bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multi-centre review of the efficacy of re-challenge with platinum doublet in patients with oesophagogastric cancer treated with first-line trastuzumab and chemotherapy.
Authors: Weaver Jamie , Ali Rufqah , Mckay Marie , Foy Victoria , Khan Adeel , Cunningham Aimee , McQueenie Esther , Owen-Holt Vikki , Williams Kate , Valpione Sara , Hubner Richard , Waddell Tom , Alchawaf Alia , Mansoor Wasat 
Published: January 2024

367 Background: HER2 amplification or overexpression is seen in 15-20% of metastatic oesophagogastric cancers. The ToGA trial showed an OS benefit for the use trastuzumab with platinum and fluoropyrimidine combination therapy (T-FP) in the first line setting. Second line trials of targeted agents have been disappointing with poor response rates and the current standard of care is paclitaxel and ramucirumab in combination. A recent phase 2 trial showed no OS benefit to continuing trastuzumab with second line chemotherapy but data regarding the efficacy of treatment beyond progression with re-introduction of first line chemotherapy (platinum and fluoropyrimidine) is limited and conflicting. Methods: We conducted a multi-centre retrospective review of patients treated with T-FP in the first-line setting between October 2014 and October 2022 at two large tertiary referral oncology centres in the United Kingdom. Baseline demographic factors and clinical data were collected and compared between responders and non-responders to re-challenge. PFS and OS were estimated using the Kaplan-Meier method. Results: Data was collected for 225 patients in total treated with first-line trastuzumab. We identified 20 patients who had received a re-challenge with FP-T. Best response to first-line treatment was partial response (PR) for 19/20 patients with 1/20 patients with stable disease (SD). There were no differences between baseline demographic factors or tumour pathological features between patients receiving a re-challenge and those treated with chemotherapy alone. The median platinum free interval was 17.8 months. For the re-challenge disease control rate was 75% with an overall response rate of 35% (7 PR, 0 CR). The median number of subsequent trastuzumab cycles was 7, with a median PFS of 6.1 months and median OS of 10 month. Multivariate Cox-regression analysis identified no factors predictive of response in the re-challenge setting. Conclusions: Re-challenge with trastuzumab plus FP chemotherapy is a possible option for patients with relapse. Larger studies will be required to identify predictive biomarkers to identify those patients most likely to benefit. The role of re-assessment of HER2 status at relapse in those receiving re-challenges requires prospective analysis.
The role of exosomal LINC00853 in gastric cancer progression.
Authors: Lee Sang Kil 
Published: January 2024

378 Background: Examination of various substances contained in exosomes (EXOs) as biomarkers is being actively conducted. Long non-coding RNAs (lncRNAs) are garnering interest in the diagnosis of gastric cancer. In this experiment, we attempted to obtain lncRNAs that drive the onset and recurrence of gastric cancer and elucidate the mechanism to observe their potential as exosomal biomarkers. Methods: LncRNA expression profiling was conducted using ArrayStar Human LncRNA array 2.0 for the patient’s tissues who underwent endoscopic resection that reflected early gastric cancer onset and recurrence. The proliferation, apoptosis, invasion, and migration of AGS and MKN74 cells were measured after treatment with pcDNA over expressing vector and two different siRNAs. To observe the interaction between lncRNA and MAP17, RNA immunoprecipitation (IP) and electrophoretic mobility shift assay were conducted. EXOs were extracted from patient samples and gastric cancer cell lines, which were then administered to gastric cancer cells. Results: Five target lncRNAs (LINC00853, LINC00634, LINC01535, GAPLINC, and AC017002.1) were selected by performing a lncRNA microarray analysis. The validation results showed that LINC00853 was upregulated in gastric cancer tissues compared to that in paired adjacent non-cancer tissues. LINC00853 induced proliferation and suppressed apoptotic signaling of AGS and MKN74 cells. LINC00853 promoted the invasion and migration of AGS and MKN74 cells. LINC00853 bound with its neighbor gene MAP-17 and activated it via the downstream PDZK1/AKT signaling pathway. LINC00853 and MAP-17 cooperatively acted as oncogenes in gastric cancer. EXOs derived from patients with gastric cancer and those from gastric cancer cell lines (AGS, MKN74) contained LINC00853. Knock-down of LINC00853 decreased LINC00853 expression in EXOs, which, in turn, reduced the oncogenicity of LINC00853 exosome in AGS cells. Cellular and exosomal LINC00853 exert an oncogenic effect via MAP-17-related cell signaling in gastric cancer. Conclusions: Exosomal LINC00853 can be a candidate biomarker of occurrence of recurrence of gastric cancer.
