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Background Dysregulation of circular RNAs (circRNAs) plays an important role in the development of gastric cancer; thus, revealing the biological and molecular mechanisms of abnormally expressed circRNAs is critical for identifying novel therapeutic targets in gastric cancer. Methods A circRNA microarray was performed to identify differentially expressed circRNAs between primary and distant metastatic tissues and between gastric cancer tissues sensitive or resistant to anti-programmed cell death 1 (PD-1) therapy. The expression of circRNA discs large homolog 1 (DLG1) was determined in a larger cohort of primary and distant metastatic gastric cancer tissues. The role of circDLG1 in gastric cancer progression was evaluated both in vivo and in vitro, and the effect of circDLG1 on the antitumor activity of anti-PD-1 was evaluated in vivo. The interaction between circDLG1 and miR-141-3p was assessed by RNA immunoprecipitation and luciferase assays. Results circDLG1 was significantly upregulated in distant metastatic lesions and gastric cancer tissues resistant to anti-PD-1 therapy and was associated with an aggressive tumor phenotype and adverse prognosis in gastric cancer patients treated with anti-PD-1 therapy. Ectopic circDLG1 expression promoted the proliferation, migration, invasion, and immune evasion of gastric cancer cells. Mechanistically, circDLG1 interacted with miR-141-3p and acted as a miRNA sponge to increase the expression of CXCL12, which promoted gastric cancer progression and resistance to anti-PD-1-based therapy. Conclusions Overall, our findings demonstrate how circDLG1 promotes gastric cancer cell proliferation, migration, invasion and immune evasion and provide a new perspective on the role of circRNAs during gastric cancer progression.

Purpose: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). Patients and Methods: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. Results: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70–1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50–0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. Conclusions: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Background Several programmed cell death ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) antibodies have been approved for cancer treatment worldwide. Their pharmacokinetic and pharmacodynamic characteristics have been reported mainly in western countries, but related data in Chinese patients are limited. This study was conducted to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamics of an anti‐PD‐1 antibody, toripalimab, in Chinese patients. Methods A single‐center phase I study was conducted in Sun Yat‐sen University Cancer Center. Eligible patients were adults with histologically confirmed, treatment‐refractory, advanced, solitary malignant tumors. Toripalimab was intravenously infused every 2 weeks in dose‐escalating cohorts at 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg. The study followed standard 3 + 3 design. Results Between 15th March 2016 and 27th September 2016, 25 patients were enrolled, of whom 3 (12.0%), 7 (28.0%), 6 (24.0%), 6 (24.0%), 3 (12.0%) received 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, and 240 mg toripalimab, respectively. After a median follow‐up time of 5.0 months (range: 1.5‐19.8 months), we observed that the commonest treatment‐related adverse events (TRAEs) were fatigue (64.0%) and rash (24.0%). No grade 3 or higher TRAEs were observed. No dose‐limiting toxicity, treatment‐related serious adverse events (SAEs), or treatment‐related death occurred. Objective response rate was 12.5%. The half‐life of toripalimab was 150‐222 h after a single dose infusion. Most patients, including those from the 0.3 mg/kg group, maintained complete PD‐1 receptor occupancy (> 80%) on activated T cells since receiving the first dose of toripalimab. Conclusions Toripalimab is a promising anti‐PD‐1 antibody, which was well tolerated and demonstrated anti‐tumor activity in treatment‐refractory advanced solitary malignant tumors. Further exploration in various tumors and combination therapies is warranted.

The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22–0.98, p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months, HR: 0.11, 95% CI: 0.01–1.22, p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04–0.68, p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21–1.05, p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM.

Background The purpose of this retrospective study was to evaluate the clinical efficacy of mineralized collagen (MC) versus anorganic bovine bone (Bio-Oss) for immediate implant placement in esthetic area. Methods Medical records of Department of Oral and Maxillofacial Surgery of Shandong Provincial Hospital were screened for patients who had been treated with immediate implant implantation in the esthetic area using either MC (Allgens®, Beijing Allgens Medical Science and Technology Co., Ltd., China) or Bio-Oss (Bio-Oss®, Geistlich Biomaterials, Wolhusen, Switzerland), between January 2018 and December 2019. All patients fulfilling the in-/exclusion criteria and following followed for a minimum period of 1 year after surgery were enrolled into the presented study. Implant survival rate, radiographic, esthetic and patient satisfactory evaluations were performed. Results Altogether, 70 patients were included in the study; a total of 80 implants were inserted. All implants had good initial stability. The survival rate of implants was 100% at 1-year follow-up. The differences in horizontal and vertical bone loss between the MC group (0.72 ± 0.26 mm, 1.62 ± 0.84 mm) and the Bio-Oss group (0.70 ± 0.52 mm, 1.57 ± 0.88 mm) were no significant difference statistically no significant 6 months after permanent restoration. Similar results occurred at 12 months after permanent restoration functional loaded. Clinical acceptability defined by pink esthetic score (PES) ≥ 6 (6.07 ± 1.62 vs. 6.13 ± 1.41) was not significantly different between groups. Patient satisfaction estimated by visual analog scale (VAS) was similar (8.56 ± 1.12 vs. 8.27 ± 1.44), and the difference was no significant difference between the two groups. Conclusions The biomimetic MC showed a similar behaviour as Bio-Oss not only in its dimensional tissues changes but also in clinical acceptability and patient satisfaction. Within the limitations of this study, these cases show that MC could be considered as an alternative bone graft in IIP

Summary This is a phase Ib/II study of regorafenib plus toripalimab for colorectal cancer. The objective response rate (ORR) is 15.2% and the disease control rate is 36.4% in evaluable patients with recommended phase II dose (80 mg regorafenib plus toripalimab). The median progression-free survival (PFS) and the median overall survival are 2.1 months and 15.5 months, respectively. Patients with liver metastases have lower ORR than those without (8.7% versus 30.0%). All patients (3/3) with lung-only metastasis respond, whereas no patients (0/4) with liver-only metastasis respond. 94.9% and 38.5% of patients have grade 1 and grade 3 treatment-related adverse events, respectively. Gut microbiome analysis of the baseline fecal samples shows significantly increased relative abundance and positive detection rate of Fusobacterium in non-responders than responders. Patients with high-abundance Fusobacterium have shorter PFS than those with low abundance (median PFS = 2.0 versus 5.2 months; p = 0.002)., Graphical abstract, Highlights Regorafenib plus toripalimab improves response and overall survival Patients with liver metastasis have lower response rate than those without Increased Fusobacterium is found in non-responders compared with responders, Wang et al. demonstrate the safety, efficacy, and survival of regorafenib plus toripalimab in colorectal cancer patients. They show the gut microbiome results that Fusobacterium is negatively correlated with response and survival. This provides a combination regimen for unselected refractory metastatic colorectal cancer patients.

