bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating endogenous peptides analysis and protease mapping for identification of potential serum biomarkers in gastric adenocarcinoma.
Authors: Forones Nora Manoukian , Oliveira Talita Mendes de , Lacerda Jose Thales , Dias Meiriellen , Mendes Maria Anita , Juliano Maria Aparecida 
Published: May 2019

e15564 Background: Gastric cancer (GC) is the third cause of cancer death in the world. In Brazil 21.000 new cases had been diagnosed in 2018 and the mortality rate is associated with late diagnosis that contributed to poor prognosis. The objective was to study endogenous peptides in serum of patients with GC. Methods: Fifteen serum samples of patients with diagnosis of gastric adenocarcinoma (TNM stage I-IV) and 15 controls were included. Endogenous peptides were extracted and pooled of random mode in 5 biological replicates (n = 3 samples) for each group. The mixture peptides was submitted to nLC-MS/MS analysis and peptide sequences identified were used to protease mapping. Results: A total of 191 peptides (≥ 7 amino acids) were identified corresponding to 36 proteins involved mainly on metabolic and immune system processes, signal transduction, platelet and neutrophils degranulation. Peptidome-based protease mapping identified 59 proteases (29 serine-, 19 metallo-, 8 cisteine- and 3 aspartic-), in which Prothrombin, Plasminogen, MMP14, MMP7 and MMP3 proteases yielded most of peptides. Twenty sequences derived from Fibrinogen A, Fibrinogen B, Complement C3 (C3f), Apolipoprotein A-I (N-terminal), Prothrombin (C-terminal of Activation peptide fragment 2; N-terminal of Thrombin light chain) and Coagulation factor XIII A (N-terminal) were significantly different (p ≤ 0.5). Between these peptides, 14 were up regulated and six downregulated in GC patients. The phosphopeptide 20ADSpGEGDFLAEGGGVR35 (Fibrinopeptide A) was significantly increased (p< 0.03) in GC serum samples, while the non-phosphorylated Fibrinopeptide A was decreased (p<0.04), suggesting a higher phosphorylation rate in this protein in GC patients. Further, the peptide 31QGVNDNEEGFFSAR44 (Fibrinopeptide B) was downregulated (p<0.04) in GC serum samples; in counterpart, the Fibrinopeptide B derived peptides NDNEEGFF (p<0.0007) and QGVNDNEEGFFS (p<0.0013) was up regulated, suggesting a higher proteolysis in GC serum samples. Conclusions: The investigation of protease/substrate activity relationship may be described such as a novel panorama for discovery of serum biomarkers.
Is there a correlation between clinic-pathological features, MSI, PD-L1 and survival outcomes in resected gastric cancer? Looking for optimal biomarkers.
Authors: Ratti Margherita , Valeri Nicola , Hahne Jens Claus , Lampis Andrea , Ghidini Michele , Tomasello Gianluca , Fassan Matteo , Donida Bianca Maria , Senti Chiara , Passalacqua Rodolfo 
Published: May 2019

e15566 Background: Identification of prognostic biomarkers for gastric cancer (GC) patient selection is compelling to improve survival outcomes. Microsatellite instability (MSI) is related with a positive prognostic effect in GC, whereas perioperative chemotherapy resulted detrimental in this subgroup. In metastatic GC, immunotherapy with anti-PD1/PD-L1 drugs has shown promising results. Nevertheless, in early stages, data on the relation between MSI, clinic-pathological features, PD-L1 expression and overall survival (OS) remains sparse, especially in Western population. In our study, the prognostic role of MSI, clinic-pathological features and PD-L1 expression in a cohort of Italian GC patients was examined. Methods: CP data of 148 consecutive stage I-III GC pts resected in Cremona Institute between 2010 and 2014 (mostly chemo and/or radio-naive) were collected. MSI analysis was performed on tissue samples for all cases by polymerase chain reaction. PDL-1 expression, evaluated by immunohistochemistry, was assessed in MSI group. Differences between subgroups were evaluated with Chi-square test; Kaplan-Meier method and Long Rank test were used to calculate OS. Results: Female sex (p=0.012), earlier TNM stages (p=0.011) and limited nodal involvement (p=0.29) significantly correlated with MSI status. MSI is significantly associated with better prognosis, exhibiting an advantage of 28.6 months in OS compared with microsatellite stable subgroup (p<0.001). Most MSI patients expressed PD-L1. MSI patients without PD-L1 expression showed higher percentage of clinical features correlated with better prognosis compared with PD-L1 expressing MSI patients and MSS subgroup. Conclusions: MSI is an independent prognostic biomarker in GC and identifies a subset of patients with better OS and specific clinic-pathological features, including high percentage of PD-L1 expression. MSI could represent a promising biomarker to select patients for chemotherapy versus immunotherapy in non-metastatic disease.