Microsatellite instability (MSI) in patients with gastric cancer (GC) and correlation with PD-L1 expression.
Authors: Sun Henian , Nered Sergey , Tryakin Alexey , Abgaryan Mikael , Artamonova Elena , Stroganova Anna , Stilidi Ivan 
Published: January 2024

389 Background: GC is a heterogeneous disease with a range of molecular subtypes. The TCGA (Cancer Genome Atlas) and ARCG (Asian Cancer Research Group) classified tumors with MSI status as a specific group. Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) are playing a progressively important role in tumor immunology and cancer treatment. The present study investigated the relationship between MSI and PD-L1 expression. Methods: We analyzed GC patients who received treatment from September 2019 to March 2023 at N.N. Blokhin National Medical Research Center of Oncology. All patients were analyzed for microsatellite instability using PCR. PD-L1 expression was assessed based on a combined positive score (CPS) using PD-L1 IHC (immunohistochemistry) 22C3 pharmDx. Results: We studied 453 localized GC and 273 metastatic GC. Of the 726 tumors, 60 (8.26%) had MSI-H tumors. The frequency of MSI-H in localized and metastatic GC is 51 (11.26%) out of 453 and 9 (3.30%) out of 273 (p<0.001). 106 patients were evaluated for expression PD-L1, 46 (43.40%) localized GC и 60 (56.60%) metastatic GC. PD-L1 is expressed in 45.28 % (48/106) of GC patients. PD-L1 CPS ≥ 1 was significantly associated with MSI-H status (P < 0.05). Details about the correlation between MSI and the expression PD-L1 can be found in the table. Conclusions: The prevalence of MSI-H in localized GC is significantly higher than metastatic GC (11.26% vs. 3.30%, p<0.001). A higher proportion showed PD-L1 expression (73.91%) in MSI-H than in MSS tumors, suggesting that MSI-H status is associated with PD-L1 (p< 0.05). These results provide a basis for identifying GC patients who may benefit from anti-PD-1/PD-L1 therapy. [Table: see text]
Oncogenic aberrations in primary gastric cancer tumors to predict metachronous peritoneal metastasis.
Authors: Zhao Joseph J , Huang Kiekyong , Chia Daryl K A , Law Jia Hao , Tan Angie Lay Keng , So Jimmy Bok Yan , Tan Patrick , Sundar Raghav 
Published: January 2024

392 Background: Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis. Yet, there are a paucity of data on underlying genomic alterations predictive of GCPM. Methods: Two-hundred and nine patients who underwent primary tumor (PT) surgical resection were included in the prospective cohort. Whole exome sequencing (WES) of these resected PT GC specimens (average coverage 129X for tumor samples, 70X coverage for matched normal/blood controls) were undertaken. Participants were followed-up longitudinally for peritoneal metastases. Results: Fifty-one (51/209, 24.4%) patients developed PM after a median follow-up duration of 87.0 months and had poorer survival outcomes compared to patients without metastasis (log-rank, p<0.001). Patients with bulkier and more advanced tumors were at increased hazard of PM (T-stage and N-stage stratified analysis, log-rank, p<0.0001). Consistent with known clinical outcomes, The Cancer Genome Atlas (TCGA) genomically stable (GS) subtype (log-rank, p=0.0059) and mesenchymal subtype GC were associated with a higher proclivity for peritoneal organotropism (log-rank, p=0.020). Among patients who developed PM, TP53 was the most commonly altered driver mutation (25/51, 49.0%), followed by ARID1A (9/51, 17.6%), CDH1 (8/51, 15.7%), PIK3CA (6/51, 11.8%). Comparing the PTs of patients with PM against those PTs without PM, ELF3, CDH1 and PIGR were significantly associated with PM (all adjusted p<0.05). Amongst TCGA GS tumors, ARID1A mutations (p=0.018) were significantly associated with PM compared to patients with GS tumors with no metastasis. CDH1 mutations were found to significantly co-occur with PIGR and RHOA mutations and was mutually exclusive to TP53. ARID1A mutations were also found to significantly co-occur with multiple other mutations such as PTEN, PIK3CA, ERBB2, and KRAS. Conclusions: CDH1, PIGR, ELF3 mutations in primary GC tumors were found to be significantly associated with metachronous PM.