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second‐line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression‐free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12‐2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62‐1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79‐1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39‐1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second‐line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype., Capecitabine plus irinotecan (XELIRI) with or without bevacizumab is noninferior to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab in terms of overall survival, regardless of UGT1A1 genotype. Additionally, modified XELIRI with or without bevacizumab showed a favorable tolerability profile that was comparable to that of FOLFIRI with or without bevacizumab among all UGT1A1 genotypes.

Large general hospitals currently play an increasingly important role in the diagnosis and treatment for acute critical patients and difficult diseases because of the development of dual referral system and hierarchical diagnosis, as well as the formation of medical treatment alliance. Patients with oral cancers are often associated with systemic diseases, which increases the complexity of the condition. Thus, meeting the demand through the traditional single medical model is difficult. As such, a multidisciplinary team (MDT) model has been proposed and has achieved a good clinical effect. To standardize the application of this model, we organized an event in which relevant experts discussed and formulated a consensus to provide standardized suggestions on the MDT process and the diagnosis and treatment of common systemic diseases as reference for clinical practice.近年来，随着双向转诊、分级诊疗和医联体的建立，大型综合医院承担急危重症和疑难疾病诊疗的功能定位日益凸显，来诊的口腔癌患者常伴有全身情况复杂的系统性疾病，传统的单一诊疗模式难以达到医疗需求。为此，多学科协作诊疗（MDT）模式应运而生并在实践中应用，取得了良好的临床效果。为了进一步规范口腔癌患者的MDT，组织专家制订了本专家共识，对诊疗流程、常见系统性疾病的诊治等给出了规范化建议，供临床医师参考。.

Metabolic reprogramming is reported to be one of the hallmarks of cancer, which is an adaptive mechanism by which fast-growing cancer cells adapt to their increasing energy demands. Recently, extracellular vesicles (EVs) known as exosomes have been recognized as crucial signaling mediators in regulating the tumor microenvironment (TME). Meanwhile, the TME is a highly heterogeneous ecosystem incorporating cancer cells, fibroblasts, adipocytes, endothelial cells, mesenchymal stem cells, and extracellular matrix. Accumulated evidence indicates that exosomes may transfer biologically functional molecules to the recipient cells, which facilitate cancer progression, angiogenesis, metastasis, drug resistance, and immunosuppression by reprogramming the metabolism of cancer cells and their surrounding stromal cells. In this review, we present the role of exosomes in the TME and the underlying mechanism of how exosomes exacerbate tumor development through metabolic reprogramming. In addition, we will also discuss the potential role of exosomes targeting metabolic process as biomarkers for tumor diagnosis and prognosis, and exosomes-mediated metabolic reprogramming as potential targets for cancer therapy. Furthermore, a better understanding of the link between exosomes and metabolic reprogramming, and their impact on cancer progression, would provide novel insights for cancer prevention and treatment in the future.

The present study is the first phase II clinical trial aimed to evaluate the efficacy and safety of S-1 plus nanoparticle albumin-bound paclitaxel (Nab-PTX) as first-line chemotherapy for advanced gastric cancer (AGC). Previously untreated patients with metastatic gastric adenocarcinoma received S-1 in oral doses of 40 mg (BSA

The purpose of this study was to investigate the efficacy of microvascular coupler for arterial anastomosis in head and neck reconstruction during a 2-year period at the Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital.Twenty-one cases of microvascular free flaps from October 2013 through December 2014 were retrospectively reviewed. Flap survival and thrombosis of the arterial anastomoses were determined in these cases.A total of 21 consecutive patients underwent microsurgical head and neck reconstruction, including 7(33.33%) radial forearm, nine(42.86%) fibular and 5(23.81%) anterior lateral thigh free flaps. There was 1 complication related to arterial thrombosis in this series, requiring surgical reexploration and a sutured anastomosis was performed. There were no complications related to technical performance of the coupling device.Use of a coupler device shows reliability for arterial anastomosis in head and neck reconstruction. With proper vessel selection and sufficient experience using the microvascular coupler, arterial coupling may be performed in an expeditious, safe, and reliable fashion with minimal morbidity. Though not commonly practiced, use of coupling device for arterial anastomosis can significantly save time, which is a viable alternative to sutured anastomosis.

Background This study assessed the preliminary safety, pharmacokinetics (PK) and anti-tumor effects of aflibercept in combination with 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in Chinese patients with previously-treated advanced solid malignancies. Patients and Methods This open-label single-arm Phase I study conducted at two centers in China included adult (≥18 years) patients with metastatic or unresectable solid malignancies who had received ≥1 prior treatment. Patients received aflibercept 4 mg/kg IV on Day 1 followed by FOLFIRI over Days 1 and 2 every 2 weeks, and were assessed for safety, tumor response, PK parameters and immunogenicity. Post-hoc analyses included calculation of progression-free survival (PFS) for patients with colorectal cancer (CRC). Results A total of 20 patients were enrolled. The most common Grade 3/4 adverse events included neutropenia (35%), hypertension (30%), stomatitis (20%) and proteinuria (20%), and no anti-aflibercept antibodies were detected. Six patients achieved a partial response, and in 15 patients with CRC median PFS was 5.95 months (95% CI: 5.29–8.77). Free aflibercept remained in excess of VEGF-bound aflibercept for the majority of the study treatment duration. The mean free aflibercept values for Cmax (64.8 μg/mL) AUC (291 μg.day/mL), CL (0.92 L/day) and Vss (5.9 L) were similar to those measured in Caucasian patients. The addition of aflibercept did not influence the PK of the chemotherapy agents. Conclusion For Chinese patients with pre-treated advanced solid malignancies, 4 mg/kg of aflibercept in combination with FOLFIRI was well-tolerated, demonstrated preliminary anti-tumor activity and had a PK profile consistent with that in Caucasian patients.

