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The present study aimed to evaluate the prognostic significance of preoperative serum lactate dehydrogenase (SLDH) levels for resected gastric cancer and construct prognostic nomograms for risk prediction. The study cohort consisted of 619 patients with D2-resected gastric cancer. The relationship of SLDH levels with clinicopathological features and clinical outcomes was evaluated. Prognostic nomograms were created using identified prognosticators to predict 3-year overall survival (OS) and 3-year disease-free survival (DFS), and bootstrap validation was performed. High SLDH levels were correlated with old age but not depth of invasion or lymph node metastasis. When assessed as a continuous variable, high SLDH levels were independently associated with poor OS and DFS. Internal validation of the developed nomograms revealed good predictive accuracy (bootstrap-corrected concordance indices: 0.77 and 0.75, respectively for prediction of OS and DFS). The preoperative SLDH levels, an identified unfavorable prognosticator, were incorporated into nomograms along with other clinicopathological features to refine the prediction of clinical outcomes for patients with D2-resected gastric cancer.

// Zhe-Zhen Li 1, * , Feng Wang 1, * , Zi-Chen Zhang 2, * , Fang Wang 2 , Qi Zhao 3 , Dong-Sheng Zhang 1 , Feng-Hua Wang 1 , Zhi-Qiang Wang 1 , Hui-Yan Luo 1 , Ming-Ming He 1 , De-Shen Wang 1 , Ying Jin 1 , Chao Ren 1 , Miao-Zhen Qiu 1 , Jian Ren 3 , Zhi-Zhong Pan 4 , Yu-Hong Li 1 , Jiao-Yong Shao 2 , Rui-Hua Xu 1 1 Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China 2 Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China 3 State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, P. R. China 4 Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China * These authors have contributed equally to this work Correspondence to: Rui-hua Xu, e-mail: xurh@sysucc.org.cn Jian-Yong Shao, e-mail: shaojy@sysucc.org.cn Keywords: colorectal cancer, mutation profile, RAS mutations, OncoCarta™ Panel, Chinese Received: February 17, 2016 Accepted: March 16, 2016 Published: April 1, 2016 ABSTRACT An increasing number of studies reveal the significance of genetic markers in guiding target treatment and refining prognosis. This retrospective observational study aims to assess the mutation profile of metastatic colorectal cancer (mCRC) in Chinese population with the help of MassARRAY ® technique platform and OncoCarta™ Panel. 322 Chinese patients with mCRC who received clinical molecular testing as part of their standard care were investigated. 80 patients received cetuximab palliative treatment. 238 common hot-spot mutations of 19 cancer related genes in the OncoCarta™ Panel were tested. 44 mutations in 11 genes were detected in 156 cases (48.4%). At least one mutation was identified in 38.5% (124/322) of all tested cases, two concomitant mutations in 9.0% (29/322) and three mutations in 3 cases (

e15645 Background: PI3Kα is the only subtype in PI3K family of which activated mutations occur frequently in tumors. CYH33 is a potent PI3Kα–selective inhibitor with anti-tumor activity in xenograft models. An open-label, Phase I dose-escalation & expansion study of CYH33 monotherapy (NCT03544905) is underway in patients (pts) with advanced solid tumors. Methods: This study evaluates the safety, pharmacokinetics (PK), and anti-tumor activity of CYH33 administered daily orally in 28-day cycles until intolerable toxicity or disease progression (PD). Adult pts with advanced solid tumors who have progressed despite standard therapies are enrolled to this trial, and pts with or without PIK3CA mutant are eligible for dose-escalation and pts with PIK3CA mutant are eligible for dose-expansion. Results: As of the cut-off date 20 Dec 2019, 17 pts (median age 47.0 y) were enrolled in the first 6 dose levels (1mg, 5mg, 10mg, 20mg, 40mg and 60mg) of the dose-escalation cohorts, and 3 pts were enrolled in expansion cohort of 40 mg. Cohorts 1 mg to 20 mg were completed without dose-limiting toxicities (DLT), cohort 40mg was completed with 1 DLT (Grade 3 hyperglycemia) out of 6 evaluable pts, and 3 enrolled pts at 60 mg are still in the DLT evaluation. Most frequent treatment-related adverse events (TRAEs) (all grades, ≥ 20%) included hyperglycemia (17 pts, 85%), decreased appetite (5 pts, 25%), diarrhea (4 pts, 20%). Grade≥3 TRAEs were hyperglycemia (8 pts, 40%), nausea (1 pt, 5%) and decreased appetite (1 pt, 5%). Hyperglycemia was generally manageable with anti-hyperglycemic medications. The preliminary PK profile of CYH33 showed dose proportionality across the tested dose levels, half-life (t1/2) was about 20 hours with minimum accumulation, and the maximum concentration (Cmax) achieved 2-4 hours after dosing. Over all, among 15 tumor response evaluable pts, partial response (PR) was observed in 2 pts treated with 40mg (1 colorectal cancer with unknown PIK3CA mutation status, 1 breast cancer with PIK3CA mutant), and stable disease (SD) was observed in 3 pts with unknown PIK3CA mutation status. After the cut-off date, 1 more pt (ovarian cancer with PIK3CA mutation) treated with 40mg achieved PR, so that 2 out of 3 enrolled PIK3CA mutant pts treated with 40mg achieved PR. Conclusions: The first-in-human study of the PI3Kα selective inhibitor CYH33 demonstrated a manageable safety profile, linear PK, and encouraging preliminary anti-tumor activity. CYH33 single agent and in combination with other anti-tumor agents have be planned in future studies. Clinical trial information: 03544905.

3550 Background: MRG003 is a novel antibody drug conjugate (ADC) composed of a fully human anti-EGFR IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG003 is presently being tested in an ongoing phase I study for safety, pharmacokinetics, and preliminary antitumor activity in patients (pts) with solid tumors (CTR20180310). Methods: In the phase I dose escalation study of a traditional (3+3) design, pts with relapsed or refractory cancers received single agent MRG003 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. The starting dose of MRG003 is 0.1 mg/kg, followed by 0.3, 0.6, 1.0, 1.5, 2.0, 2.5, and 3.0 mg/kg. Observations included adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity which is assessed every two cycles. Results: A total of twenty-two pts with colorectal (CRC, n = 15), nasopharyngeal (NPC, n = 3), head and neck (H&N, n = 2), esophageal (EC, n = 1), and duodenal (DC, n = 1) cancer were enrolled in the dose escalation. The median age of pts was 56.5 years. The MTD identified was 2.5 mg/kg. Commonly observed adverse events were anemia (50%), AST increase (41%), decreased appetite (41%), rash (36%), pruritus (36%), asthenia (36%), and proteinuria (32%). Majority of AEs were mild to moderate in severity. EGFR expression in patients’ tumor samples was determined retrospectively by a validated IHC method in a central laboratory. Nine out of 22 pts tested were EGFR positive. Among these 9 EGFR positive pts, one with NPC in the 2.5 mg/kg cohort had partial response, four had stable disease (one with H&N in the 1.5 mg/kg, one each with NPC and H&N in the 2.0 mg/kg, and one with EC in the 2.5 mg/kg cohorts). The disease control rate (DCR) at doses ≥1.5 mg/kg was 100% for the EGFR positive pts. Conclusions: The dose escalation study of MRG003 showed manageable safety profiles and encouraging preliminary antitumor activity in pts with EGFR-positive solid tumors. MRG003 is currently being evaluated as a single agent in phase I dose expansion cohorts to further assess safety, PK, and antitumor activity. Clinical trial information: CTR20180310 .

Background: Epstein–Barr virus-associated gastric cancer (EBVaGC) has unique clinicopathologic features and our present understanding of its treatment outcome is limited. Here, we investigated the clinical outcomes of resectable and metastatic EBVaGC cases with regards to their respective treatment. Methods: We retrieved the data of EBVaGC patients treated at our center from October 2014 to June 2019. The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) for stage I–III patients, progression-free survival (PFS) and objective response rate (ORR) for stage IV patients. Results: Patients classified as stage I–III accounted for 83.7% of the total 197 cases analyzed. Two patients had mismatched repair-deficiency. The 5-year OS rate of the entire cohort was 63.51% [95% (confidence interval (CI): 52.31–72.76%]. Tumor-node-metastasis (TNM) stage and gastric stump cancer were identified as independent prognostic factors for OS. The 3- and 5-year DFS rate for stage I–III patients were 83.72% (95% CI: 75.86–89.19%) and 73.83% (95% CI: 60.39–83.32%), respectively. TNM stage III, neural invasion, lymphovascular invasion, and baseline plasma EBV-DNA positive were correlated with shorter DFS. The ORR and disease control rate (DCR) for metastatic EBVaGC patients to first-line therapy were 29.0% and 90.3% (median PFS: 9.8 months), respectively, and to second-line therapy were 25.0% and 75.0%, respectively. Seven patients received anti-PD1 therapy and had an ORR of 28.5% and a median PFS of 2.8 months. Conclusions: EBVaGC patients have few metastases, long DFS, and high DCR. TNM stage and gastric stump cancer were independent prognostic factors for OS.