Identification of clinically actionable mutations and immunotherapy biomarkers in Chinese esophageal squamous cell carcinoma patients.
Authors: Wang Minghui , Zhang Junkai , Gu Weiquan , Li Yun , Song RongFeng , Wang Wenjing , Cui Qiang , Zhang Shuirong , Chen Xiaoqian , Shi Weiwei 
Published: May 2019

e15576 Background: Esophageal squamous cell carcinoma (ESCC), the major esophageal cancer histological type in East Asia, has limited therapeutic options and is associated with poor prognosis. Here, we identified clinically actionable genomic alteration (GA) for potential targeted and immunotherapy in Chinese ESCC patients by next generation sequencing (NGS). Methods: Clinical data were collected from 150 ESCC patients from March 2011 to December 2018, with a median follow-up of 34 months. NGS-panel sequencing of 466 cancer genes was performed on FFPE tumor and matched blood sample. Tumor mutational burden (TMB) was assessed in all patients by standard NGS algorithms. PD-L1 expression was evaluated in 61 samples by IHC (28-8 Ab). Results: Overall, 75.5% of ESCC patients harbored at least one clinically actionable GAs with the most frequent being CCND1 (40%), CDKN2A (40%), CDKN2B (24%), PIK3CA (14%) and FGFR1 (8%). Most clinically actionable GAs occurred in genes involved with cell cycle (61%) and with PI3K pathway (23%). Clinically actionable GAs also distributed in BRCA2 (5%), ATM (3%), MET amp (3%), KIT (3%), EGFR mut (2%), PDGFRA (2%) and ERBB2 amp (1%). The lowest 25% (TMB-L), median and highest 25% TMB (TMB-H) value was 4.6, 6.9 and 9.2 muts/Mb, respectively. Compared with younger patients, patients ≥50 years had higher TMB ( p= 0.047). Compared with TMB-L ESCCs, frequencies of NOTCH2 (15.9% vs 0%, p= 0.015), PIK3CA (22.7% vs 2.8%, p= 0.019) and KMT2D (25.0% vs 5.6%, p= 0.031) were significantly higher in TMB-H. Notably, amplification in 11q13 region, MDM2/ MDM4 and EGFR, which potentially relates to immunotherapy hyperprogression, accounted for 48% of TMB-H. Eleven patients (18%) showed PD-L1≥1%, in which 7 pts were also TMB-H. Conclusions: In Chinese ESCCs, clinically actionable GAs were detected in most patients, which highlights the promise of molecularly directed therapies. Patients with PD-L1 positive/TMB-H/both, who could potentially benefit from immunotherapy, accounted for 41%. Older age, NOTCH2, PIK3CA and KMT2D mutations correlated with TMB-H.
The regulation effect of EGFR signaling pathway on PD-L1 expression on esophageal squamous cell carcinoma cell lines.