Background To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients. Methods A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS). Results In the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5.80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86–5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95–1.58); (hazard ratio [HR] 0.30; 95% CI 0.15–0.59; P

Background The first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach. Patients and methods A total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics. Results The ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3–4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3–4 AEs. High AUC0–24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS. Conclusions Two-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC. ClinicalTrials.gov identifier NCT02090153

The clinicopathologic relevance and prognostic value of tumor deposits in colorectal cancer has been widely demonstrated. However, there are still debates in the prognostic value of tumor deposits and the applicability of N1c category in rectal cancer with preoperative radiotherapy. In this study, rectal cancer with preoperative radiotherapy followed by resection of primary tumors registered in Surveillance, Epidemiology and End Results (SEER) database from 2010-2012 were analyzed. There were 4,813 cases eligible for this study, and tumor deposits were found in 514 (10.7%) cases. The presence of tumor deposits was significantly associated with some aggressive characteristics, including poorer tumor differentiation, more advanced ypT category, ypN category and ypTNM stage, distant metastasis, elevated carcinoembryonic antigen, higher positive rates of circumferential resection margin and perineural invasion (all P < = 0.001). Tumor deposit was also an independent negative prognostic factor for cancer-specific survival in rectal cancer with preoperative radiotherapy (adjusted HR and 95% CI: 2.25 (1.51 – 3.35)). N1c category had significant worse survival compared with N0 category (adjusted HR and 95% CI: 2.41 (1.24 – 4.69)). In conclusion, tumor deposit was a significant and independent prognostic factor, and the N1c category by the 7th edition of AJCC/TNM staging system was applicable in rectal cancer with preoperative radiotherapy.

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.

This study retrospectively investigated the prognostic significance of the preoperative albumin-globulin score (AGS) and albumin/globulin ratio (AGR) in esophageal squamous cell carcinoma (ESCC). A cohort of 458 newly diagnosed ESCC patients who underwent radical esophagectomy in Sun Yat-sen University Cancer Center (Guangzhou, China) between January 2006 and December 2010 were selected into this study. The optimal cut-off value was identified to be 45.6 g/L, 26.9 g/L and 1.30 for albumin (ALB), globulin (GLB) and AGR in terms of survival, respectively. Patients with low ALB levels (< 45.6 g/L) and high GLB levels (≥ 26.9 g/L) were assigned an AGS of 2, those with only one of the two abnormalities were assigned an AGS of 1, and those with neither of the two abnormalities were assigned an AGS of 0. Univariate survival analysis showed that low AGS (0) was significantly associated with favorable disease free survival (DFS) [hazard ratio (HR), 0.635; 95% confidence interval (CI), 0.441–0.914; P = 0.015] and overall survival (OS) (HR, 0.578; 95% CI, 0.387–0.862; P = 0.007), and it remained an independent predictor for OS (HR, 0.630; 95% CI, 0.418–0.952; P = 0.028), but not for DFS (HR, 0.697; 95% CI, 0.479–1.061; P = 0.060) in multivariate models. High AGR (≥ 1.30) was also correlated with favorable DFS (HR, 0.626; 95% CI, 0.430–0.910; P = 0.014) and OS (HR, 0.622; 95% CI, 0.422–0.916; P = 0.016) in univariate analysis, but it failed to be an independent prognostic indicator for DFS (HR, 0.730; 95% CI, 0.494–1.078; P = 0.114) or OS (HR, 0.759; 95% CI, 0.507–1.137; P = 0.181) by multivariate analysis. Low preoperative AGS could serve as a valuable and convenient biochemical marker to predict favorable long-term survival in ESCC patients.

// 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 (

To explore the validity of using bioelectrical impedance analysis (BIA)-derived 50 kHz phase angle (PhA) in predicting protein-energy wasting (PEW) in Chinese maintenance hemodialysis (MHD) patients.The design was a cross-sectional study. A total of 173 of MHD patients and 173 healthy adults were enrolled in the study. The prevalence of PEW in patients was performed by the International Society of Renal Nutrition and Metabolism criteria. The PhA, body cell mass, fat mass, body fat percentage, fat-free mass, and extracellular water/total body water were measured by InBody S10 body composition analyzer. The biochemical indices and anthropometric measurements were assessed using the way published elsewhere. The PhA, other values of BIA and its relationship with age, visceral protein, anthropometric measurements of the MHD patients were compared with the healthy group. The independent variables for predicting PEW and its cutoff values were explored using logistic regression model and receiver operating characteristic curve analysis, respectively.The MHD patients' PhA value was significantly lower than the healthy group (4.89°± 1.19 vs. 6.32°± 2.23, P .01). A total of 34.1% MHD patients with PEW had significantly lower PhA values compared with well-nourished patients (P.05). The PhA decreased more significantly with age in MHD (r = -0.35, P .001), compared with controls (r = -0.26, P .001). The PhA values were positively associated with nutritional indices related to serum albumin, prealbumin, fat-free mass, and mid-arm muscle circumference. PhA values were not associated significantly with fat mass and body fat percentage (P .05). Multivariate logistic regression analysis showed that PhA and body mass index were independent predictors of PEW, but the PhA was the stronger predictor (odds ratio = 4.48, P .05). Receiver operating characteristic curve analysis suggested that the optimal PhA cutoff value to predict PEW was 4.6°.BIA-derived PhA appears to be a useful bioelectrical marker for predicting PEW in Chinese hemodialysis patients with a cutoff value of 4.6°.