Prognostic and predictive markers are needed to predict the clinical outcomes of patients with advanced colorectal cancer (CRC) who receive standard first-line treatments. We performed a prospective cohort study in advanced CRC patients to identify a miRNA signature that could predict the benefit of receiving first-line chemotherapy for these patients. Twenty-one paired tumours and adjacent normal tissues were collected from advanced CRC patients and analysed by miRNA microarrays. Between tumour and normal tissues, 33 miRNAs were differentially expressed and was confirmed by qRT-PCR from another group of 67 patients from a prospective cohort study. A two-miRNA-based signature was obtained using the LASSO Cox regression model based on the association between the expression of each miRNA and the PFS of individual patients. Internal and external validation cohorts, including 40 and 44 patients with advanced CRC, respectively, were performed to prove the prognostic and predictive value of this signature. A signature was built based on two miRNAs, miR-125b-2-3p and miR-933. CRC patients were classified into low- and high-risk groups for disease progression based on this tool. The patients with low risk scores generally had better PFS than those with high risk scores. In the training set, the median PFS in the low- and high-risk groups were 12.00 and 7.40 months, respectively. In the internal validation set, the median PFS in the low- and high-risk groups were 9.90 and 5.10 months, respectively. In the external validation set, the median PFS in the low- and high-risk groups were 9.90 and 6.40 months, respectively. Furthermore, we detected miR-125b-2-3p associated with CRC cell sensitivity to first-line chemotherapy. Our two-miRNA-based signature was a reliable prognostic and predictive tool for tumour progression in patients with advanced CRC, and might be able to predict the benefit of receiving standard first-line chemotherapy in CRC.

Epstein-Barr virus (EBV)-associated gastric carcinomas (EBVaGCs) may account for 8-9% of all gastric cancer (GC) patients. All previous reports on EBVaGC were retrospective. Prospective study is warranted to evaluate the exact role of EBV status in predicting the prognosis of GC. It is of special interest to figure out whether dynamic detection of plasma EBV-DNA load could be a feasible biomarker for the monitor of EBVaGC. From October 2014 to September 2017, we consecutively collected GC patients (n = 2,760) from Sun Yat-sen University Cancer Center for EBER examination. We detected EBV-DNA load in plasma and tissue samples of EBVaGC patients at baseline. Subsequently, plasma EBV-DNA load was dynamically monitored in EBVaGC patients. The overall prevalence of EBVaGC is 5.1% (140/2,760). The incidence rate of EBVaGC decreased with advanced AJCC 7th TNM stage (p < 0.001), with the corresponding percentages of 9.3, 9.9, 6.7 and 1.4% for Stage I, II, III and IV patients. EBVaGC patients were predominately young males with better histologic differentiation and earlier TNM stage than EBV-negative GC (EBVnGC) patients. EBVaGC patients were confirmed to had a favorable 3-year survival rate (EBVaGC vs. EBVnGC: 76.8% vs. 58.2%, p = 0.0001). Though only 52.1% (73/140) EBVaGC patients gained detectable EBV-DNA and 43.6% (61/140) reached a positive cutoff of 100 copies/ml, we found the plasma EBV-DNA load in EBVaGC decreased when patients got response, while it increased when disease progressed. Our results suggested that plasma EBV-DNA is a good marker in predicting recurrence and chemotherapy response for EBVaGC patients.

Yuxiang Deng,1,* Jianhong Peng,1,* Yujie Zhao,1 Qiaoqi Sui,1 Ruixia Zhao,2 Zhenhai Lu,1 Miaozhen Qiu,3 Junzhong Lin,1 Zhizhong Pan1 1Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Public Health, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Background: Recent studies have suggested that the lymph node ratio (LNR) is a prognostic indicator for various malignancies. However, LNR has not been evaluated in colorectal liver-only metastasis (CRLM). This study aimed to investigate the prognostic value of LNR in patients with CRLM after curative resection. Patients and methods: We retrospectively investigated the clinicopathologic features of 154 CRLM patients who underwent curative resection between 2005 and 2015. We classified patients into low and high groups based on their LNR by using the X-tile software. Survival curves were plotted through Kaplan–Meier method and compared by log-rank test. Cox proportional hazards analysis was performed to identify the factors associated with recurrence-free survival (RFS) and overall survival (OS). Results: The patients were divided into two groups in which 124 patients were identified as LNR ≤0.33 and 30 patients as LNR >0.33. Compared to low LNR, high LNR was significantly associated with poor 3-year RFS (47.2% vs 16.7%, P=0.001) and OS (72.8% vs 45.3%, P=0.003) rates. Multivariate analysis indicated that the LNR was an independent predictor for 3-year RFS (hazard ratio, 2.124; 95% CI, 1.339–3.368; P=0.001) and OS (HR, 2.287; 95% CI, 1.282–4.079; P=0.005). However, the node (N) stage and lymph node distribution were not significantly associated with the 3-year RFS (P=0.071, P=0.226) or OS (P=0.452, P=0.791) in patients with CRLM. Conclusion: This study demonstrated that LNR was an independent predictor for 3-year RFS and OS in patients with CRLM who underwent curative resection and that its prognostic value was superior to that of N stage and lymph node distribution. Keywords: colorectal cancer, liver metastases, lymph node ratio, N stage, prognosis

Background: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for gastric cancer incorporated several new changes. We aimed to assess the comparative prognostic values of the 7th and 8th AJCC pTNM staging systems in patients with gastric cancer (GC), and accordingly, to put forward a refined staging classification. Methods: The SEER database was queried to identify GC patients between 2004 and 2009. GC patients from Sun Yat-sen University Cancer Center (SYSUCC) were used as external validation data. The Kaplan-Meier method and Cox proportional hazards regression models were used to analyze cause-specific survival (CSS). The prognostic performance of different staging schemes was assessed using the concordance index (c-index), Akaike's information criterion (AIC), and likelihood ratio χ2 test. Results: In the SEER cohort, stage migration occurred in 8.74% of patients. Survival analysis showed that it was better to treat T4bN0M0 + T4aN2M0 as stage IIIB and T4bN3bM0 as stage IV. Based on this, we established a new staging system which exhibited a superior c-index (0.7501) to the 7th and 8th AJCC staging systems (0.7498 and 0.7500, respectively). The new staging system also outperformed the 7th and 8th AJCC staging systems in terms of AIC and the likelihood ratio χ2 test. The predictive superiority of the new staging system remained valid in the SYSUCC database. Conclusions: We demonstrated that some stage modifications in the 8th AJCC pathologic staging were unnecessary. Therefore we established a new staging system, which was superior to the 7th and 8th staging systems.

Background Ovarian cancer is a deadly disease. Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. Overexpression of IAPs proteins has been correlated with tumorigenesis, treatment resistance and poor prognosis. Reinstalling functional cell death machinery by pharmacological inhibition of IAPs proteins may represent an attractive therapeutic strategy for treatment of ovarian cancer. Methods CCK-8 and colony formation assay was performed to examine cytotoxic activity. Apoptosis was analyzed by fluorescence microscopy, flow cytometry and TUNEL assay. Elisa assay was used to determine TNFα protein. Caspase activity assay was used for caspase activation evaluation. Immunoprecipitation and siRNA interference were carried out for functional analysis. Western blotting analysis were carried out to test protein expression. Ovarian cancer cell xenograft nude mice model was used for in vivo efficacy evaluation. Results APG-1387 demonstrated potent inhibitory effect on ovarian cancer cell growth and clonogenic cell survival. APG-1387 induced RIP1- and TNFα-dependent apoptotic cell death in ovarian cancer through downregulation of IAPs proteins and induction of caspase-8/FADD/RIP1 complex, which drives caspase-8 activation. NF-κB signaling pathway was activated upon APG-1387 treatment and RIP1 contributed to NF-κB activation. APG-1387 induced cytoprotective autophagy while triggering apoptosis in ovarian cancer cells and inhibition of autophagy enhanced APG-1387-induced apoptotic cell death. APG-1387 exhibited potent antitumor activity against established human ovarian cancer xenografts. Conclusions Our results demonstrate that APG-1387 targets IAPs proteins to potently elicit apoptotic cell death in vitro and in vivo, and provide mechanistic and applicable rationale for future clinical evaluation of APG-1387 in ovarian cancer.

The hematogenous metastatic pattern of gastric cancer (GC) was not fully explored. Here we analyzed the frequency and clinicopathological features of metastasis to liver, lung, bone, and brain from GC patients. Data queried for this analysis included GC patients from the Surveillance, Epidemiology, and End Results Program database from 2010 to 2014. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). All statistical tests were two‐sided. Totally, there were 19 022 eligible patients for analysis. At the time of diagnosis, there were 7792 patients at stage IV, including 3218 (41.30%) patients with liver metastasis, 1126 (14.45%) with lung metastasis, 966 (12.40%) with bone metastasis and 151 (1.94%) with brain metastasis. GC patients with lung or liver metastasis have a higher risk of bone and brain metastasis than those without lung nor liver metastasis. Intestinal subtype had significantly higher rate of liver and lung metastasis, while diffuse type was more likely to have bone metastasis. Proximal stomach had significantly higher risk to develop metastasis than distal stomach. African‐Americans had the highest risk of liver metastasis and Caucasian had the highest prone to develop lung and brain metastasis. The median survival for patients with liver, lung, bone, and brain metastasis was 4 months, 3 months, 4 months and 3 months, respectively. It is important to evaluate the status of bone and brain metastasis in GC patients with lung or liver metastasis. Knowledge of metastatic patterns is helpful for clinicians to design personalized pretreatment imaging evaluation for GC patients.

