From imaging to clinical outcome: dual-region CT radiomics predicting FOXM1 expression and prognosis in hepatocellular carcinoma.

Background: Liver cancer, especially hepatocellular carcinoma (HCC), remains a significant global health challenge. Traditional prognostic indicators for HCC often fall short in providing comprehensive insights for individualized treatment. The integration of genomics and radiomics offers a promising avenue for enhancing the precision of HCC diagnosis and prognosis. Methods: From the Cancer Genome Atlas (TCGA) database, we categorized mRNA of HCC patients by Forkhead Box M1 (FOXM1) expression and performed univariate and multivariate studies to pinpoint autonomous HCC risk factors. We deployed subgroup, correlation, and interaction analyses to probe FOXM1's link with clinicopathological elements. The connection between FOXM1 and immune cells was evaluated using the CIBERSORTx database. The functions of FOXM1 were investigated through analyses of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). After filtering through TCGA and the Cancer Imaging Archive (TCIA) database, we employed dual-region computed tomography (CT) radiomics technology to noninvasively predict the mRNA expression of FOXM1 in HCC tissues. Radiomic features were extracted from both tumoral and peritumoral regions, and a radiomics score (RS) was derived. The performance and robustness of the constructed models were evaluated using 10-fold cross-validation. A radiomics nomogram was developed by incorporating RS and clinical variables from the TCGA database. The models' discriminative abilities were assessed using metrics such as the area under the curve (AUC) of the receiver operating characteristic curves (ROC) and precision-recall (PR) curves. Results: Our findings emphasized the overexpression of FOXM1 as a determinant of poor prognosis in HCC and illustrated its impact on immune cell infiltration. After selecting arterial phase CT, we chose 7 whole-tumor features and 3 features covering both the tumor and its surroundings to create WT and WP models for FOXM1 prediction. The WT model showed strong predictive capabilities for FOXM1 expression by PR curve. Conversely, the WP model did not demonstrate the good predictive ability. In our study, the radiomics score (RS) was derived from whole-tumor regions on CT images. The RS was significantly associated with FOXM1 expression, with an AUC of 0.918 in the training cohort and 0.837 in the validation cohort. Furthermore, the RS was correlated with oxidative stress genes and was integrated with clinical variables to develop a nomogram, which demonstrated good calibration and discrimination in predicting 12-, 36-, and 60-month survival probabilities. Additionally, bioinformatics analysis revealed FOXM1's potential role in shaping the immune microenvironment, with its expression linked to immune cell infiltration. Conclusion: This study highlights the potential of integrating FOXM1 expression and radiomics in understanding HCC's complexity. Our approach offers a new perspective in utilizing radiomics for non-invasive tumor characterization and suggests its potential in providing insights into molecular profiles. Further research is needed to validate these findings and explore their clinical implications in HCC management.

Improving the immunomodulatory function of mesenchymal stem cells by defined chemical approach.

Mesenchymal stem cell (MSC) is a potential therapeutic material that has self-renewal, multilineage differentiation, and immunomodulation properties. However, the biological function of MSCs may decline due to the influence of donor differences and the in vitro expansion environment, which hinders the advancement of MSC-based clinical therapy. Here, we investigated a method for improving the immunomodulatory function of MSCs with the help of small-molecule compounds, A-83-01, CHIR99021, and Y27632 (ACY). The results showed that small-molecule induced MSCs (SM-MSCs) could enhance their immunosuppressive effects on T cells and macrophages. In vivo studies showed that, in contrast to control MSCs (Ctrl-MSCs), SM-MSCs could inhibit the inflammatory response in mouse models of delayed hypersensitivity and acute peritonitis more effectively. In addition, SM-MSCs showed the stronger ability to inhibit the infiltration of pro-inflammatory T cells and macrophages. Thus, small-molecule compounds ACY could better promote the immunomodulatory effect of MSCs, indicating it could be a potential improving method in MSC culture.

PROZ Associated with Sorafenib Sensitivity May Serve as a Potential Target to Enhance the Efficacy of Combined Immunotherapy for Hepatocellular Carcinoma.