Summary Aims This study investigated the neuroprotective properties of icariin (an effective component of traditional Chinese herbal medicine Epimedium) on neuronal function and brain energy metabolism maintenance in a triple-transgenic mouse model of Alzheimer's disease (3 × Tg-AD). Methods 3 × Tg-AD mice as well as primary neurons were subjected to icariin treatment. Morris water maze assay, magnetic resonance spectroscopy (MRS), Western blotting, ELISA, and immunohistochemistry analysis were used to evaluate the effects of icariin administration. Results Icariin significantly improved spatial learning and memory retention in 3 × Tg-AD mice, promoted neuronal cell activity as identified by the enhancement of brain metabolite N-acetylaspartate level and ATP production in AD mice, preserved the expressions of mitochondrial key enzymes COX IV, PDHE1α, and synaptic protein PSD95, reduced Aβ plaque deposition in the cortex and hippocampus of AD mice, and inhibited β-site APP cleavage enzyme 1 (BACE1) expression. Icariin treatment also decreased the levels of extracellular and intracellular Aβ1-42 in 3 × Tg-AD primary neurons, modulated the distribution of Aβ along the neurites, and protected against mitochondrial fragmentation in 3 × Tg-AD neurons. Conclusions Icariin shows neuroprotective effects in 3 × Tg-AD mice and may be a promising multitarget drug in the prevention/protection against AD.

Infection with Epstein-Barr virus (EBV) and its encoded latent membrane protein 1 (LMP1) play oncogenic roles in Burkitt's lymphoma (BL). Flow cytometry was used to measure cellular reactive oxygen species (ROS) concentrations, and cellular lactate generation and diphenylene iodonium (DPI) cytotoxicity were determined by analyzing lactate concentrations and cell viability. We also measured NAD(P)H oxidase (NOX) activity. Reverse transcriptase PCR and qPCR assays were used to analyze LMP1 levels, and protein expression was measured by immunoblotting. In the present study, EBV was able to induce NOX activity and ROS generation in the BL cells. Inhibition of NOX activity by DPI suppressed ROS levels and elevated lactate levels. DPI treatment first resulted in a G2-M phase cell cycle arrest and then induced significant apoptosis. Immunoblot analysis demonstrated that DPI suppressed the expression of c-Myc and Cdc25A within 6 h, which may have caused the cell cycle arrest. Collectively, these findings indicate a close relationship between EBV infection and NOX activation, permitting a deeper understanding of ROS inhibition in cell cycle regulation and providing a novel therapeutic target for BL treatment.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, in which the NF-κB pathway plays an important role and is constitutively activated. Better understanding of the molecular pathogenesis of HCC and the NF-κB pathway are needed to improve patient outcomes. Herein, we identified an unappreciated protein involved in NF-κB-induced activation, Golgi phosphoprotein 3 (GOLPH3). The mRNA and protein expression levels of GOLPH3 were frequently up-regulated in HCC and GOLPH3 expression correlated closely with clinical stage and survival in both the testing and validation cohorts. Ectopic over-expression of GOLPH3 in PLC/PRF/5 (PLC) and Huh7 HCC cells protected against cisplatin-induced apoptosis, promoted angiogenesis and proliferation and increased the aggressiveness of HCC cells in vitro and in vivo, whereas inhibition of GOLPH3 led to decreased aggressiveness. Through analysis of two published HCC patient profiles, GOLPH3 expression significantly correlated with NF-κB signalling. Furthermore, we demonstrated that GOLPH3 promoted K63-linked polyubiquitination of tumour necrosis factor receptor-associated factor 2 (TRAF2), receptor interacting protein (RIP) and NF-κB essential modulator (NEMO) and substantially sustained the activation of NF-κB in HCC cells. Taken together, our findings provided evidence that GOLPH3 is a prognostic and/or potential therapeutic biomarker for HCC patients and plays an important role in activation of the NF-κB pathway during HCC progression.

Genomic alterations of tumor suppressorsoften encompass collateral protein-coding genes that create therapeutic vulnerability to further inhibition of their paralogs. Here, we report that malic enzyme 2 (ME2) is frequently hemizygously codeleted with SMAD4 in gastric cancer. Its isoenzyme ME1 was upregulated to replenish the intracellular reducing equivalent NADPH and to maintain redox homeostasis. Knockdown of ME1 significantly depleted NADPH, induced high levels of reactive oxygen species (ROS), and ultimately cell apoptosis under oxidative stress conditions, such as glucose starvation and anoikis, in ME2-underexpressed cells. Moreover, ME1 promoted tumor growth, lung metastasis, and peritoneal dissemination of gastric cancer in vivo. Intratumoral injection of ME1 siRNA significantly suppressed tumor growth in cell lines and patient-derived xenograft–based models. Mechanistically, ME1 was transcriptionally upregulated by ROS in an ETV4-dependent manner. Overexpression of ME1 was associated with shorter overall and disease-free survival in gastric cancer. Altogether, our results shed light on crucial roles of ME1-mediated production of NADPH in gastric cancer growth and metastasis. Significance: These findings reveal the role of malic enzyme in growth and metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/8/1972/F1.large.jpg. Cancer Res; 78(8); 1972–85. ©2018 AACR.

Tumor progression and metastasis is the main cause of death in colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) are critical regulators in various diseases including human cancer. In this study, we found that lncRNA XIST was overexpressed in CRC cell lines and tissues. High expression of lncRNA XIST was associated with adverse overall survival in CRC patients. Knockdown of lncRNA XIST remarkably inhibited CRC cell proliferation, invasion, epithelial–mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and metastasis in vivo. Further study indicated that knockdown of lncRNA XIST markedly increased the expression of microRNA-200b-3p (miR-200b-3p) that has been found to be downregulated in CRC tissues and cell lines, and luciferase activity assay indicated that lncRNA XIST could bind directly with miR-200b-3p. Moreover, knockdown of lncRNA XIST significantly reduced the expression of ZEB1, which was the direct target of miR-200b-3p, and the tumor suppressive effects caused by knockdown of lncRNA XIST could be rescued by re-expression of ZEB1 in CRC cells. Overall, our study demonstrated how lncRNA XIST regulates CRC progression and metastasis by competing for miR-200b-3p to modulate the expression of ZEB1. lncRNA XIST may be used as a biomarker to predict prognosis in CRC patients.

