bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of enhanced epithelial-mesenchymal transition signature with tumor microenvironment, angiogenesis, and survival in gastric cancer.
Authors: Oshi Masanori , Yan Li , Kunisaki Chikara , Endo Itaru , Takabe Kazuaki 
Published: June 2023

e16002 Background: Among the hallmarks of cancer, epithelial-mesenchymal transition (EMT) that epithelial cancer cells gain the characteristics of mesenchymal cells, is one of the key mechanisms of cancer cell metastasis. On the other hand, the clinical relevance of EMT that occurs in gastric cancer patients has not been clearly shown. Methods: To measure the level of EMT in gastric cancer, gene set variation analysis was used to score total of 807 gastric cancer patient samples from two independent large cohorts; TCGA and GSE84437. Results: EMT high gastric cancer was significantly associated with worse overall survival (hazard ratio (HR)=1.74, p=0.011 in the TCGA, and HR=2.01, p<0.001 in the GSE84437), and the association was stronger with EMT signature score compared to expressions of each EMT-related genes, CDH1, CDH2, VIM, or FN1. EMT signature levels were not significantly different among gastric cancer, hepatocellular carcinoma, colorectal cancer, breast cancer, and pancreatic ductal adenocarcinoma, and high level of EMT signature was associated with survival only in gastric cancer. Among the histological types, mucinous and diffuse type had high EMT level compared to tubular, papillary, or signet gastric cancer ( p<0.001). EMT signature level was significantly correlated with tumor depth and AJCC stage (all p<0.001), but not consistently with lymphatic metastasis. Interestingly, the EMT score was independent factor for patient survival including clinicopathological features, not only for overall survival but also disease-specific survival in the TCGA cohort (multivariate; p=0.006 and 0.032, respectively). EMT high gastric cancer was associated with low fraction of Th1 cells and high fraction of dendritic cells and M1 macrophages (all p<0.001 in both cohort), but not with interferon-gamma immune response. EMT high gastric cancer tended to be inversely correlated with cell proliferation-related gene sets, and significantly associated with high infiltration fraction of stromal cells, including fibroblasts, adipocytes (all p<0.001). On the other hand, they significantly enriched multiple pro-cancerous gene sets, such as TGF-β signaling, hypoxia, and angiogenesis, consistent with infiltration of angiogenesis-related stromal cells such as microvascular and lymphatic endothelial cells, and pericytes (all p<0.001). These results were shown consistently in two large cohort; TCGA and GSE84437. Conclusions: EMT signature in a bulk tumor was associated with cancer aggravating pathways such as TGF-β signaling, hypoxia, and angiogenesis, as well as with worse survival in gastric cancer patients.
Liquid biopsy effectiveness of esophageal cancer-related genes and their correlation in clinical research.
Authors: Jiang Bo , Lin Yangui , Hui Hongliang , Li Huaming , Zhou Yujun , Chen Yaru , Zhang Weishuang , Cheng Shaochen , Zhang Yiqian 
Published: June 2023

e16004 Background: Esophageal cancer ranks as the sixth most common cause of cancer-related deaths worldwide. The occurrence and development of esophageal cancer is a complex process that involves multiple genetic variants, including changes in gene function, which could be a crucial factor in its development. Hence, studying the molecular genetic changes specific to esophageal cancer is essential for understanding its mechanism and guiding clinical treatment. In this study, we analyzed and documented genetic variations and clinical information of 82 esophageal cancer patients to provide new insights into the correlation between genes and clinical symptoms. Methods: The tissue and blood-based DNA samples from 82 patients were analyzed using 680-gene targeted capture sequencing for CNV, fusion, SNV, indel, MSI, and TMB. Coverage of tissue with 2200X, cfDNA 20000X, and control gDNA 10000X. Additionally, the level of PD-L1 expression was assessed in the tissue samples. TMB was classified as TMB-H ( > 10 mutations/megabase) and TMB-L ( < 10). MSI-H was determined with instability ≥20% of 117 sites for detection, while < 20% was determined as MSS. Results: The analysis revealed 786 SNV/indel mutations in 82 patients, of which 346 (44.02%) mutations were detected in both tissue and plasma, 296 (37.66%) only found in tissue, and 144 (18.32%) only found in plasma. 