bluuebunny/crossref_metadata_2025_split huggingface dataset:
The efficacy and safety of neoadjuvant sintilimab combined with chemotherapy in elderly patients with locally advanced esophageal squamous cell carcinoma.
Authors: Lv Huilai , Huang Chao , Li Jiachen , Zhang Fan , Gai Chunyue , Liu Zhao , Xu Shi , Wang Mingbo , Li Zhenhua , Tian Ziqiang 
Published: January 2023

378 Background: Neoadjuvant PD-1 inhibitor combined with chemotherapy has been reported to improve the pathologic response of locally advanced esophageal squamous cell carcinoma (ESCC). However, systematic report of efficacy and safety data in elderly Chinese patients is lacking. This study we report the efficacy and safety outcomes of neoadjuvant sintilimab combined with chemotherapy in elderly patients with locally advanced ESCC. Methods: Elderly patients (70 years or older) with locally advanced ESCC received neoadjuvant sintilimab combined with albumin-bound paclitaxel and nedaplatin in our institution between July 2019 and September 2022 were reviewed. Efficacy including pathologic response, short-term survival outcomes, and safety profile retrospectively were evaluated. Results: Thirty-one eligible patients were included in the analysis, with median age 72 years (range 70-78 years), male 18 (58.1%), Upper/middle/lower tumors 2(6.5%)/15(48.4%) /14(45.2%), ECOG PS 0/1-2 15 (48.4%)/16 (51.6%), clinical stage II/III 14 (45.2%)/17 (54.8%). The median number of neoadjuvant cycles was 3 (range 2-4). All 31 patients achieved R0 resection. Postoperative pathology showed pCR rate was 45.2% (95CI 27.3%-64.0%), MPR rate was 58.1% (95CI 39.1%-75.5%), tumor down-staging rate was 90.3% (95CI 74.2%-98.0%). With a median follow-up of 15.9 months (range 3.0-32.3), 1 (4.2%) patient had disease recurrence and died. The median DFS and median OS had not been reached yet, 2-year DFS rate was 95.0% (95%CI 85.9%-100.0%). Grade 3-4 Surgical complications occurred in 1 (4.2%) patient, with a grade 3 pulmonary infection. The median operation time was 332 min (range, 142–470 min), and the median intraoperative blood loss was 150 ml (range, 80–300 ml). The median hospital stay was 12.5 days (range 7-22). There was no perioperative death. Grade 3-4 TRAEs were Neutropenia (9.7%), leukopenia (9.7%), abnormal liver function (6.5%), anemia (6.5%), sensory neuropathy (3.2%), pneumonia (3.2%). Conclusions: Our results preliminarily confirms that Chinese elderly patients with locally advanced ESCC can benefit from neoadjuvant sintilimab combined with chemotherapy, similarly with this combination treatment in all age patients.
The usefulness of indocyanine green (ICG)–guided lymphadenectomy in robotic gastrectomy for advanced gastric cancer: A single-center retrospective study.