Mountain of studies has showed that right‐sided colon cancer (RSCC) and left‐sided colon cancer (LSCC) have different clinical presentation and biologic features and should be considered as two distinct disease entities. The survival difference between RSCC and LSCC remains controversial. Using Surveillance, Epidemiology, and End Results (SEER) database, we identified colon adenocarcinoma patients from 2004 to 2013. The 5‐year cause‐specific survival (CSS) was our primary endpoint. All statistical analyses were performed using the Intercooled Stata 13.0. All statistical tests were two‐sided. The study included 95,847 (58.72%) RSCC and 67,385 (41.28%) LSCC patients. RSCC patients were older, more often females, more Caucasian, more unmarried, more advanced T and N stage, larger tumor sizes, and more poorly differentiated tumor, while LSCC patients had more stage IV diseases. Location was an independent prognostic factor in the multivariable analysis. Compared with RSCC patients, the hazard ratio for LSCC was 0.87, 95% CI: 0.85–0.89 P

// Haibo Chen 1, * , Dingyuan Luo 2, * , Lin Zhang 3, 4, * , Xiaofeng Lin 1 , Qiuyun Luo 3 , Hanjie Yi 3 , Jing Wang 5 , Xianglei Yan 3 , Baoxia Li 3 , Yuelei Chen 6 , Xingguang Liu 1 , Hong Zhang 1 , Sheng Liu 1 , Miaozhen Qiu 7 , Dajun Yang 3, 8 and Ningyi Jiang 1 1 Department of Nuclear Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China 2 Department of Vascular and Thyroid Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China 3 Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China 4 Department of Clinical Laboratory, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China 5 Department of Pharmacy, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510080, China 6 The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China 7 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou 510120, China 8 Suzhou Ascentage Pharma Inc., Jiangsu 215123, China * These authors have contributed equally to this work Correspondence to: Dajun Yang, email: yangdj@sysucc.org.cn Ningyi Jiang, email: ningyij0@163.com Keywords: dedifferentiated thyroid cancer, radioiodine, anti-tumor, MDM2-p53 interaction, apoptosis Received: February 10, 2017 Accepted: April 06, 2017 Published: April 24, 2017 ABSTRACT Dedifferentiated papillary thyroid cancer (DePTC) is characterized by aggressive growth, recurrence, distant metastasis, and resistance to radioactive iodine (RAI) therapy. DePTC is also accompanied by poor prognosis and high early-mortality. Nevertheless, most DePTC cells show intact p53 downstream functionality. In cells with wild-type p53, the murine double minute2 (MDM2) protein interacts with p53 and abrogates its activity. Inhibition of the MDM2-p53 interaction restores p53 activity and leads to cell cycle arrest and apoptosis. Restoring p53 function by inhibiting its interaction with p53 suppressors such as MDM2 is thus a promising therapeutic strategy for the treatment of DePTC. The novel MDM2-p53 interaction antagonist APG115 is an analogue of SAR405838, and is being tested in a phase I clinical trial. In this study, we evaluated the efficacy of APG115 as a single-agent to treat DePTC. APG115 diminished the viability of p53 wild-type DePTC cells and induced cell cycle arrest and apoptosis. In a human xenograft mouse model, APG115 elicited robust tumor regression and cell apoptosis. These data demonstrate that further research is warranted to determine whether APG115 can be used to effectively treat DePTC patients.

Background: BRAFV600E-mutated colorectal carcinoma (CRC) is a refractory disease with poor prognosis and limited therapeutic approaches. Recently, researches have indicated that the recruitment of Tregs in tumor tissue promoted by BRAFV600E is responsible for the weakened antitumor immunity. Whereas, as the main targeting therapy for this intractable carcinoma, BRAFV600E inhibitor has little response. In addition, FAK, being the novel therapeutic target in CRC, is considered to have an impact on the release of chemokines. In this study, we sought to explore the capacity of FAK inhibitor restricting Treg infiltration in tumor and its mechanism, as well as the synergistic antitumor effect with the present therapeutic strategy for BRAFV600E-mutated CRC. Methods: Cell proliferation was determined by CCK-8 assay and colony formation assay. Migration ability was detected by transwell assay. Cell cycle and cell group analysis were assessed by flow cytometry. Western blot, Elisa and RT-qPCR analysis were conducted for mechanism exploration. Immunohistochemistry and immunofluorescence analysis were performed to confirm the link between BRAFV600E, FAK and Tregs. CRC xenograft models were established to detect the Treg recruitment and evaluate the synergistic antitumor effect in vivo. Results: BRAFV600E-mutated CRC was of higher expression of FAK, and hence more sensitive to FAK inhibitor APG-2449. Besides, BRAFV600E-mutated in CRC was linked with more Treg infiltration in tumor site, therefore contributed to the attenuated antitumor immunity. What’s more, despite directly inhibiting tumor proliferation and migration, one of the important mechanisms of FAK blockade restricting the growth of BRAFV600E-mutated CRC, was by downregulating the release of Treg chemokine CCL5 from tumor cells through FAK-IL33 axis. With the recruitment of Tregs decreasing induced by FAK inhibitor APG-2449, the number of CD8+T cells relatively elevated in tumor tissue. In BRAFV600E-mutated CRC xenotransplantation models, we revealed that the combination of FAK inhibitor APG-2449 and Vemurafenib was of no significant difference with the combination of Vemurafenib and cetuximab. While adding APG-2449 to the current combination strategy achieved greater tumor suppressing effect than not adding. Conclusions: BRAFV600E-mutated CRC is associated with a higher expression level of FAK, as well as the tumor infiltration of Tregs. FAK inhibitor APG-2449 can promote antitumor immunity by restricting Treg number in tumor tissue, and shows a synergistic effect with the present therapeutic strategy for BRAFV600E-mutated CRC treatment. Citation Format: Luping Yuan, Wentao Pan, Suna Zhou, Qiuyun Luo, Xianglei Yan, Yuxin Zhang, Mengxian Pan, Lin Zhang, Miaozhen Qiu, Dajun Yang. FAK inhibition reduces tumor infiltration of Tregs via restricting CCL5 release and boosts the present therapeutic regimen for BRAFV600E-mutated colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3958.

Background: Gastric cancer (GC) is the fourth most common type of malignant tumor and is the second leading cause of cancer-related mortality. Surgery and chemotherapy play important role in the treatment of GC, however the overall survival of gastric cancer patients is not promising. APG-1252-12A specifically binding to Bcl-2 and Bcl-xl has shown efficacy in some solid tumor. We intend to investigate the anticancer effect and combination enhancement of Fluorouracil (5-FU) in gastric cancer. Materials and methods: Human gastric cancer cell lines (AGS, NCI-N87, SGC7901, BGC823, MKN45 and NUGC3) were treated with different concentrations and time of APG-1252-12A. CCK-8, survival assays, flow cytometry and western blot were used to assess cell survival, cell cycle progression and apoptosis. In vivo, xenograft mouse models (NCI-N87) were established to analyze the anticancer effect and combination enhancement of 5-FU. Results: In vitro, APG-1252-12A inhibited proliferation of gastric cancer cell lines, without cell-cycle arrest. Meanwhile, APG-1252-12A increased protein expression of apoptosis signal pathway. The combination of APG-1252-12A and 5-FU resulted in the accumulation of apoptosis protein such as PARP and cleaved caspase3, which indicating an increasing of chemosensitivity. In xenograft mouse models, single therapy with APG-1252-12A obviously suppressed tumor growth, especially in 100mg/kg group. Combination group delayed tumor growth more significantly compared with APG-1252-12A and 5-FU single therapy. By analyzing proliferation marker Ki67 in xenograft tumor specimens, we found that the number of proliferating cells significantly decreased in tumors receiving combination treatment of APG-1252-12A and 5-FU compared with tumors receiving single treatment. The results strongly confirmed the antitumor capacity of APG-1252-12A combined with 5-FU. Conclusions: The results strongly suggest that Bcl-2 and Bcl-xl inhibitor APG-1252-12A may serve not only as a single therapy, but also as an effective adjunct to current chemotherapeutic regimens for treating gastric cancer through apoptosis signal pathway. Citation Format: Xianglei Yan, Hanjie Yi, Qiuyun Luo, Luping Yuan, Suna Zhou, Wentao Pan, Lin Zhang, Miaozhen Qiu, Dajun Yang. A novel Bcl-2/Bcl-XL inhibitor APG-1252-12A as a potential therapeutic strategy for gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2054.

Background: The amplification of Murine Double Minute 2 (MDM2) and mutation of P53 are significant processes in the incidence of gastric cancer. APG-115, a small molecular inhibitor of MDM2-P53, is a novel potential anticancer agent. We aim to investigate the anticancer effect of APG-115 in gastric cancer. Methods: We selected 87 pairs of gastric cancer tissues (primary tumors and metastatic tissues). Using Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH), we examined the expression and amplification of MDM2 and P53. Using MTS, we examined the anti-proliferation activity of APG-115 in five gastric cancer cell lines (AGS, MKN-45, BGC-823, NCI-N87, NUGC-3) by CCK-8 assay. We used western blot analysis and siRNA interference for mechanism exploration to examine the anti-cancer activity of APG-115 in p53 wild type gastric cancer cell lines. Gastric cancer cell xenograft nude mice models were used for in vivo efficacy evaluation. Results: We examined 87 pairs of gastric cancer tissues in IHC. The results suggested that the primary tumors and metastatic tissues with high expression of MDM2 and P53 have shortened survival. The proliferation inhibition of APG-115 on p53 wild-type gastric cancer cells of AGS and MKN45 was concentration and time dependent. APG-115 induced apoptosis in gastric cancer cells. APG-115 can induced cell-cycle arrest in G1/G0 phase in the p53 wild-type of gastric cancer cells. APG-115 exhibited potent antitumor activity against established human gastric cancer xenografts. Conclusions: APG-115 can inhibitor tumor growth in p53 wild-type gastric cancer cells by inducing apoptosis and cell cycle arrest both in vitro and vivo. APG-115 can serve as an effective and precise therapeutic strategy for gastric cancer. Citation Format: Lin Zhang, Luo Qiuyun, Yan Xianglei, Xueping Wan, Luping Yuan, Yuxing Zhang, Suna Zhou, Wentao Pan, Mengxian Pan, Miaozhen Qiu, Shijuan Mai, Dajun Yang. A novel small molecule inhibitor of MDM2-p53 (APG-115) has antitumor activity in gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2061.

