quality was evaluated through the Pittsburgh sleep quality index (PSQI). Results: Poor sleep quality could lead to PLC through the MR analysis (P = 0.026). The case-control study uncovered that Actinobacteria had mediation effects on the relationship between PSQI score, self-sleep quality, and the occurrence of PLC (P = 0.048, P = 0.046). Actinobacteria and Bifidobacterium could inhibit the development of PLC caused by short night sleep duration (P = 0.021, P = 0.022). Erysipelotrichales could weaken the influence of daytime dysfunction on PLC (P = 0.033). Roseburia modulated the contribution of nocturnal insomnia and poor sleep quality to PLC (P = 0.009, P = 0.017). Conclusion: Poor sleep quality was associated with PLC. Gut microbiota' mediation/moderation effects on poor sleep quality and the occurrence of PLC prompted an insightful idea for the prevention of PLC.

Synergistic activity of Enterococcus Faecium-induced ferroptosis via expansion of IFN-γ+CD8+ T cell population in advanced hepatocellular carcinoma treated with sorafenib.

The gut microbiota plays an important role in the development and treatment of hepatocellular carcinoma (HCC). However, the implication of specific gut microbiota in targeted sorafenib therapy for advanced HCC and the microbiota mode of action, remain to be elucidated. Here, we confirmed that four bacterial genera, Lachnoclostridium, Lachnospira, Enterobacter and Enterococcus, are associated with the therapeutic efficacy of Sorafenib, and that Enterobacter faecium (Efm) plays a crucial role in modulating the sorafenib activity. The effective colonization by Emf induced the IL-12 and IFN-γ production and an increased proportion of IFN-γ+CD8+ T cells in the tumor microenvironment. Finally, exopolysaccharides (EPS) from Efm were the primary inducer to prompt IFN-γ+CD8+ T cells to secrete IFN-γ, which together with sorafenib instigated ferroptosis in HCC cells. Collectively, these results indicate that Efm is a promising probiotics that enhances the efficacy of sorafenib treatment in advanced HCC.

Survival Benefit of Surgical Treatment for Elderly Patients with Intrahepatic Cholangiocarcinoma: A Retrospective Cohort Study in the SEER Database by Propensity Score Matching Analysis.

Despite a rising trend in intrahepatic cholangiocarcinoma (ICC) incidence in the elderly population worldwide, the benefit of surgery for those patients is still controversial. Data from 811 elderly patients diagnosed with non-metastatic ICC were obtained from the US surveillance, epidemiology, and end results (SEER) program database. Propensity score matched (PSM) was conducted for the better balance of baseline. The associations between tumor characteristics and surgery with overall survival (OS) and cancer specific survival (CSS) were estimated using hazard ratios (HR) and 95% confidence intervals (CI). The results showed that ICC patients above 60 years old taking surgery had better OS (hazard ratio [HR], 0.258; 95% CI, 0.205-0.324) and CSS (hazard ratio [HR], 0.239; 95% CI, 0.188-0.303) than patients without surgery. Similar trends in patients above 65 years old, above 70 years old, above 75 years old, and above 80 years old were observed, separately. This benefit was also showed in lymph node-negative (N0) and lymph node-positive (N1) subgroups and N0 patients are more likely to take an advantage from surgery than N1 patients. The different outcomes between surgery and non-surgery suggest that surgical treatment may be recommended for elderly ICC if the tumor is resectable to ensure optimal treatment.