378 mutations were detected in CNV, with 181 mutations (47.88%) in tissue and blood, 186 mutations only found in tissue (49.21%), and 11 mutations only in plasma (2.91%). The high-frequency mutation genes identified in this study were TP53, CCND1, FGF19, FGF3/4, NOTCH1, and PIK3CA, which are also listed as high frequency mutated genes in the IntoGen database (7 cohorts, 945 samples). However, the genes CCND1, FGF19, FGF3/4, and PIK3CA in the CNV results were not in the IntoGen high frequency mutated gene list. The results of tTMB vs bTMB were consistent in 80 out of 82 patients (97.56%). Among the 82 samples, 79 had low expression of PD-L1, while 3 had high PD-L1 expression and TMB-L, MSS. Conclusions: Fibroblast growth factor (FGF) signaling system may plays an important role in tumorigenesis and progression. Increase in the expression of FGFs and fibroblast growth factor receptor genes, might lead to genetic alterations in their protein structures and activation of the FGFs-FGFR signaling pathway, which may contribute to the onset of esophageal cancer. In conclusion, the results of our study suggest that the detection of tissue mutations in the blood of esophageal cancer patients is challenging and cannot be reliably determined by a single blood sample. The incidence of PD-L1 expression was low in all esophageal cancer tissues. Further investigation into the correlation between CCND1, FGF19, FGF3/4, and PIK3CA genes and esophageal cancer is warranted.
Effect of system analysis of reactive oxygen species on prognosis and treatment decisions for patients with esophageal squamous carcinoma.
Authors: Lu Qiang , Yang Qi , Zhao Jinbo , Li Guizhen , Zhang Jipeng , Jia Chenghui , Ji Gang , Wan Yi , Chen Yan 
Published: June 2023

e16005 Background: The prevalence of esophageal cancer has recently grown, particularly esophageal squamous cell carcinoma (ESCC). Combining conventional treatment with targeted therapy and immunotherapy has shown unexpectedly positive results in improving the prognosis of patients with ESCC. More study is needed to determine the prognosis for patients with ESCC and establish the appropriate course of treatment. ROS controls different aspects of cell death from signaling to death, and ROS also regulates the tumor environment, affecting various stromal cells that provide metabolic support, blood supply, and immune response to tumors. Although reactive oxygen species (ROS) play an important role in tumorigenesis, it is difficult to reliably predict the effects of ROS-modulating therapies. Methods: This study aimed to establish a ROS-related score (ROSS) model to individually predict the overall survival and therapeutic effects for ESCC patients. Clinical data were derived from the TCGA-ESCA cohort through "UCSC", as well as the whole genome data. The driver ROS genes were identified based on univariate Cox regression. Following that, ROSS was created via a systematic machine-learning pipeline. The association of ROS with immune infiltration and biological function was subsequently assessed by systematic bioinformatics analysis. Finally, we evaluated the predictive efficacy of ROSS for immunotherapy sensitivity using predictive algorithms and real-world immunotherapy cohorts. Results: Patients with significant ROSS had fewer favorable outcomes, according to the data. The proliferation of ESCA cells treated with core ROS gene knocked down was also detected by CCK8. Both univariate and multivariate Cox regression indicated ROSS to be an independent prognostic factor for ESCC patients; however, subgroup analysis eliminated this finding. The functional assay revealed that immune response and cytotoxicity pathways are associated with ROSS, as the subgroup with low ROSS has an active immune microenvironment. Furthermore, patients with low ROSS responded better to chemotherapy, targeted therapy, and immunotherapy. Conclusions: In this study, we systematically analyzed the ROS-related genes in ESCC and developed a ROSS model to assess prognosis and provide guidelines for treatment decisions. This discovery gave rise to a fresh concept for novel therapeutic procedures for the clinical treatment of ESCC.
Identification of novel actionable SNVs via targeted comprehensive genome profiling in patients with gallbladder and cholangiocarcinoma cancer.