To investigate the effect of NaF on proliferation and mineralization of human periodontal ligament cells (hPDLCs).hPDLCs were isolated and characterized. The proliferation of hPDLCs treated with different concentration of NaF was tested by CCK-8. Four moderate concentrations were chosen for subsequent experiments. The mineralization was investigated using ALP activity assay, Alizarin red S staining and quantitative real-time polymerase chain reaction(RT-PCR). The data were statistically analyzed with SPSS20.0 software package.Immunohistochemistry showed that the isolated cells were hPDLCs. 5×105×10

Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC. Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated. The Clauss method was utilized to measure the preoperative plasma fibrinogen level. Correlations between the fibrinogen level and clinicopathologic characteristics and survival analysis were performed. The effects of fibrinogen on malignant behaviors, including tumor cell viability, colony formation, migration, and invasion, were also investigated. The optimal cut-off value for plasma fibrinogen level was defined as 4.0 g/L according to recommendations. Thus, the proportion of hyperfibrinogenemia was 24.8% (112/452). Preoperative plasma hyperfibrinogenemia was significantly associated with advanced tumor length, deep tumor invasion, advanced tumor–node–metastasis stage, alcohol consumption, a higher white blood cell count, a higher platelet count, and high globulin levels. Univariate survival analysis revealed that compared to those with normal plasma fibrinogen levels, patients with hyperfibrinogenemia tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.692; 95% confidence interval (CI), 1.304–2.196; P

Primary small cell carcinoma of the esophagus (SCCE) is characterized as highly aggressive with a poor prognosis. To identify potential prognostic factors and to assess the role of surgical procedures, chemotherapy, and radiotherapy for SCCE, we retrospectively analyzed patients with SCCE from three large institutions in China.All of the SCCE patients between 1998 and 2012 were identified from three clinical databases of the Sun Yat-Sen University Cancer Center, Peking Union Cancer Hospital and Shantou Cancer Hospital. Potential prognostic factors were analyzed with univariate analysis and a Cox regression model. Subgroup analysis based on the 2002 American Joint Committee on Cancer staging system for esophageal cancer was applied to examine the effect of treatment on survival.In patients with stage I/II SCCE, 85% underwent operations and showed improved survival (median survival time [MST] 29 vs 17.4 months, p = 0.082). However, chemotherapy did not further improve survival. In patients with stage IIB/III SCCE, chemotherapy, instead of operation, improved survival (MST 13.0 vs 6.1 months, p = 0.003), and radiotherapy resulted in improved survival. In stage IV patients, chemotherapy improved survival (MST 12.5 vs 4.0 months, p0.001), and chemotherapy combined with radiotherapy was superior to chemotherapy alone (MST 13.2 vs 8.9 months, p = 0.014).Surgical procedures alone can be recommended for stage I/IIA patients. In patients with stage IIB disease or above, chemotherapy should be the main treatment approach, and chemotherapy combined with radiotherapy tended to improve survival.

Many access devices have been developed for laparoendoscopic single-site surgery (LESS) during recent years. However, investigations are needed to determine which port is most suitable for this relatively new technique. The aim of this study was to evaluate commonly used ports using mechanical approaches in a training simulator. Any port that required less force and shorter surgery times had superior maneuverability.The following three commercially available access devices were evaluated: Multi-ports, TriPort, and single-incision laparoscopic surgery (SILS) Port. A LESS mechanical evaluation platform was developed to investigate the forces that acted on the instruments in the ports while moving along horizontal and vertical axes. In addition, a strain-force measurement system was used to compare the average load on the ports when performing standard maneuvers. Additionally, the task completion time was recorded when the maneuvers in these ports were completed.During the horizontal displacement of the instrument, the traction forces of the Multi-ports were lower than those of the SILS Port, which were lower than those of the TriPort. The average traction forces were significantly different in pairwise multiple comparisons (P0.05). When the instrument was inserted into the ports, the vertical friction forces of the Multi-ports were the lowest and those of the TriPort were the highest. On extraction of the instrument, the friction forces of the Multi-ports remained the lowest, followed by those of the TriPort and SILS Port. There were statistically significant results among all the devices (P0.05). The average load required to perform the task was less for the SILS Port than that for the TriPort (P0.05). Similarly, the average load for the Multi-ports was significantly less than that for the TriPort (P0.001). The participants who used the Multi-ports had significantly faster task times than those who used the SILS Port or TriPort (P0.005).Compared with the TriPort and SILS Port, the Multi-ports was associated with the least average load and the shortest task performance times in a training simulator. This study demonstrates that the Multi-ports may offer superior maneuverability for LESS.

