bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of SM08502, a novel, oral small-molecule inhibitor of Wnt pathway signaling, on gene expression and antitumor activity in colorectal cancer (CRC) models.
Authors: Bossard Carine , Chiu Kevin , Chung Heekyung , Nguyen John Duc , Creger Emily , Eastman Brian , Mak Chi Ching , Do Long , Cho Shawn , KC Sunil , Phalen Timothy , Tambiah Jeyanesh , Cha Steven 
Published: May 2019

e15185 Background: Aberrant activation of Wnt signaling contributing to tumorigenesis is most commonly associated with CRC (90% harbor Wnt pathway mutations). SM08502, a novel, oral Wnt signaling pathway inhibitor, was evaluated in preclinical CRC models. Methods: In vitro Wnt signaling: assessed using TOPflash β-catenin/TCF reporter assay in SW480 human CRC cells. In vitro Wnt pathway gene expression: measured by qRT-PCR in SW480 and Wnt3a-stimulated cells (HEK-293T, IEC-6), and with the Nanostring Wnt pathway array (180 genes) across a panel of 16 CRC cell lines. In vitro cell proliferation: 17 CRC cell lines were used to test cell viability following treatment. In vivo antitumor activity: Oral SM08502 was tested in CRC mouse xenografts (SW480, HCT 116) and a PDX model over 20-21 days (QD, QOD). 24-hr pharmacodynamic (PD) analysis of Wnt pathway gene expression was done in SW480 tumor explants from mice following one 25 mg/kg dose. Results: SM08502 inhibited Wnt pathway signaling (EC50 = 46 nM) in SW480 cells. Wnt pathway gene expression was inhibited by SM08502 (0.3-3 µM) in Wnt3a-stimulated cells ( AXIN2, LEF1) and SW480 ( AXIN2, CTNNB1, LEF1, MYC, TCF7, TCF7L2) at 24 hrs ( P < .05 vs. vehicle) . Corresponding effects on protein expression were confirmed for all genes except CTNNB1, suggesting SM08502 acted independently of β-catenin. Nanostring array screening identified inhibition of LRP5, DVL2, BTRC, and ERBB2 by SM08502. Cell proliferation was inhibited in all 17 lines (avg. EC50 = 177 nM). In vivo, SM08502 was well tolerated and induced dose-dependent antitumor effects in xenografts and PDX models. Tumor growth inhibition for 25 mg/kg QD (max dose) was 83%, 56%, and 70% in SW480, HCT 116, and PDX, respectively. PD analysis showed significant inhibition ( P< .05 vs. vehicle) of TCF7, MYC, LRP5, DVL2, and BTRC expression 8 hrs post treatment. Conclusions: In preclinical CRC models, SM08502 was a potent inhibitor of Wnt pathway signaling and gene expression. It showed strong antitumor activity in human tumor models with activating Wnt pathway mutations. The safety, tolerability, and PK of SM08502 are being evaluated in an ongoing phase 1 study (NCT03355066).
Correlation of CHAF1A with adjuvant chemotherapy outcome and microsatellite instability in gastric cancer.
Authors: Wang Deqiang , Chen Deyu , Shen Bo , Chen Xiaofeng , Qi Martin , Li Xiaoqin , Shu Yongqian 
Published: May 2019

e15511 Background: Clinical outcomes of adjuvant chemotherapy in gastric cancer (GC) have considerable stage-independent variability, which underscores the need for predictive molecular markers. Previous studies indicated that CHAF1A played a critical role in tumor growth, but whether it was associated with adjuvant chemotherapy in GC was still unknown. This retrospective study investigated the prognostic value of CHAF1A in adjuvant chemotherapy of GC. Methods: A total of 325 stage IB-III patients with fluoropyrimidines (FU)-based adjuvant chemotherapy after curative D2 gastrectomy meeting eligibility criteria were selected. CHAF1A protein expression was determined by immunohistochemical method. The primary outcomes were Overall survival (OS) and Disease-free survival (DFS). Kaplan-Meier method was used to estimate survival curve and Cox model for multifactor analysis. Results: CHAF1A mRNA was overexpressed in GC tissues and positive CHAF1A protein expression was not associated with OS and DFS in overall patients treated by FU-based chemotherapy ( P = 0.391 and 0.511, respectively). However, as stratified by tumor sites, positive CHAF1A expression was associated with poor OS and DFS in non-cardia cancer ( P = 0.009 and 0.007, respectively) but not in cardia cancer ( P = 0.229 and 0.112, respectively). Multivariate analysis indicated that CHAF1A expression level was still an independent predictor for both OS (HR = 2.42; 95% CI: 1.12-5.20; P = 0.024) and DFS (HR = 1.91; 95% CI: 1.03-3.54; P = 0.039) in non-cardia GC. Furthermore, CHAF1A was correlated with the status of microsatellite instability ( P = 0.025). Conclusions: CHAF1A might be a predictor for outcomes of FU-based adjuvant chemotherapy in patients with non-cardia GC, but needed further prospective studies to confirm.
