124I-labeled anti-CD147 antibody for noninvasive detection of CD147-positive pan-cancers: construction and preclinical studies.

Extracellular matrix metalloproteinase inducer CD147 is a glycoprotein on the cell surface. There is minimal expression of CD147 in normal epithelial and fetal tissues, but it is highly expressed in a number of aggressive tumors. CD147 has been implicated in pan-cancer immunity and progression. With the development of CD147-targeting therapeutic strategy, accurate detection of CD147 expression in tumors and its changes during the therapy is necessary. In this study we constructed a novel radiotracer by labeling the anti-CD147 mAb with radionuclide 124/125I (124/125I-anti-CD147) for noninvasive detection of CD147 expression in pan-cancers, and characterized its physicochemical properties, affinity, metabolic characteristics, biodistribution and immunoPET imaging with 124I-IgG and 18F-FDG as controls. By examining the expression of CD147 in cancer cell lines, we found high CD147 expression in colon cancer cells LS174T, FADU human pharyngeal squamous cancer cells and 22RV1 human prostate cancer cells, and low expression of CD147 in human pancreatic cancer cells ASPC1 and human gastric cancer cells BGC823. 124/125I-anti-CD147 was prepared using N-bromine succinimide (NBS) as oxidant and purified by PD-10 column. Its radiochemical purity (RCP) was over 99% and maintained over 85% in saline or 5% human serum albumin (HSA) for more than 7 d; the RCP of 125I-anti-CD147 in blood was over 90% at 3 h post injection (p.i.) in healthy mice. The Kd value of 125I-anti-CD147 to CD147 protein was 6.344 nM, while that of 125I-IgG was over 100 nM. 125I-anti-CD147 showed much greater uptake in CD147 high-expression cancer cells compared to CD147 low-expression cancer cells. After intravenous injection in healthy mice, 125I-anti-CD147 showed high initial uptake in blood pool and liver, the uptake was decreased with time. The biological half-life of distribution and clearance phases in healthy mice were 0.63 h and 19.60 h, respectively. The effective dose of 124I-anti-CD147 was estimated as 0.104 mSv/MBq. We conducted immunoPET imaging in tumor-bearing mice, and demonstrated a significantly higher tumor-to-muscle ratio of 124I-anti-CD147 compared to that of 124I-IgG and 18F-FDG in CD147 (+) tumors. The expression levels of CD147 in cells and tumors were positively correlated with the maximum standardized uptake value (SUVmax) (P < 0.01). In conclusion, 124/125I-anti-CD147 displays high affinity to CD147, and represents potential for the imaging of CD147-positive tumors. The development of 124I-anti-CD147 may provide new insights into the regulation of tumor microenvironment and formulation of precision diagnosis and treatment programs for tumors.

Endoplasmic reticulum stress induced LOX-1+ CD15+ polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma.

A recent study indicated that Lectin-type oxidized LDL receptor-1 (LOX-1) was a distinct surface marker for human polymorphisms myeloid-derived suppressor cells (PMN-MDSC). The present study was aimed to investigate the existence LOX-1 PMN-MDSC in hepatocellular carcinoma (HCC) patients. One hundred and twenty-seven HCC patients, 10 patients with mild active chronic hepatitis B, 10 liver cirrhosis due to hepatitis B, 10 liver dysplastic node with hepatitis B and 50 health control were included. LOX-1+  CD15+ PMN-MDSC were significantly elevated in HCC patients compared with healthy control and patients with benign diseases. LOX-1+  CD15+ PMN-MDSC in circulation were positively associated with those in HCC tissues. LOX-1+  CD15+ PMN-MDSCs significantly reduced proliferation and IFN-γ production of T cells with a dosage dependent manner with LOX-1-  CD15+ PMNs reached negative results. The suppression on T cell proliferation and IFN-γ production was reversed by ROS inhibitor and Arginase inhibitor. ROS level and activity of arginase of LOX-1 + CD15+ PMN were higher in LOX-1+  CD15+ PMN-MDSCs than LOX-1-  CD15+ PMNs, as well as the expression of the NADPH oxidase NOX2 and arginase I. RNA sequence revealed that LOX-1+ CD15+ PMN-MDSCs displayed significantly higher expression of spliced X-box -binding protein 1 (sXBP1), an endoplasmic reticulum (ER) stress marker. ER stress inducer induced LOX-1 expression and suppressive function for CD15+ PMN from health donor. For HCC patients, LOX-1+  CD15+ PMN-MDSCs were positively related to overall survival. Above all, LOX-1+  CD15+ PMN-MDSC were elevated in HCC patients and suppressed T cell proliferation through ROS/Arg I pathway induced by ER stress. They presented positive association with the prognosis of HCC patients.