Background: Esophageal squamous cell carcinoma (ESCC) is a fatal disease with poor prognosis and lack of effective targeted therapy. Recently, some researches have shown that BTK can be a novel therapeutic target for esophageal cancer, while the mechanism remains unknown. In addition, FAK is one of the important factors to promote the metastasis of esophageal cancer. In this study, we sought to explore the synergistic antitumor effect and underline mechanism of combining BTK inhibitor Ibrutinib with a novel FAK inhibitor APG-2449 for esophageal squamous cell carcinoma. Methods: Cell viability and growth inhibition were determined by CCK-8 assay and colony formation assay. Migration ability was detected by Transwell assay. EMT markers and ki67 were measured by RT-qPCR. Cell cycle analysis and apoptosis were confirmed by flow cytometry. Western Blot analysis and siRNA interference for mechanism exploration. ESCC xenograft models were established to evaluated the synergistic antitumor effect in vivo. Results: We found that ESCC cell lines harbor EGFR or c-myc-amplified exhibited more sensitive to Ibrutinib inhibition. Moreover, Ibrutinib combined with APG-2449 showed synergistic inhibition of cell proliferation in ESCC cell lines. By analyzing data from the Gene Expression Profiling Interactive Analysis database, we found that EGFR expression positively correlated with FAK expression in ESCC samples. The combination of Ibrutinib and APG-2449 exerted obviously synergistic apoptosis induction and colony formation inhibition. Furthermore, we found that Ibrutinib combined with APG-2449 could induce more cancer cells arrested in G1/S phase. In addition, the co-treatment of Ibrutinib and APG-2449 could significantly suppress ESCC cells migration by upregulating E-cadherin. Ibrutinib alone could down-regulate the protein expression of p-EGFR and p-ERK. Moreover, combination treatment significantly reduced the expression of p-Akt and p-c-myc, and upregulated P21 and PUMA expression. In ESCC xenotransplantation models, single therapy with either Ibrutinib or APG-2449 was equivalent in delaying tumor growth, while the combination therapy demonstrated more significantly tumor growth suppression. Conclusions: Taken together, our data strongly suggest that the combination of FAK inhibitor APG-2449 and Ibrutinib provide an effective and precise therapeutic strategy for treating esophageal squamous cell carcinoma. Citation Format: Qiu-Yun Luo, Su-Na Zhou, Wen-Tao Pan, Meng-xian Pan, Lu-ping Yuan, Lin Zhang, Xiang-Lei Yan, Yu-xin Zhang, Jian Sun, Miaozhen Qiu, Da-Jun Yang. FAK blockade enhances antitumor effect of BTK inhibitor in esophageal squamous cell carcinoma via EGFR-ERK-Akt pathway inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 309.

The monoclonal antibody trastuzumab has brought survival benefit to patients with advanced gastric cancer (AGC) that have human epidermal growth factor receptor 2 (HER2) over expression or amplification. This study was designed to compare the clinical outcomes of HER2-negative and HER2-positive AGC patients with or without trastuzumab treatment. There were three groups of patients enrolled for analysis. Group A was 51 HER2-positive AGC patients treated with trastuzumab and chemotherapy; group B was a matched control group of 47 HER2-positive patients who received chemotherapy only; group C was a matched group of 251 HER2-negative patients who received chemotherapy. All the patients were enrolled at Sun Yat-sen University Cancer Center or Zhongshan Hospital, Fudan University between January 2010 and December 2012. The primary endpoint was overall survival (OS). The Kaplan-Meier method and log-rank test were used for survival analysis. The median duration of follow-up was 13.5 months (range 5-18.6 months). The median OS of these three groups of patients was 14.8 months, 11.3 months and 14.4 months respectively (p < 0.001). The survival difference between group A and B was significant, p < 0.001. Similarly, there was significant difference between group B and C, p < 0.001. Moreover the survival between group A and C was comparable, p = 0.281. The median progression-free survival for these three groups was 7.4, 6.0 and 7.2 months. Multivariate analysis confirmed that trastuzumab treatment was an independent prognostic factor in group A and B patients (p = 0.017). HER2 positive was an independent adverse prognostic factor in group B and C patients (p = 0.013).

CXCL12/CXCR4 has been studied as an important biomarker for many human malignancies, but studies are limited for esophageal squamous cell carcinoma (ESCC). In this study, an effective RNAi sequence targeting the CXCR4 gene was selected, a lentiviral shRNA vector was constructed to specifically silence CXCR4 expression in the EC9706 ESCC cell line, and the effects of CXCR4 silencing on cell growth in vitro and tumour growth in nude mice were then evaluated. The expression of CXCR4 in EC9706 was significantly downregulated after transfection with a lentiviral shRNA vector. The expression of the apoptosis-related gene Bcl-2 was decreased. In addition, after CXCR4 inhibition, cell growth was considerably inhibited, increased apoptosis in the EC9706 cells was found, the G0/G1 percentage was significantly increased, and the number of cells in S phase was reduced. Moreover, tumour growth in nude mice was inhibited. In conclusion, the downregulation of CXCR4 expression by transfection with a lentiviral shRNA vector in ESCC cells could inhibit tumour proliferation. Our data may provide an avenue for finding new ESCC treatments.

BackgroundLong non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor progression. However, the role and molecular mechanism of lncRNA XIST in gastric cancer is still unknown.MethodsReal-time PCR analysis was performed to measure the expression levels of lncRNA XIST in gastric cancer tissues and cell lines, the correlation between lncRNA XIST expression and clinicopathological characteristics and prognosis was analyzed in gastric cancer patients. The biological function of lncRNA XIST on gastric cancer cells were determined both in vitro and in vivo. The regulating relationship between lncRNA XIST and miR-101 was investigated in gastric cancer cells.ResultslncRNA XIST was significantly up-regulated in gastric cancer tissues and cell lines. Overexpression of lncRNA XIST was markedly associated with larger tumor size, lymph node invasion, distant metastasis and TNM stage in gastric cancer patients. Functionally, knockdown of lncRNA XIST exerted tumor-suppressive effects by inhibiting cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo. Furthermore, an inverse relationship between lncRNA XIST and miR-101 was found. Polycomb group protein enhancer of zeste homolog 2 (EZH2), a direct target of miR-101, could mediated the biological effects that lncRNA XIST exerted.ConclusionslncRNA XIST is up-regulated and is associated with aggressive tumor phenotypes and patient survival in gastric cancer, and the newly identified lncRNA XIST/miR-101/EZH2 axis could be a potential biomarkers or therapeutic targets for gastric cancer patients.

OBJECTIVES: Pathological complete response has shown a better prognosis for patients with locally advanced rectal cancer after preoperative chemoradiotherapy. However, correlations between post-chemoradiotherapy clinical factors and pathologic complete response are not well confirmed. The aim of the current study was to identify post-chemoradiotherapy clinical factors that could serve as indicators of pathologic complete response in locally advanced rectal cancer. METHODS: This study retrospectively analyzed 544 consecutive patients with locally advanced rectal cancer treated at Sun Yat-sen University Cancer Center from December 2003 to June 2014. All patients received preoperative chemoradiotherapy followed by surgery. Univariate and multivariate regression analyses were performed to identify post-chemoradiotherapy clinical factors that are significant indicators of pathologic complete response. RESULTS: In this study, 126 of 544 patients (23.2%) achieved pathological complete response. In multivariate analyses, increased pathological complete response rate was significantly associated with the following factors: post-chemoradiotherapy clinical T stage 0-2 (odds ratio=2.098, 95% confidence interval=1.023-4.304, p=0.043), post-chemoradiotherapy clinical N stage 0 (odds ratio=2.011, 95% confidence interval=1.264-3.201, p=0.003), interval from completion of preoperative chemoradiotherapy to surgery of >;7 weeks (odds ratio=1.795, 95% confidence interval=1.151-2.801, p=0.010) and post-chemoradiotherapy carcinoembryonic antigen ≤2 ng/ml (odds ratio=1.579, 95% confidence interval=1.026-2.432, p=0.038). CONCLUSIONS: Post-chemoradiotherapy clinical T stage 0-2, post-chemoradiotherapy clinical N stage 0, interval from completion of chemoradiotherapy to surgery of >;7 weeks and post-chemoradiotherapy carcinoembryonic antigen ≤2 ng/ml were independent clinical indicators for pathological complete response. These findings demonstrate that post-chemoradiotherapy clinical factors could be valuable for post-operative assessment of pathological complete response.