Authors: Jeon Chul Hyo , Seo Ho Seok 
Published: January 2023

390 Background: In performing radical gastrectomy for advanced gastric cancer, the method to evaluate the achievement of lymphadenectomy is under debate. According to the current guideline, obtaining at least 16 lymph nodes is recommended, but in previous studies on advanced gastric cancer, some suggested mid-20 or 30 as a cut-off. This study aimed to find significant factors affecting successful lymphadenectomy for gastric cancer by applying a more stringent condition than the current guideline. Methods: A total of 1 948 patients who underwent laparoscopic and robotic gastrectomy for gastric cancer between January 2016 and February 2022 at Seoul St. Mary’s Hospital were recruited in this study. After exclusion, 393 patients with a pathologically advanced stage were included in the analysis, and their clinicopathological data, including the information about the indocyanine green (ICG)-guided lymphadenectomy, were retrospectively reviewed. Results: Among 393 patients, there were 288 patients in the conventional laparoscopy group (G1), 61 patients in the ICG-guided laparoscopy group (G2), and 44 patients in the ICG-guided robotic surgery group (G3). Patients in the G3 group had a significantly higher proportion of younger patients and a lower proportion with comorbidity. There was a similar trend in stage II and III ratio between the groups and the number of examined lymph nodes (ELNs) did not show a significant difference between groups (45.2±20.3 vs. 51.6±24.5 vs. 50.8±19.6, P=0.058). The ratio of 30 or fewer ELNs was the lowest in G3 (24% vs. 19.7% vs. 9.1%, P=0.050). The rate of exceeding 30 ELNs was increased in the case of higher node stage and more advanced cancer. In the multivariable analysis, the ICG-guided robotic surgery group was confirmed to be a significant factor for more than 30 ELNs (OR=3.151, 1.074~9.245, P=0.037). Conclusions: ICG-guided robotic gastrectomy could be useful in obtaining >30 ELNs compared to conventional laparoscopic gastrectomy in selected cases.
Phase 1 trial of the anti-LAG3 antibody favezelimab plus pembrolizumab in advanced gastric cancer.
Authors: Rha Sun Young , Miller Wilson H. , de Miguel María José , Im Seock-Ah , Lugowska Iwona , Wermke Martin , Kotani Daisuke , Bauer Todd Michael , Takashima Atsuo , Palcza John , Chaney Marya F. , Dobrenkov Konstantin , Garralda Elena 
Published: January 2023

394 Background: In the dose-confirmation phase of this multicohort trial (NCT02720068), the anti-LAG-3 antibody favezelimab had a manageable safety profile and promising antitumor activity in patients (pts) with advanced solid tumors, confirming preliminary RP2D. Here we present results on the safety of favezelimab (fave) plus pembrolizumab (pembro) in all treated pts and efficacy in pts with advanced gastric cancer. Methods: In this phase 1b trial eligible pts aged ≥ 18 years were enrolled into 7 cohorts across 3 tumor types: Cohorts A (3L+ CRC), B (1L/2L CRC), C (PD-1 naïve HNSCC), D (PD-1 refractory HNSCC), E (PD-1 naïve gastric cancer), F (all solid tumors), and G (PD-1 naïve 3L CRC). Pts with gastric cancer in cohort E received either 200 mg fave + 200 mg pembro, or 700 mg fave + 200 mg pembro Q3W up to 35 cycles. Treatment continued until progression, unacceptable toxicity, or pt withdrawal. Primary endpoint was safety and tolerability of fave + pembro. Secondary endpoint was ORR per RECIST 1.1 by investigator assessment. Exploratory endpoints were PFS per RECIST 1.1, and OS. Data cutoff date was March 21, 2022. Results: At data cutoff, 397 pts were enrolled: 38 to fave, 368 to fave + pembro including 9 who crossed over from fave alone. Of these, 80 pts had gastric cancer; 50 (62.5%) of which had ≥2 lines of treatment, and 48 (60.0%) had PD-L1 CPS≥ 1. Among 368 pts treated with fave + pembro, treatment-related adverse events (TRAEs) occurred in 232 (63.0%) with fave + pembro. Grade ≥3 TRAEs occurred in 66 (17.9%) pts with fave + pembro. There were no grade 5 TRAEs. Immune-mediated adverse events (AEs) occurred in 121 (32.9%) pts with fave + pembro. Grade ≥3 immune-mediated AEs occurred in 27 (7.3%) pts with fave + pembro. No grade 5 immune-mediated AEs occurred. In pts with gastric cancer, the overall ORR was 11.3% (95% CI, 5.3-20.3 [3.8% CR; 7.5% PR]) with fave + pembro. In 2 arms, higher dose of fave (700mg) showed increased ORR and 12 months PFS rate. The table summarizes antitumor activity in the gastric cancer cohort. Conclusions: Favezelimab alone or in combination with pembrolizumab had an acceptable safety profile. The combination therapy showed antitumor activity in line with other checkpoint inhibitors in advanced gastric cancer though higher antitumor activity was seen in PDL1 CPS≥ 1 tumors, particularly at higher dose. Clinical trial information: NCT02720068 . [Table: see text]
Identification of HER2+ malignant cells in gastric tumors from single-cell RNAseq data.
