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BACKGROUND Targeted therapy based on pathway analysis of hepatitis B-related hepatocellular carcinoma (HCC) may be a promising remedy. CASE SUMMARY The present case involved an advanced hepatocellular carcinoma (HCC) patient who did not receive local regional therapy and was intolerant to sorafenib. Total RNA extracted from the patient’s tumor tissue was used to obtain the gene mutation profile. The c.3676A>T and c.4402A>T stop-gain mutations in adenomatous polyposis coli (APC) were the most prevalent (42.2% and 35.1%, respectively). MutationMapper analysis indicated that the functional domain of APC was lost in the two APC mutant genes. APC is a major suppressor of the Wnt signaling pathway. Thus, the Wnt pathway was exclusively activated due to APC dysfunction, as other elements of this pathway were not found to be mutated. Aspirin has been reported to suppress the Wnt pathway by inducing β-catenin phosphorylation through the activation of glycogen synthase kinase 3 beta via cyclooxygenase-2 pathway inhibition. Therefore, aspirin was administered to the patient, which achieved four years of disease control. CONCLUSION Exclusive mutations of APC of all the Wnt pathway elements could be a therapeutic target in HCC, with aspirin as an effective treatment option.

Fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) demethylase, participates in tumor progression and metastasis in many malignancies, but its role in colorectal cancer (CRC) is still unclear. Here, we found that FTO protein levels, but not RNA levels, were downregulated in CRC tissues. Reduced FTO protein expression was correlated with a high recurrence rate and poor prognosis in resectable CRC patients. Moreover, we demonstrated that hypoxia restrained FTO protein expression, mainly due to an increase in ubiquitin-mediated protein degradation. The serine/threonine kinase receptor associated protein (STRAP) might served as the E3 ligase and K216 was the major ubiquitination site responsible for hypoxia-induced FTO degradation. FTO inhibited CRC metastasis both in vitro and in vivo. Mechanistically, FTO exerted a tumor suppressive role by inhibiting metastasis-associated protein 1 (MTA1) expression in an m6A-dependent manner. Methylated MTA1 transcripts were recognized by an m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), which then stabilized its mRNA. Together, our findings highlight the critical role of FTO in CRC metastasis and reveal a novel epigenetic mechanism by which the hypoxic tumor microenvironment promotes CRC metastasis.

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.

CD45+CD71+ erythroid cells generated through splenic extramedullary erythropoiesis have recently been found to suppress anti-infection and tumor immunity in neonates and adults with malignances. However, their role in tumor microenvironment has not been investigated. In the present study, we found that the number of CD45+CD71+ erythroid cells was significantly elevated in hepatocellular carcinoma (HCC) tissues compared to that in paratumor region and circulation. Additionally, they were more abundant in HCC tissues compared to some immune suppressive cells as well as CD45-CD71+ erythroid cells. CD45+CD71+ erythroid cells suppressed T cells through generation of reactive oxygen species, IL-10, and TGF-β in a paracrine and cell-cell contact manner, and their suppressive effect was stronger than that of myeloid-derived suppressor cells. The abundance of CD45+CD71+ erythroid cells in tumor tissue, as illustrated via immunofluorescence, predicted disease-free survival and overall survival, and its prognostic value was better than that of Cancer of the Liver Italian Program score. This study demonstrated that accumulation of intratumoral CD45+CD71+ erythroid cells in HCC tissues could play a superior immunosuppressive role in tumor microenvironment and may serve as a valuable biomarker to predict recurrence of HCC.

CD36 plays a critical role in lipid metabolism, which is closely associated with human immunity. However, the role of CD36 in cancer remains unclear. We performed a pan-cancer analysis to elucidate the potential role of CD36 in cancer by investigating its prognostic value and current predictors for the efficacy of immune checkpoint inhibitors (ICIs) in multiple cancer types. CD36 expression in cancer cell lines, tumor tissue, and their adjacent normal tissues displayed heterogeneity among different cancers. Immunohistochemistry was used to detect CD36 expression and confirmed the results. CD36 expression significantly affects prognosis in the six cancer types. High CD36 expression was marginally associated with poorer prognosis in four of them and improved prognosis in the remaining two types. CD36 expression was significantly correlated with the 6 immune infiltrates in most cancer types. In addition, CD36 gene expression was positively correlated with Stromal score, Immune score, and ESTIMATE score. A total of 47 immune checkpoint genes were collected and their relationship with CD36 expression was analyzed. CD36 expression was significantly associated with multiple stimulatory and inhibitory checkpoint molecules with a disease-specific pattern. As to the genes reported to positively relate to the efficacy of ICIs, CD36 expression was positively correlated with most of them but negatively associated with a small proportion of cancer type-specific patterns. Concerning the genes negatively related to the efficacy of ICIs, CD36 expression was positively correlated with NRP1 and TNFSF15 in multiple cancers. CD36 expression was negatively correlated with tumor neoantigen burden in most cancer types. However, CD36 expression was negatively correlated with tumor mutation burden in most cancer types. The correlation between CD36 expression and the four methyltransferases was also significant in multiple cancers, but also with a cancer type-specific pattern. In summary, the current study found CD36 expression and its prognostic value in multiple cancer types. In addition, the expression of CD36 was significantly associated with current predictors for the efficacy of ICIs. The practical application value of CD36 is disease specific.

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.