Targeted combined immunotherapy has significantly improved the prognosis of patients with advanced hepatocellular carcinoma and has now become the primary treatment for advanced hepatocellular carcinoma. However, some patients still have poor efficacy or are resistant to treatment. The further exploration of molecular markers related to efficacy or finding molecular targets to increase efficacy is an urgent problem that needs to be resolved. In this research, we found that PROZ was a gene related to KDR expression that had significantly low expression in cancer tissue by analyzing the differential genes of cancer tissue and adjacent tissue and the intersection of KDR-related genes in hepatocellular carcinoma. The correlation analysis of clinical data showed that the low expression of PROZ was significantly correlated with the poor prognosis of hepatocellular carcinoma, and further studies found that PROZ was closely related to the expression of p-ERK and VEGFR2 in hepatocellular carcinoma. In addition, intracellular detection also showed that the expression of p-ERK increased and VEGFR2 expression decreased after PROZ interference, and PROZ downregulation with increased p-ERK and decreased VEGFR2 was also detected in sorafenib-resistant strains. At the same time, our analysis found that PROZ was negatively correlated with genes related to immunotherapy efficacy such as CD8A, CD274 and GZMA, and was also negatively correlated with T-cell infiltration in tumor tissue. Conclusion: PROZ is a gene related to the prognosis of hepatocellular carcinoma and it is closely related to the efficacy of sorafenib and immunotherapy. It may serve as a potential molecular target to improve the efficacy of targeted combined immunotherapy.

Fatigue Fracture Analysis on 2524 Aluminum Alloy with the Influence of Creep-Aging Forming Processes.

The different creep-aging forming processes of 2524 aluminum alloy were taken as the research object, and the effects of creep-aging temperature and creep stress on the fatigue-crack propagation properties of the alloy were studied. The research results showed the following under the same sintering time of 9 h, at creep-aging temperatures of 100 °C, 130 °C, 160 °C, and 180 °C, respectively, with an increase in creep-aging temperature: the fatigue-crack propagation rate was promoted, the spacing of fatigue striations increased, and the sizes of dimples decreased while the number was enlarged; this proves that the fatigue property of the alloy was weakened. Compared with the specimens with creep deformation radii of 1000 mm and 1500 mm, the creep deformation stress was the smallest when the forming radius was 1800 mm, with a higher threshold value of fatigue-crack growth in the near-threshold region of fatigue-crack propagation (ΔK ≤ 8 MPa·m1/2). Under the same fatigue cycle, the specimens under the action of larger creep stress endured a longer fatigue stable-propagation time and a faster fracture speed. Comparing the effect of creep-aging temperature and creep stress, the creep-aging temperature plays a dominant role in the fatigue-crack propagation of creep-aged 2524 aluminum alloy.

Algicidal effect of tryptoline against Microcystis aeruginosa: Excess reactive oxygen species production mediated by photosynthesis.

Cyanobacterial blooms significantly decrease water quality and can damage ecosystems and, as such, require efficient control methods. Algicidal bacteria and their associated substances are promising tools for controlling cyanobacterial blooms; however, their specific algicidal mechanisms remain unclear. Therefore, the current study sought to investigate the algicidal mechanism of tryptoline (1,2,3,4-tetrahydro-9 h-pyrido[3,4-b]indole) against Microcystis aeruginosa, with a specific focus on the contribution made by reactive oxygen species (ROS), the underlying mechanisms of ROS increase, as well as the photosystem response. Results show that the algicidal ratio of tryptoline significantly and positively correlates with algal ROS. Moreover, 93.79% of the algicidal ratio variation is attributed to ROS in the tryptoline group, while only 47.75% can be attributed to ROS in the tryptoline + N-acetyl-L-cysteine (NAC) group, where ROS are partially scavenged by NAC. In the presence of tryptoline, algicidal effect and ROS levels were significantly enhanced in the presence of light as compared to those in the dark (P < 0.001). Hence, the increase in ROS production attributed to tryptoline is primarily affected by the presence of light and photosynthesis. Additionally, tryptoline significantly reduces Fv/Fm, PIABS, ETo/RC, and the expression of psaB and psbA genes related to photosynthesis, while increasing Vj and DIo/RC (P < 0.05). These results suggest that tryptoline hinders algal photosynthesis by significantly decreasing photosynthetic efficiency and carbon assimilation, inhibiting photochemical electron transfer, and increasing closed reaction centers and energy loss. Moreover, following partial blockade of the photosynthetic electron transfer from QA to QB by diuron (3-(3-4-dichlorophenyl)-1,1-dimethylurea), the ROS of algae exposed to tryptoline is significantly decreased. Thus, tryptoline inhibits electron transfer downstream of QA, which increase the number of escaping electron and thereby increase ROS generation. Collectively, this study describes the algicidal mechanism of tryptoline against M. aeruginosa and highlights the critical factors associated with induction of algicidal activity.

Synergistic effects of α-Mangostin and sorafenib in hepatocellular carcinoma: New insights into α-mangostin cytotoxicity.