Comparison of five models for end-stage liver disease in predicting the survival rate of patients with advanced hepatocellular carcinoma.

Prognosis of patients with advanced hepatocellular carcinoma (HCC) is under expectation. Life expectancy more than 3 months is one inclusion criteria for molecular targeted drugs in clinical trials. The main purpose of this research is to compare Model for End-Stage Liver Disease (MELD) and four MELD-based prognostic models in predicting the survival rate of advanced HCC patients. One hundred eighty-three patients with advanced HCC who were not amendable to standard anti-tumor therapy were retrospectively analyzed. Data were collected to classify patients according to MELD, Model for End-Stage Liver Disease with the incorporation of serum sodium (MELD-NA), Model for End-Stage Liver Disease to ascites and sodium (MELD-AS), integrated Model for End-Stage Liver Disease (iMELD), and Model for End-Stage Liver Disease to sodium (MESO) scores at diagnosis. 1-, 3-, and 6-month survivals were the end points used in the analysis. When predicting 1-month survival, MELD-AS, MELD, and MESO were the top 3 ranking staging systems. When predicting 3-month survival, area under the receiver operating characteristic curve (AUC) of MELD-AS is significantly higher than that of the other models (P < 0.05). When predicting 6-month survival, AUCs of MELD-AS and MELD-NA are significantly higher than those of the other models (P < 0.05). Cutoff point of MELD-AS is 23.11 with 40.5 % sensitivity and 93.8 % specificity at 1 month, 9.5 with 76.9 % sensitivity and 59.5 % specificity at 3 months, and 18.5 with 27.0 % sensitivity and 89.1 % specificity at 6 months. MELD-based scores of death group are significantly higher than those of survivors within 1 and 3 months (P < 0.001). Independent prognostic factors identified by multivariate analysis included persistent ascites, serum sodium, and thrombosis. MELD-AS is the best model in the prediction of short and intermediate survival among the five models for end-stage liver disease analyzed for Chinese advanced HCC 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.

Platelet-to-lymphocyte ratio acts as a prognostic factor for patients with advanced hepatocellular carcinoma.

The platelet count, as an inflammation marker, is involved in the progress of tumor invasion. However, the prognostic value of platelet counts and the platelet-to-lymphocyte ratio (PLR) has not been investigated in patients with advanced hepatocellular carcinoma (HCC). This study aimed to determine the prognostic value of platelet counts and PLR in HCC patients. A total of 243 ethnic Chinese advanced HCC patients from two major hospitals, not receiving systemic sorafenib, were analyzed retrospectively. The prognostic value of differential blood cell counts and PLR for overall survival (OS) was determined by integrating the Cancer of the Liver Italian Program (CLIP) score system and model for end-stage liver disease by using a stepwise model of multivariate Cox regression. The Kaplan-Meier method and receiver operating characteristic (ROC) curves were utilized accordingly. PLR was confirmed to be an independent predictor for OS (p < 0.01), while the remaining parameters had no predictive value. Then, advanced HCC patients were dichotomized into two groups based on the PLR value (≤111.23 or >111.23), according to ROC analysis. Patients with a high PLR had a lower 3-month survival rate (37.6 vs. 57.6%) compared with patients with a low PLR. PLR was associated with aggressive malignant behavior, characterized by distant metastasis and portal vein thrombosis. Additionally, PLR was not associated with the CLIP score and Child-Pugh grade. PLR was identified as an independent prognostic factor for advanced HCC patients not receiving systemic sorafenib; the predictive ability of PLR partially relies on its association with the aggressive nature of HCC.