Authors: Wang Ran Lin , Li Tao , Huang Jianming , Lv Jiahua 
Published: May 2019

e15577 Background: To explore the effect of radiation combined with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKI) on the expression of PD-L1 in ESCC cell lines, and to provide theoretical support for radiotherapy combined with EGFR-TKI for esophageal cancer. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) method was used to assess EGFR and PD-L1 mRNA expression on ESCC cell lines when different doses of X-ray irradiation were conducted on ESCC cell lines TE-1 and ECA-109 combining with EGFR-TKI or not. Results: In ESCC cell lines TE-1 and ECA-109, the expression of EGFR and PD-L1 mRNA was increased significantly by the activation of EGFR signaling pathway and decreased after the use of gefitinib (P > 0.01). Both EGFR (P < 0.01) and PD-L1(P < 0.01) mRNA expression of ESCC cell lines TE-1 and ECA-109 were increased by radiotherapy alone. EGFR-TKI could block the increase of both EGFR mRNA (P < 0.01) and PD-L1 mRNA (P < 0.01) which was induced by radiation. Conclusions: EGFR signaling pathway is involved in the regulation of PD-L1 expression in ESCC cell lines. Radiation could up-regulate the expression of EGFR and PD-L1 mRNA in ESCC cells which could be blocked by the use of EGFR-TKI.
Surveillance and outcomes after curative resection for gastroesophageal adenocarcinoma (GEAC).
Authors: Jiang Di Maria , Suzuki Chihiro , Espin-Garcia Osvaldo , Lim Charles Henry , Ma Lucy Xiaolu , Sun Peiran , Sim Hao-Wen , Natori Akina , Chan Bryan Anthony , Yokom Daniel , Moignard Stephanie , Chen Eric Xueyu , Liu Geoffrey , Swallow Carol Jane , Darling Gail Elizabeth , Wong Rebecca , Jang Raymond Woo-Jun , Elimova Elena 
Published: May 2019

e15579 Background: Although commonly performed, evidence supporting routine surveillance testing (SvT) in patients (pts) with resected GEAC is lacking. We evaluated patterns of relapse, frequency of salvage therapy and outcomes among pts with resected GEAC who underwent surveillance. Methods: Between 2011 and 2016, 210 consecutive pts with GEAC followed at Princess Margaret Cancer Center after resection were reviewed. SvT was any investigation performed in the absence of pt-reported symptoms, abnormal physical exam findings, or bloodwork. Relapse patterns were classified as locoregional (LRR; surgical anastomosis/gastroesophageal lumen/regional nodes) or distant (DR; beyond locoregional). Time-to-relapse (TTR) and overall survival (OS) were calculated from initial diagnosis, post recurrence survival (PRS) from initial relapse. Results: Median age was 64.1 years. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%), surgery plus perioperative chemotherapy (26%) or surgery plus chemoradiation (45%). SvT included imaging (71%), endoscopy (19%), tumor markers (6%), and clinical visits alone (9%). After median follow-up of 38.3 months (mo) (range 5.6-122.3), 3- and 5-year OS rates were 68% (95% confidence interval (CI) 62-75%) and 56% (95% CI 49-64%) respectively. Among 97 relapses (46%), 51 were detected by SvT, 45 by symptoms. Relapse patterns included LRR alone (4%), DR alone (86%) and both (10%). The majority of relapses (93%) occurred within 3 years. Pts with SvT-detected relapse had similar median TTR (16.2 vs 13.3 mo, p = 0.40) but longer PRS (16.5 vs 4.6 mo, p < 0.001) and OS (36.2 vs 23.7 mo, p = 0.004) than pts with symptomatic relapse. Salvage therapy in 4 pts (2%) resulted in post recurrence disease-free survival ≥2 years. Duration of palliative chemotherapy was similar between 28 pts with SvT-detected relapse and 18 pts with symptomatic relapses (3.9 vs 3.3 mo, p = 0.64). Conclusions: Following curative resection, 96% of relapses were distant. Routine SvT rarely enabled successful salvage therapy and did not extend duration of palliative chemotherapy. Longer OS in SvT-detected relapses was not due to earlier disease detection. These findings do not support routine SvT in pts with resected GEAC.