Authors: Zhang Zhiming , Yang Xiufeng 
Published: January 2023

417 Background: Gastric cancer is the 4th leading cause of cancer death worldwide with high incidence in East Asia. Despite recent developments in treatment options, gastric cancer survival rate remains low, partially attribute to tumor heterogeneity. Here we performed a comprehensive single cell analysis of malignant cells from gastric tumor samples. In addition to characterizing heterogenous transcriptional patterns, we developed a framework to identify HER2+ malignant cells, which may complement standard diagnostics for treatment decisions. Methods: Published and in-house generated 10x Genomics single cell RNAseq data in tumor and normal samples from gastric cancer patients were aggregated, including 64 tumor samples and 27 pre-cancerous samples and 12 adjacent normal samples. The R package Seurat (version 4.0) was applied for data QC and downstream analysis. High quality cells were clustered using highly variable genes and cell types were annotated by curated marker genes. To identify malignant epithelial cells, a gastric cancer signature was derived using matched tumor and normal samples from TCGA gastric cancer patients. Gastric tumor samples were also leveraged to develop a HER2 signature and TCGA breast tumor samples were used to validate the signature. HER2+ malignant cells were identified by re-clustering malignant epithelial cells using the HER2 signature. Results: 345,361 high-quality single cells were profiled, representing major cell types within tumor microenvironment. Among 59,861 epithelial cells, 22,770 malignant cells were identified with high expression of a gastric cancer signature. Copy number alterations (aneuploid) were highly enriched in inferred malignant cells compared with non-malignant cells (48.6% vs 1.4%, p<2.2×10-16, Fisher’s exact test). Further clustering analysis identified 10 subclusters with divergent expression of cancer oncogenic pathways, highlighting the vast heterogeneity of tumor origin. A Her2 amplification signature was derived using TCGA gastric cancer cohort (AUC=0.99) and validated in breast cancer cohort (AUC=0.93). Applying this signature to malignant cells, HER2+ cells were identified in a majority of tumors, with various proportions. In an independent data set, the percentage of HER2+ malignant cells is highly concordant with clinical HER2+ status, indicating the potential use of single cell data to supplement HER2+ clinical testing for treatment selection. Conclusions: This meta-analysis of single cell RNAseq data provides a comprehensive snapshot of tumor heterogeneity in gastric cancers, with aberrance in multiple oncogenic pathways observed in patients. The HER2+ cell classifier developed here holds the potential to complement standard clinical testing and enable personalized medicine, warranting further validation.
Inhibition of gastric cancer by a new controlled releasing compound of TLR-7/8 agonist via immune activation in a gastric cancer xenograft mice model.