Marital status was found to be an independent prognostic factor for survival in various cancer types. In this study, we used the Surveillance, Epidemiology and End Results database to analyze the survival difference among different marital status in the United States. Gastric adenocarcinoma patients from 2004–2012 were enrolled for study. The 5-year cause specific survival (CSS) was our primary endpoint. Totally 29,074 eligible patients were identified. We found that more male patients were married than female. Asian patients had the highest percentages of married than the other races. More married patients were covered by the insurance. Married patients had better 5-year CSS than unmarried, 30.6% vs 25.7%, P

The aim of the present study was to determine whether C-reactive protein (CRP)–based systemic inflammatory response scores (modified Glasgow prognostic score, mGPS; prognostic index, PI) have prognostic value superior to that of scores based on circulating white cells (neutrophil/lymphocyte ratio, NLR; platelet/lymphocyte ratio, PLR) or in combination with albumin (prognostic nutritional index, PNI) in patients with pancreatic cancer. The medical records of 177 patients with pancreatic adenocarcinoma were reviewed. Kaplan–Meier methodology and a multivariable Cox proportional hazards model were used to evaluate the potential prognostic factors. NLR > 5 was associated with higher white cell count, higher PLR, elevated CRP, hypoalbuminemia, increased mGPS, PI and PNI, poorer performance status (PS), greater weight loss and poorer tumor differentiation. On multivariate analysis, only NLR (HR, 2.537; 95 % CI, 1.313–4.902; p = 0.006), PS, tumor–node–metastasis (TNM) staging, type of surgery and palliative chemotherapy were associated independently with survival, whereas PLR, mGPS, PI and PNI were not. NLR > 5 predicted poorer overall survival (OS) compared with NLR ≤ 5 (median OS, 4.133 and 9.300, respectively; p = 0.006). On the subgroup analysis, the median OS of patients with NLR > 5 was 5.767 months, whereas patients with NLR ≤ 5 who had received palliative chemotherapy had a median OS of 10.200 months (p

The incidence of gastric cancer in young has increased steadily in the last decades. Little is known about the clinicopathologic features and prognostic factors of young adult gastric cancer patients. The clinicopathological characteristics of 294 young adult gastric cancer patients between 20 and 50 years old were reviewed retrospectively from hospital records in Sun Yat-Sen University Cancer Center between 1996 and 2006. They were compared with 706 elder patients 51 years of age or over. A steady increasing in the proportion of female in the gastric carcinoma patients as the age decreasing was found. The distinguishing histological features of young adult patients were higher percentage of poorly differentiated grade and distant metastasis. The distribution of tumor-nodes-metastasis (TNM) stage was similar between these two groups. The 5-year disease-specific survival rate in the young adult group was significantly higher than in the elderly group. More patients receiving adjuvant chemotherapy were found in the young adult group. Multivariable analysis demonstrated that TNM stage and presence of angiolymphatic invasion were the independent negative predictors of survival for young patients with gastric cancer. Gastric cancer in young patients differs from that in elderly patients including a lack of male predilection, more aggressive histologic features, and better survival rate.

Gastric cancer patients with negative nodes were considered to have better outcomes, however, some of them still suffered from disease recurrences or distant metastases after radical resection. A total of 1,020 gastric carcinoma patients receiving treatment in our center between 2003 and 2008 were selected for the analysis. All patients received gastrectomy and D2 lymphadenectomy. Survival analysis was performed with Cox regression model. The final study includes 222 patients. The overall 5-year disease-specific survival rate was 73.0%. Factors bearing significant association with lower survival on univariate analysis included the age of 58 years old or more (P = 0.021), tumor size longer than 4 cm (P < 0.001), presence of angiolymphatic invasion (P = 0.006), proximal site (P = 0.030), serosal invasion (T3+T4, P = 0.003), and higher TNM stage (P < 0.001). Only three factors including serosal invasion, tumor size at least 4.0 cm, and presence of angiolymphatic invasion remained independent negative predictors of survival in multivariable analysis. These parameters can be employed to select node-negative gastric cancer patients for an adjuvant setting and close follow-up scheduling.

The impact of hypoxia-inducible factor (HIF)-1α and hexokinase-II (HK-II) expression on prognosis of gastric adenocarcinoma patients has not been clearly established. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as gastric adenocarcinoma and underwent radical gastrectomy between January 1999 and December 2001. We used immunohistochemistry to determine the expressions of HIF-1α protein and HK-II in the surgical sections. We identified 188 patients with gastric adenocarcinoma for the final analysis. The positive rate of HIF-1α and HK-II were 110/188 (54.6%) and 40/188 (21.3%), respectively. Both HIF-1α and HK-II were all positively correlated with tumor size, lower differentiation, and tumor stage. Univariate analysis showed that advanced tumor stages (P < 0.001), tumor size (P = 0.003), HIF-1α expression (P < 0.001), and HK-II expression (P < 0.001) were all significantly associated with shorter survival. The multivariate Cox analysis revealed that tumor stage (P < 0.001), HIF-1α expression (P < 0.001), and HK-II expression (P = 0.002) remained independent prognostic variables for survival. In addition, there was a positive correlation of HIF-1α protein expression and HK-II (P = 0.022). Both HIF-1α and HK-II were overexpressed in gastric adenocarcinoma. The multivariate Cox analysis revealed that both of them were independent factors on survival of gastric adenocarcinoma patients.

BACKGROUND AND OBJECTIVE Little is known about the incidence of hepatitis B virus (HBV) infection in Hodgkin's lymphoma patients. This study was to evaluate the impact of HBV infection on the survival of Hodgkin's lymphoma patient. METHODS Clinical data of 120 Hodgkin's lymphoma patients treated at the Sun Yat-sen University Cancer Center between January 2004 and October 2007 were collected. The impact of prognostic factors including HBV infection on survival was examined by univariate and multivariate analyses. A log-rank test was used for univariate analysis and the Cox proportional hazards regression model was used for multivariate analysis. RESULTS Of the 120 patients, 18 (15.0%) were hepatitis B virus surface antigen HBsAg-positive. The HBsAg-positive patients had lower 5-year survival rate than did the HBsAg-negative ones (66.9% vs. 91.3%, P = 0.006). When the patients were divided into early-stage (I + II) and advanced-stage (III + IV) groups, the 5-year survival rate was significantly different between the HBsAg-positive and -negative patients in early-stage group (64.8% vs. 96.0%, P < 0.001), while not significantly different in advanced-stage group (75.0% vs. 84.8%, P = 0.667). Both univariate and multivariate analyses showed that radiotherapy and HBV infection were independent prognosis factors for the patients with early-stage Hodgkin's lymphoma (P = 0.006 and 0.014, respectively). CONCLUSIONS The incidence of HBV infection is similar between Hodgkin's lymphoma patients and normal population. HBV infection is an independent prognosis factor for survival in the patients with early-stage Hodgkin's lymphoma.

Background: Despite advances in the treatment of non-Hodgkin's lymphoma (NHL), refractory NHL remains a major clinical challenge. The B-cell lymphoma protein-2 (BCL-2) family is frequently overexpressed in NHL, which is associated with poor prognosis by promoting cell growth and resistance to antitumorigenic agents. In this study, by using different BCL-2 family protein inhibitors, we aim to further classify the survival dependency of NHL for anti-apoptotic BCL-2 family members and explore novel approaches to rationally develop combination therapies by completely blocking the activity of the Bcl-2 family proteins. Methods: Cell viability was determined by CCK-8 assay. Apoptotic activity was confirmed by Annexin V-propidium iodide (PI) apoptosis detection, Western blot analysis and mitochondrial membrane potentials detection analysis. In vivo, NHL xenograft models were established to analyze the antitumor effect of the BCL-2 family protein inhibitors. Results: We evaluated the inhibitory effect of of Bcl-2 targeted inhibitors and synergy in combination with other molecular targeted agents in NHL. While those NHL cell lines with only high levels of BCL-2 protein are sensitive to Bcl-2 selective inhibitor, the dual Bcl-2/Bcl-xL inhibitor APG-1252 and its active metabolite APG-1252-M1 potently induced mitochondria-dependent apoptosis in NHL cell lines that possess high expression of both BCL-2 and BCL-XL proteins. After the treatment of APG-1252-M1, apoptosis including caspase-3 activation, PARP cleavage, and mitochondrial membrane potentials change was observed rapidly within four hours. We further demonstrated that APG-1252-M1 showed synergistic effects with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in those sensitive cell lines by modulating STAT3 signaling pathways. However, cell lines harboring high expression of anti-apoptotic protein MCL-1 were resistant to APG-1252-M1. Furthermore, we observed that APG-1252-M1 exhibited strong synergistic effect with dual PI3K/mTOR inhibitors NVP-BEZ235 in those resistant cell lines with high levels of Mcl-2 protein. Conclusions: Taken together, our data provide an effective and precise therapeutic strategy for NHL through determining NHL addiction to anti-apoptotic BCL-2 family proteins, and then target-guided application of BCL-2 family inhibitors as a monotherapy or in combination with other molecular targeted agents to completely block the Bcl-2 family proteins, thus to restore the apoptotic cell death. Citation Format: Qiu-Yun Luo, Han-Jie Yi, Xiang-Lei Yan, Miaozhen Qiu, Bao-Xia Li, Lin Zhang, Wen-Tao Pan, Lu-Ping Yuan, Zhen-Yi Liu, Douglas D. Fang, Yifan Zhai, Jian Sun, Da-Jun Yang. Targeting the anti-apoptotic BCL-2 family protein provides an effective and precise therapeutic strategy for NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 301.