Prostate cancer (PCa) is the most prevalent cancer among men and the second leading cause of tumor‐associated deaths worldwide, with increasing incidence rates over the last 10 years. Recently, miR‐195 was reported to be hypermethylated at its promoter CpG island and down‐regulated in hepatocellular carcinoma. However, the function of miR‐195 and the underlying mechanisms in PCa remain unknown. Here, we report that a significant down‐regulation of microRNA‐195 (miR‐195) in PCa tissues and cell lines was associated with promoter methylation status. Overexpression of miR‐195 significantly suppressed cell proliferation, migration, invasion and epithelial–mesenchymal transition (increased E‐cadherin and decreased N‐cadherin) in PCa cells. We further demonstrated that transfection with a miR‐195 inhibitor reversed the inhibitory effect of the DNA methyltransferase inhibitor 5‐azacytidine on the proliferation, migration and invasion ability of PCa cells. In summary, our findings suggest that miR‐195 may function as a crucial tumor suppressor in PCa., The tumor environment of prostate cancer promotes the methylation of microRNA‐195 (miR‐195) promoter, thereby inhibiting the expression of miR‐195, and the methyltransferase inhibitor 5‐azacytidine can reverse the methylation, promote the expression of miR‐195, and inhibit the proliferation, migration and invasion of tumor cells.

Although androgen deprivation therapy remains the standard treatment for the initial therapy of advanced prostate cancer (PC), castration does not eliminate persistent intratumoral androgens within the prostate tumor microenvironment, which is capable of activating androgen receptor. Abiraterone effectively target adrenal and tumor androgen production in castration-resistant PC (CRPC). However, abiraterone-resistant CRPC is now common challenge in clinic via multiple mechanisms.In this study, human CRPC cell line PC3 and androgen-sensitive cells LNCaP were used. The authors investigated the role of autophagy during the therapy of abiraterone in CRPC by analysis of transmission electron microscopy (TEM), Western blot and immunofluorescence assay. Cell cycle and apoptosis using flow cytometry analysis.The analysis of TEM showed more autophagic vesicles (AVs) in PC3 cell line than that in LNCaP cell line and indicated the high basic cellular autophagy in CRPC cell line PC3, which was confirmed by the upregulation of autophagy-related protein LC3, Atg5, and Beclin1. Interestingly, the treatment of abiraterone reduced the level of autophagic vesicles in two cell lines and inhibited the expressions of autophagic markers LC3, Atg5 and Beclin1 in parallel with decreased cell vitality and induced G2/M arrest in PC3 cell line and LNCaP cell line. Moreover, the addition of the autophagy inhibitor 3-methyladenine to the treatment of abiraterone inhibited the formation of AVs with downregulated autophagic markers, and inhibition of autophagy promoted the efficiency of cytotoxicity of abiraterone with further impaired cell vitality and G2/M arrest.These data suggested that inhibition of autophagy by its inhibitor benefits the treatment of abiraterone for CRPC patients.

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.

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.

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.

Purpose: Tumour cells produce energy through glycolysis and lactate dehydrogenase (LDH) is a key part of glycolysis. Elevation of serum LDH may indicate poor prognosis in primary duodenum adenocarcinoma. We aim to explore the prognostic significance of LDH in this disease. Methods and materials: Two hundred forty-four patients diagnosed with primary duodenum adenocarcinoma who were treated at the Sun Yat-sen Cancer Center from February 1996 to January 2016 were retrospectively analysed. We collected routine clinical data, including baseline LDH. Patients were classified into a normal LDH group (≤ 245U/L) and higher LDH group (>245U/L). Correlations of the LDH level and other clinicopathological characteristics were explored using the Chi-square test. Prognostic factors for overall survival were identified using univariate and multivariate analyses. Results: Two hundred seven patients (84.9%) had normal LDH levels, while 37 patients (15.1%) had abnormally high LDH levels. Higher LDH levels were significantly associated with more distant metastasis, node metastasis, poor differentiation and TNM stage Ⅲ-Ⅳ (P

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 (P2.22). The OS time of the high LMR group was significantly longer compared with the low LMR group (P

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

// Yan-Fang Xing 1, 2, 3, * , Jin-Xiang Lin 4, * , Xing Li 4, * , Qu Lin 4, * , Xiao-Kun Ma 4, * , Jie Chen 4 , Dong-Hao Wu 4 , Li Wei 4 , Liang-Hong Yin 1, 2 , Xiang-Yuan Wu 4 1 Department of Nephrology, First Affiliated Hospital of Jinan University, Guangzhou 510630, People’s Republic of China 2 School of Medicine, Jinan University, Guangzhou 510632, People’s Republic of China 3 Department of Nephrology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, People’s Republic of China 4 Department of Medical Oncology, Guangdong Key Laboratory of Liver Disease Research, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China * These authors contributed equally to this work Correspondence to: Liang-Hong Yin, email: 13725251458@126.com Xiang-Yuan Wu, email: wuxiangy@mail.sysu.edu.cn Keywords: advance directive, medical decision making, cancer, patients’ preference Received: February 08, 2017 Accepted: March 21, 2017 Published: April 28, 2017 ABSTRACT 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.

// Xing Li 1, 2, 3 , Yan-Fang Xing 4 , Ai-Hua Lei 1, 2 , Qiang Xiao 1, 2 , Zhi-Huan Lin 3 , Ying-Fen Hong 3 , Xiang-Yuan Wu 3 , Jie Zhou 1, 2 1 Program in Immunology, Affiliated Guangzhou Women and Children’s Medical Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China 2 Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China 3 Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China 4 Department of Nephrology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Correspondence to: Xiang-Yuan Wu, email: wuxiangy@mail.sysu.edu.cn Jie Zhou, email: zhouj72@mail.sysu.edu.cn Keywords: neutrophil counts, hepatocellular carcinoma, patient selection, prognosis, myeloid derived suppressor cell Received: October 07, 2016 Accepted: February 06, 2017 Published: February 17, 2017 ABSTRACT Myeloid Derived Suppressor Cell (MDSC) has been raised to be a novel target for multiple cancers. However, target agents on MDSC have not display promising efficacy. One of the critical reasons shall be less optimal patient selection. In the present study, we aimed to identify clinical parameters relevant to MDSC level in hepatocellular carcinoma (HCC) patients for future MDSC targeted therapy. In the present study, a series of 55 HCC patients (testing group) and 20 healthy donors were analyzed investigating frequencies of MDSC in peripheral blood mononuclear cells (PBMC). As a result, we found that MDSC level was increased in HCC patients compared to healthy donors (10.33% vs 1.54%, p < 0.0001). The monocytes (r 2 = 0.2875, p < 0.0001), neutrophils (r 2 = 0.3630, p < 0.0001) and platelet counts (r 2 = 0.0828, p = 0.0331) in circulation was positively associated with MDSC level. Then, the prognostic value of the above predictors was determined in a retrospective database of 255 HCC patients (validation group). The baseline characteristics of testing and validation group were similar. Multivariate analysis by Cox regression revealed that neutrophil count was an independent predictor for overall survival (OS) ( p = 0.000, HR 1.065, 95% CI 1.028–1.103), with the rest parameters failed to reach a significant result. In summary, the present study firstly identified blood neutrophil counts was a predictor of MDSC level in PBMC for HCC patients. And, patients with higher neutrophil count level might be the optimal patient subgroup for MDSC targeted therapy.