Molecular profiling of hepatoid adenocarcinoma and adenocarcinoma with enteroblastic differentiation.
Authors: Matsumoto Yosuke , Hatakeyama Keiichi , Terashima Masanori , Soneda Wataru , Koseki Yusuke , Kenichiro Furukawa , Fujiya Keiichi , Tanizawa Yutaka , Tadakazu Shimoda , Sugino Takashi , Bando Etsuro 
Published: January 2024

394 Background: Hepatoid adenocarcinoma (HAD) and adenocarcinoma with enteroblastic differentiation (ACED) are rare types of gastric cancer that produce alpha-fetoprotein (AFP) and morphologically resemble liver or fetal gut cells. The molecular characteristics of these tumors are poorly understood. We aimed to investigate the molecular profile of HAD and ACED in the comparison with common type of gastric cancer. Methods: We analyzed tissue and blood samples from 496 patients who underwent gastrectomy for gastric cancer and participated in the Project HOPE (High-tech Omics-based Patient Evaluation) in our hospital, from 2014 to 2019. We excluded patients with other special types of gastric cancer, remnant gastric cancer and preoperative chemotherapy. We analyzed gene mutation, copy number, and gene expression between 10 HAD/ACED and 486 common types of gastric cancers. Results: The mutated genes with high frequency (> 20%) in HAD/ACED were TP53 (100%) CSMD3 (30%), LRP1B, FAT3, TG, APOB, CREBBP, PASK, DROSHA and STK40 (20%). The tumor mutation burden (TMB) of all the cases were less than 10. TMB of HAD/ACED was equivalent to that of common type of gastric cancer with microsatellite stable type. The copy number of 20q13.2 encoding SALL4 was significantly gained in HAD/ACED ( p = 0.03). Furthermore, 17 genes were highly expressed in these tumors, and many of these genes were associated with hepatocytes and fetal organs, including LIN28B, IGF2BP1, and HMGA2, which are related to TP53 mutation. Conclusions: Our molecular profiling revealed similarities between HAD/ACED and hepatocytes/fetal organs and high expression of LIN28B, IGF2BP1 and HMGA2, which are associated with TP53 inactivation. These results suggest that these genes may define morphological features of HAD/ACED.
Comprehensive genomic profiling of advanced anal adenocarcinoma.
