bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apatinib affects the proliferation, migration and apoptosis of esophageal cancer cells both in vitro and in xenografts by regulating Ras/Raf/MEK/ERK and JAK2/STAT3 signaling pathways.
Authors: Yu Jingping 
Published: May 2019

e15501 Background: To investigate the effects of apatinib on esophageal cancer cells in vitro and xenograft models, and discuss the mechanisms of its actions. Methods: Used various assays to measure the different biological processes of esophageal cancer cells: used MTT assay to measure the proliferation rate; used transwell assay to determine the migration capacity and used colony formation assay to assess the clone formation rate. The effect of apatinib on cell cycle and apoptosis was analyzed by flow cytometry. The expression levels of VEGF and VEGFR2 were measured by qRT-PCR. The concentration of VEGF in the supernatant of cancer cell was assessed by ELISA. The expression levels of MEK, ERK, p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 after VEGF stimulation were detected by western blot. We also established human esophageal squamous carcinoma xenograft model in nude mice. The mice were randomly divided into healthy control group, low dose group (250mg) and high dose group (500mg), with 6 mice in each group. The tumor growth rate of each group was calculated, and the expression levels of VEGF and VEGFR2 in tumor tissues were detected by immunohistochemistry. Results: Apatinib inhibited the proliferation of esophageal cancer cell in a time-dependent (P < 0.05) and concentration-dependent (P < 0.05) manner; it also inhibited the cell migration capacity (P < 0.05) and colony formation rate (P < 0. 05). In addition, apatinib induced apoptosis in esophageal cancer cells and increased the proportion of cells in G2 / M phase (P < 0.05). The mRNA levels of VEGF (P < 0.05) and VEGFR2 (P < 0.05) and the protein levels of VEGF (P < 0.05) were also suppressed by apatinib. Western blot showed that apatinib could down-regulate the expression of p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 (P < 0.05). The inhibition rates of apatinib in esophageal carcinoma xenograft model was 29.25% and 19.96% for 250mg and 500mg drug treatment groups. Compared with healthy control group, the VEGF levels in drug treatment groups were not significantly different (P > 0.05), but the VEGFR2 levels were significantly decreased (P < 0.05). Conclusions: Apatinib can induce apoptosis of esophageal cancer cell KYSE-150 and ECA-109, and inhibit the cell proliferation, migration and colony formation. Moreover, apatinib can inhibit the tumor growth in esophageal carcinoma xenograft models. This inhibitory action of apatinib is related to the alterations in VEGF-related pathways such as Ras / Raf / MEK / ERK and JAK2 / STAT3 pathways.
Clinical implication of telomere length-related polymorphisms in gastric cardia adenocarcinoma.
Authors: Zhang Nasha , Yang Ming 
Published: May 2019

e15502 Background: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. Methods: We systematically screened GWAS-identified candidate SNPs and tested the impact of thirty polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1,024 GCA patients and 1,118 controls. Results: We observed that CXCR4 rs6430612, TERT rs10069690 and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype ( P= 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers ( P= 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype ( P= 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients was 1.35 compared with the GG genotype ( P= 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers ( Pinteraction=9.7×10-5) and nondrinkers ( Pinteraction= 4.6×10-5). Conclusions: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.
A multicenter, single-armed, prospective phase II study of apatinib combined with chemotherapy neoadjuvant for locally advanced gastric cancer.
Authors: Lin JianXian , Huang Changming 
Published: May 2019