Authors: Raut Nirmal Vivek , Bhonde Mandar , Bose Chirantan , Chopra Rakesh , Kad Trupti , Prajapati Sangeeta , Hariramani Kanchan , Mobeen Fauzul , Basavalingegowda Madhura , Haldar Sumit , Mehra Vatsal , Kumaran Manoj Kumar , Jadhav Vikas Balasaheb Leelavati , Joshi Sujit Krishnarao , Shah Mithun , Shah Pankaj Manubhai , Vasudevan Aravindan , Khandare Jayant , Shafi Gowhar 
Published: June 2023

e16006 Background: Liquid biopsy approach has paved the way for selecting targeted therapies. When the tissue is absent, the advent of comprehensive Next Generation Sequencing (NGS) using CcfDNA has further allowed significant advances in precision oncology by pinpointing rare, novel, and actionable alterations in oncogenes, tumor suppressor genes, and cellular signaling pathways. Methods: Retrospective NGS-based genome profiling was performed on ccfDNA (circulating cell-free DNA) samples from 11 patients using OncoIndx proprietary gene panel that targets exonic regions of 600 cancer-related genes. Illumina-compatible libraries were prepared by the target hybridization method and sequenced on Nextseq 2000 platform in a pair-end fashion. Variant calling was performed using an in-house developed bioinformatics pipeline. The 11 cases comprised 5 gallbladder and 6 cholangiocarcinoma patients. Results: We uncovered several novel mutations such as MTORK1452N, ERBB2H878Y, JAK1A634T, SMAD3R287W, IDH1R132C, PRKNK161N and FGFR2Y105C. Although ERBB2H878Y and IDH1R132C are known in cholangiocarcinoma, this is the first report of gallbladder cancer. In addition to SMAD3 and PARKIN, alterations were also observed in tumor suppressor proteins APC, BARD1, BRCA1/2, and GATA2. High genomic instability as demonstrated by HRD and LOH correlated with FGFR2, PRKN, and IDH1 mutations. FAT domain mutations in mTOR such as MTORK1452N are known to be responsive to rapamycin. Similarly, ERBB2H878Y is known to respond to rapamycin as well as a TKI. The FGFR2Y105C activating mutation has previously been reported in one case of atypical Crouzon Syndrome but has never been reported in cancer. This could have potential implications for the use of FGFR2 targeting agents in cholangiocarcinoma. IDH1R132C mutation is known in ~11% of cholangiocarcinoma patients, however, this alteration has not been reported in gallbladder cancer. This observation has therapeutic implications for the use of IDH1 inhibitors in gallbladder cancer based on its promising data in cholangiocarcinoma. Conclusions: We report, for the first-time novel and actionable SNVs in key oncogenes and tumor suppressors related to critical signaling pathways in a population of gallbladder and cholangiocarcinoma patients. The data strongly underscores the importance of comprehensive NGS-based in-depth assessment in gaining clinically viable therapeutic insights for patients.
Expression profiles of MUC5AC glycoforms in neoplastic and non-neoplastic pancreatic tissue.
Authors: Manne Ashish , Cheng Xiang , Tsung Allan , Esnakula Ashwini K 
Published: June 2023

e16008 Background: MUC5AC, secretory mucin, exists in two major glycoforms, heavily-glycosylated mature (MM) and less-glycosylated immature (IM) isoforms. Prior IM-based tissue expression studies could not establish the clinical significance of MUC5AC in pancreatic ductal adenocarcinoma (PDA). Despite having strong pre-clinical evidence of MM’s role in local invasion, metastasis, and drug (gemcitabine) resistance, its impact on PDA outcomes is unclear. In this study, for the first time, we examined the differential expression of MM and IM by immunohistochemistry in primary PDA (pPDA), metastatic PDA (mPDA), normal pancreatic tissue adjacent to tumor (NAJ), neuroendocrine tumors (NET), Pancreatitis (P), normal pancreas (N) using tissue microarrays (TMA). Methods: Commercially available TMA (PA2081c, tissuearray.com, Derwood, MD) constructed from 96 patients, including 38 pPDA (14-stage 1, 22-Stage 2, and 2-stage 3), 5 mPDA, 24 NAJ, 11 NET, 8 P and 10 N was used in this study. Two separate 1 mm cores represented each case. Immunohistochemistry