Authors: Ogura Nozomu , Hirano Hidekazu , Shiraishi Kouya , Fujii Hiroyuki , Hirose Toshiharu , Shoji Hirokazu , Okita Natsuko Tsuda , Takashima Atsuo , Koyama Takafumi , Kato Ken 
Published: January 2024

4 Background: Anal adenocarcinoma (anal AD) is a rare and aggressive gastrointestinal malignancy. Because of its rarity, no standard therapy is established and treatment strategy for advanced rectal adenocarcinoma (rectal AD) is extrapolated. Little is known for genetic alterations (GAs) and their therapeutic implications in advanced anal AD. We aim to investigate to clarify genomic profiles of advanced anal AD in comparison of advanced rectal AD. Methods: We retrospectively extracted data on patients with advanced anal AD and advanced rectal AD who underwent comprehensive genomic profiling (CGP) tests and were registered for the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. CGP tests were performed by NCC Oncopanel or FoundationOne CDx. We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB). TMB-high was defined as ≥10 mutations/Mb. Actionable GAs were counted if they were classified as “pathogenic/oncogenic” or “likely pathogenic/likely oncogenic” variants. Druggable GAs are actionable GAs with approved drugs for anal AD or other types of cancer or clinical trials showing efficacy for either anal AD or different types of cancer. Results: From June 2019 to April 2023, 45 patients with anal AD and 1915 patients with rectal AD were enrolled into the C-CAT database. In the anal AD group, most common actionable GAs were TP53 (89%), KRAS (51%), ERBB3 (22%), MYC (20%), SMAD4 (20%), and ERBB2 (11%). Compared with the rectal AD group, the anal AD group had a significantly higher frequency of actionable GAs in ERBB3 (22% vs. 2%, p < 0.01), MYC (20% vs. 8%, p < 0.01), and BRCA2 (7% vs. 1%, p < 0.01), and a significantly lower frequency of actionable GAs in APC (7% vs. 85%, p < 0.01). The proportion of MSI-high and TMB-high in the anal AD group and the rectal AD group were 0% vs. 0.2% (p = 0.79), and 7% vs. 5% (p = 0.54). Common druggable GAs in anal ADs included KRAS G12D mutation (22%), ERBB2 amplification (7%), BRCA2 mutation (7%), BRAF V600E mutation (2%). Compared with the rectal AD group, the anal AD group had a significantly higher frequency of druggable GAs in BRCA2 mutation (7% vs. 1%, p < 0.01). Conclusions: The present study showed that anal AD had a different profile of GAs compared with advanced rectal AD. CGP tests are useful tool for identifying druggable GAs in advanced anal AD for expanding therapeutic opportunities.
Evaluation of a real-world clinico-genomics database of patients with upper gastrointestinal (GI) malignancies in Japan.
Authors: Peter Senaka A. , Rogers James R. , Liu Xinyue , Chen Cai 
Published: January 2024

400 Background: The genomic profile of gastrointestinal (GI) cancers provides essential information for precision medicine, however, there is limited availability of real-world data in Asian populations as they are not well-represented in most publicly accessible clinico-genomic databases. In this retrospective study, we evaluated the clinical and genomic characteristics of upper GI cancer patients in the database from an academia-industry collaborative nationwide cancer genome screening project in Japan. Methods: The Screening Projectfor Individualized Medicine in Japan (J-SCRUM) GI-SCREEN enrolled advanced GI cancer patients from 26 sites before planned or during systemic therapy from 2015 to 2019. Archived formalin-fixed paraffin-embedded tumor tissue was analyzed by next-generation sequencing (NGS) using Oncomine Cancer Research Panel and Oncomine Comprehensive Assay. Patients with gastric (GC), esophageal (EC) and pancreatic (PC) cancers were identified in the database. The frequency of key actionable genomic alterations in each cancer cohort was explored and compared to similar upper GI cohorts in The Cancer Genome Atlas (TCGA), a publicly available genomics database initiated in 2005 and concluded sample collection in 2013 with most samples from White cancer patients. Results: A total of 872 GC (mean age at registration [SD]: 64y [12]; percent males: 65%), 265 EC (64y [9]; 78%) and 495 PC (64y [10]; 60%) patients were identified. The majority (>70%) of samples were obtained from primary sites. Adenocarcinoma was the most common histological type for GC (85%) ad PC (76%), while squamous cell (76%) was the most common among EC patients. In the GC cohort, the prevalence of key actionable genomic alterations in J-SCRUM GI-SCREEN vs TCGA (N = 380) was, TP53 mutation (49% vs 49%), ERBB2 amplification (14% vs 13%), PIK3CA mutation (11% vs 14%), MYC amplification (9% vs 12%) and MET amplification (2% vs 3%). In the EC cohort, the prevalence in J-SCRUM vs TCGA (N = 182) was TP53 mutation (77% vs 87%), NFE2L2 mutation (21% vs 10%), PIK3CA mutation (9% vs 9%) and CDKN2A mutation (8% vs 8%). In the PC cohort, the prevalence in J-SCRUM vs TCGA (N = 150) was KRAS hotspot mutation (90% vs 93%), KRAS G12D (43% vs 41%), KRAS G12V (32% vs27%), TP53 mutation (58% vs 64%), BRCA1/2 deleterious mutation (5% vs 5%), ATM deleterious mutation (6% vs 5%) and MYC amplification (5% vs 5%). Conclusions: As part of a nationwide cancer genome screening project, J-SCRUM GI SCREEN database provides comprehensive genomic information for Asian population (Japan). The prevalence of key actionable gene alterations in each tumor type was highly comparable between J-SCRUM GI-SCREEN and TCGA data.