Background: Colorectal carcinoma is the third leading cause of cancer-related mortality in China. MDM2-p53 inhibitor APG-115 is a novel potential anticancer agent. We aim to investigate the anticancer effect and radiosensitivity enhancement of APG-115 in colorectal cancer. Materials and methods: Human colorectal cancer cell lines (LOVO, HCT116, RKO, HT29, SW480 and SW620) were treated with the APG-115 alone or with radiation (0-8Gy). Transwell, clonogenic survival assays, CCK-8, flow cytometry, RT-qPCR, Western blot were used to assay cell invasion, cell survival, cell cycle progression, quantification of mRNA expression and DNA damage repair. In vivo, xenograft mouse models (RKO Cell line) were established to analyze the anticancer effect and radiosensitivity enhancement of APG-115. Results: In vitro, APG-115 not only inhibited invasion and proliferation of colorectal cell lines, but also induced cell-cycle arrest in G1/S phase. Meanwhile, APG-115 increased the mRNA and protein expression of p53 downstream targets dependent on MDM2-p53 signal pathway. The combination of APG-115 and radiation caused cells to accumulate in G2/M and resulted in the accumulation of H2AX-related DNA damage, indicating an increasing of radiosensitivity. In xenograft mouse models, single therapy with either radiation or APG-115 was equivalent in delaying tumor growth, although APG-115 slightly outperforming therapy with radiation alone. Combination therapy delayed tumor growth more significantly compared with either single agent therapy. By analyzing proliferation marker Ki67 in xenograft tumor specimens, we found that the number of proliferating cells significantly decreased in tumors receiving combination treatment of APG-115 and radiation compared with tumors receiving single agent treatment. These results strongly confirmed the enhanced antitumor capacity of APG-115 when combined with radiation. Conclusions: Our data strongly suggest that MDM2-p53 inhibitor APG-115 may serve not only as a stand-alone therapy, but also as an effective adjunct to current radiotherapeutic regimens for treating colorectal cancer dependent on MDM2-p53 axis. Citation Format: Han-Jie Yi, Xiang-Lei Yan, Qiu-Yun Luo, Luping Yuan, Baoxia Li, Wentao Pan, Lin Zhang, Miao-Zhen Qiu, Guangfeng Wang, Yifan Zhai, Da-Jun Yang. A novel MDM2-p53 antagonist APG-115 induces p53-mediated apoptosis and enhances radiosensitivity in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 314.

Despite the fact that malignancies are associated with hematological abnormalities, some clinical studies have been unable to detect such a relation. The aim of our study was to detect the prevalence of pretreatment hematologic abnormalities in patients with common solid tumors and to determine if such a profile could be used for prognostic evaluations. We identified all patients in Cancer Center of Sun Yat-sen University who were diagnosed as solid tumors (breast carcinoma, hepatocellular carcinoma, nasopharyngeal carcinoma, esophageal carcinoma, gastric cancer, cervical carcinoma, endometrial cancer, renal cell carcinoma, and non-small cell lung cancer) between January 2000 and August 2009. All subjects were investigated regarding levels of white blood cells, platelets, and hemoglobin concentration. We identified 3,180 patients with solid tumors and 285 patients with benign diseases for the final analysis. The percentages of leukocytosis, anemia, and thrombocytosis in patients with solid tumors ranged from 4.0% to 25.6%, 3.3% to 29.2%, and 2.1% to 9.7%, respectively. The multivariate Cox analysis revealed that anemia was an independent prognostic factor in patients with breast cancer (P = 0.006), hepatocellular carcinoma (P = 0.002), nasopharyngeal carcinoma (P = 0.008), and esophageal carcinoma (P = 0.001). Leukocytosis was an independent prognostic factor in patients with cervical cancer (P = 0.007). The incidence of hematological abnormalities in Chinese patients with solid tumors was relatively lower than that of the counterparts in the Western countries. A pretreatment anemia or leukocytosis can serve as a useful marker to predict outcome of patients in some of the solid tumors.

2593Background: APG-1387 is a bivalent small molecule Smac mimetic that antagonizes the IAPs. Preclinical studies have shown its dose- and schedule-dependent, strong antitumor activities in multipl...

Pretreatment hematologic abnormalities have been reported to have prognostic value in patients with solid tumors. The aim of our study was to determine the prevalence of abnormalities in the hematologic profile in patients with colorectal cancer before treatment and to evaluate if such a profile could be used for prognostic evaluations. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as colorectal cancers between May 2005 and August 2009. All subjects were investigated regarding levels of white blood cells, platelets, and hemoglobin concentration. Survival was compared by using the log-rank test on the Kaplan-Meier life table. Multivariate Cox regression analysis was used to evaluate if the pretreatment hematologic profile was independent prognostic factor. We identified 363 patients with colorectal cancer and 315 patients with benign diseases for the final analysis. The percentages of leukocytosis, anemia, and thrombocytosis were significantly higher in colorectal cancer patients than in patients with benign diseases. Univariate analysis showed that advanced tumor stages, leukocytosis, anemia, thrombocytosis, and low histological grade were all significantly associated with shorter survival. The multivariate Cox analysis revealed that low histological grade, tumor stage, pretreatment anemia, and thrombocytosis remained independent prognostic variables for survival. The cumulative effect of anemia and thrombocytosis yielded shorter survival. Anemia and thrombocytosis can be considered as useful prognostic markers in patients with colorectal cancer.

Background: The prognosis of patients with advanced gastric cancer (AGC) remains poor, and no single chemotherapy regimen is recognized as a global standard. A phase II trial was conducted to determine the efficacy and tolerability of capecitabine and oxaliplatin (XELOX) given every 3 weeks in combination in patients with AGC. Methods: Patients with previously untreated AGC received intravenous oxaliplatin 130 mg/m2 over 2 h on day 1 plus oral capecitabine 1,000 mg/m2 twice daily on days 1–14, every 3 weeks. Treatment was continued for 8 cycles or until disease progression or intolerable toxicity. Results: Fifty patients were enrolled. In total, 210 cycles of XELOX were delivered. The OVERALL response rate was 42% (95% CI 28.6–56.7), with 2 complete and 19 partial responses. At 15.2 months of median follow-up, median time to progression and overall survival were 5.8 (95% CI 3.4–8.2) and 11.1 (95% CI 5.6–16.5) months, respectively. The most common hematological adverse event was neutropenia (56% of patients); grade 3–4 neutropenia was observed in 6 patients, with neutropenic fever in only 2 patients. The most common non-hematological toxicities were vomiting (34%), hand-foot syndrome (26%), diarrhea (24%) and neurosensory toxicity (22%). There were no treatment-related deaths. Conclusions: XELOX is active for the first-line treatment of AGC with a manageable tolerability profile.

The aim of this study is to evaluate the safety and efficacy of the combination of capecitabine and oxaliplatin (XELOX) as first-line treatment in Chinese patients with metastatic colorectal carcinoma (mCRC). Furthermore, we aimed to explore whether a maintenance therapy with oral capecitabine in patients who were non-progression to the XELOX regimen was able to improve the duration of disease control (DDC). One hundred twenty-four patients with mCRC received a 3-weekly regimen of oxaliplatin plus capecitabine (XELOX) as first-line treatment. Patients without progressive disease after six cycles of XELOX could stop treatment or continue to receive oral capecitabine until disease progression or unacceptable toxicity. A total of 637 cycles (median 6 cycles) of XELOX were given to 124 patients (males 58.1%, median age 52 years). The response rate was 49.1% (complete response in 11 patients and partial response in 50 patients). The median overall survival and progression-free survival were 20.0 and 8.0 months, respectively. Main drug-related grade 3–4 toxicities included neutrapenia (5.6%), nausea/vomiting (4%), thrombocytopenia (2.4%), diarrhea (2.4%) and hand–foot syndrome (2.4%). Among 62 patients achieving objective response or stable disease after at least 6 cycles of XELOX, there were 22 patients received oral capecitabine as maintenance therapy. The median DDC was significantly longer for maintenance therapy group than those of no maintenance group (14 vs. 9 months; P = 0.041). XELOX is a highly effective first-line treatment for Chinese mCRC patients. The response rate, TTP, and overall survival of patients treated with this regimen are similar to those treated with FU/leucovorin/oxaliplatin. Furthermore, our preliminary data show maintenance therapy with capecitabine for those patients without progressive disease after at least six cycles of XELOX can significantly improve DDC; and further prospective randomized control trial is warranted.