Authors: Kim Hyun Myong , Jeong Kyoungyun , Yoo Jaeun , Yoo Yie-Ri , Shin Ji-Yeon , Lim Leena , Jeong Juhee , Yoon Changhwan , Ryeom Sandra , Yoon Sam S. , Park Do Joong , Lee Hyuk-Joon , Yang Han-Kwang , Oh Do-Youn , Jung Keehoon , Lim Yong Taik , Kong Seong-Ho 
Published: January 2023

420 Background: TLR-7/8 agonist has been suggested to be an effective immunotherapeutic agent, possible systemic side effect has forbid its clinical usage. A new controlled-releasing compound of TLR-7/8 agonist was developed to overcome the limitations, and this study aimed to evaluate efficacy and safety of this new compound in xenograft mouse model using cell-lines derived from triple conditional (Tcon) mouse which develop gastric cancer spontaneously. Methods: A cell line was established by tumor tissue in Tcon mouse which was developed by activation of Kras and suppression of E-cadherin and P53. Tcon cell line was evaluated its growth rate, sensitivity to anticancer agents and in vivo tumorigenicity. Tcon cell line was subcutaneously injected to the flank of the syngeneic mice, and 5-FU and/or TLR-7/8 agonist were administered into 4 groups of mice (control group, 5-FU alone, TLR-7/8 agonist alone, and combination of 5-FU and TLR-7/8). 5-FU was administered i.p(intra-peritoneal) in once a week and TLR-7/8 agonist was injected i.t(intra-tumoral) 3 times a week. Tumor size and mouse weight were measured for drug efficacy and safety. Immune profile of the tumor was analyzed by fluorescence-activated cell sorting. Results: Tcon cell-line show a rapid growth with 24 hours of doubling time, and good in vivo tumorigenicity in syngeneic mice. Cell-line showed moderate sensitivity to 5-FU and paclitaxel but resistance to oxaliplatin. Tumors in 5-FU alone group showed slight decrease in size compared with that in control group, However, TLR-7/8 agonist alone and combination significantly inhibited tumor growth. Weight loss or any significant side effect was not observed in any group. In immune profiling, TLR-7/8 mono or combination group showed increased levels of infiltrating CD4, CD8 T cells, and recruited NK cell as well as significantly increase M1/M2 ratio of macrophages compared to 5-FU alone or control group. Conclusions: A new controlled releasing system of TLR-7/8 agonist with or without 5-FU showed a excellent tumor inhibition efficacy with low toxicity in gastric cancer xenograft model. The effect seemed to be through multiple immune activations including cell-mediated immune response, M1 macrophage polarization as well as innate NK cells.
A novel immune monitoring platform for patients with gastrointestinal cancer.
Authors: Zhu Mojun , Ma Wen Wee , Yoon Harry H. , Hubbard Joleen M. , McWilliams Robert R. , Dong Haidong 
Published: January 2023

424 Background: Understanding the impact of anticancer therapies on immune system is critical to successful design and incorporation of immunotherapies. We developed a novel immune monitoring platform that measures the relative amount of circulating effector T cells and antitumor cytotoxicity of circulating immune cells. We previously showed that this assay can differentiate patients’ clinical response to anti-PD-1 therapy. Here, we applied this assay to patients with gastric or gastroesophageal junction adenocarcinoma (GGEA) who received chemoradiation or chemotherapy-based therapies. Methods: Patients underwent peripheral blood collection at baseline and during follow-up. Levels of circulating effector T cells (CX3CR1+NKG7+/CD3+CD8+) were quantified by flow cytometry using peripheral blood mononuclear cells (PBMCs). Antitumor cytotoxicity of circulating immune cells was evaluated by co-culturing CD3/CD28 activated PBMCs with calcein-AM labeled GGEA tumor cells (FLO-1). Antitumor cytotoxicity of individual patients’ PBMCs was calculated based on the amount of calcein released by dead tumor cells. Results: In a pilot study of 8 patients with mismatch repair-proficient (pMMR) GGEA, the changes in the frequency of effector T cells appeared to be associated with radiographic response to treatment based on RECIST (3 partial response [PR], 3 stable disease [SD], and 2 progressive disease [PD]). The median interval between sequential blood collections was 64 days and an increase in effector T cells was observed in patients with PD. Antitumor cytotoxicity was evaluated in 4 patients who did not receive targeted therapies or immune checkpoint inhibitors. Two of these patients (a, b) had blood collected at the time of diagnosis (treatment naïve) and after neoadjuvant therapy. One developed pulmonary metastases after chemoradiation while the other had significant tumor shrinkage after chemotherapy. The decrease in antitumor cytotoxicity of PBMCs was less in the patient with PD (-19.4%) than the one with PR (-48.5%). Two patients (c, d) had blood collected twice while receiving the same chemotherapy for metastatic disease (not treatment naïve). The decrease in antitumor cytotoxicity of PBMCs was less in the patient with SD (-0.3%) than the one with PR (-14.5%). Conclusions: We demonstrated the feasibility of using PBMCs to monitor immune response to anticancer therapies. Our data raise the possibility that the amount of circulating effector T cells and antitumor cytotoxicity of PBMCs may be associated with tumor burden in patients with pMMR solid tumors. [Table: see text]
Ex vivo oncolytic and immune activity of CF33-hNIS-antiPDL1 against fresh peritoneal cells from patients with gastric cancer with and without peritoneal metastases.