Cisplatin and nedaplatin show significant antitumor activity and have been widely used for esophageal squamous cell carcinoma (ESCC). However, it is still unclear whether the efficacy and safety of nedaplatin-based regimens are comparable to those of cisplatin-based regimens in patients with metastatic/recurrent or advanced ESCC. Therefore, we conducted a systematic review and meta-analysis to compare the efficacy and safety of these two regimens for the treatment of metastatic/recurrent and advanced ESCC. We systematically searched Pubmed, Web of Science, and the Cochrane Database, as well as abstracts presented at conferences (all up to January 2015), for randomized-controlled and nonrandomized clinical trials that compared cisplatin-based and nedaplatin-based regimens in patients with metastatic/recurrent or advanced ESCC. Data were extracted from the original studies by two independent reviewers. This meta-analysis was performed using Review Manager (RevMan) Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) software. Ten eligible trials, including 598 patients diagnosed with metastatic/recurrent or advanced ESCC, were included in our analysis. Our results demonstrated that the nedaplatin-based regimens were comparable to the cisplatin-based regimens in terms of overall survival (OS) (hazard ratio, HR: 1.22, 95% confidence interval, CI: 0.86-1.74, p = 0.26) and overall response rate (ORR) (risk ratio, RR: 0.92, 95% CI: 0.77-1.10, p = 0.37) and generated fewer grade 3 and 4 side effects including nausea (RR: 3.41, 95% CI: 1.67-6.96, p 0.001) and vomiting (RR: 3.62, 95% CI: 1.77-7.40, p 0.001) and fewer grade 1 and 2 adverse events including nausea (RR: 1.54, 95% CI: 1.23-1.93, p 0.001), vomiting (RR: 1.76, 95% CI: 1.76-2.30, p 0.001), peripheral neuropathy (RR: 1.75, 95% CI: 1.08-2.84, p = 0.02) and renal dysfunction (creatinine) (RR: 3.28, 95% CI: 1.37-7.84, p = 0.008). This systematic review and meta-analysis indicated that the efficacy of nedaplatin-based regimens was comparable to that of cisplatin-based regimens for patients with metastatic/recurrent or advanced ESCC, and that nedaplatin-based regimens were associated with less toxicity and better tolerability. However, this study was a meta-analysis of previously released data; therefore, there is a potential publication bias and heterogeneity among the included trials. Future, well-designed RCTs with large cohorts are warranted.

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.

Detection of KRAS mutation status is a routine clinical procedure for predicting response to anti-EGFR therapy in colorectal cancer (CRC) patients. Previous studies showed high concordance of KRAS mutation status in primary lesion and corresponding metastatic sites in CRC. However, the data were mostly from Caucasians. The aim of this study is to compare KRAS mutation and other molecules mutation status between primary tumor and corresponding metastatic lesion in Chinese patients with CRC. In this retrospective study, Chinese CRC patients with paired samples of primary tumor and metastatic site were detected for KRAS codon 12 and 13 with quantitative real-time PCR, or detected for OncoCarta™ panel of 19 genes with MassARRAY(®) technique, including KRAS, BRAF, NRAS and PIK3CA et al. Forty-eight paired CRC samples were analyzed for KRAS codon 12 and 13 using quantitative real-time PCR. Ten paired samples were analyzed by 19 genes OncoCarta™ Panel with MassARRAY(®) technique. KRAS mutation was found in 15 (25.9 %) primary tumors and 18 (31.0 %) metastases. The discordance of KRAS was observed in 11 (19.0 %) patients. Alteration of mutation points in primary site with mutant KRAS was not observed. In the 10 patients with multiple gene detection, PIK3CA mutation showed concordant mutation status in primary tumor and metastatic site, whereas discordance in BRAF, NRAS and AKT1 was detected. A concordance rate of 81.0 % was detected in KRAS mutation between primary tumor and metastatic lesion in Chinese patients with CRC. Discordance of BRAF, NRAS and AKT1 mutation status in primary tumor and metastases was observed.

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 safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.

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

Objective The aim of this study was to evaluate the clinical characteristics and survival outcomes of patients with primary mediastinal germ cell tumor (PMGCT) by identifying the prognostic factors and efficacies of different treatment modalities. Methods Fifty-five patients with PMGCT who were treated consecutively at Cancer Center, Sun Yat-sen University, Guangzhou, from 1988 to 2010 were evaluated retrospectively. Results Fifty-two men and 3 women with a median age of 25 years were identified, of whom 17 (30.9%) had pure seminomatous, 38 (69.1%) had nonseminomatous histology, 27 (49.1%) had tumor located at mediastinum, 20 (36.4%) had lung metastases and/or effusions, and 8 (14.5%) had distant metastases. Three treatments surgery, chemotherapy, and radiotherapy were performed in 11 (20%) patients, two treatments chemotherapy plus surgery or radiotherapy were performed in 25 (45.6%), and single treatment surgery or chemotherapy was performed in 17 (30.9%). The other two patients (3.6%) received no treatment. After a median follow-up time of 31.4 months, the 5-year survival rate was 52%. The median overall survival time was 87.9 months. Patients who received two treatments had the longest survival time of 118.3 months, P = 0.000. Those who had pure seminoma histology, whose tumor confined to the mediastinum and who achieved complete or partial remission at initial evaluation, who had complete resection and radiotherapy were considered to have better prognosis according to univariate analysis. On multivariate analysis, extension and response rate at initial evaluation were independently predictive of survival. Conclusions Primary mediastinal germ cell tumor is rare with a dominant frequency in young male patients. Chemotherapy combined with local therapy like surgery or radiotherapy is a reasonable treatment strategy recommended. Extension and initial remission rate are independent prognostic factors.

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.

Summary Background and objective: 5-fluorouracil (5-FU) is still a widely used anticancer drug. More than 85% of the 5-FU administered is catabolized by dihydropyrimidine dehydrogenase (DPD) in the liver. However, mutations in the DPD gene have been found to be associated with low DPD activity causing severe complications. The purpose of this study was to determine the mutation frequency of four exons in Chinese cancer patients and the relationship between genotype and DPD activity. Methods: Samples from 142 cancer patients were investigated in this study. The DPD activity was determined by reversed-phase HPLC. Exons 2, 13, 14 and 18 were amplified by polymerase chain reaction (PCR), sequenced and analysed from both sense and antisense directions. Nonparametric one-sample Kolmogorov–Smirnov test was used for distribution analysis; two independent samples t-test and one-way anova was performed for two groups and three groups analyses, respectively. Results and discussion: Plasma-DPD activities in the 142 cancer patients followed a Gaussian distribution. The mean plasma-DPD activity in women was lower than that in men (P = 0·006). Four mutations, 85T>C(DPYD*9A), 1627A>G(DPYD*5), 1896T>C and 2194G>A(DPYD*6), were found in the 142 cancer patients. The following mutations reported by others were not detected: 61C>T, 62G>A, 74A>G, 1601G>A(DPYD*4), 1679T>G(DPYD*13), 1714C>G, 1897delC(DPYD*3) and IVS 14 + 1G>A. No significant correlation was found between three mutations [85T>C(DPYD*9A), 1627A>G (DPYD*5) and 1896T>C], and DPD activity was found. Conclusion: No clear correlation between the mutations studied and DPD activity could be established in this study. However, larger-scale prospective studies are needed to better assess the reported genotype–phenotype correlations.