e15508 Background: Molecular targeted therapy has made great progress in the treatment of gastric cancer. In some previous studies, apatinib, an oral small molecular of VEGFR-2 tyrosine kinase inhibitor, had been confirmed can improve OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. However, there is limited evidence about the safety and feasibility of apatinib combined with SOX regimen as neoadjuvant therapy for locally advanced gastric cancer (LADG). Methods: This is a multicenter, single-armed, prospective study. Patients with LAGC (cT2-4N+M0) without prior anti-cancer strategies were included. Patients were received 3 to 5 cycles (21 days a cycle) of neoadjuvant therapy using S-1 (po, 40-60 mg bid, day1-day14), oxaliplatin (iv, 130 mg/m2, day1), and apatinib (po, 500 mg qd). Apatinib was prohibited in the last cycle. The operation should be performed 2 to 4 weeks later of the neoadjuvant therapy. The primary outcome was safety of the neoadjuvant therapy. The secondary outcomes included R0 resection rate, objective response rate (ORR), and disease control rate (DCR). Results: A total of 30 patients from 7 centers in China were recruited between Sep. 1, 2017 and Aug. 31, 2018. There were 21 males and 9 females. The median age was 66 years (range 41-75 years). There were 25 patients with tumor response evaluation, 18 patients had partial response (PR), 6 patients had stable disease (SD), and 1 patient had progressive disease (PD). The ORR and DCR were 72.0% (18/25) and 96.0% (24/25), respectively. 10 patients discontinued the study (withdrew consent 8 patients, physical deterioration in performance status 1 patient, and Disease progression 1 patient). 20 patients received gastric surgery, the R0 resection rate was 100%, 3 patients had postoperative complication: one had intestinal obstruction and two had pneumonia (all Clavien-Dindo classification less than grade II). All patients were included for safety analysis. The incidence of adverse events (AEs) and grade 3/4 AEs were 56.7% (17/30) and 6.7% (2/30), respectively. The most common AEs were leucopenia (33.3%), liver function damage (6.7%), up-GI hemorrhage (6.7%), and hypertension (6.7%). Conclusions: This prospective study shows that neoadjuvant therapy using apatinib plus SOX brings clinical benefit to LAGC with a high disease control rate and tolerable adverse reactions. This study is registered at ClinicalTrials.gov and carries the following ID number: NCT 03192735. Clinical trial information: NCT 03192735.
Efficacy and safety of conversion therapy using chemotherapy plus anti-angiogenic therapy in unresectable gastric cancer.
Authors: Chen Lu chuan 
Published: May 2019

e15510 Background: Conversion therapy has been a promising option for patients with unresectable gastric cancer (GC) (including Phase IV gastric cancer, N3, lymph node fusion and local progression patients). We aimed to investigate the efficacy and safety of S1/oxaliplatin chemotherapy plus apatinib, a novel inhibitor of VEGFR-2, in the conversion therapy for unresectable GC. Methods: This was a single-center, single-arm, open-label study. unresectable GC patients with unresectable factors were eligible for this study. Apatinib (500mg, qd) was administrated continuously, oxaliplatin (130mg/m2) on day 1, and S1 (<1.25m2, 40mg*2/d; 1.25-1.5m2, 50mg*2/d; >1.5m2, 60mg*2/d) on day 1-14 every 3 weeks. Treatment was given for 4-6 cycles preoperatively, but the last cycle did not include apatinib. The primary objective included R0 resection rate and safety profile of preoperative treatment. Results: Total 17 patients were enrolled, the median age was 57 (55.12±10.08) years old. The histological types were mainly signet ring cell carcinoma 10 (58.82%), poorly differentiated adenocarcinoma 5 (29.41%), and moderately differentiated adenocarcinoma 2 (11.76%). Among the 17 patients eligible for preoperative efficacy evaluation, 13 achieved partial response (PR), 3 achieved stable disease (SD), and 1 had progressive disease (PD), the overall response rate (ORR) was 76.5% and disease control rate was 94.1%. Of the 13 pts with PR, 1 refused consents for surgery, 12 patients underwent surgery and 9(75%) achieved R0 resection. During preoperative treatment, the incidence of adverse events (AEs) was 76.5%. The common hematologic AEs were neutropenia (64.7%), leukopenia (64.7%) and hemoglobin decrease (11.8%), and nonhematologic AEs included hyperbilirubinemia (11.8%), hand-foot syndrome (17.6%), oral mucositis (29.4%), fatigue (70.6%), proteinuria (5.9%). Conclusions: Combination of apatinib with S1/oxaliplatin chemotherapy could induce a sufficient conversion rate and achieve a relative high R0 resection rate for initially unresectable GC, with tolerable safety profile. Clinical trial information: ChiCTR-ONC-17010430 trial.
Impact of adjuvant treatment according to gastric cancer molecular subtypes.
Authors: De Castria Tiago Biachi , Amorim Larissa Costa , Ramos Marcus Fernando Kodama Pertille , Pereira Marina Alessandra , de Mello Evandro Sobroza , Faraj Sheila , Sabbaga Jorge , Hoff Paulo Marcelo 
Published: May 2019