Sorafenib remains the standard first-line treatment for advanced hepatocellular carcinoma (HCC), although other clinical trials are currently underway for treatments that show better curative effects. However, some patients are not sensitive to sorafenib. α-Mangostin, extracted from the pericarp of the mangosteen, which is widely used as a traditional medicine, has anticancer and anti-proliferative properties in various types of cancers, including HCC. In the present study, we found that combining sorafenib and α-Mangostin could be synergistically toxic to HCC both in vitro and in vivo. We then demonstrated that the combination of sorafenib and α-Mangostin enhances the inhibition of cell proliferation in HCC cell lines. Combination therapy leads directly to apoptosis. In xenograft mouse models, the in vivo safety and effectivity was confirmed by a reduction in tumor size after combination treatment. RNA sequencing and protein testing showed that the expression of LRRC8A and RNF181 genes and mTOR and MAPK pathways may be associated with the synergistic effect of the two drugs. In conclusion, our results highlight the synergistic effect of the combination of sorafenib and α-Mangostin, which indicates a potential treatment for advanced HCC for patients that are not sensitive to sorafenib therapy.

MicroRNA-126 Inhibit Viability of Colorectal Cancer Cell by Repressing mTOR Induced Apoptosis and Autophagy.

OBJECTIVE: Colorectal cancer (CRC) is a fatal disease, and tumor development is a complex cellular event involving a multistep cascade process involving proliferation, invasion, and migration. In recent years, it has been shown that microRNA-126 (miR-126) plays a key role in the tumorigenesis of CRC, but further studies are required to investigate the regulatory mechanisms through which this miRNA affects cell viability, autophagy, and apoptosis in CRC. We aimed to study the effect of miR-126 in gene regulation in CRC HCT116 cells. METHODS: CRC biopsy samples and normal colorectal tissue samples were used for miRNA profiling. Real-time quantitative PCR and WB were utilized to detect RNA and protein levels. MTT and colony formation assays were performed to examine cell viability. Furthermore, an immunofluorescence assay and Annexin V/PI flow cytometry were performed to detect autophagy and apoptosis, respectively. RESULTS: The expression of miR-126 was downregulated in CRC biopsies and cell lines compared with that in normal cells and tissues. The upregulation of miR-126 resulted in impaired viability and growth of CRC cells. Furthermore, with the overexpression of miR-126, cell autophagy was increased, as evidenced by LC3-I/II transformation and p62 degradation. Meanwhile, apoptosis induction was also observed because of the increased miR-126 levels. The autophagy inhibitor Bafilomycin A1 (BafA1) repressed both autophagy and apoptosis, indicating that miR-126 induced autophagy was responsible for the induction of apoptosis. A dual-luciferase reporter assay (DLRA) and bioinformatics prediction revealed that miR-126 silenced the mTOR gene by targeting the 3'-UTR. mTOR mRNA levels in CRC biopsy tissues and cell lines were upregulated to a greater extent than that in normal cells and tissues. Furthermore, HCT116 cells transfected with an miR-126 mimic showed a decreased expression of mTOR. In addition, the overexpression of mTOR counteracted miR-126 on autophagy and apoptosis. CONCLUSION: Our study demonstrated that miR-126-induced can regulate the activity of CRC cells via autophagy and apoptosis and suggested a new mechanism of miR-126-mTOR interaction in CRC pathogenesis.

Efficacy of Oxaliplatin/5-Fluorouracil/Capecitabine-Cetuximab Combination Therapy and Its Effects on K-Ras Mutations in Advanced Colorectal Cancer.

BACKGROUND The aim of this study was to perform an accurate exploration on the efficacy of oxaliplatin/5-fluorouracil/capecitabine-cetuximab combination therapy and its effects on K-Ras mutations in advanced colorectal cancer. MATERIAL AND METHODS Among 96 patients who suffered metastatic colorectal cancer without mutated K-Ras, 41 patients who were receiving treatment with oxaliplatin/5-fluorouracil/capecitabine and administered cetuximab as the initial treatment comprised the observation group; the remaining 55 patients receiving cetuximab as an alternative treatment comprised the control group. RESULTS The observation group experienced significantly higher objective response rates (ORRs), and disease control rates (DCRs), than the control group (P<0.05 for both). The median progression-free survival (PFS) rates of the observation group and the control groups were 11.2 months (95% confidence interval [CI]: 10.1-12.3 months) and 7.4 months (95% CI: 6.6-8.2 months). The median overall survival (OS) rates were 16.8 months (95% CI: 15.2-18.4 months) and 12.4 months (95% CI: 11.6-13.2 months), respectively. The observation group had significantly longer PFS and OS in comparison to the control group (P<0.05). The patients who underwent cetuximab treatment for ≥10 months had a slightly higher rate of K-Ras mutations than those treated with cetuximab for <10 months (9.1% versus 7.3%). CONCLUSIONS Oxaliplatin/5-fluorouracil/capecitabine plus cetuximab exhibited better efficacy as initial treatment than the alternative treatment; it was also highly safe. Unfortunately, some patients might develop K-Ras mutations after long duration of cetuximab treatment, suggesting that K-Ras mutations are correlated with tumor progression and depend on the duration or dose of cetuximab treatment.

Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer.

BACKGROUND: Pancreatic cancer is a major cause of cancer-related death, with a 5-year overall survival rate being below 5%. The main causes of poor prognosis in pancreatic cancer include easy metastasis, high recurrence rate, and robust drug resistance. Gemcitabine is a first-line drug for patients with unresectable pancreatic cancer. However, due to drug resistance, the clinical effect is not satisfactory. ADAM28 is reported as a tumor promoter in some cancers, but its role in pancreatic cancer and gemcitabine chemoresistance in pancreatic cancer has not been elucidated. AIM: To identify if ADAM28 can act as an important target to reverse the gemcitabine drug resistance in pancreatic cancer. METHODS: RNA-sequence analysis was applied to explore the potential targets involved in the gemcitabine of pancreatic cancer. SW1990 pancreatic cancer cells were treated with an increased dose of gemcitabine, and the mRNA levels of ADAM28 were evaluated by RT-PCR. The protein and mRNA levels of ADAM28 were confirmed in the gemcitabine resistant and parallel SW1990 cells. The ADAM28 expression was also assessed in TCGA and GEO databases, and the results were confirmed in the collected tumor and adjacent normal tissues. The overall survival (OS) rate and relapse-free survival (RFS) rate of pancreatic cancer patients with high ADAM28 level and low ADAM28 level in TCGA were evaluated with Kaplan-Meier Plotter. Furthermore, the OS rate was calculated in pancreatic cancer patients with high tumor mutation burden (TMB) and low TMB. CCK-8 assay was used to examine the effect of ADAM28 on the viability of SW1990 cells. The ADAM28 and its co-expressed genes were analyzed in the cBioPortal for cancer genomics and subjected to GSEA pathway analysis. The correlations of ADAM28 with GSTP1, ABCC1, GSTM4, and BCL2 were analyzed based on TCGA data on pancreatic cancer. RESULTS: RNA-sequence analysis identified that ADAM28 was overexpressed in gemcitabine-resistant cells, and gemcitabine treatment could induce the expression of ADAM28. The mRNA and protein levels of ADAM28 were elevated in gemcitabine-resistant SW1990 cells compared with parallel cells. Also, the expression of ADAM28 was upregulated in pancreatic tumor tissues against normal pancreatic tissues. Notably, ADAM28 was highly expressed in the classical type than in the basal tumor type. Furthermore, the high expression of ADAM28 was associated with low OS and RFS rates. Interestingly, the high levels of ADAM28 was associated with a significantly lower OS rate in the high TMB patients, but not in the low TMB patients. Moreover, overexpression of ADAM28 could reduce the cell viability inhibition by gemcitabine, and knockdown of ADAM28 could enhance the proliferation inhibition by gemcitabine. The GSEA analysis showed that ADAM28 was related to the regulation of drug metabolism, and ADAM28 was significantly positively correlated with GSTP1, ABCC1, GSTM4, and BCL2. CONCLUSION: This study demonstrates that ADAM28 is overexpressed in pancreatic cancer, and closely involved in the regulation of gemcitabine resistance. Overexpression of ADAM28 is a novel prognostic biomarker in pancreatic cancer.

The Prognostic Value of aspartate aminotransferase to lymphocyte ratio and systemic immune-inflammation index for Overall Survival of Hepatocellular Carcinoma Patients Treated with palliative Treatments.