Prognostic value and clinicopathological significance of programmed cell death ligand 1 (PD-L1) expression in resected gastric cancer: A meta-analysis.
Authors: Yu Shuixiu , Ning Jing , Ouyang Wei , Ding Lingzhi , Lin Kaisu , Qi Martin , Zhu Hong 
Published: May 2019

e15512 Background: Programmed death ligand 1 (PD-L1) expression has become a promising biomarker in predicting the efficacy of immune checkpoint inhibitors in various advanced cancers, including gastric cancer (GC). However, the prognostic value and clinicopathological significance of PD-L1 in GC is still not clearly identified. Hence, we carried out a meta-analysis to investigate the potential role of PD-L1 in GC, expecting to provide new clues for the judgement of prognosis in resected gastric cancer. Methods: A literature search strategy was performed from the PubMed, Web of Science, EMBASE, and the Cochrane Library database as of December 1, 2018. Relevant data was rigorously extracted from the included literatures. Hazard ratios (HRs) and Odds ratios (ORs) along with 95% confidence intervals (95% CIs) were used to evaluate the prognostic value or clinicopathological significance of PD-L1 expression in GC. Results: A total of 21 studies containing 6021 patients fitted into our meta-analysis. The pooled HRs indicated that PD-L1 high-expression accompanied with a worse overall survival (OS) (HR=1.28, 95% CI: 1.01-1.62, P=0.04) in GC, while no correlation with disease-free survival (DFS) (HR=0.88, 95%CI: 0.53-1.45, P=0.61). Subgroup analysis showed that PD-L1 high-expression was negatively associated with distant metastasis groups (OR=0.66, 95%CI:0.48-0.89, P=0.01), but was positively related to elderly(OR=1.19, 95%CI: 1.01-1.40, P=0.04), lymph-node metastasis(OR=1.63, 95%CI: 1.08-2.46, P=0.02), deeper tumor infiltration(OR=1.73, 95%CI: 1.08-2.79, P=0.02), Epstein-Barr virus infection positive (EBV+) (OR=8.01, 95%CI: 3.10-20.72, P<0.0001), and MET positive (MET+) groups (OR=1.78, 95%CI: 1.05-3.00, P=0.03). Conclusions: Our meta-analysis found that the high-expression of PD-L1 accompanied with a poor OS. Moreover, PD-L1 high-expression was related to age, lymph-node metastasis, depth of infiltration, distant metastasis, EBV infection, and MET status.
Second-line treatment of metastatic gastric cancer in the era of predictive biomarkers: A cost-effectiveness analysis.
Authors: Lauren Brianna , Silver Elisabeth , Ingram Myles , Oh Aaron , Kumble Lindsay , Ostvar Sassan , Laszkowska Monika , Chu Jacqueline N. , Manji Gulam Abbas , Neugut Alfred I. , Hur Chin 
Published: May 2019

e15517 Background: Gastric cancer is the third leading cause of cancer-related mortality, with only a 30% five-year survival rate. Patients who progress after one round of systemic therapy face an especially poor prognosis. The National Comprehensive Cancer Network guidelines include both pembrolizumab (PEM) and ramucirumab plus paclitaxel (RAM/PAC) as second-line (2L) therapy for gastric cancer based on data from the Phase II KEYNOTE-059 and Phase III RAINBOW trials, respectively. Recently, the Phase III KEYNOTE-061 trial reported on the effectiveness of PEM for patients with programmed death-ligand 1 (PD-L1) expression and high microsatellite instability (MSI-H). Given the high prices of targeted therapies, it is important to determine if cost-effectiveness is possible using personalized treatment strategies. The aim of this study was to assess the cost-effectiveness of these regimens in both the general patient population and specific biomarker populations. Methods: A decision-analytic (Markov) model was constructed using data from the KEYNOTE-059, KEYNOTE-061, RAINBOW, and REGARD trials. The analysis compared PEM and RAM/PAC for all patients, as well as PEM for patients based on MSI status or PD-L1 expression (combined positive score of 1% or 10%) in the 2L setting. Comparators were paclitaxel monotherapy (PAC) for all patients and best supportive care (BSC) for all patients. Costs (USD) and utility values were estimated from Medicare and the literature. The primary outcome was the incremental cost-effectiveness ratio (ICER) with a willingness-to-pay (WTP) threshold of $100,000. Results: The only cost-effective strategy was PAC monotherapy for all patients, with an ICER of $53,705/QALY. PEM for MSI-H patients and RAM/PAC for microsatellite stable patients was the most effective strategy (greatest QALYs), but was not cost-effective with an ICER of $1,074,620/QALY. Conclusions: Despite their effectiveness, PEM and RAM/PAC are not cost-effective as 2L treatments for metastatic gastric cancer. Although personalizing treatment based on biomarkers improved cost-effectiveness, the ICERs surpassed the WTP threshold at current drug prices.
Clinical efficacy and safety in gastric cancer patients treated with apatinib: A retrospective real-world study.
Authors: Li Ning , Du Yali , Deng Wenying , Ma Yijie , Yang Xinyi , Bie Liangyu , Wu Qiong , Yang Haiying , Luo Suxia 
Published: May 2019

e15522 Background: This study aimed to explore the efficacy, safety of apatinib and analyze the effects of HER2 mutation status and treatment lines on gastric cancer (GC) patients (pts) treated with apatinib in real-world clinical practice. Methods: We retrospectively analyzed the study data from Linkdoc database with 270 pts who were pathologically or cytologically diagnosed GC and treated with apatinib during January 2015 to November 2018 in Henan Cancer Hospital. Survival was estimated by Kaplan-Meier method. Results: In this study, there were 180 (66.7%) male, with median age of 59 years. The vast majority of pts (259/95.9%) had adenocarcinoma and 86.3% of pts were in stage IV. HER2 was positive in 33.0% of 100 treated pts undergoing HER2 mutation testing. Apatinib was mainly used as second-line treatment (122/45.2%), followed by third-line (82/30.4%), first-line (56/20.7%), fourth- and further-line (22/8.1%), adjuvant (12/4.4%) and neoadjuvant treatment (1/0.4%). Pts received apatinib alone or combined with chemotherapy were 175 (64.8%) and 119 (44.1%), with 53.6% administered at an initial dose of 500 mg. Of all the 270 enrolled pts, the median progression free survival (mPFS) and median overall survival (mOS) were 4.3 months (95% CI: 3.5-5.0) and 6.1 months (95% CI: 5.1-8.4), respectively. For treatment lines subgroup, the mOS was 12.6 months (95% CI: 3.5-NE) in adjuvant treatment; 8.9 months (95% CI: 4.3-12.6) in first-line; 7.3 months (95% CI: 5.0-9.7) in second-line; 6.2 months (95% CI: 5.1-9.9) in third-line; 4.0 months (95% CI: 1.6-6.9) in fourth- and further-line treatment. For HER2-negative pts, the mOS was slightly longer than those of HER2-positive pts (5.7 months vs. 4.5 months), however, the difference was not statistically significant ( p = 0.5185). The most common adverse events were fatigue (25.9%), anemia (24.8%), hypertension (9.3%) and vomiting (9.3%). Conclusions: This real world study revealed that the clinical efficacy of apatinib in GC pts was satisfying and the toxicity was tolerable and controllable. Pts received apatinib in ≤ second-line treatment may gain better survival benefits, and little difference was found in survival outcomes between pts with or without HER2 mutations.
Distribution of urokinase-type plasminogen activator and its receptor in malignant tissues of gastric adenocarcinoma.
Authors: Kozlova Larisa S. , Kit Oleg I. , Frantsiyants Elena M. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Samoylenko Nikolay S. , Kharagezov Dmitry A. , Milakin Anton G. , Gabrichidze Petr N. 
Published: May 2019

e15530 Background: Peritoneal metastases are the most common recurrence of gastric cancer, even after radical surgery. Urokinase-type plasminogen activator (uPA) system, including its receptor uPAR, is crucial in the proteolysis activation for the cleavage of the extracellular matrix and basement membrane. The purpose of the study was to determine the antigen form uPA-Ag, active form uPA-act and the uPAR receptor in tissues of adenocarcinoma of the stomach, its perifocal tissues (PT), greater omentum and peritoneum in patients with stomach cancer T3-4аN0-3M1 and T3-4аN0-3M0. Methods: Tissues of patients with gastric adenocarcinoma T3-4аN0-3M1 (n = 21: 10 men, 11 women) and T3-4аN0-3M0 (n = 24: 15 men, 9 women) aged 61.23±4.8 years were studied. Controls: non-cancer patients aged 39.1±3.2 years (n = 17: 6 men, 11 women). Levels of uPA-act, uPA-Ag and uPAR were determined by ELISA using standard test systems. Statistical analysis was performed using the SPSS 11.5 software package for Windows. Results: In T3-4аN0-3M1, the highest uPAR levels were observed in tissues of the tumor, greater omentum and peritoneum, compared to T3-4аN0-3M0 and controls (p < 0.01). In PT of T3-4аN0-3M1, uPAR levels were lower than in tumor (p < 0.01) but higher than in resection line tissues. Tumor levels of uPA-act in T3-4аN0-3M1 and T3-4аN0-3M0 were similar and in both cases higher than in PT. In the greater omentum in T3-4аN0-3M1, uPA-act levels were similar to tumor levels and exceeded the values in T3-4аN0-3M0 (p < 0.01). Peritoneal uPA-act did not differ in T3-4аN0-3M1 and T3-4аN0-3M0 but was higher than in controls (p < 0.05). Tumor levels of uPA-Ag in T3-4аN0-3M1 exceeded the levels in T3-4аN0-3M0 and in both PT (p < 0.05). Levels of uPA-Ag in the greater omentum in T3-4аN0-3M1 were higher than in T3-4аN0-3M0 and lower than in controls (p < 0.01). Comparable uPA-Ag levels in T3-4аN0-3M1 and T3-4аN0-3M0 were lower than in controls (p < 0.01). Conclusions: Gastric adenocarcinoma secretes uPAR and uPA, and uPAR levels in the tumor are associated with omental or peritoneal metastases. Levels of uPAR and uPA-act in the greater omentum and peritoneum in T3-4аN0-3M1 are increased even higher than in T3-4аN0-3M0; uPAR can serve as a marker of a pre-metastatic niche in peritoneal tissues.
tPA and PAI-1 in malignant tissues of gastric adenocarcinoma can be tumor-associated.
Authors: Samoylenko Nikolay S. , Kit Oleg I. , Frantsiyants Elena M. , Kozlova Larisa S. , Soldatkina Natalya V. , Tumanyan Sergey V. , Gevorkyan Yuriy A. , Aleynov V. I. , Milakin Anton G. , Poluektov Sergey I. , Duritskiy Maksim N. 
Published: May 2019

e15533 Background: Plasminogen regulator system is considered to be involved in migration, invasion and proliferation of malignant cells. The role of tissue plasminogen activator (tPA) and PAI-1 in cancer is still discussed. Our purpose was to study the antigen and active forms of tPA and PAI-1 (tPA-Ag, tPA-act and PAI-1-Ag, PAI-1-act) in tissues of gastric adenocarcinoma (GA), greater omentum and peritoneum with and without metastases (mts). Methods: We studied tissues of patients with GA T3-4аN0-3M1 (n = 21, 10 men, 11 women) and T3-4аN0-3M0 (n = 24, 15 men, 9 women) aged 61.23±4.8 years. Control group included 17 non-cancer patients aged 39.1±3.2 years (6 men, 11 women). Levels of tPA-act, tPA-Ag, PAI-1-act and PAI-1-Ag were measured by ELISA using standard test systems. Statistical analysis was performed using the SPSS 11.5 software package for Windows. Results: Levels of both forms of tPA and PAI-1 in GA with and without mts were 1-2 orders of magnitude higher than in resection line tissues. Levels of tPA-Ag and PAI-1-Ag in GA without mts were 1.7 and 2.5 times higher than in GA with mts, while levels of tPA-act and PAI-1-act were similar. In tissues of the greater omentum, levels of tPA-Ag with mts exceeded that in tissues without mts and in controls by 5.0 and 1.7 times, respectively; levels of tPA-act were similar to controls, while without mts they were 1.6 times lower than in controls. PAI-1-Ag with mts was 3.2 and 4.5 without mts and in controls, respectively; PAI-1-act with mts was 1.8 and 1.5 times higher than in controls and without mts, respectively. In tissues of the peritoneum, tPA-Ag with mts was 1.6 and 1.4 times higher than without mts and in controls, respectively; tPA-act with and without mts was 1.4 (p = 0.0412) and 1.5 times lower than in controls. PAI-1-Ag in the peritoneum with and without mts 1.4 times (p = 0.0428) exceeded control, and PAI-1-act was higher than in controls by 1.6 and 2.8 times, respectively. The results demonstrated that GA with and without mts secreted PAI-1 and tPA, and levels of tPA-Ag and both forms of PAI-1 were elevated in tissues of the peritoneum and omentum with and without mts. Conclusions: Levels of tPA-Ag and both forms of PAI-1 in the greater omentum and peritoneum without mts indicate possible formation of a pre-metastatic niche.
Prevalence of esophageal malignant and premalignant lesions in a Michigan cohort, 2013-2017.
Authors: Tatineni Shilpa , Nemakayala Divyesh Reddy , Enofe Ikponmwosa , Wang Ling , Laird-Fick Heather 
Published: May 2019

e15541 Background: Esophageal cancer is diagnosed in roughly 4 per 100,000 US population. Older men are most frequently affected. Adenocarcinoma is most common and incidence is increasing. EGD with biopsy is important for diagnosis. Many patients present with metastases, limiting treatment options. EGD can identify Barrett’s esophagus, a precursor lesion for adenocarcinoma, but evaluation of biopsy specimens is difficult. This study describes findings from esophageal biopsies in a large community-based Michigan cohort. Methods: Patients aged ≥18 years undergoing EGD with esophageal biopsies in Sparrow Health System were identified. Pathology reports were abstracted for sociodemographics, procedure information, and pathologic findings. Only patients with complete data were included for analysis. Statistical comparisons were assessed by chi-square tests or Fisher’s exact test in contingency tables for categorical variables, or t-tests for continuous variables as appropriate. Results: 4,471 patients were included. 3,279 (73.3%) had benign findings, 1,117 (25%) premalignant changes, 69 (1.54%) malignancy including adenocarcinoma, poorly differentiated cancer or high-grade dysplasia, 1 (0.022%) squamous cell cancer, and 5 (0.11%) neuroendocrine tumors. The latter six were excluded from analyses.Most procedures were performed for inpatients (70.5% for benign, 72.5% malignant and 76.3% pre-malignant; p< 0.001 for all comparisons). Patients with malignancy were older than those with premalignancy [mean 69.8 (SD = 10.4) vs 62.6 (SD = 12.2) years; p< 0.001], who were older than those with benign findings [62.6 (SD = 12.2) vs 56.2 (SD = 14.7) years; p< 0.001]. Patients with premalignancy came from areas with higher average household incomes ($42,179 vs $41,247; p< 0.01). There were no other socioeconomic or sex differences between groups. Conclusions: In a community sample, esophageal malignancy was uncommon but premalignant changes common. Most procedures occurred during hospitalizations. Ensuring appropriate post-discharge follow up for premalignant changes could be challenging. Association between premalignant changes and higher average household income is intriguing and merits additional study.
The ratio of negative lymph node count inside the thoracic cavity to the positive lymph count is a prognostic factor in esophageal squamous cell carcinoma.
Authors: Zhang Jinling , Heng Xueyuan , Che Fengyuan 
Published: May 2019

e15545 Background: It was reported that the number of positive lymph nodes (PLN) and negative lymph nodes (NLN) resected in lymphadenectomy were both independent prognostic factors in esophageal squamous cell carcinoma (ESCC). However, it is unclear which kind of combination of them would have a stronger impact on the prognosis of the ESCC patients. Methods: A total of 229 patients with ESCC were retrospectively investigated. The Cox Proportional Hazards Model was used to investigate the relationship between the PLN or NLN and the overall survival of patients. Survival analysis was performed using the Kaplan-Meier method, and the survival difference between sub-groups were explored with log-rank tests. The cut-off number of the ratio of NLN count to PLN count resulted in an improved outcome for patients was investigated by a series of log-rank tests. Results: The numbers of PLN and NLN were both independent prognostic factors, supported by the results of Cox regression model analysis (hazard ratio [HR], 1.12, P < 0.001 and HR, 0.97, P = 0.024, respectively).The survival differences among sub-groups from N0 to N3 stage were statistically significant (P < 0.001). Analysis using a Cox regression model revealed that the number of NLN inside the thoracic cavity had a stronger impact on the prognosis compared to the number of NLN outside the thoracic cavity (HR,0.959, P = 0.042 vs.HR, 0.973, P = 0.179). As a combination analysis consisting of the number of PLN and NLN, the log-rank test result demonstrated that patients with the ratio of NLN count inside thoracic cavity to the PLN count less than 8 could achieve a better survival. Conclusions: The ratio of NLN count inside thoracic cavity to the PLN count was a independent prognostic factor.
Investigation of enhanced antitumor effects via co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR signaling pathways in human gastric cancer.
Authors: Choi Moon Young , Cho Min-Hee , Chang Hye Jung , Lee Soon-Nam , Lee Kyoung Eun 
Published: May 2019

e15553 Background: Gastric cancer, a highly aggressive malignancy, frequently recurs despite curative surgery and metastasizes to lymph node and distant sites. Epithelial-mesenchymal transition (EMT) is the main phenomenon of cancer progression, including invasion and metastasis. It is regulated by crosstalks between diverse intracellular signaling pathways such as Wnt/β-catenin and phosphatidylinositol-3-kinase(PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathways. Here, this study elucidated the effects of co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways on gastric cancer. Methods: It is known that Wnt/β-catenin signaling pathways are constitutively activated in two of gastric cancer cell lines, AGS and MKN-28. ICG-001 (β-catenin transcription inhibitor) and rapamycin (mTOR inhibitor) were used for dual blockade, and then the combinatory effects were examined. Results: As a result, both cell lines were significantly affected by the β-catenin transcription inhibitor, ICG-001, and addition of the mTOR inhibitor, rapamycin induced marginal inhibitory effects on cancer cell proliferation and target gene expression. In addition, invasive activity was 62.3 ± 15.7% and 53 ± 14.4% inhibited by single treatment, but it was 79 ± 13.3% inhibited by co-treatment. Moreover, migratory activity was 33 ± 13%, 42 ± 9% inhibited by single treatment, but it was 82 ± 4% by co-treatment. Interestingly, Snail, one of the important regulatory protein during EMT process, was significantly decreased by co-treatment. Conclusions: Taken together, these results suggest that co-inhibition of Wnt/β-catenin and PI3K/Akt/mTOR pathways could effectively enhance antitumor effects on gastric cancer via the inhibition of invasion and migration as well as decrease of Snail expression.