Real world prevalence of biomarkers for treatment of advanced gastric cancer or gastroesophageal junction cancer in a cohort of Colombian patients.
Authors: Ballen Diego Felipe , Ojeda Kelman , Gualdron Ana , Tellez Nicolas , Molina Pimienta Luisana 
Published: January 2024

402 Background: Gastric cancer (GC) is the leading cause of cancer-related deaths in Colombia, GLOBOCAN estimated 6.451 deaths in 2022. Development of immune checkpoint inhibitors and HER2 target therapy with chemotherapy had improved overall survival in advanced setting, but we do not have data about the prevalence of biomarkers used for selection of these patients in Colombia or Latin-America. Our aim is to describe the prevalence of biomarkers used currently for selection of treatment in a real-world multicenter cohort of advanced gastric and gastroesophageal junction (GEJ) cancer. Methods: We did a retrospective observational multicenter study of patients with advanced GC/GEJ cancer treated at three reference cancer centers in Bogota, Colombia between January 1, 2023 and July 31, 2023. We reviewed medical history and pathology reports looking for the prevalence of biomarkers used for selection of first line systemic therapy. Ventana 4B5 for HER2 IHQ evaluation and Dako 22C3 for PDL1 expression by CPS were used. MMR proteins were evaluated by IHQ nuclear expression. Results: 101 patients with advanced GC/GEJ were included. The median age was 61 years (range 18-83), 53,5% of patients were men, 92.1% were gastric cancer and 87,1% were de novo stage IV. Signet ring cells were found in 40%, peritoneal carcinomatosis was documented in 59% and 75,2% were distal tumors (no cardias or GEJ involvement). PDL1 positivity, defined as CPS ≥1 was found in 30.6%, using CPS ≥ 5 cutoff just 22.7% of them were positive. HER2 positivity and MMR deficiency were found in the same proportion of patients 5%. Among young patients (< 50 years) 80% had diffuse histology, 30% were CPS ≥5. HER2 status and PDL1 testing was unknown in 21% and 29% respectively. Conclusions: Among these real-world patients, both HER2 and PDL1 positivity was lower than reported in other regions. Higher incidence of distal tumors, signet ring cells and diffuse histology could explain this difference. Correlation of PDL1 positivity between 22C3 and 28.8 was unknown in our population. Our study remarks the high medical need for investigation of biomarkers and developing of prospective studies for correlation and other targets like Claudins and FGFR2b.[Table: see text]
Association of methylation silencing of ULK2 via epithelial-mesenchymal transition and differentiated gastric cancers.