e15513 Background: The four subtypes of gastric adenocarcinoma (GC) identified by the Cancer Genome Atlas project (TCGA) have different molecular signatures and prognosis. Several centers have tried to classify GC using immunohistochemistry (IHC) and in situ hybridization (ISH), examining the tumors according to Epstein–Barr virus (EBV) status, microsatellite instability (MSI), aberrant E-cadherin expression and TP53 status. Here we aim to verify the impact of adjuvant/perioperative chemotherapy (ACT/PCT) or adjuvant chemoradiation (CRT) according to the molecular subtypes profile. Methods: We retrospectively reviewed all GC patients who underwent gastrectomy and D2-lymphadenectomy at our institution from a prospective collected medical database. Deficient DNA mismatch repair (dMMR), E-cadherin and p53 were evaluated by IHC for determining the MSI, genomically stable (GS) and chromosomal instability (CIN, with and without p53 aberrant) subtypes, respectively. EBV positivity was detected by ISH. Results: Among the 178 stage II/III patients included, 67 had surgery alone, 47 received ACT/PCT and 64 CRT. 16 had aberrant E-cadherin (GS, 9%), 33 dMMR (MSI, 18.5%), 74 aberrant p53 expression (CIN p53-aberrant, 41.6%), 104 normal p53 expression (CIN p53-normal, 58.4%) and 18 EBV-positivity (EBV, 10.1%). Two or more altered status were present in GC of 16 patients. When analyzed independently, Kaplan-Meier survival analysis showed that EBV, dMMR, CIN p53-normal and GS subtypes did not obtain any benefit of ACT/PCT or CRT in disease free survival (DFS) (p = 0.71; p = 0.33; p = 0.41; p = 0.21, respectively). Meantime, those treatments impact positively in DFS for EBV-negative, proficient MMR and non-GS (p = 0.01; p = 0.007; p = 0.01). CIN subtype with p53 aberrant obtained most benefit for ACT/PCT or CRT (p < 0.001). Conclusions: In accordance with other studies we achieved no benefit for adjuvant chemotherapy in patients with EBV, dMMR and GS GC subtypes. Patients with p53 aberrant expression had greater benefit for ACT/PCT or CRT. This simple method of classification can potentially help to tailor adjuvant treatment.
Apatinib in the treatment of non-operable or advanced gastric cancer: Evidence of efficacy and safety in a real-world study.
Authors: Xing Ligang , Cao Wei , Cui Gang , Zhang Huanhu , Shi Yiran , Wei Xin , Dong Yuting , Guo Chengye , Wang Bingping , Zhang Shu , Zou Zhiqiang , Zhang Zizhi , Sun Yahong , Yu Guohua , Guo Hongliang , Wang Deyou , Meng Qi , Li Changzheng , Wang Xixun , Yu Jinming 
Published: May 2019

e15515 Background: Apatinib, a small molecule tyrosine kinase inhibitor, has been approved to use in patients with advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma after at least two systemic chemotherapy regimens in China. This study aims to observe the efficacy and safety of apatinib in real word clinical practice and preliminarily explore the characteristics of population with more clinical benefit. Methods: This study included patients with non-operative or advanced gastric cancer confirmed by histopathology or cytology, and did not intervene the regimen which was entirely determined by the clinicians and patients. Results: From April 16, 2018 to January 12, 2019, 732 patients enrolled, and all patients had been followed up at least once. Total 342 patients were eligible for efficacy evaluation. Among them, 43 patients achieved partial response (PR), 209 patients achieved stable disease (SD) and 90 patients experienced progression disease (PD). The overall response rate (ORR) was 12.55%, and the disease control rate was 73.6%. The mPFS have not yet reached. For patients ≥65 years, the ORR was 26.32%, and for patients < 65 years, ORR was 8.33%. For patients with non-signet ring cell carcinoma and signet ring cell carcinoma, the ORRs were 15.22% and 6.0%. For patients with and without organ metastasis, the ORRs were 15.25% and 3.75% respectively. The PFS analysis showed that, Combined chemotherapy and age > 65 may predict longer PFS. The OS analysis showed that, ECOG 0-1, combined chemotherapy, AFP positive and male predict longer OS. The overall incidence of adverse events was 84%. The most common adverse events were hypertension (28.8%), fatigue (22.4%), hand-foot syndrome (17.3%), anorexia (12.8%) and nausea (10.5%). Conclusions: Apatinib showed promising antitumor activity in patients with non- operable or advanced Gastric Cancer in this real word study. The prolonging survival benefits maybe could be attenuated by age <65, without organ metastasis, ECOG score >1, treatment regimen, normal AFP, and pathological diagnosis of non-signet ring cell carcinoma. Clinical trial information: ChiCTR1800015701.
Neoadjuvant versus adjuvant chemoradiotherapy for stage II–III esophageal squamous cell carcinoma: A propensity score-matched analysis.
Authors: Lv Jiahua , Li Tao , Wang Qifeng , Han Yongtao , Song Yuzhe , Liang Long , Chen Meihua , Fan Yu , Wu Lei , Peng Lin , Lang Jinyi 
Published: May 2019