One of the main advantages of gene therapy over traditional therapy is the potential to target the expression of therapeutic genes in desired cells or tissues. To achieve targeted gene expression, we developed a novel heat-inducible gene expression system in which thermal energy generated by Mn-Zn ferrite magnetic nanoparticles (MZF-NPs) under an alternating magnetic field (AMF) was used to activate gene expression. MZF-NPs, obtained by co-precipitation method, were firstly surface modified with cation poly(ethylenimine) (PEI). Then thermodynamic test of various doses of MZF-NPs was preformed in vivo and in vitro. PEI-MZF-NPs showed good DNA binding ability and high transfection efficiency. In AMF, they could rise to a steady temperature. To analyze the heat-induced gene expression under an AMF, we combined P1730OR vector transfection with hyperthermia produced by irradiation of MZF-NPs. By using LacZ gene as a reporter gene and Hsp70 as a promoter, it was demonstrated that expression of a heterogeneous gene could be elevated to 10 to 500-fold over background by moderate hyperthermia (added 12.24 or 25.81 mg MZF-NPs to growth medium) in tissue cultured cells. When injected with 2.6 or 4.6 mg MZF-NPs, the temperature of tumor-bearing nude mice could rise to 39.5 or 42.8 degrees C, respectively, and the beta-gal concentration could increase up to 3.8 or 8.1 mU/mg proteins accordingly 1 day after hyperthermia treatment. Our results therefore supported hyperthermia produced by irradiation of MZF-NPs under an AMF as a feasible approach for targeted heat-induced gene expression. This novel system made use of the relative low Curie point of MZF-NPs to control the in vivo hyperthermia temperature and therefore acquired safe and effective heat-inducible transgene expression.

The aim of this study was to study in vitro and in vivo the killing effect and the bystander effect of herpes simplex virus-thymidine kinase gene/ganciclovir (HSV-TK/GCV) suicide gene system on the gastric cancer cell line, SGC-7901.GINaTK retroviral vector containing the HSV-TK gene was transduced into the PA317 packaging cell by lipofectin. The gastric cancer cell line, SGC-7901, was infected by a high-titer viral supernatant. SGC-7901/TK cells and SGC-7901 cells were used in the in vitro and in vivo studies. In the in vitro study, sensitivity of the SGC-7901/TK cells to GCV and the bystander effect were observated by a mononuclear cell direct cytotoxicity assay test. In the in vivo study, SGC-7901/TK cells and SGC-7901 cells were injected subcutaneously into the flanks of BALB/C nude mice, GCV was administrated intraperitoneally, a reverse transcriptase polymerase chain reaction was applied to detect the expression of the HSV-TK gene. A statistical analysis of the data was performed by using the analysis of variance.The SGC-7901 cells transferred with the GINaTK gene displayed a higher antitumor effect than the parent cells. In the in vitro study, when the ratio of SGC-7901/TK cells reached 10%, the tumor cell-killing proportion was 53%. In the in vivo study, all BALB/C nude mice developed tumors in 7 days after tumor cells were implanted, the ratio of tumors formation is 100%. GCV could suppress tumor formation of the SGC-7901/TK cells. After the BALB/C nude mice treated with GCV, compared with the control tumors the median tumor volume of the mice implanted with SGC-7901/TK cells and BALB/C nude mice with cells mixed was, respectively, decreased to 52.8% and 69.4%.The test showed that the HSV-TK gene can be transducted into the gastric cancer cell line, SGC-7901, under the mediation of a retrovirus and be stably expressed, and that the HSV-TK/GCV suicide gene therapy system could improve antitumoral efficiency. The bystander effect could be observated in the HSV-TK/GCV system both in vitro and in vivo.

The elevation of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) has been demonstrated to predict worse prognosis in various malignancies; however, their prognostic value in esophageal squamous cell carcinoma has not been well studied. We conducted a retrospective study of 906 patients with esophageal squamous cell carcinoma to explore their prognostic value for overall survival. The optimal cutoff points for ALP and LDH were determined. We analyzed the association between the levels of ALP and LDH and clinicopathological characteristics. Their prognostic value for overall survival was explored by univariate and multivariate analysis. We also proposed the ALP and LDH classification and examined its prognostic value in the general population and subgroups. The optimal cutoff points of ALP and LDH to predict overall survival were 90.7 and 361.5 U/L respectively. Higher levels of ALP and LDH were both associated with more advanced TNM stage (P = 0.003 and 0.002, respectively) and more distant metastasis (P = 0.001 and P 0.001, respectively). Both ALP (≤90.7/90.7 U/L) and LDH (≤361.5/361.5 U/L) were independent prognostic factors for overall survival in esophageal squamous cell carcinoma (P = 0.004 and P 0.001 by multivariate analysis). The ALP and LDH classification categorized patients into three subgroups with distinct prognosis (P 0.001 by multivariate analysis) and identified a small group of patients who had extremely poor overall survival with a median of 4.2 months. In conclusion, ALP and LDH were both independent prognostic factors for overall survival. A combination of the two indexes might contribute to further identification of survival differences in esophageal squamous cell carcinoma.

To study the influence of nodal liquefaction portion in the measurement of the ADC value of metastatic lymph nodes in patients with oral squamous cell carcinoma (OSCC) on DW-MRI images.According to the postoperative histopathological examination results, the DW-MRI data of 25 OSCC patients was analyzed. The ADC values of both solid portions of metastatic lymph nodes and the whole metastatic lymph nodes with internal liquefaction were selected and measured. Further comparison between the 2 groups was processed for 2 independent samples t test with SPSS 17.0 software package.Eleven patients out of all cases were diagnosed with cervical lymph node metastasis, and 15 metastatic lymph nodes were detected, among which 8 metastatic lymph nodes had obvious internal liquefaction. The average ADC values of solid portions of metastatic lymph nodes (group SMLN) and the whole metastatic lymph nodes with internal liquefaction (LMLN group) ADC were (872.1 ± 22.65) × 10⁻⁶ mm²/s (n=15) and (1073 ± 16.99) × 10⁻⁶ mm²/s (n=8), respectively. Two independent samples t test showed statistically significant difference of ADC values between group SMLN and group LMLN (P0.05).The internal liquefaction in OSCC metastatic lymph nodes can lead to an increased average ADC value. If the measurement of OSCC metastatic lymph nodes includes obvious liquefaction portions, it may reduce the diagnostic accuracy of DW-MRI for discrimination of lymph node metastasis.