Genome-wide copy number alteration (CNA) of circulating cell-free DNA (cfDNA) as a prognostic biomarker in esophageal squamous cell carcinoma (ESCC).
Authors: Im Hyeon-Su , Bang Yeonghak , Jeong Hyehyun , Kang Jihoon , Cho Eunhae , Jang Ja-Hyun , Lee Junnam , Park Sook Ryun 
Published: May 2019

e15582 Background: Although neoadjuvant chemoradiation (nCRT) plus surgery or definitive CRT (dCRT) are the standard treatment for locally advanced ESCC, there are no reliable clinical tools for predicting prognosis or monitoring treatment response for CRT in ESCC. We aimed to identify a biomarker for predicting outcomes using cfDNA in ESCC patients (pts) receiving CRT. Methods: This prospective biomarker study analyzed pretreatment plasma cfDNA from pts with nCRT plus surgery (n = 23) and pts with dCRT for locally advanced ESCC (n = 17) at Asan Medical Center in South Korea from Jul. 2017 to Jun. 2018. Low depth whole-genome sequencing of cfDNA was used to identify CNA and I-score was developed to express genomic instability. I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The pathologic complete response (pCR) was achieved in 7 pts (30.4%) in the nCRT group, and the clinical complete response (cCR) was achieved in 3 pts (17.6%) and clinical partial response (cPR) in 8 pts (47.1%) in the dCRT. The baseline cfDNA concentrations were no significant association with the clinical T stage (cT 1-2 vs. cT 3-4; 0.27 vs. 0.28 ng/μL; p = 0.752), pathologic response (pCR vs. non-pCR; 0.26 vs. 0.30 ng/μL; p = 0.270), ypT stage (ypT 0-2 vs. ypT 3-4; 0.28 vs. 0.36 ng/μL; p = 0.161) and ypTNM stage (ypTNM 1 vs. ypTNM 2-4; 0.26 vs. 0.36 ng/μL; p = 0.065). When analyzing cfDNA concentration before and after CRT, cfDNA concentration was significantly increased after CRT (0.31 vs. 0.55 ng/μL; p = 0.007). The baseline I-score was not associated with baseline clinical stage, but was significantly associated with ypT stage (ypT 1-2 vs. 3-4; 30.4 vs 839.1; p = 0.009), time to progression (median TTP; 11.8 mo in the I-score-low group vs. 6.1 mo in the I-score-high group; p = 0.036), and overall survival (median OS; not reached vs. 10.4 mo; p = 0.046) in the nCRT group. In the dCRT group, I-score was significantly associated with higher disease progression rate (33.3 vs. 58.8%; p = 0.024) with tendency of distant metastasis (33.5 vs. 57.1%; p = 0.490), and short response duration (median, 5.7 mo in the I-score-high group vs not reached in the I-score-low group). Conclusions: The cfDNA concentration is not a good biomarker for prognostication and monitoring the course of treatment in ESCC pts treated with CRT. But the I-score, an indicator of genomic instability in ctDNA, was a significant predictor of poor prognosis.
Genomic analysis of hepatocellular carcinoma (HCC) with active hepatitis B virus (HBV) replication.