Authors: Zhang Zhifang , Yang Annie , Chaurasiya Shyambabu , Park Anthony K , Kim Sang-In , Lu Jianming , Valencia Hannah , Fong Yuman , Woo Yanghee 
Published: January 2023

430 Background: No effective therapy exists for peritoneal metastases (PM) from gastric cancer (GC), which remain fatal within months of diagnosis. We investigated a novel chimeric oncolytic virus platform, CF33-OV, for its anti-cancer potential against peritoneal cancer cells from GC patients. Methods: We prospectively collected fresh ascites or peritoneal washings from 30 GC patients between 2019 and 2020. These included 16 males (53.3%) and 14 females (46.7%) with a mean age of 51.3 ± 15.1 years. Of the 30 patients, 23 (90%) had cytology or biopsy-proven PM. Cells isolated from the peritoneal fluid were analyzed using flow cytometry for immune cell markers and/or treated with PBS, CF33-GFP (MOI=3), or CF33-hNIS-antiPDL1 (MOI=3) for 15 hours. We evaluated the treated cells for virus infection, replication, CD8+ and CD4+ expression with exhaustion markers, virus infection, replication, and cytotoxicity. We evaluated ex vivo CD274 (PD-L1) blockade by virus-encoded anti-PD-L1 scFv and the release of growth factors and cytokines following CF33-hNIS-antiPDL1 treatment. Results: The CD45- cancer cell percentage was higher, and the CD8+ T cell percentage was significantly lower in the ascites group than in the peritoneal washing group. At baseline, low levels of CD274 (PD-L1), CD252 (OX40L), and EGFR were identified on the surface of cancer cells. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. After 15 hours of treatment, CF33-GFP infected, replicated in, and killed cancer cells ex vivo with a significantly higher dead cell percentage than the PBS control group (10.8% treated vs. 3.1% control, p-value <0.05). Of the live cancer cells, 69% were GFP+ by flow cytometry. Fluorescence microscopy results confirmed virus-encoded GFP expression in the ex vivo cells. Moreover, CF33-hNIS-antiPDL1 produced functional anti-PD-L1 scFv, which blocked phycoerythrin labeled anti-PD-L1 binding to PD-L1 on live cancer cells. Virus treatment increased CD8+CD107α+ and CD4+CD107α+ T cell percentages while decreasing the release of growth factors (EGF and PDGF) and inhibitory immune factors (soluble anti-PD-L1, GM-CSF, and IL-10). Conclusions: CF33-hNIS-antiPDL1 is oncolytic with immune-activating effects against GCPM ex vivo and has solid potential for intraperitoneal therapy of GCPM patients.
The Gastric Cancer Registry Genome Explorer: A tool for genomic discovery.
Authors: Almeda Alison Figueroa , Grimes Susan M. , Shin Giwon , Lee Hojoon , Wichmann Ignacio Alberto , Greer Stephanie , Ji Hanlee P. 
