bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changing HER2-status of the primary gastric tumor after neoadjuvant trastuzumab-based therapy.
Authors: Orlova Rashida , Beliak Natalia P. , Kutukova Svetlana , Zhukova Natalia V. , Avramenko Inna , Popova Natalia V. , Ivanova Anastasia , Androsova Alexandra , Zorina Ekaterina 
Published: May 2020

e16529 Background: Aproximetly 16 % of patients with metastatic gastric cancer (GC) have HER2+ tumors. With localized stages, the detection rate of HER2+ is known to be lower. Addition of trastuzumab (T) to chemotherapy (CT) improved survival in metastatic, HER2+ GC. Unlike the metastatic disease, Her-2 did not represent an independent prognostic biomarker for early stages during exploratory analysis of MAGIC trial. The aim of the study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer, to evaluate the contribution of trastuzumab to the effectiveness of neoadjuvant treatment in this rare patient population. Methods: We assessed HER2 expression using immunohistochemistry in pre-treatment biopsied specimens and post-treatment resected specimens obtained from 10 patients with locally advanced HER2-positive (3+) gastric cancer receiving trastuzumab-based neoadjuvant chemotherapy: 8 men (80%) and 2 women (20%), from 30 to 80 years old, the median age was 63,5 years. Included 7 patients with resectable adenocarcinoma of the stomach and 3 patients with adenocarcinoma of the esophageal-gastric junction. All patients received neoadjuvant therapy with trastuzumab (100%) + chemotherapy: FLOT (2 patients), FOLFOX (7 patients), XELOX (1 patient). All patients underwent R0 gastrectomy. Tumor regression grading (TRG) after treatment were determined according to Mandard system. Results: Two patients showed a complete pathomorphological response of the tumor (20%,TRG1), therefore, the determination of postoperative HER2 status was not possible. Two patients (20%) maintained the HER2-positive status and six patients (60%) had a change in HER2 expression from positive to negative. Three patients had a (y)pT3 and 5 had a (y)pN+ tumor. Basing on histological changes the tumor regression TRG3 ( < 10% residual tumor cells) was observed in 5 patients (50%). TRG 4-5(preponderance of tumor cells/tumors without changes of regression) observed in 3 patients (30%). The follow-up period is too short for disease-free survival or overall survival to be assessed. Conclusions: HER2 expression can change after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after neoadjuvant treatments may be utilized to determine whether the continued use of trastuzumab is advisable.
Clinicopathological features and outcomes of patients with esophageal cancer undergoing neoadjuvant chemoradiation (chemoRT) in Southern Brazil: A comparison to the Worldwide Esophageal Cancer Collaboration.
Authors: Gössling Gustavo Cartaxo de Lima , Pinto Bruno Siliprandi , Martins Eduardo Ferreira , Silva Rafaela Kathrine da , Peruzzo Nicolas , Schwartsmann Gilberto , Parikh Aparna Raj 
Published: May 2020

e16535 Background: Despite low- and middle-income countries representing 80% of esophageal cancer global burden, TNM staging is based on data from the Worldwide Esophageal Cancer Collaboration (WECC) that is mainly composed of patients from developed countries. Notably, 87.8% of patients staged after neoadjuvant chemoRT in the WECC were from North America or Europe and only 0.09% (N = 7) from Latin America (LA), raising questions about its applicability. We wanted to see if the characteristics of patients undergoing neoadjuvant chemoradiation in LA were representative of patients in the WECC. Methods: We retrospectively identified patients with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) who underwent chemoRT at Hospital de Clínicas de Porto Alegre (HCPA), an academic hospital in southern Brazil, and compared their clinicopathological features, treatments and outcomes data with WECC patients. WECC data were extracted from previous publications. Results: Compared to WECC, there were no differences in age (ESCC: 61±7.7 vs. 61±9.4, P = 0.91; EAC: 62±7.2 vs. 61±9.8, P = 0.67) and sex (female: 30.0% vs. 33.2%, P = 0.64; 30.8% vs. 11.6%, P = 0.06). However, we found statistically significant differences in histology (ESCC: 79.4% vs. 26.5%, P < 0.001), PS 0/1/≥2 (ESCC: 24/70/6% vs. 50.6/41.7/7.7%, P = 0.002; EAC: 38.5/61.5/0% vs. 34.9/61.5/3.6%, P = 0.91), active tobacco use (62% vs 27.8%, P < 0.001; 38.5% vs. 15.7%, P < 0.001), weight loss (8.4±5.8Kg vs. 2.6±6Kg, P < 0.001; 14.0±11.6Kg vs. 3,6±7,1Kg, P < 0.001), location (upper/middle/lower: 0/30/70% vs. 16.3/46.6/37.1%, P < 0.001; 0/0/100% vs. 0.7/3/96.3%, P = 0.63) and lymphadenectomy extension ( > 20 resected lymph nodes: 8.6% vs. 38.1%, P < 0.001; 0% vs. 37.9%, P = 0.027). There were no statistically significant differences in pathologic stage (Table) or overall survival in 30 days and 1 year from treatment decision (97.7% vs 98%, P = 0.69; 74.7% vs 75%, P = 0.78). Conclusions: Despite clinically significant differences in presentation were found, they did not implicate worse prognosis in this analysis. [Table: see text]
Novel target discovery in pembrolizumab-resistant gastric cancer using a comprehensive RNA-seq analysis pipeline.
Authors: Lee Jeeyun , Kim Seung Tae , Kim Kyoung-Mee , Schultz Eric , Skrzypczak Stan , Patro Rob , Kingsford Carl 
Published: May 2020