e15524 Background: Many clinical trials have explored the value of neoadjuvant or adjuvant chemoradiation therapy in stage II–III squamous cell carcinoma (ESCC). However, these studies have produced conflicting results. This retrospective study was performed to investigate whether patients with stage II/III ESCC should receive neoadjuvant or adjuvant therapy in addition to surgery. Methods: A total of 206 patients with clinical stage II and III ESCC who underwent esophagectomy and either neoadjuvant or adjuvant chemoradiation were included. On the basis of the sequence of surgery and chemoradiation, the patients were divided into two groups: Neoadjuvant chemoradiation followed by surgery (neoadjuvant CRT group) and surgery followed by postoperative chemoradiation (adjuvant CRT group). Propensity score matching analysis was used to identify 62 well-balanced patients in each group for outcome comparison. Results: In all, 69 and 137 patients were in the neoadjuvant CRT group and adjuvant CRT group, respectively. Before matching, no differences were observed in the overall survival among the patients in these two groups (P = 0.209). After matching, the survival was similar between neoadjuvant CRT group and adjuvant CRT group (P = 0.933). The median survival times and 1, 3, 5-year overall survival (OS) rates for the neoadjuvant and adjuvant CRT groups were 40.4 versus 41.0 months, 83.3% versus 95.1%, 54.6% versus 54.0%, 37.0% versus 30.7%, respectively. In the subgroup analysis, patients with clinical T3/4 stage and N1 stage tumors were more likely to demonstrate an overall survival benefit from neoadjuvant CRT compared with adjuvant CRT. Conclusions: No survival and perioperative complications difference were observed among esophageal cancer patients in the neoadjuvant CRT and adjuvant CRT groups. However, neoadjuvant CRT is recommended for patients with clinical T3/4 stage and N1 stage tumors.
Paratracheal lymph node metastasis in operable localized esophageal and gastroesophageal junction adenocarcinoma.
Authors: Harada Kazuto , Hwang Hyunsoo , Wang Xuemei , Abdelhakeem Ahmed , Iwatsuki Masaaki , Blum Murphy Mariela A. , Maru Dipen M. , Weston Brian , Lee Jeffrey H , Rogers Jane E. , Thomas Irene , Shanbhag Namita , Bhutani Manoop S. , Nguyen Quynh , Ikoma Naruhiko , Badgwell Brian D. , Hofstetter Wayne Lewis , Baba Hideo , Ajani Jaffer A. 
Published: May 2019

e15526 Background: Paratracheal lymph node (LN) is considered regional for esophageal cancer, but its metastatic rate and influence to survival remain unclear. We aimed to evaluate the frequency of paratracheal LN metastasis and its prognostic influence. Methods: 1199 patients with localized esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. 1R, 1L, 2R, 2L, 4R, and 4L according to 8th AJCC classification were defined as paratracheal LN. Results: Of 1199 patients, 73 (6.1%) had positive parataracheal LN at diagnosis. The median overall survival (OS) in 73 patients with initial paratracheal LN involvement was 2.10 years (range, xx). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed positive paratracheal LN recurrences as first recurrence. The median time to recurrence was 1.28 years (range; 0.28-5.96 years) and the median OS after recurrence was 0.95 years (range; 0.03-7.89). OS in 35 patients who had only patatracheal LN recurrence was significantly longer than in patients who had with other distant recurrences (median 2.26 vs 0.51 years; p < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (OR 5.10, 95% CI 1.46-17.89). We segregated patients in 3 groups based on the distance from esophagogastric junction to tumor proximal edge (lower; ≤2cm, middle; 2.0-7.0cm, higher; > 7.0cm), positive paratrachal LN metastases were more frequent in the proximal tumors (lower 4.2%, middle 12.0%, higher 30.3%; Cochran-Armitage Trend test, p < 0.001). Conclusions: Paratracheal LN metastases were associated with shorter survival in localized EAC patients. Careful investigation and surveillance for paratracheal LN are warranted.
Predictors of peritoneal metastasis in gastric cancer.
Authors: Kaplieva Irina V. , Kit Oleg I. , Frantsiyants Elena M. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Samoylenko Nikolay S. , Kharagezov Dmitry A. 
Published: May 2019