This study intends to identify biomarkers that could refine the selection of patients with metastatic colorectal cancer (mCRC) for bevacizumab treatment. Pretreatment 36 plasma cytokines and angiogenic factors (CAFs) were first measured by protein microarray analysis in patients who received first-line bevacizumab-containing therapies (discovery cohort, n = 64) and further evaluated by enzyme-linked immunosorbent assay in patients treated on regimens with or without bevacizumab (validation cohort, n = 186). Factor levels were correlated with clinical outcomes, predictive values were assessed using a treatment by marker interaction term in the Cox model. Patients with lower pretreatment levels of hepatocyte growth factor (HGF) or VEGF-A121 gain much more benefit from bevacizumab treatment as measured by progression-free survival (PFS) and overall survival (OS), while angiopoietin-like 4 (ANGPTL4) levels negatively correlated with PFS and response rate following bevacizumab (all adjusted interaction P

Disadvantaged populations face many barriers to cancer care, including limited support in navigating through the complexities of the healthcare system. Family members play an integral role in caring for patients and provide valuable care coordination; however, the effect of family navigators on adherence to cancer screening has not previously been evaluated. Training and evaluating trusted family members and other support persons may improve cancer outcomes for vulnerable patients. Guided by principles of community based participatory research (CBPR), “Evaluating Coaches of Older Adults for Cancer Care and Healthy Behaviors (COACH)” is a community-based randomized controlled trial to assess the effectiveness of a trained participant-designated coach (support person or care giver) in navigating cancer-screening for older African American adults, 50–74 years old. Participants are randomly assigned as dyads (participant + coach pair) to receiving either printed educational materials only (PEM—control group) or educational materials plus coach training (COACH—intervention group). We defined a coach as family member, friend, or other lay support person designated by the older adult. The coach training is designed as a one-time, 35- to 40-minute training consisting of: 1) a didactic session that covers the role of the coach, basic facts about colorectal, breast and cervical cancers (including risk factors, signs and symptoms and screening modalities), engaging the healthcare provider in cancer screening, insurance coverage for screening, and related healthcare issues, 2) three video skits addressing misconceptions about and planning for cancer screening, and 3) an interactive role-play session with the trainer to reinforce and practice strategies for encouraging the participant to get screened. The primary study outcome is the difference in the proportion of participants completing at least one of the recommended screenings (for breast, cervix or colorectal cancer) between the control and intervention groups. Building on trusted patient contacts to encourage cancer screening, COACH is a highly sustainable intervention in a high-risk population. It has the potential to minimize the effect of mistrust of the medical establishment on screening behaviors by mobilizing participants’ existing support networks. If effective, the intervention could have a high impact on health care disparities research across multiple diseases. ClinicalTrials.gov ( NCT01613430 ). Registered June 5, 2012

After the approval of bevacizumab for the first-line treatment of metastatic colorectal cancer (mCRC) in China, published information was still limited. This observational cohort study enrolled 175 mCRC patients who initiated bevacizumab-containing first-line chemotherapies at Sun Yet-sen University Cancer Center. Backbone chemotherapies included FOLFIRI (45.6 %), FOLFOX (34.9 %), and XELOX (19.5 %). Effectiveness data, safety profiles, and treatment patterns were collected and compared between oxaliplatin- and irinotecan-based groups. The median treatment durations of bevacizumab in first-line and total were equivalent between oxaliplatin- and irinotecan-based group (5.0 vs. 4.8 and 6.0 vs. 5.9 months, respectively). Median progression-free survival (PFS) was 10.6 months, and median overall survival (OS) was 24.2 months in entire population. No significant difference was found between irinotecan- and oxaliplatin-based groups in PFS (10.8 vs. 10.1 months, p = 0.21) or in OS (27.5 vs. 23.7 months, p = 0.68). Overall response rate in entire population was 38.3 %, and the disease control rate was 86.3 %. Bevacizumab-associated serious adverse events included hypertension (4.2 %), bleeding (3.6 %), proteinuria (3.0 %), venous thromboembolism (0.6 %), and wound-healing complications (0.6 %). Curative-intent surgery after conversion chemotherapy was carried out in 23 patients (13.7 %). Multivariate analyses showed that maintenance therapy (p = 0.001), resection of metastatic sites (p = 0.002), and disease-free interval (p = 0.003) were independent prognostic factors for OS survival. In spite of small discrepancies in treatment patterns, irinotecan- and oxaliplatin-based chemotherapeutic regimens are equally compatible partners for bevacizumab in first-line Chinese mCRC treatment.

Tumor response to preoperative chemoradiotherapy and postoperative survival differs among patients with locally advanced rectal cancer. The objective was to find correlations of mutated oncogenes and clinical outcomes in locally advanced rectal cancer. A total of 70 patients with preoperative preoperative chemoradiotherapy followed by radical surgery at a single cancer center between 2006 and 2012 were enrolled. Pretreatment tumor biopsy samples were assayed for 238 mutation hotspots harboring 19 oncogenes by time-of-flight mass spectrometry and OncoCarta Array. Oncogene mutations were found in 48.6% of patients (34/70). KRAS was the most frequent driver mutation, found in 35.7% of patients (25/70), followed by PIK3CA (14.3%), NRAS (5.7%), FLT3 (2.9%), and BRAF (1.4%). Multiple gene mutations were observed in eight patients (11.4%). Tumors with KRAS mutations responded poorly to preoperative chemoradiotherapy (p = 0.044). Patients with oncogene mutations had worse 3-year disease-free survival than those without mutations (67.2% vs 94.2%, p = 0.010). Patients with KRAS or RAS mutations had lower 3-year disease-free survival (68% vs 88.3%, p = 0.016; 65.5% vs 92.3%, p = 0.004, respectively) and 3-year overall survival (88% vs 95.4%, p = 0.020; 89.7% vs 94.9%, p = 0.036, respectively) than those without KRAS or RAS mutations. Oncogene mutation status affected tumor response to treatment and long-term survival in locally advanced rectal cancer.

4065 Background: Familial clustering is seen in 10 % of gastric cancer cases and approximately 1-3 % of gastric cancer arises in the setting of hereditary diffuse gastric cancer (HDGC). Little is known about the incidence rate and clinical-pathologic features of HDGC in Chinese patients. Methods: We retrospectively collected gastric adenocarcinoma patients who were diagnosed in Sun Yat-sen University Cancer Center between January 2002 and December 2014. All the patients had detailed record of family history and Lauren classification. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). Results: 7431 patients were enrolled for analysis. The incidence rate of HDGC was 3.97% (295/7431). There were 124 (42.03%) male and 171 (57.97%) female patients. The median age was 35 (Mean ±SD: 35.23±7.50). The most common sites were gastric body (49.47%) and fundus (35.09%) . The distribution of AJCC 7thTNM stage was 47 (16.32%) stage I, 59 (20.49%) stage II, 88 (30.55%) stage III and 94 (32.64%) stage IV. Only 92 patients received the HER2 immunohistochemistry test. 4 (4.35%) patients were HER2 IHC +++ and 8 (8.70%) patients were ++. The median survival was 80 months for the whole population and 15 months for stage IV patients. Conclusions: The incidence rate of HDGC was 3.97% in China. About one third of the patients were diagnosed at stage IV. Early detection of HDGC was warranted in China.

AIM: To explore the association between AT-rich interactive domain 1A (ARID1A) protein loss by immunohistochemistry and both clinicopathologic characteristics and prognosis in patients with colorectal cancer. METHODS: We retrospectively collected clinicopathologic data and archived paraffin-embedded primary colorectal cancer samples from 209 patients, including 111 patients with colon cancer and 98 patients with rectal cancer. The tumor stage ranged from stage I to stage IV according to the 7th edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. All patients underwent resection of primary colorectal tumors. The expression of ARID1A protein in primary colorectal cancer tissues was examined by immunohistochemical staining. The clinicopathologic association and survival relevance of ARID1A protein loss in colorectal cancer were analyzed. RESULTS: ARID1A loss by immunohistochemistry was not rare in primary colorectal cancer tumors (25.8%). There were 7.4%, 24.1%, 22.2% and 46.3% of patients with ARID1A loss staged at TNM stage I, II, III and IV, respectively, compared with 20.0%, 22.6%, 27.7% and 29.7% of patients without ARID1A loss staged at TNM stage I, II, III and IV, respectively. In patients with ARID1A loss, the distant metastasis rate was 46.3%. However, only 29.7% of patients without ARID1A loss were found to have distant metastasis. In terms of pathologic differentiation, there were 25.9%, 66.7% and 7.4% with poorly, moderately and well differentiated tumors in patients with ARID1A loss, and 14.2%, 72.3% and 13.5% with poorly, moderately and well differentiated tumors in patients without ARID1A loss, respectively. ARID1A loss was associated with late TNM stage (P = 0.020), distant metastasis (P = 0.026), and poor pathological classification (P = 0.035). However, patients with positive ARID1A had worse overall survival compared to those with negative ARID1A in stage IV colorectal cancer (HR = 2.49, 95%CI: 1.13-5.51). CONCLUSION: ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.

Background A high neutrophil to lymphocyte ratio (NLR) is a strong predictor of poor survival in patients with colorectal, breast, pancreatic and lung cancers, while the prognostic value of NLR in gastric cancer is still controversial. The aim of our study was to determine the prognostic value of pretreatment NLR in a Chinese population of patients with gastric adenocarcinoma. Methods Our retrospective study used an unselected cohort of gastric adenocarcinoma patients treated in the Cancer Center of Sun Yat-sen University between January 2001 and December 2008. We used the data from 341 healthy individuals as controls to understand the difference of NLR between the gastric cancer patients and normal individuals. A total of 706 patients had a complete blood count (CBC) record prior to treatment. Cox regression analysis was used to evaluate the prognostic value of NLR. Results Gastric adenocarcinoma patients had a significantly higher NLR as well as neutrophilic granulocyte and lower lymphocyte counts compared with healthy individuals. By combining the nearby groups of NLR whose survival had no significant difference, we got a cutoff value for NLR of 3. Patients with a high NLR had a significantly lower survival rate than patients with a low NLR. On multivariate analysis, after adjusting for tumor stage and other clinicopathologic factors, high NLR turned out to be an independent risk factor for poor survival (p=0.016). Conclusions Gastric cancer patients had a significantly higher incidence rate of high NLR compared with healthy individuals. High pretreatment NLR in gastric cancer was an independent prognostic factor.