Background: Lymphocytes were reported to play a significant part in host anticancer immune responses and influence tumour prognosis. Few studies have focused on the prognostic values of aspartate aminotransferase (AST) to lymphocyte ratio (ALRI), aspartate aminotransferase to platelet count ratio index (APRI) and systemic immune-inflammation index (SII) in hepatocellular carcinoma (HCC) treated with palliative treatments. Methods: Five hundred and ninety-eight HCC patients treated with palliative therapies were retrospectively analysed. We randomly assigned patients into the training cohort (429 patients) and the validation cohort I (169 patients). Receiver operating characteristic (ROC) curves were used to identify the best cut-off values for the ALRI, APRI and SII in the training cohort and the values were further validated in the validation cohort I. Correlations between ALRI and other clinicopathological factors were also analysed. A prognostic nomogram including ALRI was established. We validated the prognostic value of the ALRI, SII and APRI with two independent cohorts, the validation cohort II of 82 HCC patients treated with TACE and the validation cohort III of 150 HCC patients treated with curative resection. In the training cohort and all the validation cohorts, univariate analyses by the method of Kaplan-Meier and multivariate analysis by Cox proportional hazards regression model were carried out to identify the independent prognostic factors. Results: The threshold values of ALRI, APRI and SII were 86.3, 1.37 and 376.4 respectively identified by ROC curve analysis in the training cohort. Correlation analysis showed that ALRI>86.3 was greatly associated with higher rates of Child-Pugh B&C, portal vein tumor thrombosis (PVTT) and ascites (P < 0.05). Correspondingly, ALRI level of HCC patients with Child-Pugh B&C, PVTT and ascites was evidently higher than that of HCC patients with Child-Pugh A, without PVTT and without ascites (P < 0.001). In the training cohort and the validation cohort I, II, III, the OS of patients with ALRI >86.3 was obviously shorter than patients with ALRI ≤86.3 (P <0.001). We identified ALRI as an independent prognostic factor by univariate and multivariate analyses both in training Cohort (HR=1.481, P=0.004), validation cohort I (HR=1.511, P=0.032), validation cohort II (HR=3.166, P=0.005) and validation cohort III (HR=3.921, P=0.010). The SII was identified as an independent prognostic factor in training cohort (HR=1.356, P=0.020) and the validation cohort II (HR=2.678, P=0.002). The prognostic nomogram including ALRI was the best in predicting 3-month, 6-month, 1-year, 2-year survival And OS among TNM, ALRI, ALRI-TNM and nomogram. Conclusions: The ALRI was a novel independent prognostic index for the HCC patients treated with palliative treatments.

Comparison of five staging systems in predicting the survival rate of patients with hepatocellular carcinoma undergoing trans-arterial chemoembolization therapy.

The majority of patients with unresectable hepatocellular carcinoma (HCC) undergo trans-arterial chemoembolization (TACE). However, the prognosis of HCC remains poor. In the present study, five staging systems were compared to predict the survival rate of patients with HCC undergoing TACE treatment. A total of 220 patients with HCC were examined according to the model to estimate survival for hepatocellular carcinoma (MESH), hepatoma arterial embolization prognostic score (HAP), modified HAP (mHAP), performance status combined Japan Integrated Staging system (PSJIS) and tumor-node-metastasis (TNM) staging systems. The endpoints of the study were 3-month survival, 6-month survival, 1-year survival and overall survival (OS) rates. Receiver operating characteristic curve analysis indicated that the area under the curve of MESH, HAP, mHAP, PSJIS and TNM was 0.858, 0.728, 0.690, 0.688 and 0.699, respectively, in predicting 3-month survival rates; 0.822, 0.747, 0.720, 0.722 and 0.715, respectively, in predicting 6-month survival rates and 0.725, 0.664, 0.672, 0.645 and 0.654, respectively, in predicting 1-year survival rates. Discriminatory ability, homogeneity, monotonicity and prognostic stratification ability was evaluated using a likelihood ratio test and Akaike information criterion values among the five staging systems, and revealed that the MESH system was the optimal prognostic staging system for HCC. In conclusion, the results of the present study suggest that the MESH system is the most accurate prognostic staging system of 3-month survival, 6-month survival, 1-year survival and OS rates among the five systems analyzed in patients with HCC who have received TACE treatment.

Albumin-to-Alkaline Phosphatase Ratio as an Independent Prognostic Factor for Overall Survival of Advanced Hepatocellular Carcinoma Patients without Receiving Standard Anti-Cancer Therapies.