Autophagic LC3B overexpression correlates with malignant progression and predicts a poor prognosis in hepatocellular carcinoma.

Autophagy is a process that involves lysosomal degradations of cellular organelles and closely related to tumor occurrence and progression. However, its importance in hepatocellular carcinoma (HCC) was still controversial. Therefore, this study is aimed to address the clinicopathologic effect of microtubule-associated protein 1 light chain 3B (LC3B) and Beclin-1, as autophagic markers, in HCC patients. Tissue microarray-based immunohistochemistry was used to examine the expression of LC3B and another autophagy key regulator (Beclin-1) in 156 operable HCC patients. Kaplan-Meier analysis, chi-square test, and Spearman's correlation analysis were used to analyze correlation of LC3B and Beclin-1 and their influence on clinical characteristics and prognosis. We found that the expression level of LC3B was significantly associated with vascular invasion (P = 0.008), lymph node metastasis (P < 0.001), and Beclin-1 expression level (P < 0.001). However, LC3B was not related to other clinicopathological features, including hepatitis B virus infection, liver cirrhosis, tumor number, tumor size, pathology grade, and tumor-node-metastasis (TNM) stage. Besides, correlation between the expression of Beclin-1 and clinicopathological features were not identified. Survival analysis showed that patients with high LC3B expression had a poorer 5-year overall survival (OS) rate than those with low LC3B expression (high vs. low: 79.5 % vs. 20.5 %, P = 0.026). And high LC3B expression tended to be related with shorter progression-free survival (PFS) (P = 0.074), whereas the expression level of Beclin-1 did not show statistically significant association with OS or PFS. Further multivariate analysis revealed that lymph node metastasis (P = 0.047) and LC3B expression level (P = 0.047) were independent factors to predict the prognosis of OS in all patients. Our study demonstrated that high expression of LC3B, correlated with vascular invasion and lymph node metastasis, might be a novel prognostic biomarker and would be a potential therapy target for HCC, especially in operable patients.

Neutrophil-to-lymphocyte ratio acts as a prognostic factor for patients with advanced hepatocellular carcinoma.

Few studies investigated the prognosis of patients with advanced hepatocellular carcinoma (aHCC). This study was aimed to determine the prognostic value of differential blood cell counts including blood white cells, neutrophil, lymphocyte, neutrophil-lymphocyte ratio (NLR), and platelet in patients with aHCC. A total of 205 ethnic Chinese aHCC patients receiving non-systematic sorafenib were analyzed retrospectively. The prognostic value of differential blood cell counts and NLR for overall survival (OS) was determined by integration into Cancer of the Liver Italian Program (CLIP) score system using backward elimination model of multivariate Cox regression. As a result, NLR was confirmed to be an independent predictor for OS (p = 0.001) with the rest parameters presented negative results. Then, aHCC patients were dichotomized into two groups according to NLR values ≤ 2.43 or >2.43. Patients with low NLR presented lower CLIP score and higher 6-month survival rate (56.1 vs 25.9%) compared with patients with high NLR level. Besides, low NLR level was associated with favorable prognostic factors such as lower α-fetoprotein, alkaline phosphatase, and total bilirubin, as well as decreased incidence of ascites, portal vein thrombosis, and metastasis. Besides, low NLR level was associated less white cells and neutrophil granulocytes, as well as more lymphocyte. In summary, the present study firstly indentified NLR as an independent prognostic factor in aHCC patients receiving no systematic sorafenib.

Prognosis value of mitotic kinase Aurora-A for primary duodenal adenocarcinoma.