The aim of our study is firstly to evaluate the prevalence and prognostic value of nutrition risk in gastric cancer patients and secondly to explore whether the nutrition support can prolong the survival of advanced gastric cancer patients. It contained two study periods. In the first period, we prospectively evaluated the nutritional risk of gastric adenocarcinoma patients from 2009 to 2011 using the method of European Nutritional Risk Screening (NRS) 2002. The Kaplan-Meier method and log-rank test were used to evaluate the prognostic value of high nutrition risk. The second period was between 2012 and 2013. We prospectively gave the nutrition support to stage IV gastric cancer patients whose NRS is ≥3. There were 830 patients in the first period, 50.7 % patients with a NRS ≥ 3. Patients with NRS ≥ 3 presented a significantly higher percentage of stage IV diseases, elevated values of C-reactive protein, and hypoproteinemia. The median survival was significantly higher in NRS

The purpose of this study was to identify microRNAs (miRNAs) involved in the pathology of colorectal cancer (CRC) liver metastasis and investigate their underlying mechanisms. A total of 39 miRNAs were identified to be differentially expressed between 16 primary CRC tissues with liver metastases and 16 CRC tissues without liver metastases from 32 patients by Affymetric miRNA microarrays. A panel of eight miRNAs were confirmed to be significantly and differentially expressed between CRC tissues with and without liver metastases through quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis in the 32 patients. In a validated cohort of 99 CRC patients (44 with and 55 without liver metastases), only miR-214 was validated to be significantly down-regulated in CRC with liver metastases, which was associated with an unfavorable prognosis. Ectopic expression of miR-214 suppressed proliferation, migration, and invasion in vitro, tumor growth and liver metastasis in an in vivo xenograft mouse model, whereas miR-214 knockdown promoted proliferation, migration, and invasion in CRC cell lines. Further studies indicated that fibroblast growth factor receptor 1 (FGFR1) was a potential target of miR-214. Restoring miR-214 expression in CRC cells decreased endogenous FGFR1 messenger RNA (mRNA) and protein levels. FGFR1 knockdown mimicked the tumor suppressive effect of miR-214 on CRC cells, while reintroduction of FGFR1 abolished the tumor suppressive effect of miR-214 on CRC cells. Moreover, miR-214 expression levels were inversely correlated with FGFR1 in CRC patients. Conclusion: Down-regulation of miR-214 expression was correlated with increased FGFR1 expression levels, which may contribute to increased CRC liver metastasis. miR-214 may serve as a potential marker to predict survival, and the miR-214-FGFR1 axis may be a therapeutic target in CRC patients. (Hepatology 2014;60:598–609)

Although palliative chemotherapy has been shown to prolong survival and improve quality of life, the survival of advanced gastric cancer (AGC) patients remains poor. With the advent of targeted therapy, many molecular targeted agents have been evaluated in clinical studies. Trastuzumab, an anti-HER2 monoclonal antibody, has shown activity against HER2-positive AGC and becomes the first targeted agent approved in AGC. Drugs that target epidermal growth factor receptor, including monoclonal antibody and tyrosine kinase inhibitor, do not bring survival benefit to patients with AGC. Additionally, vascular endothelial growth factor inhibitors are also under investigation. Ramucirumab has shown promising result. Other targeted agents are in preclinical or early clinical development, such as mammalian target of rapamycinm inhibitors and c-MET inhibitors.

Period1 (Per1) and Period2 (Per2) are members of the circadian genes. Mounting evidence suggests that the deregulation of the circadian clock plays an important role in the development of mammalian cancer. However, the expression and clinical significance of Per1 and Per2 in gastric cancer is still unexplored. Here, we evaluated the expression pattern of Per1 and Per2 in 246 gastric cancer specimens and their adjacent, non-tumorous tissues using immunohistochemical assays. Per1 expression was significantly associated with clinical stage (p < 0.001), depth invasion (p < 0.001), lymph node metastasis (p < 0.001) and pathologic differentiation (p < 0.001). On the other hand, Per2 was associated with clinical stage (p = 0.021) and depth invasion (p = 0.007). Per1 expression was positively correlated with Per2 expression in the 246 gastric cancer patients (r = 0.378, p < 0.001), and the expression levels of Per1 and Per2 were down-regulated in gastric cancer tissues when compared with adjacent, non-tumorous tissues in 45 gastric cancer samples (p < 0.001, p = 0.003). Patients with lower Per1 and Per2 tumor expression had a shorter survival time than those with higher expression. Univariate and Multivariate analyses indicated that Per2 expression is an independent prognostic factor (p = 0.023). Our results demonstrate that Per1 and Per2 may play important roles in tumor development, invasion and prognosis, and Per2 may serve as a novel prognostic biomarker of human gastric cancer.

Background Metabolic syndrome and/or its components have been demonstrated to be risk factors for several cancers. They are also found to influence survival in breast, colon and prostate cancer, but the prognostic value of metabolic syndrome in gastric cancer has not been investigated. Methods Clinical data and pre-treatment information of metabolic syndrome of 587 patients diagnosed with early stage gastric cancer were retrospectively collected. The associations of metabolic syndrome and/or its components with clinical characteristics and overall survival in early stage gastric cancer were analyzed. Results Metabolic syndrome was identified to be associated with a higher tumor cell differentiation (P = 0.036). Metabolic syndrome was also demonstrated to be a significant and independent predictor for better survival in patients aged >50 years old (P = 0.009 in multivariate analysis) or patients with proximal gastric cancer (P = 0.047 in multivariate analysis). No association was found between single metabolic syndrome component and overall survival in early stage gastric cancer. In addition, patients with hypertension might have a trend of better survival through a good control of blood pressure (P = 0.052 in univariate analysis). Conclusions Metabolic syndrome was associated with a better tumor cell differentiation in patients with early stage gastric cancer. Moreover, metabolic syndrome was a significant and independent predictor for better survival in patients with old age or proximal tumors.

Background It has been proved that hepatitis B virus (HBV) infection alters the metastatic pattern and affects survival in colorectal cancer (CRC) and hepatocellular carcinoma (HCC), while the influence of HBV infection on metastatic pattern and survival in patients with pancreatic cancer (PC) has not been investigated yet. Methods We conducted an investigation to evaluate the impact of HBV infection on metastatic pattern and overall survival in PC. We collected the data of 460 PC patients treated in our hospital from 1999 to 2010. Serum HBV markers were tested with enzyme-linked immunosorbent assay. The impact of HBV infection on metastatic pattern and overall survival was analyzed. Results We found that the incidence of synchronous liver metastasis was significantly higher in patients with HBsAg positive than those with HBsAg negative (46.0% vs 32.0%, P < 0.05), and higher in chronic HBV infection (CHB) group than both non HBV infection and resolved HBV infection group (61.1% vs 33.9%, P < 0.05, and 61.1% vs 28.7%, P < 0.05, respectively). What’s more, Kaplan-Meier analysis showed that CHB, resolved HBV infection and non HBV infection group had significant longer overall survival (OS) compared with inactive HBsAg carriers (IC) group (P=0.037, P=0.009, and P=0.019 respectively). But, in the multivariate analysis, only the CHB and non HBV infection group had significant better overall survival compared with IC group (P=0.010 and P=0.018 respectively). Conclusions Our study found that HBV infection increased synchronous liver metastasis rate, and HBV infection status was an independent prognostic factor in PC patients.

Background Primary small cell carcinoma of the esophagus (SCCE) is a highly aggressive disease characterized by early dissemination and poor prognosis. Because of the rarity of this disease, few previous studies have investigated the biomarkers associated with its prognosis. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is a stem cell marker and a member of the canonical Wnt-signaling cascade. However, the clinical role of Lgr5 in SCCE remains unknown. Methods Tissue sections were obtained from 44 patients diagnosed with SCCE and expression of Lgr5 was examined by immunohistochemistry. The correlations between Lgr5 expression, and clinical parameters and prognostic significance were evaluated. Results Lgr5 was expressed in SCCE cancer tissues. High Lgr5 expression was significantly correlated with lymph node metastasis (p = 0.003), late stage (p = 0.003) and unfavorable response to chemotherapy (p = 0.013) according to RECIST 1.0 criteria. Patients with higher Lgr5 expression levels had shorter overall survival times than those with lower expression levels. Conclusions These results demonstrated that overexpression of Lgr5 was significantly correlated with lymph node metastasis, tumor stage, and response to chemotherapy. Furthermore, high levels of Lgr5 expression appeared to be associated with poorer survival in patients with SCCE.

The monoclonal antibody trastuzumab has brought survival benefit to patients with advanced gastric cancer (AGC) that have human epidermal growth factor receptor 2 (HER2) over expression or amplification. This study was designed to compare the clinical outcomes of HER2-negative and HER2-positive AGC patients with or without trastuzumab treatment. There were three groups of patients enrolled for analysis. Group A was 51 HER2-positive AGC patients treated with trastuzumab and chemotherapy; group B was a matched control group of 47 HER2-positive patients who received chemotherapy only; group C was a matched group of 251 HER2-negative patients who received chemotherapy. All the patients were enrolled at Sun Yat-sen University Cancer Center or Zhongshan Hospital, Fudan University between January 2010 and December 2012. The primary endpoint was overall survival (OS). The Kaplan-Meier method and log-rank test were used for survival analysis. The median duration of follow-up was 13.5 months (range 5-18.6 months). The median OS of these three groups of patients was 14.8 months, 11.3 months and 14.4 months respectively (p0.001). The survival difference between group A and B was significant, p0.001. Similarly, there was significant difference between group B and C, p0.001. Moreover the survival between group A and C was comparable, p = 0.281. The median progression-free survival for these three groups was 7.4, 6.0 and 7.2 months. Multivariate analysis confirmed that trastuzumab treatment was an independent prognostic factor in group A and B patients (p = 0.017). HER2 positive was an independent adverse prognostic factor in group B and C patients (p = 0.013).