Background Albumin-to-Alkaline Phosphatase Ratio (ALB/ALP ratio, AAPR), a newly developed index of liver function, has been rarely discussed about its prognostic value in malignancies. The current study attempted to evaluate the prognostic prediction of AAPR in advanced HCC. Methods 237 advanced HCC patients who refused any standard anti-cancer therapies were retrospectively analyzed. The threshold value of AAPR was determined by receiver operating characteristic (ROC) curve. Univariate analyses using Kaplan-Meier method and log-rank test, and multivariate analysis using Cox proportional hazards regression model were conducted. Comparisons of ROC curves and likelihood ratio test (LRT) were utilized to compare the value of different factors in predicting survival. Results ROC curve analysis confirmed 0.38 as the optimal cutoff value of AAPR in evaluating overall survival (OS). Patients with an AAPR > 0.38 exhibited significantly lower frequencies of ascites, portal vein tumor thrombus, Child-Pugh grade B & C, and KPS < 70 (all P < 0.05). These patients also displayed a longer median survival time than those with an AAPR ≤ 0.38 (5.8 m vs 2.4 m, P < 0.01). Univariate and multivariate analyses identified AAPR as an independent prognostic indicator (HR = 0.592, P = 0.007). Furthermore, we integrated AAPR with TNM system and found that area under curve of AAPR-TNM system was significantly larger than that of TNM system when predicting 3-month survival (0.670 vs 0.611, P < 0.01). Moreover, LRT indicated that AAPR-TNM system had a significantly larger χ2 (26.4 vs 16.4, P < 0.01) and a significantly smaller Akaike information criterion value (1936 vs 1948, P < 0.01) comparing with TNM system. Conclusions Our study implied that AAPR was a potentially valuable prognostic index for advanced HCC patients without receiving any standard anti-cancer therapies. AAPR-TNM system preceded TNM system in predicting overall survival in this study.

Combination of ULK1 and LC3B improve prognosis assessment of hepatocellular carcinoma.

BACKGROUND: Autophagy involves in both prevention and promotion in cancer, and its role probably changed during tumor development. Defined the dynamic function of autophagy in cancer may advance precision diagnostics, treatment, and guide drug design. Autophagy related protein ULK1 is key regulator of autophagy, and its role in hepatocellular carcinoma (HCC) was still unclear. This study aims to investigate ULK1's capacity along with other autophagic markers in predicting prognosis of HCC and explore position of these biomarkers in dynamic function of autophagy during HCC progression. METHODS: The expression of ULK1 and other autophagic marker (LC3B) were test by Tissue microarray-based immunohistochemistry in 156 operable HCC patients. Survival analysis and correlation analysis were used to analysis influence of ULK1 and combined biomarker on clinical characteristics and prognosis. RESULTS: The expression level of ULK1 was not related to all clinicopathological features, however, high expression of the ULK1 as well as LC3B overexpression suggested large tumor size (P=0.035), high levels of serum AFP (P=0.049), more frequency of node metastasis (P=0.015), later TNM stage (P=0.009). Survival analysis showed that ULK1 expression were negatively correlated with PFS rather than OS in HCC patients (P=0.021), while LC3B were suggested to be negatively related with patients' PFS, However, Simultaneous high expression of ULK1 and LC3B had a poorer 5-year overall survival (OS) rate (P=0.002) and shorter 5-year progression free survival (PFS)(P=0.003), Further multivariate analysis revealed that the two combined biomarkers were independent factors to predict the prognosis of OS and PFS in all patients, while ULK1 alone or LC3B alone were only an independent predict factor for OS or PFS respectively. CONCLUSION: ULK1 were demonstrated to be an important prognostic factor for HCC patient, and it combined LC3B would improve prognosis assessment of the patients. Combined autophagic biomarkers would better represent dynamic stage of autophagy and It might provide a potential therapeutic way that how to interfere autophagy in HCC.

Serum Golgi protein 73 is a prognostic rather than diagnostic marker in hepatocellular carcinoma.

Serum Golgi protein 73 (sGP73) is a candidate diagnostic biomarker for hepatocellular carcinoma (HCC). However, current evidence of its diagnostic value is conflicting, primarily due to the small sample sizes of previous studies, and its prognostic role in HCC also remains unclear. In the present study, sGP73 levels in 462 patients with HCC, 186 patients with liver cirrhosis, and 83 healthy controls were evaluated using ELISA, and it was identified that the median sGP73 levels were significantly higher in the HCC (18.7 ng/ml) and liver cirrhosis (18.5 ng/ml) patients than in the healthy controls (0 ng/ml; both P<0.001); however, the levels did not significantly differ between the HCC and liver cirrhosis groups (P=0.632). sGP73 had an inferior sensitivity and specificity for HCC diagnosis (27.79 and 77.96%, respectively) compared with α-fetoprotein (57.36 and 90.96%, respectively; P<0.001). In the HCC group, a high level of sGP73 was associated with aggressive clinicopathological features and independently predicted poor overall survival (OS) time (P<0.001). Additionally, in patients with resectable HCC, a high level of sGP73 was associated with significantly decreased disease-free survival (P<0.001) and OS (P=0.039) times compared with a low level of sGP73. This study demonstrated that sGP73 is unsuitable as a diagnostic marker for the early detection of HCC; however, it is an independent negative prognostic marker, providing a novel risk stratification factor and a potential therapeutic molecular target for HCC.