Others and we have demonstrated that hypoxia-inducible factor 1α (HIF-1α) and transcriptionally upregulated Aurora-A are required for disease progression in several tumors. We investigated the clinicopathological value of HIF-1α and Aurora-A in primary duodenal adenocarcinoma (PDA). Using immunohistochemistry, we evaluated Aurora-A and HIF-1α expression semiquantitatively in 140 PDA cases. There were 76 cases from one institute that formed the training set; 64 cases from another two institutes were used as the testing set to validate the prognostic value of Aurora-A and HIF-1α expression. Aurora-A expression was high or sufficient in the tumor zone, whereas expression was low in the adjacent normal epithelia. High Aurora-A expression, identified using the training set receiver operator characteristic (ROC) analysis-generated cutoff score, predicted poorer overall survival both in the testing set (18.0 vs. 45.1 %, P = 0.001) and training set (23.1 vs. 53.9 %, P = 0.011). Multivariate Cox regression confirmed that Aurora-A was an independent prognostic factor. Contrary to previous studies, we did not detect any correlation between Aurora-A and HIF-1α. Survival analysis showed that HIF-1α level was not correlated with patient outcome (P = 0.466). Activation of Aurora-A, an independent negative prognostic biomarker, might be used to identify particular PDA patients for more selective therapy.

An optimized antiviral modification strategy for prevention of hepatitis B reactivation in patients undergoing prophylactic lamivudine and chemotherapy: a pilot study.

In patients receiving prophylactic lamivudine (LAM) and chemotherapy, hepatitis B virus (HBV) reactivation cannot be eliminated without knowing the latent causes and optimal management. In our previous study, virus breakthrough and relapse were highly suspected as potential virologic causes for HBV reactivation. Therefore, we reviewed 24 previous studies and 447 patients who underwent chemotherapy and prophylactic LAM, with an incidence of 7.2 % HBV reactivation. Virus breakthrough and relapse were seldom investigated in these studies. In addition, 72 patients that underwent prophylactic LAM and chemotherapy at our centers were also analyzed. Among them, eight patients developed virus breakthrough, with another nine developing virus relapse after discontinuation of LAM. Eight patients received antiviral modification, which included administration of adefovir for patients with virus breakthrough or resumption of LAM for patients with virus relapse and none of them developed HBV reactivation. In contrast, of the nine patients who did not receive antiviral modification, six developed HBV reactivation and two died. In conclusion, this study demonstrated that virus breakthrough and relapse were the critical causative factors of HBV reactivation in patients receiving chemotherapy and prophylactic LAM. An optimized antiviral modification strategy could effectively prevent HBV reactivation in patients with virus breakthrough or relapse.

Clinicopathological study of malignant peripheral nerve sheath tumors in the head and neck: Case reports and review of literature.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma that poses a major diagnostic and therapeutic challenge. CASE SUMMARY: We retrospectively reviewed patients with head and neck MPNSTs treated in our hospital from 2000 to 2021. The clinical features, pathological manifestations, treatments, and prognoses were summarized. We also reviewed the literature, focusing on MPNST in the mandible and maxilla. The study population consisted of five women and five men aged 22-75 years (mean age, 49 years). Of the 10 patients, 7 were initial cases and 3 were recurrent cases. All lesions were sporadic. The most common site was the mandible. The most frequently encountered symptoms were a progressive mass and local swelling. Complete or partial loss of trimethylation at lysine 27 of histone H3 (H3K27me3) was evident on staining in four of nine cases (one case was excluded due to lack of tissue for evaluation of loss of H3K27me3). The 2- and 5-year disease-specific survival rates were 86% and 43%, respectively. The average survival time was 64 mo. CONCLUSION: MPNST is a highly malignant tumor with a poor prognosis, prone to a high risk of recurrence and distant metastasis. Complete surgical resection is the main treatment.