Authors: Lim Huat Chye , Gordan John Dozier 
Published: May 2019

e15593 Background: HBV replication contributes to HCC initiation and is associated with worse patient outcomes. Prior tumor genomic studies of HBV-positive and -negative (HBV+/-) HCC have used detection of HBV surface antigen (HBsAg) in serum to annotate HBV status. However, a substantial proportion of HBsAg+ patients lack HBV replication in tumor, suggesting a potentially distinct patient subset. In this study, we determined HBV status by measuring tumor HBV RNA, a proxy for active replication. We then investigated HBV RNA+/- association with somatic mutations, gene sets, homologous recombination deficiency (HRD) and tumor mutation burden (TMB). Methods: RNA-Seq data for 371 HCC tumors were obtained from TCGA. Tumors were classified as HBV RNA+ if they harbored more than 1 HBV RNA read per million human reads, as measured using GATK PathSeq software. Associations between HBV RNA status and somatic mutations, gene sets, HRD and TMB were investigated. HRD score was calculated as the sum of 3 independent HRD measures (large scale state transitions, loss of heterozygosity and telomeric allelic imbalance). Results: HBV RNA+ status was associated with a higher rate of nonsynonymous somatic mutations in multiple genes, including the tumor suppressors TP53, CDKN2A, CHD5 and TET1, as well as AXIN2 and the proto-oncogene BCL11A ( p < 0.05 for all), while HBV RNA- status was associated with a higher rate of nonsynonymous mutations in the chromatin modifier BAP1 ( p = 0.03). In gene set enrichment analysis of normalized RNA-Seq expression data, HBV RNA+ status was associated with increased transcription of DNA repair genes, as well as genes upregulated by mTORC1 and MYC (FDR < 0.03 for all). HBV RNA status was also associated with HRD score (22.19 for HBV RNA+ vs. 15.97 for HBV RNA-, p = 1e-6), but not with TMB. A substantial subset of HBV RNA+ patients (33/100) were not annotated as HBV+ in the TCGA clinical database. Conclusions: HBV status based on tumor HBV RNA detection identifies a genetically distinct subset within all HBV-infected HCC patients that is associated with nonsynonymous somatic mutations in several genes and differential transcription of gene sets, some of which have not been previously reported, as well as with HRD score. These findings suggest potential for differential responsiveness to targeted therapies.
The impact of geography and center volume on access to care and outcomes in advanced hepatocellular carcinoma (HCC): A retrospective population based study.
Authors: Yu Irene S. , Liu Shiru Lucy , Zaborska Valeriya O. , Raycraft Tyler , Lim Howard John , Gill Sharlene , Davies Janine Marie 
Published: May 2019

e15597 Background: Treatment of advanced HCC is complex and involves specialized multidisciplinary care. We aimed to characterize the impact of geography and center volume on access to care and outcomes in HCC patients (pts). Methods: HCC pts who received sorafenib in British Columbia from 2008 to 2016 were included. Pts were stratified by rural vs urban status (distance from cancer center), and high volume (HVC) vs lower volume (LVC) centers. Chi-square tests and Kaplan Meier were used to test for differences between groups. Results: Of 288 pts identified, median was age 62 (IQR 56-72), 81% male, 40% Asian, 82% ECOG 0/1 and 90% Child Pugh A. Hepatitis C (32%), hepatitis B (31%) and alcohol (25%) related liver disease were most common. Most pts resided within 100 km (85%) and 173 (60%) were treated at HVC. Ethnicity, liver disease etiology, ECOG and M1 disease varied by stratification (Table). Rural pts were more likely to see an internist (30% vs 16%, p=0.04); access to other subspecialists was similar (all p>0.05). HVC pts were more likely to see a hepatologist (83% vs 19%), hepatobiliary surgeon (57% vs 42%), and/or interventional radiologist (32% vs 13%) compared to LVC pts (all p<0.01). Number of specialists seen correlated with survival (36.4 vs 20.3 vs 12.6 mo for ≥ 3 vs 2 vs 1 specialist(s), p<0.01). Median OS from time of diagnosis was higher for HVC pts (24.7 vs 13.2 mo, p<0.01), but similar when stratified by distance (p=0.44) and from sorafenib initiation (p=0.66). Conclusions: HCC patients treated at a HVC are more likely to see specialized clinicians and have improved survival outcomes. Further research is needed to understand social and clinical factors that influence these findings. [Table: see text]
ET140202 t-cells: A novel therapy targeting AFP/MHC complex, that is both safe and effective in treating metastatic hepatocellular carcinoma.