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.

// Dong-liang Chen 1, 2 * , Dong-sheng Zhang 1, 2 * , Yun-xin Lu 1, 2 , Le-zong Chen 1, 2 , Zhao-lei Zeng 1, 3 , Ming-ming He 1, 2 , Feng-hua Wang 1, 2 , Yu-hong Li 1, 2 , Hui-zhong Zhang 1, 4 , Helene Pelicano 5 , Wei Zhang 6 , Rui-hua Xu 1, 2 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China 2 Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China 3 Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China 4 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China 5 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Department of Pathology, Unit 85, Center for RNAi and Non-Coding RNA, University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Rui-hua Xu, e-mail: xurh@sysucc.org.cn Keywords: microRNA, microRNA-217, EZH2, gastric cancer, metastasis Received: January 9, 2015 Accepted: February 25, 2015 Published: March 26, 2015 ABSTRACT microRNA-217 (miR-217) is frequently dysregulated in cancer. Here, we report that miR-217 levels were lower in tumor tissue compared with the adjacent normal tissue. Low levels of miR-217 were associated with aggressive tumor phenotypes and poor overall survival in gastric cancer patients. The ectopic expression of miR-217 inhibited cell proliferation, migration and invasion in vitro and tumor growth and metastasis in vivo , whereas knockdown of endogenous miR-217 increased cell proliferation and invasion. Further experiments revealed that Polycomb group protein enhancer of zeste homolog 2 (EZH2) was a direct target of miR-217 in gastric cancer cells. Knockdown of EZH2 mimicked the tumor-suppressive effects of miR-217 in gastric cancer cells, whereas the reintroduction of EZH2 abolished its effects. Taken together, these results demonstrated that miR-217 may be used as a prognostic marker, and the newly identified miR-217-EZH2 axis may be a potential target in the development of therapeutic strategies for gastric cancer patients.

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.

Inhibitors of angiogenesis and tumor metastasis are increasingly emerging as promising agents for cancer therapy. Here, we report λ-carrageenan oligosaccharides (λ-COs), highly-sulfated oligosaccharides acting as a basic fibroblast growth factor (bFGF) antagonist and heparanase inhibitor. λ-COs with degree of polymerization (DP) from 2 to 8 degraded by λ-carrageenase were separated and purified. The structures were identified by mass spectrometry. The activities of λ-COs are closely related with DP. λ-COs showed no cytotoxicity, but inactivated bFGF-induced cell proliferation; among them, λ-carraheptaose showed highest capability. Only λ-carraheptaose can effectively bind to bFGF. Binding kinetics showed that λ-carraheptaose and suramin had different binding modes, i.e., suramin displayed a fast association and fast dissociation, but λ-carraheptaose exhibited a slow association and slow dissociation. In addition, λ-COs showed the highest heparanase inhibitory ability and abolished the endothelial cell invasion. Thus, λ-COs may provide a tool to develop of new carbohydrate-based therapeutics against cancer and angiogenesis.

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

To investigate the expression of p53 and Beclin1 in salivary pleomorphic adenoma (PA) and its clinical significance.The expression of p53 and Beclin1 were assessed by immunohistochemistry in 108 cases of PA and 20 cases of carcinoma in pleomorphic adenoma(CIPA). The results were used to analyze the relationship between gene expressions and the development of PA as well as the clinical pathological features. Statistic analysis was conducted with SPSS 20.0 software package.The positive expressions of p53 in PA samples (9%) were significantly lower than that in CIPA(14%) (P0.001). The positive expressions of autophagy-related gene Beclin1 in PA samples(91%) were significantly higher than that CIPA (11%) (P0.001). The expression levels of these genes were not associated with gender, age, clinical course, tumor size, and location of PA(P0.05). There was a negative correlation between p53 and Beclin1 expression in PA (r=-0.330,P0.05).The expression levels of Beclin1 and p53 protein are closely related to the development of PA. Reduced autophagy and enhanced anti apoptosis coexist in the process of tumor formation. Thus, raising the autophagy ability may become another alternative choice for cancer therapy.

Several large studies have reported an extremely low incidence of MET gene amplification (GA) in patients with radically resected gastric cancer. This study was conducted to evaluate the prevalence and prognostic role of MET in patients with recurrent=metastatic gastric cancer who received chemotherapy.MET GA and protein expression of recurrent=metastatic gastric cancer samples were evaluated by fluorescence in situ hybridization and immunohistochemistry (IHC), respectively.This retrospective study included 232 patients with recurrent=metastatic gastric cancer. MET GA and strong protein expression(IHC31) were observed in 8.3% (19 of 230 samples) and 9.6% (22 of 229 samples) of samples, respectively. A significant correlation was observed between MET GA and protein expression (r = 0.378; P.001). MET GA was correlated with poor performance status(P.001) and poorly differentiated tumors (P=.0015). Both MET GA and IHC 31 expression were associated with a substantially shorter median overall survival (OS) and progression-free survival (PFS). The median OS and PFS for patients with MET GA versus those without MET GA were 5.7 months versus 15.5 months (P.001) and 3.6 months versus 6.9 months (P.001), respectively. The median OS and PFS for patients with MET IHC 31 expression versus IHC 0 to 21 expression were 6.3 months versus 15.1 months(P.001) and 3.6 months versus 7.0 months (P.001), respectively.In patients with recurrent=metastatic gastric cancer,MET amplification and strong protein expression are not rare and appear to be significantly associated with unfavorable clinical outcomes.