Purpose The purpose of this study was to investigate the predictive capability of neutrophil-to-apolipoprotein A1 ratio (NAR) for predicting overall survival (OS) among patients with hepatocellular carcinoma (HCC) receiving transarterial chemoembolization (TACE). Patients and Methods We investigated the clinical features of 554 patients with HCC receiving TACE and assessed NAR's predictive value for OS with 222 patients (the discovery cohort) and 332 patients (the validation cohort). The association of NAR with circulation lectin-type oxidized low-density lipoprotein receptor-1–positive (LOX-1+) polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) was illustrated. Results Multivariate Cox regression revealed that lymphocyte count; Tumor, Node, Metastasis (TNM) stage; and NAR were independent prognostic factors in the discovery cohort. The validation cohort confirmed the independent prognostic value of TNM stage and NAR. Patients with low NAR ( Conclusion This study identified NAR as an independent predictor for OS among patients with HCC receiving TACE. NAR reflected circulation LOX-1+ PMN-MDSC level. Implications for Practice The present study identified neutrophil-to-apolipoprotein A1 ratio (NAR) as an independent predictor for overall survival among patients with hepatocellular carcinoma receiving transarterial chemoembolization. NAR reflected circulation level of lectin-type oxidized low-density lipoprotein receptor-1–positive polymorphonuclear myeloid-derived suppressor cells.

Background: Blood-based tumor mutational burden (bTMB) was recently found to be suboptimal in predicting overall survival (OS) benefits of atezolizumab over docetaxel among patients with advanced non-small cell lung cancer (NSCLC). The maximum somatic allele frequency (MSAF) is an indicator of the proportion of tumor-derived plasma DNA, which could affect the concordance between bTMB and tissue-based TMB. Therefore, we aimed to evaluate the utility of MSAF, alone or in combination with bTMB, to identify NSCLC patients with or without survival benefit from atezolizumab over docetaxel.Methods: We analyzed the individual patient-level data from the randomized POPLAR and OAK studies. The bTMB and MSAF were derived from the pre-treatment blood-based genomic data.Results: In both the bTMB-high (i.e., bTMB ≥ 13) and bTMB-low subgroups, atezolizumab significantly improved OS compared with docetaxel (hazard ratio [HR] = 0.43 [95% CI, 0.29–0.65], P < 0.001 and HR = 0.73 [95% CI, 0.61–0.87], P < 0.001, respectively). Among patients with a low MSAF (i.e., MSAF < 10.3%), OS significantly favored atezolizumab (HR = 0.59 [95% CI, 0.48–0.72], P < 0.001), whereas OS with atezolizumab was similar to that with docetaxel in the MSAF-high subgroup (HR = 0.91 [95% CI, 0.68–1.20], P = 0.500; interaction test P = 0.017). Among patients from the bTMB-low and MSAF-high subgroup, OS was numerically worse with atezolizumab than with docetaxel (HR = 1.06 [95% CI, 0.78–1.45], P = 0.710); in contrast, OS was significantly improved with atezolizumab compared with docetaxel in those with either a high bTMB or low MSAF (HR = 0.57 [95% CI, 0.47–0.69], P < 0.001; interaction test P < 0.001). Consistent findings were obtained for progression-free survival data.Conclusions: MSAF alone or in combination with bTMB can effectively distinguish patients with or without survival benefit from atezolizumab compared with docetaxel. MSAF and the combined bTMB-MSAF classification may become practical predictive markers for atezolizumab in advanced NSCLC.

Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) constitutes the largest subpopulation in EBV-associated tumors worldwide. To date, 44 mature EBV-encoded microRNAs (EBV miRNAs) have been identified, but their roles in EBVaGC development are still poorly understood. In this study, we aimed to investigate the roles and targets of ebv-miR-BART10-3p (BART10-3p) and ebv-miR-BART22 (BART22) in EBVaGC. EBV miRNA expression in EBVaGCs was evaluated by deep sequencing and qRT-PCR, and relationships between BART10-3p or BART22 expression and clinicolpathological characteristics and survival rates of patients with EBVaGC were analyzed. The roles of BART10-3p and BART22 and their underlying mechanisms were further investigated through exogenous overexpression or silencing in EBVaGC cells, and validated in clinical EBVaGC tissue samples. BART10-3p and BART22 were found to be highly expressed in the EBVaGC cell lines SNU719 and YCCEL1. Higher expression of BART10-3p or BART22 in primary EBVaGC samples was significantly associated with lymph node metastasis and a worse 5-year overall survival. BART10-3p and BART22 promoted cell migration and invasion by targeting adenomatous polyposis coli (APC) and Dickkopf 1 (DKK1), thereby activating the Wnt signaling pathway and, consequently, upregulating downstream Twist and downregulating downstream E-cadherin. In 874 primary gastric carcinoma samples, APC and DKK1 were found to be lower expressed in EBVaGC than in EBV-negative samples, and their expression levels were inversely correlated with those of BART10-3p and BART22 in 71 EBVaGC samples. From our data we conclude that BART10-3p and BART22 play vital roles in promoting EBVaGC metastasis by targeting APC and DKK1 and, subsequently, activating the Wnt signaling pathway, thereby providing novel prognostic biomarkers and potential therapeutic targets for EBVaGC.