Authors: Liu Chang , Liu Hong , Wang Yun , Zhang Xiaogang , Fan Fengling , Wang Ruitao , Qu Kai , Nejadnik Bijan , Shi Bingyin , Liu Cheng 
Published: May 2019

e15614 Background: CAR-T cells has emerged as novel cancer treatment, particularly for hematologic malignancies. However, treatment of solid tumors using redirected T-cells remains challenging. We developed a novel T-cell platform ET140202 targeting AFP/MHC complex enhanced by GPC3-guided co-stimulation. Herein we report a case study of ET140202 for a male subject with 3 liver HCC lesions, multiple lung metastases and with no response to sorafenib and regorafenib. Methods: The schedule and dose of ET140202 T cell infusion was summarized in Fig 1a. The subject received 16 i.v. infusions of ET140202 T cells at doses ranging from 0.42-6 ×106 cells/kg, totaling 2.461×109 cells. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 3, 5, 9 and 12. Results: T-cell expansion was observed shortly after each infusion. No treatment-related Grade 3 or higher AEs observed. Grade 1 or 2 events that were possibly attributable to therapy included dry mouth, dry skin peeling from hand and foot, and voice hoarseness and oral mucosal ulceration. All events resolved in 3-5 days with symptomatic treatment. At Day 40, the subject developed Grade 2 mucositis, which improved in 5 days following vitamin C treatment and oral hygiene care. The subject did not experience any signs of CRS or neurotoxicity. Cytokines including IL-2, IL-6, GM-CSF, INFg and TNFa were below detection at most time points post-infusion. All 3 liver lesions regressed at month 5 and the regression persisted to the last follow-up timepoint at month 12. All 4 lung nodules appeared to slightly increase in size at month 1, which may be attributed to pseudo-progression and substantially decreased at month 5. The decrease of the lung lesions also persisted to month 12. AFP levels were increased above the baseline shortly after T-cell infusion, possibly due to the lysis of tumor and gradually decreased to the normal level of 10 ng/mL on Day 135 and persisted to the last follow-up on day 365. Conclusions: ET140202 T cells has the potential to be used safely and effectively in AFP+/HLA-A2+ HCC to induce regression of primary and metastatic lesions.
An exploratory analysis based on tumor location of REACHIN, a randomized double-blinded placebo-controlled phase II trial of regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (nonresectable) and metastatic biliary tract tumors.
Authors: Demols Anne , Borbath Ivan , Van Den Eynde Marc , Houbiers Ghislain , Peeters Marc , Maréchal Raphaël , Delaunoit Thierry , Goeminne Jean Charles. , Laurent Stéphanie , Holbrechts Stephane , Paesmans Marianne , Van Laethem Jean-Luc 
Published: May 2019

e15622 Background: The REACHIN trial met its primary endpoint of improving PFS for patients with biliary tract cancer (BTC) treated with regorafenib (R) as compared to placebo (P): Median (m) PFS for R was 3.0 months (mo) (95% CI: 2.3-4.9) and 1.5 mo (95% CI : 1.2-2.0) for P with an HR= 0.49 (95% CI: 0.29-0.81), p=0.005 (Demols A et al, ASCO-GI 2019, Abstr 345). We exploratory analyzed the benefit of R according to tumor location: intra-hepatic (ICC), extra-hepatic (ECC), gallbladder (GB) or peri-hilar (PH). Methods: Tumor locations were recorded at randomization of patients in REACHIN (NCT02162914), a multicenter double-blinded P-controlled randomized phase II study to evaluate the safety and efficacy of R in patients with locally advanced (non resectable) and metastatic histologically proven BTC, progressing after gemcitabine-platinum. We analyzed mPFS according to tumor location and their respective 95% CI. Results: 66 patients were randomized and the mPFS data are summarized in the table. Conclusions: Most of the patients had ICC location (64%). The mPFS in the P arm is similar according to the tumor location. Despite its exploratory value and the small number of patients per tumor location, R seems superior to P in ICC, GB and PH. Data in ECC are not conclusive. Additional biomarkers (FGFR, NGS analysis) are ongoing and will be presented at the meeting. Clinical trial information: NCT02162914. [Table: see text]