Disulfiram combined with chemoimmunotherapy potentiates pancreatic cancer treatment efficacy through the activation of cGAS-STING signaling pathway via suppressing PARP1 expression.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality globally with limited effective treatment options. Although the combination of immunotherapy and chemotherapy has been attempted in clinical trials to treat PDAC, the results are not promising. Therefore, in this study, we explored the application of a novel combination strategy with disulfiram (DSF) to enhance the treatment efficacy of PDAC as well as its underlying molecular mechanism. We compared the antitumor effects between single agents and the combination therapy by using mouse allograft tumor model and found DSF combined with chemoimmunotherapy significantly suppressed the growth of subcutaneous PDAC allograft tumor in mice and prolonged the survival of mice. To further investigate the alterations in the immune microenvironment of tumors from different treatment groups, we employed flow cytometry and RNA-seq analysis to examine the composition of tumor-infiltrating immune cells as well as the expression level of a variety of cytokines. Our results revealed that the proportion of CD8 T cells was notably elevated and that multiple cytokines were upregulated in the combination therapy group. Furthermore, qRT-PCR results indicated that DSF could upregulate the mRNA levels of IFNα and IFNß, which could be reversed by STING pathway inhibitor. Mechanistically, we found that DSF activated STING signaling pathway through Poly (ADP-ribose) polymerases (PARP1) inhibition. Taken together, our findings highlight the potential clinical application of this novel combination strategy using DSF and chemoimmunotherapy in the treatment of patients with PDAC.

Development of sarcopenia-based nomograms predicting postoperative complications of benign liver diseases undergoing hepatectomy: A multicenter cohort study.

Background: Sarcopenia has a remarkable negative impact on patients with liver diseases. We aimed to evaluate the impact of preoperative sarcopenia on the short-term outcomes after hepatectomy in patients with benign liver diseases. Methods: A total of 558 patients with benign liver diseases undergoing hepatectomy were prospectively reviewed. Both the muscle mass and strength were measured to define sarcopenia. Postoperative outcomes including complications, major complications and comprehensive complication index (CCI) were compared among four subgroups classified by muscle mass and strength. Predictors of complications, major complications and high CCI were identified by univariate and multivariate logistic regression analysis. Nomograms based on predictors were constructed and calibration cures were performed to verify the performance. Results: 120 patients were involved for analysis after exclusion. 33 patients were men (27.5%) and the median age was 54.0 years. The median grip strength was 26.5 kg and the median skeletal muscle index (SMI) was 44.4 cm2/m2. Forty-six patients (38.3%) had complications, 19 patients (15.8%) had major complications and 27 patients (22.5%) had a CCI ≥ 26.2. Age (p = 0.005), SMI (p = 0.005), grip strength (p = 0.018), surgical approach (p = 0.036), and operation time (p = 0.049) were predictors of overall complications. Child-Pugh score (p = 0.037), grip strength (p = 0.004) and surgical approach (p = 0.006) were predictors of major complications. SMI (p = 0.047), grip strength (p < 0.001) and surgical approach (p = 0.014) were predictors of high CCI. Among the four subgroups, patients with reduced muscle mass and strength showed the worst short-term outcomes. The nomograms for complications and major complications were validated by calibration curves and showed satisfactory performance. Conclusion: Sarcopenia has an adverse impact on the short-term outcomes after hepatectomy in patients with benign liver diseases and valuable sarcopenia-based nomograms were constructed to predict postoperative complications and major complications.

Machine Learning to Predict the Response to Lenvatinib Combined with Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma.

BACKGROUND: Lenvatinib and transarterial chemoembolization (TACE) are first-line treatments for unresectable hepatocellular carcinoma (HCC), but the objective response rate (ORR) is not satisfactory. We aimed to predict the response to lenvatinib combined with TACE before treatment for unresectable HCC using machine learning (ML) algorithms based on clinical data. METHODS: Patients with unresectable HCC receiving the combination therapy of lenvatinib combined with TACE from two medical centers were retrospectively collected from January 2020 to December 2021. The response to the combination therapy was evaluated over the following 4-12 weeks. Five types of ML algorithms were applied to develop the predictive models, including classification and regression tree (CART), adaptive boosting (AdaBoost), extreme gradient boosting (XGBoost), random forest (RF), and support vector machine (SVM). The performance of the models was assessed by the receiver operating characteristic (ROC) curve and area under the receiver operating characteristic curve (AUC). The Shapley Additive exPlanation (SHAP) method was applied to explain the model. RESULTS: A total of 125 unresectable HCC patients were included in the analysis after the inclusion and exclusion criteria, among which 42 (33.6%) patients showed progression disease (PD), 49 (39.2%) showed stable disease (SD), and 34 (27.2%) achieved partial response (PR). The nonresponse group (PD + SD) included 91 patients, while the response group (PR) included 34 patients. The top 40 most important features from all 64 clinical features were selected using the recursive feature elimination (RFE) algorithm to develop the predictive models. The predictive power was satisfactory, with AUCs of 0.74 to 0.91. The SVM model and RF model showed the highest accuracy (86.5%), and the RF model showed the largest AUC (0.91, 95% confidence interval (CI): 0.61-0.95). The SHAP summary plot and decision plot illustrated the impact of the top 40 features on the efficacy of the combination therapy, and the SHAP force plot successfully predicted the efficacy at the individualized level. CONCLUSIONS: A new predictive model based on clinical data was developed using ML algorithms, which showed favorable performance in predicting the response to lenvatinib combined with TACE for unresectable HCC. Combining ML with SHAP could provide an explicit explanation of the efficacy prediction.