for MUC5AC was performed using CHL2 clone (ab77576, abcam, Boston, MA) for the IM isoform and 45M1 clone (ab369, abcam, Boston, MA) for the MM isoform. The immunostains were optimized as per the manufacturer's recommendations using appropriate controls. The sections are evaluated for the intensity of expression (0-3) and the percentage of reactive cells, and an H-score is derived from the product of these measurements. Cases are categorized as having negative/weak (score <10) or positive (score >10) expression. For every positive case, the pattern of expression in terms of Apical (Ap), cytoplasmic (Cy), and extracellular (EC) expression was recorded. Results: MUC5AC (MM and IM) is not expressed in N, NAJ, and P. MM expression is only noted in 44% of PDAs (19/43; 18 pPDA and 1 omental mPDA lesion). Three different expression patterns were noted, including Ap (63%), Cy (84%), and EC (47%). IM expression was detected in 60% of PDAs (26/43, 25 pPDA and omental mPDA lesion) and 18% NET (2/11). IM expression was noted in cases with EC MM expression (9/43, 21%), suggesting that IM was further glycosylated to MM and expressed extracellularly in some patients. MM and MM were co-expressed in 40% of PDA (17/43). Liver and abdomen metastatic lesions in the TMA did not express IM or MM. Pertinent clinical information was not available to study the impact of MM’s expression on PDA outcomes. Conclusions: Our study shows that MUC5AC is primarily expressed in PDAs and can be a useful biomarker. Larger studies are ongoing to correlate tissue expression patterns in PDAs for evidence of any association with early recurrence or treatment failure. Preliminary data suggests that only MM isoform is expressed extracellularly and could be detected in patient serum and serve as a potential non-invasive biomarker for treatment selection (for gemcitabine resistance) and monitor the response in certain cases.
Influence of high COL19A1 expression on the effectiveness of neoadjuvant immunotherapy plus chemotherapy and long-term survival in patients with esophageal squamous cell carcinoma.
Authors: Liu Jianhua , Zhang Jia-Tao , Zhu Changbin , Li Weiwei , Li Qian , Huang Zhan , Qiao Guibin , Wu Yi-Long 
Published: June 2023

e16013 Background: Neoadjuvant immunotherapy plus chemotherapy may enhance the resectability rate in locally advanced Esophageal Squamous Cell Carcinoma (ESCC). Nevertheless, due to the complex nature of the tumor immune microenvironment, an unmet need remains for biomarkers to identify NPC patients used to identify patients who benefit most from this neoadjuvant treatment strategy. Methods: Two independent cohorts of ESCC patients were enrolled in the study., including retrospective cohort (N=66) and prospective cohort (N=37). A total of 103 NPC FFPE samples were subjected to RNA sequencing. Single sample GSEA (ssGSEA) were performed to explore the Tumor microenvironment (TME). Differential genes associated with survival were analyzed using logistic regression and Kaplan-Meier methods. To reveal the expression of biomarker and TME, immunohistochemistry and multiplex immunofluorescence were used. Results: We demonstrated that COL19A1 high expression facilitates anti-PD-1 therapy [ COL19A1 high, OR (95% CI): 0.31 (0.1−0.97), p = 0.044]. COL19A1high patients could benefit more from neoadjuvant immunotherapy (p < 0.01), high mortality (63.3%, p < 0.01), and have a trend towards a better RFS (p = 0.13) and OS (p = 0.056). Further analyses confirmed increased B cells infiltration and COL19A1 high expression could be seen in the immune-activated subgroup, which resulted in favorable survival and response to neoadjuvant immunotherapy plus chemotherapy. Conclusions: This study revealed an ESCC subpopulation presenting high COL19A1 expression, which responded well to neoadjuvant immunotherapy plus chemotherapy and was associated with good prognosis. It provided a convincing basis for designing biomarker-guided individual treatment.
Genomic alterations of cerebrospinal fluid cell-free DNA in leptomeningeal metastases of gastric cancer.