Prognostic value of serum HIF-1α change following transarterial chemoembolization in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) induces a change in serum HIF-1α level in patients with hepatocellular carcinoma (HCC). This study investigated the prognostic value of change in serum HIF-1α following TACE treatment in HCC patients. A total of 61 hepatocellular carcinoma patients treated with TACE were included. Peripheral blood samples were collected within 1 week before and after TACE to determine the serum levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) by enzyme-linked immunosorbent assay (ELISA). Serum HIF-1α change was calculated as follows: ∆HIF-1α = (HIF-1α (pre-TACE) - HIF-1α (post-TACE))/HIF-1α (pre-TACE). Likewise, serum VEG-F change was calculated as follows: ∆VEG-F = (VEG-F (pre-TACE) - VEG-F(post-TACE))/VEG-F (pre-TACE). Based on the cutoffs (0.25) determined by the maximum Youden's index in receiver operating characteristic analysis, the patients were grouped into the low ∆HIF-1α group (< 0.25) and the high ∆HIF-1α group (> 0.25). After TACE treatment, HIF-1α was significantly decreased (pre-TACE 1901.62 vs. post-TACE 621.82 pg/ml, P < 0.01) but VEGF-A was significantly increased (pre-TACE 60.80 vs. post-TACE 143.81 pg/ml, P < 0.01). Multivariate logistic regression analysis demonstrated that ∆HIF-1α was a prognostic factor (OR = 58.09, 95% CI: 1.59-2127.32, P = 0.027) for the TACE treatment response. Furthermore, multivariate Cox regression analysis revealed that ∆HIF-1α was a prognostic factor for progression-free survival (PFS) (HR = 0.30, 95% CI: 0.14-0.66, P = 0.003) and overall survival (OS) (estimated HR = 0.38, 95% CI: 0.16-0.93, P = 0.034). Kaplan-Meier survival analysis showed that the high ∆HIF-1α group was more likely to have longer PFS (log-rank test, P = 0.004) and OS (log-rank test, P = 0.002) than the low ∆HIF-1α group. The change in serum HIF-1α level following TACE is a prognostic factor associated with the TACE treatment response, PFS, and OS in HCC patients following TACE.

Prognostic Value of Serum Apolipoprotein B to Apolipoprotein A-I Ratio in Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization: A Propensity Score-Matched Analysis.

INTRODUCTION: The prognosis of advanced hepatocellular carcinoma (HCC) varies in patients receiving transcatheter arterial chemoembolization (TACE). In this study, we aimed to assess the prognostic value of serum apolipoprotein B (ApoB)/apolipoprotein A-I (ApoA-I) in this group of patients. METHODS: The serum lipid levels of HCC patients undergoing TACE were obtained from routine preoperative blood lipid examination. A propensity score-matched (PSM) analysis was used to eliminate the imbalance of baseline characteristics of the high and low ApoB/ApoA-I groups. Then, univariate and multivariate analysis were conducted to evaluate the prognostic value of ApoB/ApoA-I. RESULTS: In 455 HCC patients treated with TACE, ApoB/ApoA-I was positively correlated with AFP, T stage, distant metastasis, and TNM stage (p < 0.05). Patients with high ApoB/ApoA-I had a significantly shorter overall survival (OS) than those with low ApoB/ApoA-I (median OS, 21.7 vs. 39.6 months, p < 0.001). Multivariate analysis indicated that ApoB/ApoA-I was an independent prognostic index for OS (hazard ratio [HR] = 1.42, p = 0.008). After baseline characteristics were balanced, 288 patients were included in the PSM cohort. In this cohort, high ApoB/ApoA-I still predicted inferior OS in both univariate analysis (median OS, 27.6 vs. 39.3 months, p = 0.002) and multivariate analysis (HR = 1.58, p = 0.006). CONCLUSION: Serum ApoB/ApoA-I is a useful biomarker in predicting aggressive clinicopathological characteristics and poor prognosis in HCC patients treated with TACE.

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.

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.

The Predictive Value of Albumin-to-Alkaline Phosphatase Ratio for Overall Survival of Hepatocellular Carcinoma Patients Treated with Trans-Catheter Arterial Chemoembolization Therapy.