Background Deregulation of protein translation control is a hallmark of cancers. Eukaryotic initiation factor 4A2 (EIF4A2) is required for mRNA binding to ribosome and plays an important role in translation initiation. However, little is known about its functions in colorectal cancer (CRC). Methods Analysis of CRC transcriptome data from TCGA identified that EIF4A2 was associated with poor prognosis. Immunohistochemistry study of EIF4A2 was carried out in 297 paired colorectal tumor and adjacent normal tissue samples. In vitro and in vivo cell-biological assays were performed to study the biological functions of EIF4A2 on experimental metastasis and sensitivity to oxaliplatin treatment. Bioinformatic prediction, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were carried out to unveil the transcription factor of EIF4A2 regulation. Results EIF4A2 Expression is significantly higher in colorectal tumors. Multivariate analysis suggests EIF4A2 as an independent predictor of overall, disease-free and progression-free survival. Dysfunction of EIF4A2 by genetic knock-down or small-molecule inhibitor silvestrol dramatically inhibited CRC invasion and migration, sphere formation and enhanced sensitivity to oxaliplatin treatment in vitro and in vivo. Notably, EIF4A2 knock-down also suppressed lung metastasis in vivo. qRT-PCR and immunoblotting analyses identified c-Myc as a downstream target and effector of EIF4A2. ChIP and dual-luciferase reporter assays validated the bioinformatical prediction of ZNF143 as a specific transcription factor of EIF4A2. Conclusions EIF4A2 promotes experimental metastasis and oxaliplatin resistance in CRC. Silvestrol inhibits tumor growth and has synergistic effects with oxaliplatin to induce apoptosis in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Electronic supplementary material The online version of this article (10.1186/s13046-019-1178-z) contains supplementary material, which is available to authorized users.

// Dan-Yun Ruan 1, * , Ze-Xiao Lin 1, * , Tian-Tian Wang 1, * , Hui Zhao 2 , Dong-Hao Wu 1 , Jie Chen 1 , Min Dong 1 , Qu Lin 1 , Xiang-Yuan Wu 1 , Yang Li 2 1 Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong, China 2 Department of Liver Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Yang Li, email: Liyang840920@hotmail.com Xiang-Yuan Wu, email: Wuxiangy@mail.sysu.edu.cn Keywords: hepatocellular carcinoma, Barcelona clinic liver cancer stage, resection, nomogram, survival Received: April 10, 2016 Accepted: August 10, 2016 Published: August 17, 2016 ABSTRACT 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.

As a special subtype of gastric carcinoma, Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. The Cancer Genome Atlas Research Network revealed that EBVaGC also has distinct molecular features: PIK3CA mutations, DNA hypermethylation, and JAK2, PD-L1, and PD-L2 amplification. Here, we evaluated PIK3CA, JAK2, PD-L1, and PD-L2 expression in 59 EBVaGC and 796 EBV-negative gastric carcinoma (EBVnGC) cases using immunohistochemistry and found that PIK3CA, JAK2, PD-L1, and PD-L2 were highly expressed in 75.9% and 48.8% (P

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

Background and aims Hepatitis B virus (HBV) reactivation was reported to be induced by transcatheter arterial chemoembolization (TACE) in HBV-related hepatocellular carcinonma (HCC) patients with a high incidence. The effective strategy to reduce hepatitis flares due to HBV reactivation in this specific group of patients was limited to lamivudine. This retrospective study was aimed to investigate the efficacy of prophylactic entecavir in HCC patients receiving TACE. Methods A consecutive series of 191 HBV-related HCC patients receiving TACE were analyzed including 44 patients received prophylactic entecavir. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 copies/ml higher than nadir the level, and hepatitis flares due to HBV reactivation were the main endpoints. Results Patients with or without prophylactic were similar in host factors and the majorities of characteristics regarding to tumor factors, HBV status, liver function and LMR. Notably, cycles of TACE were parallel between the groups. Ten (22.7%) patients receiving prophylactic entecavir reached virologic response. The patients receiving prophylactic entecavir presented significantly reduced virologic events (6.8% vs 54.4%, p=0.000) and hepatitis flares due to HBV reactivation (0.0% vs 11.6%, p=0.039) compared with patients without prophylaxis. Kaplan-Meier analysis illustrated that the patients in the entecavir group presented significantly improved virologic events free survival (p=0.000) and hepatitis flare free survival (p=0.017). Female and Eastern Cooperative Oncology Group (ECOG) performance status 2 was the only significant predictors for virological events in patients without prophylactic antiviral. Rescue antiviral therapy did not reduce the incidence of hepatitis flares due to HBV reactivation. Conclusion Prophylactic entecavir presented promising efficacy in HBV-related cancer patients receiving TACE. Lower performance status and female gender might be the predictors for HBV reactivation in these patients.

Mature microRNA (miRNA) 34a-5p, which is a well-known tumor suppressor in hepatitis virus-associated hepatocellular carcinoma (HCC), plays an important role in cell processes, such as cell proliferation and apoptosis, and is therefore an optimal biomarker for future clinical use. However, the role of miRNA-34a-5p in chemoresistance has yet to be identified. In the present study, the expression of miRNA-34a-5p was assessed by an in situ hybridization assay in HCC tissues and was found to be significantly decreased compared with the pericarcinomatous areas of the tissue specimens, which consisted of samples obtained from 114 patients with HCC. High expression of miRNA-34a-5p was found to be associated with a favorable overall survival time in HCC patients. Functional tests performed by transfecting miRNA-34a-5p mimics or inhibitors into MHCC-97L cells illustrated that miRNA-34a-5p inhibited proliferation, elevated apoptosis and decreased chemoresistance to cisplatin in HCC cells. AXL is the direct target of miRNA-34a-5p, as confirmed by sequence analysis and luciferase assay. Transfection of the cells with small interfering RNA for AXL (siAXL) increased the apoptosis ratio of the MHCC-97L cell line. Transfection with siAXL led to similar biological behaviors in the MHCC-97L cells to those induced by ectopic expression of miRNA-34a-5p. Thus, it was concluded that miRNA-34a-5p enhanced the sensitivity of the cells to chemotherapy by targeting AXL in hepatocellular carcinoma. In addition, low expression of miRNA-34a-5p in HCC tissues yielded an unfavorable prognosis for patients with HCC that received radical surgery, due to the promotion of proliferation and an increase in chemoresistance in HCC cells.