A distinct microbiota signature precedes the clinical diagnosis of hepatocellular carcinoma.

Oral, gut, and tumor microbiota have been implicated as important regulators in the carcinogenesis and progression of gastrointestinal malignancies. However, few studies focused on the existence and association of resident microbes within different body regions. Herein, we aim to reveal the durability of the oral-gut-tumor microbiome and its diagnostic performance in hepatocellular carcinoma (HCC). Our study included two cohorts: a retrospective discovery cohort of 364 HBV-HCC patients and 160 controls with oral or fecal samples, a prospective validation cohort of 91 cases, and 124 controls for matching samples, as well as 48 HBV, and 39 HBV-cirrhosis patients for gut microbial patterns examined by 16S rRNA gene sequencing. With the random forest analysis, 10 oral and 9 gut genera that could distinguish HCC from controls in the retrospective cohort were validated among the prospective matching participants, with area under the curve (AUC) values of 0.7971 and 0.8084, respectively. When influential taxa were merged, the AUC of the consistent classifier increased to 0.9405. The performance continued to improve to 0.9811 when combined with serum levels of alpha-fetoprotein (AFP). Specifically, microbial biomarkers represented by Streptococcus displayed a constantly increasing trend during the disease transition. Furthermore, the presence of several dominant microbiota species was confirmed in hepatic tumor and non-tumor tissues with fluorescence in situ hybridization (FISH) and 5 R 16S rRNA gene sequencing. Overall, our findings based on the oral-gut-tumor microbiota provide a reliable approach for the early detection of HCC.

Prediction of Response to Lenvatinib Monotherapy for Unresectable Hepatocellular Carcinoma by Machine Learning Radiomics: A Multicenter Cohort Study.

PURPOSE: We aimed to construct machine learning (ML) radiomics models to predict response to lenvatinib monotherapy for unresectable hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Patients with HCC receiving lenvatinib monotherapy at three institutions were retrospectively identified and assigned to training and external validation cohorts. Tumor response after initiation of lenvatinib was evaluated. Radiomics features were extracted from contrast-enhanced CT images. The K-means clustering algorithm was used to distinguish radiomics-based subtypes. Ten ML radiomics models were constructed and internally validated by 10-fold cross-validation. These models were subsequently verified in an external validation cohort. RESULTS: A total of 109 patients were identified for analysis, namely, 74 in the training cohort and 35 in the external validation cohort. Thirty-two patients showed partial response, 33 showed stable disease, and 44 showed progressive disease. The overall response rate (ORR) was 29.4%, and the disease control rate was 59.6%. A total of 224 radiomics features were extracted, and 25 significant features were identified for further analysis. Two distant radiomics-based subtypes were identified by K-means clustering, and subtype 1 was associated with a higher ORR and longer progression-free survival (PFS). Among the 10 ML algorithms, AutoGluon displayed the highest predictive performance (AUC = 0.97), which was relatively stable in the validation cohort (AUC = 0.93). Kaplan-Meier analysis showed that responders had a better overall survival [HR = 0.21; 95% confidence interval (CI): 0.12-0.36; P < 0.001] and PFS (HR = 0.14; 95% CI: 0.09-0.22; P < 0.001) than nonresponders. CONCLUSIONS: Valuable ML radiomics models were constructed, with favorable performance in predicting the response to lenvatinib monotherapy for unresectable HCC.