e15528 Background: Carcinogenesis is a complex process with still poorly understood mechanisms allowing cancer cells to disseminate from the primary tumor, spread in the body and colonize other organs forming secondary tumors – metastases. The ability of some distant organs to attract malignant cells may be caused by factors released by primary tumors. The purpose of the study was to determine levels of oncofetal proteins CA-19.9, CA-125, CA-72.4 and He-4 in tissues of gastric cancer (GC) and its metastatic niches, the peritoneum and omentum. Methods: The study included 62 patients: 21 (10 men, 11 women) – gastric cancer with peritoneal and omental metastases T3-4аN0-3M1; 24 (15 men, 9 women) – gastric cancer without metastases T3-4аN0-3M0; 17 (6 men, 11 women) – non-cancer patients (controls). Levels of oncofetal proteins were measured by ELISA in tissues of the peritoneum, greater omentum, and gastric tumors. Results: Levels of practically all studied factors were elevated in tissues of GC, omentum and peritoneum. Levels of He-4 and CA-19.9 in all tissues of patients with T3-4аN0-3M1 increased higher than in the majority of patients with T3-4аN0-3M0: in GC – respectively by 2.6 and 1.8 times (p < 0.05), in the omentum – respectively by 24.4 and 4.8 times, in the peritoneum – respectively by 2.1 and 8.5 times. Omental tissues of patients with advanced cancer showed a higher increase in levels of CA-72.4 and CA-125 as well – by 6.1 and 2.1 times, respectively. A small number of patients with T3-4аN0-3M0 gastric cancer, who had CA-19.9 in the omentum and peritoneum as high as in patients with T3-4аN0-3M1, developed metastases in the corresponding tissues 4-6 months after the study. Conclusions: The content of oncoprotein markers in tissues of the peritoneum and omentum is one of the factors associated with metastatic characteristics of GC, and CA-19.9 level can serve as an informative laboratory test for the predictive assessment of the further disease development.
Urokinase secretion by gastrointestinal adenocarcinoma.
Authors: Kozlova Larisa S. , Kit Oleg I. , Frantsiyants Elena M. , Gevorkyan Yuriy A. , Maslov Andrey A. , Dzhenkova Elena A. , Samoylenko Nikolay S. , Aleynov V. I. , Duritskiy Maksim N. 
Published: May 2019

e15529 Background: The serine protease urokinase plasminogen activator (uPA) plays an important role in growth and invasion of malignant tumors. The purpose of the study was a comparative analysis of uPA activity (uPA-act) and its antigen (uPA-Ag) content in adenocarcinoma (A) of the esophagus (EA), stomach (SA), pancreatic head (PHA), sigmoid colon (SCA) and rectum (RA). Methods: Tissues of A, perifocal tissues (PT) and resection line tissues were studied by ELISA in 144 patients (39-73 years) with EA (n = 12, G2, T2-3N0-1M0), SA (n = 28, G2, T2-3N0-1M0), PHA (n = 46, G2, Т2-4N0M0), SCA (n = 31, G2, T2-3N0-1M0) and RA (n = 26, G2,T2-3N0-1M0). Statistical analysis was performed using the Statistica 10 program. Results: The levels of uPA-Ag in gastrointestinal A decreased from SA to PHA: SA˃RA˃SCA˃EA˃PHA (p < 0.01). The uPA-Ag levels in A were higher than in the resection line in all cases (p < 0.01). PT levels of uPA-Ag decreased from SA to PHA: SA˃SCA˃RA˃EA˃PHA (p < 0.01). In EA and PHA, PT levels of uPA-Ag were lower than in resection line tissues (p < 0.01), while in SA, SCA and RA they were higher (p < 0.01). Levels of uPA-act were similar in SA and SCA, while in EA and RA they were 1.2 (p = 0.4324) and 1.3 (p = 0.4012) times lower, and in PHA – 40.0-52.5 times lower (p < 0.01) compared to all A samples. The uPA-act in PT was the highest in SCA; 1.4 times lower in SA and RA; 1.7 times lower in EA; 30.9 times lower in PHA. The levels in PT were higher than in the resection line in all cases (p < 0.01). The resection line tissues in EA showed the maximal uPA-Ag content, while their uPA-act was similar to that in other tumors. Levels of uPA-Ag and uPA-act in resection line tissues in other tumors varied but were comparable. Estimated uPA-Ag/uPA-act coefficients in the resection line in SCA and RA were 20.4 and 29.5, respectively; in EA and PHA – 102.0 and 34.8, respectively. Conclusions: Adenocarcinomas of the esophagus, stomach, pancreatic head, sigmoid colon and rectum secrete uPA-Ag and uPA-act into surrounding tissues. The rate of uPA-Ag secretion by the tumor and its activation into uPA-act in pancreatic head cancer differ from that in other tumors.