Authors: Motoo Iori , Nanjo Sohachi , Ando Takayuki , Yasuda Ichiro 
Published: January 2024

404 Background: Diffuse-type gastric cancers (DGC) typically have a poor prognosis related to their invasion and metastasis, in which the epithelial–mesenchymal transition (EMT) is the initiation step. ULK2 plays a role in the autophagy initiation, which might provide a survival advantage in cancer cells. Although knock-down of ULK2 reportedly induces autophagy and EMT in a lung cancer cell line, the mechanism of EMT via the downregulation of ULK2, as well as its clinical significance, remains yet unclear. The present study, therefore, aims at clarifying this mechanism and its clinical significance in gastric cancers. Methods: We examined ULK2 mRNA expression in gastric cancer tissues and normal gastric tissues of healthy people. The effects of knock-downed ULK2 were examined in two gastric cancer cells, which were investigated in terms of their gene expression changes by the mRNA microarray. Furthermore, to investigate the carcinogenic process from normal gastric epithelial cells, we used RGE cells, which were conditionally immortalized normal gastric epithelial cells developed from a transgenic rat. Results: ULK2 mRNA expression of gastric cancer tissues was significantly lower than H. pylori-negative normal tissues. ULK2 was strongly expressed in normal tissues and intestinal-type gastric cancers (IGC) but was scarcely expressed in DGC by immunohistochemical staining. Furthermore, we found that the ULK2 methylation level of gastric cancer tissues was higher than H. pylori-negative normal tissues and IGC. Then, we validated whether knock-down of ULK2 could induce autophagy, cell migration, and EMT in NUGC3 and MKN45 cells. Using mRNA microarray analysis, we confirmed that knock-down of ULK2 changed expressions of oncogenic genes associated with cell migration and EMT. Autophagy inhibitor suppressed cell migration and EMT induced by knock-down of ULK2 in NUGC3 and MKN45. Additionally, we found that knock-down of Ulk2 induced apoptosis in normal gastric epithelial cells. Conclusions: Methylation silencing of ULK2 in gastric cancer cells could induce cell migration and EMT by means of autophagy induction, causing transformation to poorly differentiated cancers.
Impact of DNA mismatch repair status on prognosis of patients with locally advanced gastric cancer in a Mexican population.
Authors: Diaz Romero Maria del Consuelo , Miyagui-Adame Sayako Mariana , Calderillo Ruiz German , Ruiz-Garcia Erika , Herrera Marytere , Leon-Takahashi Alberto , Lino-Silva Leonardo , Espinoza Ruelas Luis Adrián , García Elizabeth , Zilli Hernandez Stefan 
Published: January 2024

408 Background: Gastric cancer (GC) is among the five most frequent and mortal cancers in the world. In Mexico, GC is the second cause of death from cancer in men between 30 and 59 years old. The role of deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) in locally advanced gastric cancer (LAGC) is still controversial. We aimed to evaluate the overall survival (OS) of patients with LAGC, according to MMR status and treatment. Methods: Retrospective study included patients from the National Cancer Institute of México, with locally advanced gastric adenocarcinoma diagnosis between 2008 and 2017. The Kaplan Meier, Log Rank, and Cox Regression methods were used to analyze the relation between MMR status and overall survival in LAGC. MMR status was assessed using immunohistochemistry. Results: A total of 103 patients with LACG were enrolled for analysis. The prevalence of dMMR in GC was 13.59% (n=14). The median OS was 101.9 months in the dMMR group vs. 86.2 months in the proficient MMR (pMMR) group (HR 0.54, 95% CI 0.19 - 1.52, p=0.23), with a 3-year OS of 71.4% vs 65.1% respectively. Survival was also analyzed according to MMR status and choosing treatment. OS was 106.8 months in the dMMR surgery alone group, 78.4 months in the dMMR group treated with both surgery and chemotherapy, 33.1 months for pMMR group with surgery alone, and 89.2 months in the pMMR group treated with surgery plus chemotherapy (p=0.014). Conclusions: In this analysis, OS tended to improve in dMMR group. pMMR surgery alone patients had a superior OS than other groups, while adding chemotherapy to surgery treatment seems to have a role only in pMMR patients. [Table: see text]