Identification of the prognostic value of lymphocyte-to-monocyte ratio in patients with HBV-associated advanced hepatocellular carcinoma.

The inflammatory microenvironment serves an important function in the progression of hepatocellular carcinoma (HCC). Peripheral blood lymphocyte-to-monocyte ratio (LMR), as a novel inflammatory biomarker combining an estimate of host immune homeostasis with the tumor microenvironment, has been identified to be a predictor of clinical outcomes in a number of malignancies. The present study aimed at investigating the prognostic value of LMR in patients with hepatitis B virus (HBV)-associated advanced HCC. A total of 174 patients with HBV-associated advanced HCC, without fever or signs of infections, were analyzed. Clinicopathological parameters, including LMR, were evaluated to identify predictors of overall survival time. Univariate and multivariate analysis was performed using Cox's proportional hazards model. A threshold value was determined using a time-dependent receiver operating characteristic curve. Univariate and multivariate analysis identified LMR as an independent prognostic factor in overall survival (OS) time in patients with HBV-associated advanced HCC (P<0.05). The threshold value of LMR was 2.22. All patients were divided into either a low LMR group (≤2.22) or a high LMR group (>2.22). The OS time of the high LMR group was significantly longer compared with the low LMR group (P<0.001). Patients in the high LMR group exhibited a significantly increased 3-month and 6-month OS rate, compared with that of the patients within the low LMR group (P<0.001). An increased level of LMR was significantly associated with the presence of metastasis, ascites and increased tumor size (P<0.01). LMR is an independent prognostic factor of HBV-associated advanced HCC patients and an increased baseline LMR level indicates an improved prognosis.

Validation and ranking of seven staging systems of hepatocellular carcinoma.

The aim of the present study was to evaluate the ability of seven staging systems to predict 3- and 6-month and cumulative survival rates of patients with advanced hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Data were collected from 220 patients with HBV-associated HCC who did not receive any standard anticancer treatment. Participants were patients at The Third Affiliated Hospital of Sun Yat-sen University from September 2008 to June 2010. The participants were classified according to the Chinese University Prognostic Index (CUPI), the Cancer of the Liver Italian Program (CLIP), Japan Integrated Staging (JIS), China Integrated Score (CIS) systems, Barcelona Clinic Liver Cancer (BCLC), Okuda and tumor-node-metastasis (TNM) staging systems at the time of diagnosis and during patient follow-up. The sensitivity and specificity of the predictive value of each staging system for 3- and 6-month mortality were analyzed by relative operating characteristic (ROC) curve analysis with a non-parametric test being used to compare the area under curve (AUC) of the ROC curves. In addition, log-rank tests and Kaplan-Meier estimator survival curves were applied to compare the overall survival rates of the patients with HCC defined as advanced using the various staging systems, and the Akaike information criterion (AIC) and likelihood ratio tests (LRTs) were used to evaluate the predictive value for overall survival in patients with advanced HCC. Using univariate and multivariate Cox's model analyses, the factors predictive of survival were also identified. A total of 220 patients with HBV-associated HCC were analyzed. Independent prognostic factors identified by multivariate analyses included tumor size, α-fetoprotein levels, blood urea nitrogen levels, the presence or absence of portal vein thrombus, Child-Pugh score and neutrophil count. When predicting 3-month survival, the AUCs of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 0.806, 0.772, 0.751, 0.731, 0.643, 0.754 and 0.622, respectively. When predicting 6-month survival, the AUCs of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 0.828, 0.729, 0.717, 0.692, 0.664, 0.746 and 0.575, respectively. For 3-month mortality, the prognostic value of CLIP ranked highest, followed by CIS; for 6-month mortality, the prognostic value of CLIP also ranked highest, followed by JIS. No significant difference between the AUCs of CLIP and CIS (P>0.05) in their predictive value for 3-month mortality was observed. The AUC of CLIP was significantly higher compared with that of the other staging systems (P<0.05) for predicting 6-month mortality. The χ2 values from the LRTs of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 75.6, 48.4, 46.7, 36.0, 21.0, 46.8 and 7.24, respectively. The AIC values of CLIP, CIS, CUPI, Okuda, TNM, JIS and BCLC were 1601.5, 1632.3, 1629.9, 1641.1, 1654.8, 1627.4 and 1671.1, respectively. CLIP exhibited the highest χ2 value and lowest AIC value, indicating that CLIP has the highest predictive value of cumulative survival rate. In the selected patients of the present study, CLIP was the staging system best able to predict 3- and 6-month and overall survival rates. CIS ranked second in predicting 3-month mortality.

Advance directives: cancer patients' preferences and family-based decision making.