Background: We have previously reported the prognostic value of the albumin-to-alkaline phosphatase ratio (AAPR) for advanced hepatocellular carcinoma (HCC) patients who are not receiving any standard anticancer therapy. However, the prognostic value of the AAPR for HCC patients treated with trans-catheter arterial chemoembolization therapy (TACE) was not investigated. Methods: We retrospectively analysed 372 HCC patients treated with TACE (the training cohort) and applied receiver operating characteristic curves (ROC curves) to identify the best cut-off value for the AAPR in this cohort. Then, univariate analyses by the Kaplan-Meier method and multivariate analysis by a Cox proportional hazards regression model were conducted. Both comparisons of the ROC curves and the likelihood ratio test (LRT) were employed to evaluate the abilities of different factors in predicting the survival of patients in this cohort. Finally, the prognostic value of the AAPR was validated in two cohorts: one included 202 HCC patients treated with supportive care (validation cohort I), and the other included 82 HCC patients treated with TACE (validation cohort II). Results: We identified 0.439 as the best cut-off value of the AAPR by ROC curve analysis. An AAPR > 0.439 was significantly correlated with a lower frequency of Child-Pugh grade B, portal vein tumour thrombus (PVTT), T3-4 and lymph node metastasis (P < 0.05). The median overall survival (OS) of the patients with an AAPR > 0.439 was significantly longer than that of those with an AAPR ≤ 0.439 (58.4 m vs 17.8 m, respectively, P < 0.001). The AAPR was identified as an independent prognostic factor after univariate and multivariate analyses (HR = 0.636, P = 0.003). The independent prognostic value of the AAPR was also confirmed in validation cohorts I and II. Additionally, we substituted the AAPR for the Child-Pugh grade in the CLIP system and integrated the AAPR into the TNM system. We found that the area under the curve (AUC) of the AAPR-CLIP system was significantly larger than that of the CLIP and the TNM when predicting 3-month, 6-month, 1-year and 2-year survival (P < 0.05). There was no significant difference between the AUCs for the AAPR-CLIP and the AAPR-TNM. The LRT suggested that both AAPR-CLIP and AAPR-TNM had significantly larger χ2 values and smaller AIC values than that of their corresponding primary system (P < 0.05). Conclusions: The AAPR was an independent prognostic index for the HCC patients treated with TACE. Both AAPR-CLIP and AAPR-TNM outperformed their corresponding primary system in predicting OS in the current study.

Modified CLIP score with the albumin-bilirubin grade retains prognostic value in HBV-related hepatocellular carcinoma patients treated with trans-catheter arterial chemoembolization therapy.

Background: The Cancer of the Liver Italian Program (CLIP) score is commonly used for prognosis prediction of hepatocellular carcinoma (HCC). The CLIP includes the Child-Pugh grade, which is relatively subjective, for hepatic encephalopathy assessment. A newly developed scoring system called albumin-bilirubin grade (ALBI grade), consists of albumin and bilirubin to assess liver function reserve objectively. Here, we substituted the ALBI grade for the Child-Pugh grade to establish the ALBI-CLIP scoring system and validated its prognostic value in hepatitis B virus (HBV)-related HCC patients treated with trans-catheter arterial chemoembolization (TACE) therapy. Methods: We retrospectively analyzed HBV-related HCC patients who received TACE therapy. Baseline characteristics were collected and evaluated to classify patients according to ALBI-CLIP, CLIP and TNM systems. Univariate analyses using the Kaplan-Meier method and the log-rank test, as well as multivariate analysis using the Cox proportional hazards regression model, were conducted to detect independent prognostic factors for overall survival. Receiver operating characteristic (ROC) curves and a likelihood ratio test (LRT) were both utilized to compare the values of ALBI-CLIP, CLIP and TNM staging systems in predicting survival. Results: With a total of 389 patients included in the current study, 301 (77.4%) and 88 (22.6%) were classified as Child-Pugh grade A and B, respectively. However, 152 (39.1%), 227 (58.4%) and 10 (2.5%) patients were correspondingly classified into ALBI grade 1, 2 and 3. The areas under the curves of ALBI-CLIP, CLIP and TNM systems were 0.804, 0.778 and 0.734, respectively, for predicting 3-month survival; 0.796, 0.778 and 0.733, respectively, for 6-month survival; 0.697, 0.687 and 0.644, respectively, for 1-year survival; and 0.618, 0.612 and 0.569, respectively, for 2-year survival. The LRT indicated that the ALBI-CLIP and the CLIP had similar values of χ2 and Akaike information criterion (AIC) while the TNM system had the smallest χ2 value (χ2 = 12.1, 11.9, 10.5; AIC = 2620.2, 2620.5, 2621.1 for ALBI-CLIP, CLIP and TNM, respectively). Conclusions: In conclusion, our present study suggested that the ALBI-CLIP scoring system retained the prognostic value of the CLIP in HBV-related HCC treated with TACE therapy.

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.

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.