Authors: Chen Xin , Bai Kaixuan , Zhang Yu , Xu Yang , Huo Yinghao , Wang Sha , Zou Yueli , Qi Xuejiao , Guo Rongyun , Ou Qiuxiang , Zhu Minyi , Liu Dengxiang , Yin Shaohua , Chen Shubo , Bu Hui 
Published: June 2023

e16022 Background: Leptomeningeal metastases (LM) were rare in gastric cancer (GC), and GC patients with LM (GCLM) generally suffer from poor prognosis. Nevertheless, the clinical utility of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) was under-investigated in GCLM. Methods: We retrospectively studied 15 GCLM patients, and all patients had paired primary tumor tissue samples and post-LM CSF samples while 5 patients also had post-LM plasma samples. All samples were analyzed using next-generation sequencing (NGS), and the molecular and clinical features were correlated with clinical outcomes. Results: CSF had higher mutation allele frequency ( P=0.015), more somatic mutations ( P=0.032), and more copy-number variations ( P<0.001) than tumor or plasma samples. Multiple genetic alterations and aberrant signal pathways were enriched in post-LM CSF, including CCNE1 amplification and cell cycle-related genes, and CCNE1 amplification was significantly associated with patients’ overall survival ( P=0.0062). More potential LM progression-related markers were detected in CSF samples than in tumor samples, including PREX2 mutation ( P=0.014), IGF1R mutation ( P=0.034), AR mutation ( P=0.038), SMARCB1 deletion ( P<0.001), SMAD4 deletion ( P=0.0034), and TGF-beta pathway aberration ( P=0.0038). Additionally, improvement in intracranial pressure ( P<0.001), improvement in CSF cytology ( P=0.0038), and relatively low levels of CSF ctDNA ( P=0.0098) were significantly associated with better PFS. Lastly, we reported a GCLM case whose CSF ctDNA dynamic changes were well correlated with his clinical assessment. Conclusions: CSF ctDNA could more sensitively detect molecular markers and metastasis-related mechanisms than tumor tissues in GCLM patients, and our study sheds light on utilizing CSF ctDNA in prognostic estimation and clinical assessment in GCLM.
Phase 2 study of bavituximab (bavi), a first-in-class antibody targeting phosphatidylserine (PS), plus pembrolizumab (P) in advanced gastric or gastroesophageal junction (GEJ) cancer.
Authors: Lee Jeeyun , Shergill Ardaman , Park Haeseong , Lee Keun-Wook , Arkenau Hendrik-Tobias , Kang Yoon-Koo , Olowokure Olugbenga Olanrele , Kim Jong Gwang , Oh Sung Yong , Oh Do-Youn , Costin Dan , Pippas Andrew William , Chen Jen-Shi , Chaney Marya F. , Koustenis Andrew , Youssoufian Hagop , Makris Lukas , Culm Kerry , Mockbee Colleen M. , Chau Ian 
Published: June 2023

e16023 Background: Bavi, a monoclonal antibody designed to inhibit the immunosuppressive effects of PS through interaction with TIM/TAM receptor family members in the tumor microenvironment (TME), was evaluated in combination with P in patients with advanced gastric and GEJ cancer. Methods: ONCG100 was a phase 2, multicenter, open-label, two-cohort global study designed to assess the safety, tolerability, and antitumor activity of bavi (3 mg/kg, QW) plus P (200 mg, Q3W) in advanced gastric or GEJ cancer patients who progressed on ≥1 prior standard therapy (NCT04099641). Patients were checkpoint inhibitor (CPI) naive (Grp 1) or CPI relapsed (Grp 2); known MSI-H patients were excluded. RNA expression was analyzed in pre-treatment tumor tissue using the Xerna TME Panel, an RNA-based diagnostic, to prospectively test hypothesis that tumors with high immune or immune-suppressed TME subtypes (B+) are more likely to respond to bavi plus P than high angiogenic/immune-desert TME subtypes (B-). Results: A total of 80 patients enrolled (Grp 1 n=61, Grp 2 = 19). The most frequently reported Grade ≥ 3 treatment emergent adverse events (occurring in ≥10% of patients overall) were anaemia and gastric cancer progression (n= 10/AE). Key efficacy parameters for Grp 1 patients (2L 57.4%) are summarized in Table 1. In Grp 2, the ORR was 5.3% (95% CI: 0.1, 26.0), whereby 0 patients achieved a complete response and only 1 (5.3%) patient achieved a partial response as the best overall response (BOR). In the remaining patients, BOR was stable disease in 9 (47.4%) patients, progressive disease in 8 (42.1%) patients, and not evaluable in 1 (5.3%) patient. Conclusions: The combination of Bavi and P was well tolerated; observed AEs were consistent with known profiles for each agent. Higher ORRs were observed in CPI-naïve patients with B+ status and baseline NLR<4, and of note, in patients with PD-L1 CPS <1. Future studies may be planned to confirm the activity of Bavi in combination with P with patient selection based on a particular genetic signature. Clinical trial information: NCT04099641 . [Table: see text]