BACKGROUND: Advance directives are a sensitive issue among traditional Chinese people, who usually refrain from mentioning this topic until it is imperative. Medical decisions for cancer patients are made by their families, and these decisions might violate patients' personal will. OBJECTIVES: This study aimed to examine the acceptance of advance directives among Chinese cancer patients and their families and patient participation in this procedure and, finally, to analyze the moral risk involved. RESULTS: While 246 patients and their family members refused official discussion of an advance directive, the remaining 166 patients and their families accepted the concept of an advance directive and signed a document agreeing to give up invasive treatment when the anti-cancer treatment was terminated. Of these, only 24 patients participated in the decision making. For 101 patients, anti-cancer therapy was ended prematurely with as many as 37 patients not told about their potential loss of health interests. MATERIALS AND METHODS: Participants were 412 adult cancer patients from 9 leading hospitals across China. An advance directive was introduced to the main decision makers for each patient; if they wished to sign it, the advance directive would be systematically discussed. A questionnaire was given to the oncologists in charge of each patient to evaluate the interaction between families and patients, patients' awareness of their disease, and participation in an advance directive. CONCLUSIONS: Advance directives were not widely accepted among Chinese cancer patients unless anti-cancer therapy was terminated. Most cancer patients were excluded from the discussion of an advance directive.

Nomogram for preoperative estimation of long-term survival of patients who underwent curative resection with hepatocellular carcinoma beyond Barcelona clinic liver cancer stage A1.

BACKGROUND AND AIMS: This retrospective cohort study developed a prognostic nomogram to predict the survival of hepatocellular carcinoma (HCC) patients diagnosed as beyond Barcelona clinic liver cancer stage A1 after resection and evaluated the possibility of using the nomogram as a treatment algorithm reference. RESULTS: The predictors included in the nomogram were total tumour volume, Child-Turcotte-Pugh class, plasma fibrinogen and portal vein tumour thrombus. Patients diagnosed as beyond A1 were stratified into low-, medium- and high-risk groups using nomogram scores of 0 and 51 with the total points of 225. Patients within A1 exhibited similar recurrence-free survival (RFS) and overall survival (OS) rates compared with the low-risk group. Patients in the medium-risk group exhibited a similar OS but a worse RFS rates compared with patients within A1. The high-risk group was associated with worse RFS and OS rates compared with the patients within A1 (3-year RFS rates, 27.0% vs. 60.3%, P < 0.001; 3-year OS rates, 49.2% vs. 83.1%, P < 0.001). METHODS: A total of 352 HCC patients undergoing curative resection from September 2003 to December 2012 were included to develop a nomogram to predict overall survival after resection. Univariate and multivariate survival analysis were used to identify prognostic factors. A visually orientated nomogram was constructed using a Cox proportional hazards model. CONCLUSIONS: This user-friendly nomogram offers an individualized preoperative recurrence risk estimation and stratification for HCC patients beyond A1 undergoing resection. Resection should be considered the first-line treatment for low-risk patients.

Alanine aminotransferase to hemoglobin ratio is an indicator for disease progression for hepatocellular carcinoma patients receiving transcatheter arterial chemoembolization.

The prognosis of hepatocellular carcinoma (HCC) patients receiving transcatheter arterial chemoembolization (TACE) is far from being identified. The present study aimed to assess the role of blood cell counts, routine liver function tests, and alanine aminotransferase to hemoglobin ratio (AHR) in predicting the progression-free survival (PFS) of these patients. A total of 243 HCC patients receiving TACE were analyzed retrospectively. Cancer of the Liver Italian Program (CLIP) score system was indentified to be the best score system for this patient subgroup according to the Akaike information criterion (AIC) index and linear trend χ (2). Then, prognostic value of parameters was determined by integration into the CLIP score system. As a result, AHR was confirmed to be an independent predictor for the PFS of HCC patients receiving TACE (p = 0.001) with the other parameters failing to reach statistical significance. Moreover, AHR improved the performance of CLIP by adjusting into it, thus improving its discriminatory ability. AHR defined ≤0.4583 as low level and >0.4583 as high level. And, patients were also dichotomized into two groups accordingly. HCC patients receiving TACE with low AHR presented higher 1 year DCR (41.9 vs 18.1 %) compared with patients with high AHR levels. Furthermore, AHR level was associated with prognostic factors such as lower ALP, total bilirubin, and portal vein thrombosis. In summary, the present study firstly indentified AHR as an independent prognostic factor in HCC patients receiving TACE. The subgroup of HCC patients with lower AHR presented preferable disease control and were the idealistic candidates for TACE.