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.

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.

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

MicroRNAs (miRNAs) have been implicated in neoplasm growth, metastasis, vasculogenesis, and drug resistance. It has been validated that abnormal miR-195 expression was related with poor survival of prostate cancer (PC); however, its role in the resistance to chemotherapeutic drugs docetaxel (DOC) in PC is still acquainted scarcely. In our study, the lower expression of miR-195 was appeared in DOC-resistant PC cells (DU145/DOC) rather than DOC-sensitive DU145 cells. The up-regulation of miR-195 lowered the IC50 of DOC, facilitated the apoptosis and inhibited the colony formation ability in DU145/DOC cells. Moreover, we also found that miR-195 had the binding site with clusterin (CLU) by the online TargetScan database mining. Luciferase tests revealed that miR-195 binds to the 3'-UTR of CLU. MiR-195 overexpression decreased the amassment of CLU in DU145/DOC cells. Knockdown of CLU diminished the IC50 of DOC and enhanced the apoptosis of DU145/DOC cells, which was consistent with the influence of miR-195 on DOC-induced cell apoptosis. Taken together, our results illuminated that miR-195 improved the sensitivity of resistant PC cells to DOC by suppressing CLU. Hence, miR-195 may be a potentially promising molecular target for drug resistance of PC.

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.

Background: This retrospective study was aimed to investigate the efficacy of prophylactic agents in hepatocellular carcinoma (HCC) patients receiving TACE and compare the difference between lamivudine and entecavir. Materials and Methods: A consecutive series of 203 HBV-related HCC patients receiving TACE were analyzed including 91 patients given prophylactic agents. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 IU/ml higher than the nadir level, hepatitis flares due to HBV reactivation and progression free survival (PFS) were the main endpoints. Results: Some 48 (69.6%) reached virologic response. Prophylaxis significantly reduced virologic events (8.8% vs 58.0%, p=0.000) and hepatitis flares (1.1% vs 13.4%, p=0.001). Patients presenting undetectable HBV DNA levels displayed a significantly improved PFS as compared to those who never achieved undetectable HBV DNA. Prophylaxis and e-antigen positivity were the only significant variables associated with virologic events. In addition, prophylaxis was the only independent protective factor for hepatitis flares. Liver cirrhosis, more cycles of TACE, HBV DNA negativity, a lower Cancer of the Liver Italian Program score, non-metastasis and no hepatitis flares were protective factors for PFS. Prophylactic lamivudine demonstrated similar efficacy as entecavir. Conclusions: Prophylactic agents are efficacious for prevention of HBV reactivation in HCC patients receiving TACE. Achievement of undetectable HBV DNA levels displayed a significant capability in improving PFS. Moreover, persistent tumor residual lesions, positive HBV DNA and hepatitis B flares might be causes of tumor progression in these patients.

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 or111.23), 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.

Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior in a variety of cancers. In vitro, hypoxia-inducible factor 1α (HIF-1α) transcriptionally activates EZH2 and promotes the progression of breast tumor initiating cells. Here, we characterized the clinicopathological effect of EZH2 and HIF-1α in 410 breast cancer patients. We examined EZH2 and HIF-1α expression using immunohistochemistry and western blotting. We found that EZH2 and HIF-1α were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with lymphatic invasion (P=0.025), HER2 expression (P=0.005) and hypoxia (P

e15048 Background: PD-1/PD-L1 inhibitor-based monotherapies and combination therapies are being investigated to challenge microsatellite stable (MSS) mCRC. This NMA aimed to assess the efficacy of anti-PD-1/PD-L1-based therapies against active comparators (regorafenib, trifiuridine+tipiracil, and fruquintinib [R/T/F]) and negative controls (placebo and best supportive care [P/BSC]) in patients with refractory MSI-unselected mCRC, which are predominantly MSS. Methods: We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and major oncology websites for relevant RCTs comparing the above therapies with each other up to Feb 15, 2019. We used the frequentist NMA to evaluate hazard ratios (HRs) for pairwise treatment comparisons in terms of overall survival (OS). Results: Seven RCTs were included, totaling nine comparisons between five therapies (durvalumab+tremelimumab [anti-PD-L1+Tre] vs. P/BSC [n = 1], atezolizumab+cobimetinib [anti-PD-L1+Cobi] vs. R/T/F [n = 1], atezolizumab [anti-PD-L1-only] vs. R/T/F [n = 1], anti-PD-L1+Cobi vs. anti-PD-L1-only [n = 1], and R/T/F vs. P/BSC [n = 5]). No significant heterogeneity was detected in the NMA (P = 0.340 in Q test; I2= 11.6%). Compared to P/BSC, OS was significantly improved with anti-PD-L1+Tre (fixed-effects model HR, 0.72 [95% confidence interval, 0.54-0.96]; P = 0.014) and anti-PD-L1+Cobi (HR, 0.70 [0.50-0.98]; P = 0.018), but not with anti-PD-L1-only (HR, 0.83 [0.57-1.21]; P = 0.172). OS with anti-PD-L1+Tre and anti-PD-L1+Cobi did not significantly differ from that with R/T/F (P = 0.565 and P = 0.500, respectively). Conclusions: In refractory MSI-unselected mCRC, anti-PD-L1 monotherapy was ineffective but anti-PD-L1+Tre and anti-PD-L1+Cobi therapies exhibited efficacies comparable to that of R/T/F.