e16541 Background: Immune checkpoint inhibition (ICI) has made significant breakthroughs in several tumor types including gastric cancer (GC) in recent years. We recently showed that single agent pembrolizumab demonstrated remarkable and durable response in MSI and EBV GC. However, the response to ICI remains low in MSS and most patients progress after initial response. We explore novel targets in ICI-resistant GC patients by analyzing pre- and post-resistant expression. Methods: Of the 61 patients who were enrolled onto our previously reported phase II pembrolizumab trial (NCT#02589496), whole transcriptome RNA-seq analysis of 10 paired freshly collected tissue samples (all from primary gastric tumors) was performed using TruSeq. All biopsies were performed at progression following stable disease (SD) or partial response (PR) to pembrolizumab. All patients had a MSI status of MSS and EBV negative. Molecular features were extracted using the validated Ocean Genomics, Inc. gene expression analysis pipeline, which trims reads, computes transcript- and gene-level expression, predicts structural variants, assembles novel isoforms, and computes per-sample quality control metrics, among other analyses. Samples that passed quality control, with mapping rates > 88%, were selected for analysis. Differentially expressed (DE) genes between resistant and pre-resistant samples were identified using a statistical test with a study design that accounted for the pairing of samples for each patient. Results: 16 genes (GENCODE v31) had absolute log2-fold expression changes (L2FC) > 2, P-value < 10−5 and FDR-adjusted P-value < 0.05. Because sex was only partially controlled for, we excluded genes on the X and Y chromosomes. We also excluded non-protein encoding genes and pseudogenes. The 7 remaining genes are in the table. PDL-1 (CD274) was not identified as significantly DE (FDR-adjusted P-value > 0.9999). Conclusions: This is the first study to identify novel targets in pembrolizumab-resistant GC using RNA-seq algorithms beyond PDL-1. [Table: see text]
The association between hyperfibrinogenemia and clinicopathological factors, and the survival analysis of gastric cancer.
Authors: Su Yu , Zhu Xuecong , Zuo Jing , Liu Fengling , Wang Yudong , Fan Zhisong , Wang Long , Liu Feiran , Jiang Da 
Published: May 2020

e16547 Background: It is reported that hyperfibrinogenemia is commonly seen in gastric cancer. This study aim to discuss the association between fibrinogen level and preoperative clinicopathological factors and to evaluate the value as a predictor of prognosis. Methods: Retrospectively reviewed the medical records and follow-up data of patients with gastric cancer who underwent curative resection from January 2011 to December 2014 at Surgery Department of the Fourth Hospital of Hebei Medical University. Fibrinogen was measured a week before the surgery. Results: A total of 248 cases were enrolled. The means±SD of fibrinogen was 3.28±1.06g/L. Fibrinogen level was higher in older adults(≥60y), advanced tumor, poorly differentiated, deep invasion, lymph node metastasis, large tumor size and in those with high CEA, platelet count, albumin, NLR and PLR,( P< 0.05). All the people were divided by the TNM staging system and found that the plasma fibrinogen was higher in stageⅡand Ⅲ (stageⅠvs. stageⅡ: 2.84±0.72g/L vs. 3.36±1.18g/L, P= 0.009;stageⅠvs. stage Ⅲ: 2.84±0.72g/L vs. 3.43±1.07g/L, P< 0.001), however, there was no difference between stageⅡand Ