bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction cancers: A provincial population-based analysis.
Authors: Yu Irene S. , Liu Shiru Lucy , Zhao Yizhou , Lau Sally CM , Schellenberg Devin , Gill Sharlene , Lim Howard John 
Published: May 2019

e15506 Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responders (R, ≥ 35% decrease in max SUV) or PET non-responders (NR, < 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts with locally advanced DE/GEJ cancers, 232 pts were eligible for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p>0.05). Median time from end of treatment to PETs was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response rates (14% vs 13%, p=0.079) were similar for PET-R vs PET-NR, respectively. Discordance rate was 34% between PET vs pathologic response (Table). Aborted surgery rate was higher in the PET-NR group (8% vs 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the groups (PET-R 31.5 mo vs PET-NR 36.1 mo, p=0.616). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility. PET-NR were more likely to have their surgeries aborted. The predictive ability of PET in determining surgical resectability should be further investigated to avoid unnecessary high morbidity surgeries.[Table: see text]
Decreased risk of esophageal squamous cell carcinoma among metformin users in a population-based cohort study.
Authors: Wang Qiao-Li 
Published: May 2019

e15507 Background: Metformin, mainly used in the treatment of diabetes, may prevent various types of cancer, but no study has specifically examined its potential influence on the risk of esophageal squamous cell carcinoma, the major histological type of esophageal cancer. The aim of this study was to determine the association between metformin use and esophageal squamous cell carcinoma. Methods: This was a nationwide population-based prospective cohort study conducted in Sweden in 2005-2015. Among 8.4 million participants identified from the Swedish Prescribed Drug Registry, 411,603 (5%) were users of metformin. The metformin users were compared with 10 times as many frequency-matched non-users of metformin (n = 4,116,030) by age and sex. Multivariable cause-specific proportional hazards model was used to calculate hazard ratios (HR) with 95% confidence intervals (CI), adjusted for age, sex, calendar year, place of residence, tobacco smoking, alcohol overconsumption, and use of non-steroidal anti-inflammatory drugs or statins. Results: The incidence rates of esophageal squamous cell carcinoma were 3.5 per 100,000 person-years among the metformin users and 5.3 per 100,000 person-years in the non-users. Metformin users overall were at a decreased risk of esophageal squamous cell carcinoma compared with non-users (adjusted HR 0.68, 95% CI 0.54-0.85). The decrease in risk was more pronounced in new metformin users who were 56 years old when they started their metformin therapy (HR 0.44, 95% CI 0.30-0.65). Conclusions: Metformin therapy may decrease the risk of developing esophageal squamous cell carcinoma.
Association of CDH1 mutation with prognosis in gastric adenocarcinoma.
Authors: Yu Xiangyang , Yang Shimin , Du Rong , Zhang Jingbo , Fang Nan , Wang Junpo , Tang Yu , Wang Jianwei , Wu Qixi 
Published: May 2019

e15514 Background: Stomach cancer is a major cause of cancer death in East Asia. The purpose of this study was to find a predictive marker to estimate the prognosis of stomach cancer. Methods: In this study, a total of 34 gastric cancer patients receiving therapy in Tianjin Nankai Hospital were enrolled. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue sections, including carcinoma and pericarcinous tissues. Targeted regions of 549 cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina Next-Seq 500 platform. Results: 25/34 patients had tumor metastasis. 135 non-silent mutations in 62 genes were detected in 27 tumor samples, while 7 patients’ samples had no mutation detected. CDH1, BRCA2 and SMAD4 gene mutations only occurred among metastasis patients. CDH1, BRCA2 and KRAS gene mutations are associated with a lower overall survival rate. Among them, 5 patients had a CDH1 mutation, including one splicing mutation, three frameshift mutations, one non-frameshift mutation and two non-synonymous mutations. All five patients had tumor metastasis, with the survival time less than 17 months, compared with all patients’ average overall survival of 22 month. Conclusions: Previous studies showed that mutation in CDH1 is linked to gastric cancer (GC) susceptibility and tumor invasion. Our results indicated that the mutation of CDH1 was also associated with the prognosis of gastric adenocarcinoma (P < .01) and was an independent factor (P < .05).
Association between molecular subtype of esophageal squamous cell carcinoma and survival of patients.
Authors: Kutilin Denis S. , Kit Oleg Ivanovich , Maksimov Aleksey Yurievich , Petrusenko Natalia A. , Myagkova Tatiana Yu. , Kozhushko Mikhail A , Sanamyants Sergey V. , Kolesnikov Evgeniy N. 
Published: May 2019

e15520 Background: Esophageal squamous cell carcinoma (ESCC) comprises a group of heterogeneous tumors with various prognoses which does not depend on clinical signatures (TNM, tumor location). In recent years, different molecular subtypes of ESCC have been identified in different populations; however, such studies have not been conducted in the population of Southern Russia. The purpose of the study was the molecular typing of ESCC in patients of the Southern Russia, and the assessment of survival of patients with different molecular subtypes of ESCC. Methods: Tissue sections from FFPE blocks from 124 ESCC patients were studied. Tumor and normal cells were isolated using laser microdissection (Palm MicroBeam, Carl Zeiss). Molecular typing of ESCC was performed by the determination of copy number variation (CNV) of 8 genes ( CUL3, ATG7, SOX2, TP63, YAP1, VGLL4, CDK6, KDM6А) using Real-Time qPCR and 7 somatic mutations (SNP) ( NFE2L2 (c.85G > A), NOTCH1 (c.1379C > T), NOTCH1 (c.1451G > T), ZNF750 (c.414C > A), ZNF750 (c.1621G > A), SMARCA4 (p.Q758*, c.2272C > T), KMT2D (Q5170* , c.15508C > T)) using Sanger direct sequencing method. The differences were assessed by the Mann-Whitney test. For the cluster analysis (Hierarchical Clustering, Euclidean distance), we used R scripts. Survival of patients was analyzed by the Kaplan–Meier method, and differences between survivals in groups were assessed by the log-rank test. Results: Cluster analysis allowed determination of 3 clusters of ESCC samples different in CNV (p < 0.005): cluster 1 (n = 39) demonstrated increased CNV of SOX2, TP63, YAP1 and decreased CNV of CUL3, ATG7 and VGLL4, cluster 2 (n = 82) – increased CNV of CDK6 and decreased CNV of KDM6А, cluster 3 (n = 3) – decreased CNV of ATG7. Samples of cluster 1 showed c.85G > A mutation in the NFE2L2 gene, cluster 2 - c.1379C > T and c.1451G > T in NOTCH1, c.414C > A and c.1621G > A in ZNF750, and cluster 3 - p.Q758* and Q5170* in SMARCA4 and KMT2D, respectively. Thus, we differentiated 3 molecular subtypes of ESCC (1,2,3). Overall survival rates were higher in ESCC2 (16.1±2.0 months), the lowest ones – in ESCC3 (0.88±0.56 months), with intermediate values in ESCC1 (4.6±0.74 months). Differences between the groups were statistically significant (p = 0.00001). Conclusions: Based on the differential distinctions in SNP and CNV of the genes, we verified 3 molecular subtypes of ESCC with different overall survival of patients.
Can hormone receptors prevent metastatic spread of gastric cancer?
Authors: Kaplieva Irina V. , Kit Oleg I. , Frantsiyants Elena M. , Bandovkina Valeria A. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Samoylenko Nikolay S. , Aleynov V. I. , Tishchenko Irina S. , Duritskiy Maksim N. 
Published: May 2019

e15527 Background: The primary tumor and associated but distinct from it premetastatic niches include a number of important participants: immune cells, stromal cells, extracellular matrix and associated effectors, in particular hormone receptors. Cross-interaction between these components is key to tumor progression. The greater omentum and peritoneum are pre-metastatic niches for gastric cancer. The purpose of the study was to analyze levels of steroid hormone receptors in tissues of gastric cancer (GC) and its pre-metastatic niches: the peritoneum (P) and omentum (O). Methods: The main group included 21 patients with metastatic GC T3-4аN0-3M1; the comparison group – 24 patients with non-metastatic GC T3-4аN0-3M0. Tissues of tumors, intact gastric tissues, omentum and peritoneum tissues were studied. The control group included 17 non-cancer patients; omental and peritoneal tissues were studied. Levels of receptors of estrogens (RE-α, RE-β), androgens (RA) and progesterone (RP4) were measured by ELISA. Results: Levels of RE-α in tissue of GC T3-4аN0-3M1 were decreased by 1.7 times (P˂0.05) compared to controls, while in T3-4аN0-3M0 they were increased by 1.2 times (P˂0.05). RE-β and RА did not change in both cases. RР4 in T3-4аN0-3M1 was similar to control levels, and in T3-4аN0-3M0 – was increased by 3.5 times. Levels of RE-α and β, RА and RР4 in O and P in T3-4аN0-3M1 were similar to control levels, and in T3-4аN0-3M0 they were higher: RE-α - by 3.9 and 2.4 times, RE-β – by 2.5 and 1.5 times (P˂0.05), RР4 – by 2.2 and 1.5 times (P˂0.05). RA in O and P in T3-4аN0-3M0 was similar to control levels. Conclusions: Elevated levels of RE-α., RE-β and RR4 in peritoneal and omental tissues can be considered a factor associated with some characteristics of GC metastasis, and protective one at the same time. Obviously, levels of RE-α and RР in O and P correlate with the levels in tissues of GC T3-4аN0-3M0. However, this statement is disputable and requires further confirmation.
Role of angiogenesis factors in formation of metastatic niches.
Authors: Frantsiyants Elena M. , Kit Oleg I. , Kaplieva Irina V. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Dzhenkova Elena A. , Samoylenko Nikolay S. , Gabrichidze Petr N. , Milakin Anton G. , Poluektov Sergey I. 
Published: May 2019

e15534 Background: A metastatic niche indicates a particular location with a specific cell type, epidermal-mesenchymal transition proteins and diffuse signals that are necessary for the growth of metastases. The purpose of the study was to determine levels of VEGFs, their receptors and TGFβ1 in tissues of gastric cancer (GC) and its metastatic niches: the peritoneum and omentum. Methods: The main group included 21 patients with metastatic GC T3-4аN0-3M1; comparison group – 17 non-cancer patients. Levels of VEGFA, VEGFC, sVEGFR1, sVEGFR3 and TGFβ1 in tissues were determined by standard ELISA methods. Results: Levels of growth factors in GC tissues were higher than in controls: VEGFA in T3-4аN0-3M1 – by 2.7 times, in T3-4аN0-3M0 – by 2.5 times; TGFβ1 in T3-4аN0-3M1 – by 5.6 times, in T3-4аN0-3M0 – by 3.5 times. VEGFA levels in primary gastric tumors were similar in all patients, while TGFβ1 in T3-4аN0-3M1 was 1.6 times (p < 0.05) higher than in T3-4аN0-3M0. VEGFA levels in T3-4аN0-3M1 exceeded control values: in the omentum – by 2.8, in the peritoneum – by 4.2 times. TGFβ1 in the omentum and peritoneum in T3-4аN0-3M1 was increased by 2.5 and 3.1 times respectively, compared to controls. Statistically significant differences in VEGFA and TGFβ1 levels in the omentum and peritoneum in T3-4аN0-3M0 were not found. Conclusions: GC is characterized by equally elevated levels of VEGFA, regardless of the presence or absence of metastases. In the omentum and peritoneum with metastases, high VEGF levels can be considered as one of the primary factors for the formation of signaling pathways between metastatic tumor cells and local non-tumor cells in premetastatic niches. Levels of TGFβ1 in the omentum and peritoneum increase only in patients with metastases, and in GC tissue they are increased to a greater extent than in patients without metastases. Probably, in case of T3-4aN0-3M0, the factor produced by the primary tumor was insufficient for its paracrine induction in the metastatic niche, and scattered cells could not transit from “sleeping” to the active state.
Targeting of survivin to overcome cisplatin resistance in esophageal adenocarcinoma.
Authors: Douglas Rosalie V. , Stevenson Leanne , Santos Ralph , Cairns Lauren , McCabe Niamh H , Kennedy Richard D. , Blayney Jaine K. , Turkington Richard C. 
Published: May 2019

e15535 Background: The incidence of Esophageal Adenocarcinoma (EAC) has risen in the western world but response rates to chemotherapy are low and survival is poor. Increased molecular understanding is needed to develop novel treatments. Methods: Transcriptional profiling of 274 treatment naïve EAC biopsies was performed using the Almac Diagnostics Xcel array™. All patients received platinum-based neo-adjuvant chemotherapy prior to surgical resection at four United Kingdom centers between 2004-2012. Semi-supervised clustering was performed followed by functional enrichment using DAVID. Cluster membership was assessed for independence of prognostic factors using Cox proportional hazards. Candidate targets were identified by siRNA screening in OE33 cells. Treatment with the survivin inhibitor, YM155 in EAC cell lines was also assessed. Results: Semi-supervised hierarchical clustering identified two groups with significant differences in RFS [HR = 0.54 (0.29-0.99), p = 0.05] and OS [HR = 0.52 (0.28-0.96), p = 0.04]. There were significant associations between the clusters and both nodal and TNM downstaging but not with pathological response. The PI3K-AKT, p53, tight junction and HIF-1 signaling pathways were upregulated in the poor prognostic group. Eighty-four genes were selected and taken forward in a functional genomic siRNA screen. Twenty-seven genes showed a significant reduction in viability following siRNA-mediated knockdown and further verification resulted in twelve candidate genes. Finally, target knockdown in seven EAC cell lines resulted in four interrelated hits- BIRC5, JAK1, OSMR and SLC2A1. Knock down of BIRC5 (Survivin) induced apoptosis, as evidenced by PARP cleavage, in both the parental OE33 and cisplatin-resistant OE33CDDPR cell lines. YM155, a survivin inhibitor, is shown to induce apoptosis at nanomolar concentrations across a panel of parental and cisplatin-resistant EAC cell lines and further mechanistic work is ongoing. Conclusions: We have performed clustering of a large transcriptomic dataset and defined a poor prognostic group of EAC patients. We identified Survivin (BIRC5) as a mediator of cisplatin resistance in EAC and a potential novel drug target. Further pre-clinical and clinical work to assess the benefit of survivin inhibition in EAC is warranted.
Clinicopathological and prognostic significance of microsatellit instability (MSI) status and PDl-1 expression in Turkish patients with gastric cancer.
Authors: Yildiz Ibrahim , Bahsi Seyma , Erdamar Sibel , Goksel Suha , Demir Gokhan , Er Ozlem , Baca Bilgi , Karahasanoglu Tayfun , Hamzaoglu Ismail , Arican Ali , Ozer Leyla , Bozkurt Mustafa , Uras Cihan , Korkmaz Taner , Ince Umit 
Published: May 2019

e15538 Background: The aim of this study was to evaluate the prognostic role of microsatellite instability (MSI) status and PD-L1 expression in surgically resected gastric cancer and the relationship of these parameters with clinicopathological features. Methods: Eighty six gastric cancer patients which had curative surgical resection at Acibadem Atakent and Maslak Hospitals between 2010 and 2017 were analysed. Tumor samples were evaluated with MSI and PD-L1 antibodies by immunohistochemical (IHC) methods. PD-L1 IHC scoring was performed using the combined positive score (CPS). Survival analysis was accomplished using the Kaplan-Meier method. Cox proportional hazard regression model was used to identify independent risk factors that affect patients' overall survival. Results: The rate of PD-L1 expression in tumor cells was 34.9% (n = 30) and the frequency of PD-L1 expression in immune cells with CPS (≥1%) was 57% (n = 49). MSI-H was detected in 11.6%(n = 10), and more observed in PD-L1 positive cases (p = 0.021). MSI-H status was significantly correlated with older age, increased tumor size, presence of PD-L1 expression, and adenocarcinoma subtype. PD-L1 expression was associated with lymph node metastasis, adenocarcinoma subtype, microsatellite instability, presence of preoperative treatment and improved response to preoperative chemotherapy. In our study, the impact of MSI status on survival was not demonstrated, but PD-L1 expression positivity(≥1%) in both tumor cells (15.7 vs 53.4 months, p = 0.008)and in immune cells (20.4 vs NR; p = 0.027) was associated with short overall survival. PD -L1 expression in tumor cells was an independent prognostic factor for overall survival in multivariate analysis (HR: 2.28, p = 0.047). Conclusions: PD-L1 expression was related to a poor prognosis in patients with gastric cancer and can represent a rational approach for PD-1/PD-L pathway-targeted immunotherapy.
Neoadjuvant chemoradiotherapy combined with surgery in the treatment of potentially operable thoracic squamous cell carcinoma of the esophagus(ChiCTR-OIC-17011648): A phase II single center clinical study.
Authors: Liu Fang , Yan Maohui , Cai Boning , Qu Baolin , Yu Wei , Luo Yanrong , Wang Qianqian , Wang Yao , Liang Lanqing , Zeng Mingyue 
Published: May 2019

e15543 Background: To investigate the efficacy and safety of neoadjuvant radiotherapy and chemotherapy combined with surgery in the treatment of potentially operable thoracic esophageal squamous cell carcinoma. Methods: Nineteen patients with advanced thoracic esophageal squamous cell carcinoma hospitalized in our hospital from July 2016 to June 2018 were prospectively studied. All patients received neoadjuvant concurrent radiotherapy and chemotherapy: intensity modulated conformal radiotherapy (40 ∽ 44Gy/20 ∽22f, 2 Gy/f), chemotherapy (paclitaxel 150 ∽ 175 mg/m2 d1, 22+lobaplatin 25-30 mg/m2 d2, 23, 2 cycles). After radiotherapy and chemotherapy, the efficacy and safety of the operation were observed. Results: Two case (10.5%) was completely remitted after neoadjuvant radiotherapy and chemotherapy, 17 cases (89.5%) were partially remitted, and the objective effective rate was 100%. All patients underwent radical surgery successfully, the R0 resection rate was 100% and the pCR rate was 52.6%. The main adverse reactions of neoadjuvant radiotherapy and chemotherapy were granulocytopenia and grade III-IV granulocytopenia. The rate of survival was 16.7%, and anastomotic leakage occurred in 1 patients after operation. Conclusions: Neoadjuvant chemoradiotherapy for thoracic esophageal squamous cell carcinoma can effectively reduce the volume of the tumor, significantly reduce the pathological grade, improve the resection rate, and have less adverse reactions, which is worthy of clinical application. Clinical trial information: ChiCTR-OIC-17011648.
KRAS amplification and mutation as independent events in gastroesophageal adenocarcinomas (GEA).
Authors: Chao Joseph , Madison Russell , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj Mahamed , Schrock Alexa Betzig , Klempner Samuel Jacob 
Published: May 2019

e15565 Background: KRAS mutations are common oncogenic events across cancers, but effective RAS-directed therapies are lacking. However, recent studies support use of PD-1 blockade in most subsets of lung cancer with KRAS short variant mutations (KRASSV) (PMID: 28039262), and preclinical data supports combined MEK and SHP2 inhibition in KRAS amplified ( KRASa) GEA (PMID: 30093730). We sought to explore the landscape of KRAS altered GEA and compare genomic profiles of KRAS-altered and KRAS wild-type (WT) cases for biomarkers of response to targeted therapies and immune checkpoint inhibitors. Methods: 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based comprehensive genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Descriptive statistics were used to compare among subgroups. Results: KRASSV and KRASa were identified in 11% and 5.8% of gastric adenocarcinoma (GA), respectively, and in 7.2% and 17% of esophageal adenocarcinoma (EA), respectively. KRASa and KRASSV were nearly mutually exclusive, co-occurring in only 4.4% of KRAS altered cases. ERBB2 alterations were less common in KRASSV and KRASa GEA (both 9%) as compared with KRAS WT GEA (19%) (p = 1.9E-16). EGFRa was less common in KRASSV vs KRASa GEA (1.9% vs 9.3%, p = 2.6E-8), whereas PIK3CASV was more common in KRASSV vs KRASa (16% vs 5.0%, p = 1.5E-11). Median TMB for all groups was similar; however, KRASSV GEA had a higher mean TMB (9.7 mut/Mb) as compared to KRASa (5.1 mut/Mb, p = 5.0E-12) and KRAS WT cases (5.8 mut/Mb, p = 2.2E-07). KRAS codon 12/13 accounted for > 80% of predicted pathogenic mutations. MSI-high was also more prevalent in KRASSV (11.3%) vs KRASa (0.9%, p = 4.8E-15) and KRAS WT GEA (2.4%, p = 1.8E-25). MSI-high KRASSV GEA was associated with older patient age (median 72 years) and with high TMB (median 40.9 mut/mb). Conclusions: GA was enriched for KRAS mutation whereas EA was enriched for KRAS amplification. KRAS WT vs KRASSV vs KRASa each presented distinct genomic profiles. KRASa in the absence of KRAS mutation exists in 11% of GEA and warrants further exploration to inform combination treatment strategies.