e14589 Background: The aim of our research was to assess the prognostic value of ApoB to ApoA-I ratio (ApoB/ApoA-I) in hepatocellular carcinoma (HCC) patients with transcatheter arterial chemoembolization (TACE) treatment. Methods: We collected clinicopathological data of 455 HCC patients with TACE treatments. The cutoff value of ApoB/ApoAI identified by receiver-operating curve (ROC) was 0.56. Correlation analysis was carried out to explore the relationship among ApoB/ApoA-I and other clinicopathological variables. Propensity score-matched (PSM) analysis was carried out to eliminate the unbalance of baseline characteristics of high and low ApoB/ApoA-I group. Finally, 278 patients were included in the PSM cohort, 139 patients in the high APOB/APOA-I group and 139 patients in the low APOB/APOA-I group. Univariate and multivariate analysis were conducted to explore the independent prognostic value of ApoB/ApoA-I in 455 patients and in the PSM cohort. Results: ApoB/ApoA-I was significantly correlated with AFP, NCCN T stage, distant metastasis status and TNM system(P < 0.05). Patients with AFP≥400ng, T3-4, distant metastasis and TNM III-IV had significantly higher serum ApoB/ApoA-I level than that of patients with AFP ≥ 400 ng/ml, T1-2, without metastasis and TNM I-II(P

Purpose Here, we evaluate the prognostic effect of pretreatment serum lactate dehydrogenase (LDH) in locally advanced nasopharyngeal carcinoma (NPC). Methods and materials Pretreatment serum samples from a randomized controlled trial, which contained 199 neoadjuvant chemoradiotherapy patients and 201 neoadjuvant-concurrent chemoradiotherapy cases with locally advanced NPC, were collected and examined for LDH. With 5-year follow-up, the prognostic effect of pretreatment serum LDH was analysed by Kaplan–Meier analysis and multivariate Cox regression model. Results Three hundred and sixty-seven patients (91.75%) had a normal (109.0–245.0U/L) pretreatment LDH level, compared to 33 cases (8.25%) that had a higher (⩾245.0U/L) LDH level. The mean and median pretreatment LDH levels of these 400 patients were 186.6 and 174.0U/L (range, 83.0–751.0U/L), respectively. Compared with the normal subset, elevated LDH level predicted an inferior 5-year overall survival (56.9% versus 76.8%, P =0.004), disease-free survival (DFS, 45.4% versus 64.7%, P =0.001), local relapse-free survival (76.1% versus 89.6%, P =0.019) and distant metastasis-free survival (DMFS, 54.3% versus 72.2%, P =0.001). Multivariate analysis confirmed that the LDH level was an independent prognostic factor to predict death, disease progression, local relapse and distant metastasis. For the subgroup with normal LDH (median point of 177.0U/L), we detected an evident 5-year DFS (68.8% versus 59.5%, P =0.047) and DMFS advantage (77.3% versus 65.3%, P =0.016) in 109.0–177.0U/L subset than that of 178.0–245.0U/L subgroup. Conclusions Serological LDH level was an independent prognostic factor for locally advanced NPC. Combining pretreatment LDH with TNM staging might lead to more accurate risk definition.

Background This study aimed to assess the prognostic value of the serum albumin to globulin ratio (AGR) in cholangiocarcinoma patients after surgery. Methods We retrospectively enrolled 123 cholangiocarcinoma patients who underwent surgical treatment between June 2003 and September2014 at the Third Affiliated Hospital of Sun Yat-sen University. Univariate and multivariate analyses using the Cox regression model were performed to determine the prognostic value of AGR. Results Univariate analysis suggested that AGR was a predictive factor for (overall survival) OS but not for recurrence free survival (RFS). After adjustment for other risk factors, multivariate analysis showed that AGR remained independently associated with OS. The optimal cut-off point for AGR was determined to be 1.44. Kaplan–Meier curves showed that there was a significantly lower mean survival time in the low AGR group compared to the high AGR group. A low AGR was found to be significantly associated with high alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin levels and an advanced American Joint Committee on Cancer TNM stage, but a low hemoglobin level. Conclusion In summary, patients with higher AGRs have better outcomes than those with lower AGRs. Preoperative AGR can be a reliable marker for evaluating the prognosis of cholangiocarcinoma patients.

// Xiu-Rong Cai 1, 2, * , Xing Li 1, 2, * , Jin-Xiang Lin 1 , Tian-Tian Wang 1, 2 , Min Dong 1, 2 , Zhan-Hong Chen 1, 2 , Chang-Chang Jia 2, 3 , Ying-Fen Hong 1, 2 , Qu Lin 1, 2 and Xiang-Yuan Wu 1, 2 1 Department of Medical Oncology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China 2 Guangdong provincial Key Laboratory of Liver Disease Research, Guangzhou 510630, People’s Republic of China 3 Cell-gene Therapy Translational Medicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Xiang-Yuan Wu, email: wuxiangy@mail.sysu.edu.cn Qu Lin, email: linqu@mail.sysu.edu.cn Keywords: cytokine induced killer cell, liver cancer, adoptive cells therapy, immunotherapy, meta-analysis Received: June 13, 2016 Accepted: November 12, 2016 Published: February 17, 2017 ABSTRACT Background: High recurrence rate after curative treatment is the major problem for hepatocellular carcinoma (HCC). Cytokine-induced killer cells (CIKs) therapy was extensively studied among HCC patients. However, the value of CIKs therapy was controversial. A meta-analysis was performed to investigate the efficacy of adjuvant CIKs after invasive treatments among HCC patients. Methods: We searched online for literatures studying sequential CIKs therapy for HCC patients. Recurrence-free survival (RFS), progress-free survival (PFS) and overall survival (OS) were set as the main endpoints. Both overall and subgroup analysis were accomplished. Results: A total of 12 clinical trials with 1,387 patients were included. The pooled analysis showed a significant improvement of RFS, PFS and OS in CIK group (HR 0.56, 95% CI 0.47-0.67, p

Aims The prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor and testing drug efficacy in clinical trials is hazardous. This study was aimed to evaluate different prognostic scoring systems for HCC in estimating prognosis (3-month survival and overall survival (OS)). Methods From November 2008 to April 2010, 208 patients with advanced HCC who were not amendable to locoregional therapy were included in this study. Data were collected to classify patients according to the following: the Japanese integrated staging scoring system, TNM stage by the Liver Cancer Study Group of Japan criteria, TNM 6th edn, the cancer of the liver Italian program scoring system (CLIP), the advanced liver cancer prognostic system (ALCPS), the model of end-stage liver disease, the Groupe d'etude et de Traitement du Carcinome Hepatocellulaire (GETCH) scoring system, the Chinese University prognostic index staging system (CUPI), the Okuda scoring system, the Child–Pugh score, the Tokyo scoring system and the Barcelona Clinic liver cancer staging. Survival analysis and relative operating characteristic (ROC) were utilized to access the prognostic value of each scoring system. Results ALCPS performed best, with the largest area under the ROC curve in predicting 3-month OS (sensitivity 76.32%, specificity 78.72%). CLIP and CUPI were similar to ALCPS in prognostic discrimination but with relatively lower power. Conclusions ALCPS, CLIP and CUPI are the preferred scoring systems in the prediction of OS and 3-month survival among the 12 systems analyzed, and should be used as inclusion criteria in clinical trials for advanced HCC patients.

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.

Previously, we and others showed that hypoxia‐inducible factor‐1α (HIF‐1α) and transcriptionally upregulated Aurora‐A were required for disease progression in several tumors. Here, we address the clinicopathologic value of Aurora‐A and HIF‐1α in locally advanced nasopharyngeal carcinoma (NPC). Aurora‐A and HIF‐1α expression was semiquantitatively evaluated by immunohistochemistry staining in 144 cases from a randomized controlled trial. Of these patients, 69 received neoadjuvant chemotherapy plus concurrent chemoradiotherapy, and acted as the training set, and 75 cases treated with neoadjuvant chemotherapy plus radiotherapy were used as the testing set to validate the prognostic effect of Aurora‐A and HIF‐1α. We found that Aurora‐A and HIF‐1α were highly expressed in NPC, but were deficient in normal adjacent epithelia. In the testing set, Aurora‐A overexpression predicted a shortened 5‐year overall survival (59.1% vs 82.5%, P = 0.024), progression‐free survival (44.8% vs 79.8%, P = 0.004), and distant metastasis‐free survival (43.0% vs 17.3%, P = 0.016). Multivariate regression analysis confirmed that Aurora‐A was indeed an independent prognostic factor for death, recurrence, and distant metastasis both in the testing set and overall patients. Moreover, a positive correlation between Aurora‐A and HIF‐1α was detected (P = 0.037). Importantly, although HIF‐1α did not show any prognostic effect for patient outcome, the subset with Aurora‐A and HIF‐1α co‐overexpression had the poorest overall, progression‐free, and distant metastasis‐free survival (all P

The prognosis and management of acute exacerbations of hepatitis-B in patients with lymphoma after chemotherapy in combination with rituximab remain unclear. Here, we describe 19 Chinese patients with lymphoma who suffered this complication, in order to analyze their clinical characteristics. Receiver operating characteristic analysis and Kaplan-Meier survival analysis were utilized to determine potential prognostic factors. We found that key prognostic factors included the peak prothrombin time (PT), international normalized ratio (INR), and total bilirubin (TB), as well as the PT and INR on admission and the interval between acute exacerbation of hepatitis-B and the last cycle of chemotherapy. Moreover, our data suggested that shorter interval between the last cycle of rituximab and acute exacerbation of hepatitis-B might be another prognostic indicator of inferior survival. Our results revealed that the severity of hepatic damage and the interval between the last cycle of chemotherapy and hepatitis flare were the major prognostic factors of an acute exacerbation of hepatitis-B induced by immunochemotherapy. Prophylactic antiviral and rescue antiviral therapy remain to be further characterized.

4039Background: Ahead-G201, a multicenter Phase IV study, is conducting to evaluate apatinib as third-line or beyond therapy in a routine practice setting of gastric cancer patients (pts). Methods:...

e15658Background: Our previous study found that eIF4A2 was highly expressed in colorectal cancer and high eIF4A2 expression predicted poor prognosis, which was reported in ASCO GI 2018. However, th...

e16020Background: Apatinib has been approved in China for patients (pts) with advanced or metastatic gastric and gastro-esophageal junction adenocarcinoma after at least two lines of systemic chemo...

e16019Background: An open-label, multicenter, post-marketing Phase IV study of apatinib (Ahead-G201; ClinicalTrials.gov: NCT02426034) is being conducted in a broad range of gastric cancer patients ...

Recent studies have suggested that autophagy plays a pivotal role in regulation of cancer development and progression. High expression of the autophagy-related Beclin 1 protein predicted favorable patient outcome in several tumors. Here, a randomized controlled trial (RCT)-derived 128 nasopharyngeal carcinoma (NPC) patients were subjected to analysis of Beclin 1 expression and survival probability. In this RCT, 61 patients treated with induction chemotherapy plus concurrent chemoradiotherapy were used as a training set to generate a Beclin 1 cutoff score for patient outcome by receiver operating characteristic (ROC) curve analysis. For validation, the ROC-derived cutoff point was subjected to analysis of the association of Beclin 1 expression with patient outcome and clinical characteristics in testing set. The testing set comprised of 67 patients received induction chemotherapy plus radiotherapy. In the testing set and overall patients, our univariate and multivariate analysis showed that higher Beclin 1 expression, defined by the training set ROC analysis-generated cutoff score, predicted poorer overall survival, progression-free survival and distant metastasis-free survival. However, we failed to detect a correlation between Beclin 1 and local failure-free survival. Moreover, a positive relationship between Beclin 1 and HI F-1alpha expression was found. Importantly, among patients with elevated HI F-1alpha expression, a subset with lower Beclin 1 expression displayed a significant overall survival advantage than those with higher expression (p = 0.036). Contrary to previous studies, our results demonstrated that high autophagic Beclin 1 expression was an inferior prognostic marker for NPC. HI F-1alpha-associated Beclin 1 high expression might facilitate NPC cells surviving from chemoradiotherapy, suggesting a novel therapeutic molecular target for NPC.