Published: January 2023

434 Background: The Gastric Cancer Registry (GCR) collects clinical questionnaire data and biospecimens from gastric cancer (GC) patients and individuals at high risk for GC (through family history of GC or a germline CDH1 mutation). Its purpose is to facilitate research into better detection and treatment strategies for GC. In 2020, the GCR Genome Explorer (GCR-GE), a publicly accessible and interactive database of clinical and genomic data, was launched to meet this goal. Methods: We generated genomic datasets from participants when GC status and archival gastric tumor tissue were available. We processed the tumor tissue (and paired normal tissue when possible) for whole genome, whole exome, and bulk RNA sequencing. The following genomic features were identified: copy number variations, gene mutations, gene expression, microbiome composition, estimation of tumor-infiltrating immune cells, and tumor neoantigens. We populated (1) all genomic alterations identified from GCR sequencing data, and (2) demographic and pathologic data regarding the tumor that were compiled from participant questionnaires and medical records into the GCR-GE. In addition, sequencing files from the Cancer Genome Atlas (TCGA) were similarly analyzed and uploaded as external datasets. Features of the GCR-GE include cross-study comparisons, study summaries, and queries down to the individual gene, neoantigen, and patient level. Results: In total, 243 GC patients donated tumor samples. The new GCR-GE release contains genomic datasets for 214 of these tumors, as well as datasets for 443 gastric tumors and 185 esophageal tumors from TCGA. Data generation was possible thanks to 756 subjects who enrolled in the GCR from 2011-2022. Most subjects were diagnosed with GC only (N=487), but interestingly, some met multiple criteria. For instance, 10 GC patients had a family history; 10 had a germline CDH1 mutation; and 21 patients had GC, a family history, and a germline CDH1 mutation. Efforts to upload additional datasets are ongoing. All data in the GCR-GE is downloadable. Conclusions: The GCR-GE is a comprehensive resource of genomic and clinical data. Given its accessibility, ease of use, and large cohort sizes, the GCR-GE presents a highly valuable tool for accelerating GC research.
Feasibility and dynamics of preoperative circulating tumor DNA in patients with gastroesophageal cancer receiving preoperative treatment.
Authors: Deng Lei , Olewniczak Donna , Awidi Muhammad , Sharma Shruti , Palsuledesai Charuta , Jurdi Adham A , Liu Minetta C. , Mukherjee Sarbajit 
Published: January 2023

436 Background: Tumor-informed circulating tumor DNA (ctDNA) testing has shown high sensitivity and specificity for detecting molecular residual disease across solid tumors. However, the requirement of high-quality tissue specimens for upfront sequencing and designing of personalized ctDNA assays can be challenging using preoperative biopsy samples. There is a paucity of data on the feasibility of testing in preop tissue specimens in patients (pts) with gastroesophageal cancer (GEC) as well as its preop dynamics. Methods: We prospectively enrolled pts with locally advanced esophageal, gastroesophageal junctional (GEJ), or gastric cancer who were to receive preop treatment and surgery between 11/2021 and 07/2022. Tumor tissue was analyzed with next-generation sequencing to design a personalized, tumor-informed multiplex PCR assay (Signatera bespoke mPCR NGS assay) for each patient. Peripheral blood was collected for ctDNA analysis at baseline (before preoperative treatment), every 4 weeks until surgery, after surgery (before adjuvant therapy), and then every 4 weeks for patients who received adjuvant chemotherapy or every 3 months for patients who received adjuvant immunotherapy or no active treatment. Results: A total of 17 pts were enrolled, of which 7 had esophageal, 5 had GEJ, and 5 had gastric cancer. Tumor tissues from 14 (82.4%) pts passed quality control (QC), of which 11 were preoperative biopsy samples and 3 were surgically resected tissue. All 14 pts had detectable baseline ctDNA prior to preoperative treatment, with a median at 1.05 mean tumor molecules per mL of plasma (MTM/mL). Of these, 92.8% (13/14) of pts achieved ctDNA clearance by a median of 5 weeks from the start of preoperative treatment. Four pts opted for endoscopy surveillance, of whom 1 pt had transient ctDNA clearance at week 10, but had positive ctDNA at week 14, which persisted as of week 26. Conclusions: In our cohort, locally advanced GEC were ctDNA shedders. Preoperative tumor-informed ctDNA testing was feasible. Further studies to evaluate correlation between ctDNA dynamics and response to treatment are warranted. [Table: see text]