480 Background: Child-Pugh grade is widely used to assess hepatic function reserve, but it is relatively subjective for assessment of hepatic encephalopathy. A newly developed scoring system combining albumin and bilirubin, called ALBI grade, aims to assess liver function objectively. In prognosis prediction of hepatocellular carcinoma (HCC), The Cancer of the Liver Italian Program (CLIP) score is commonly used in clinical practice and includes Child-Pugh evaluation. We substituted ALBI grade for Child-Pugh grade to establish ALBI-CLIP system and conducted this study to validate the prognostic value of ALBI -CLIP in HBV-related HCC patients after TACE therapy. Methods: We retrospectively analyzed HBV-related HCC patients who received TACE therapy. Baseline data were collected and evaluated. Child-Pugh grade and ALBI grade were integrated into CLIP and ALBI-CLIP systems, respectively. Univariate and multivariate analyses were conducted to identify independent prognostic factors for overall survival. Comparisons of receiver operating characteristic (ROC) curves and likelihood ratio test (LRT) were used to compare the value of ALBI-CLIP, CLIP and TNM staging systems in predicting survival. Results: A total of 207 patients were included. 153 (73.9%) and 54 (26.1%) patients were classified as Child-Pugh grade A and B, respectively. But according to ALBI grade, 57 (27.5%), 136 (65.7%) and 14 (6.8%) of them were correspondingly divided into Grade 1, 2 and 3. Comparisons of ROC curves showed that ALBI-CLIP and CLIP had similar areas under the curve, both of which were larger than that of TNM system in predicting 3-month, 6-month, 1-year and 2-year survival. LRT indicated that both ALBI-CLIP and CLIP had larger χ2 values and smaller values of Akaike information criterion (AIC), compared with TNM system (χ2 = 29.771, 29.479, 9.105; AIC = 858.215, 858.069, 879.410 for ALBI-CLIP, CLIP and TNM, respectively). Conclusions: Our current study suggested that modified CLIP score with albumin-bilirubin grade retained prognostic value in HBV-related HCC treated with TACE therapy.

73 Background: Ahead-G201 is an ongoing open-label, multicenter, post-marketing Phase IV trial assessing safety and efficacy of apatinib in 2000+ patients (pts) with chemotherapy-refractory advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction. Proteinuria (PTN), hypertension (HTN) and hand-foot-skin reaction (HFSR) are common adverse events (AEs) related to anti-angiogenesis drugs. Methods: As of 2017/7/10, 1037 and 820 pts were evaluable for safety and survival. Clinical outcomes were compared between pts with and without PTN / PTN / HFSR using Kaplan–Meier methods and multivariate Cox regression model. Results: 200 (19.3%), 194 (18.8%) and 115 (11.1%) pts had PTN, HTN and HFSR, respectively. Similar mean daily dosage was found between pts with and without PTN, HTN or HFSR (from 520.6 to 551.0 mg/day). Pts developed PTN / HTN / HFSR had longer median medication durations (57 vs. 33 / 55 vs. 35 / 65 vs. 36 days; p

36 Background: Intestinal and diffuse gastric cancer are main histological types of gastric cancer, based on Lauren’s classification, which account for 34–47% and 46–57%, respectively. Patients (pts) with intestinal gastric cancer have better prognosis. The present study aimed to compare the safety and efficacy of apatinib between the two intestinal gastric cancer, based on data from post-marketing Phase IV study (Ahead-G201). Methods: The single-arm, open-label, multi-center, Phase IV trial enrolled advanced or metastatic adenocarcinoma of stomach or gastroesophageal junction after failure of ≥2 lines of chemotherapy. Data of pts with intestinal and diffuse gastric cancer were collected and compared. Results: As of 2017/7/10, 96 intestinal and 104 diffuse pts were recruited. Differences in age (64 vs. 55 yrs), gender (male: 77.1% vs. 57.7%) and disease duration ( > 12 months: 71.3% vs. 56.7%) were detected. Between intestinal and diffuse gastric cancer, there was no discrepancy in incidences of adverse events (AEs) (78.1% vs. 73.1%) and Grade ≥3 AEs (41.7% vs. 38.5%). The incidences of typical AEs associated anti-angiogenesis drugs were also comparable (hypertension 26.0% vs. 16.4%; proteinuria 14.6% vs. 20.2%; hand-foot-skin reaction 16.7% vs. 9.6%). No statistical difference was observed in best overall response rate (12.8% vs. 14.3%) and disease control rate (76.0% vs. 64.3%). Survival benefit in pts with intestinal gastric cancer was detected (progression free survival: 5.52 vs. 2.76 months, p = 0.036; overall survival: 8.11 vs. 4.70 months, p = 0.047). However, the multivariable Cox regression model analysis showed that histological type was not independently prognostic factors for survival, indicating that clinical benefit of pts with intestinal gastric cancer was influenced by other factors. Conclusions: Compared with diffuse gastric cancer, pts intestinal gastric cancer have more clinical benefit after treated by apatinib. However, histological type based on the Lauren’s classification was not independently prognostic factors for survival, which needs to be further analyzed, considering the small sample size. Clinical trial information: NCT02426034.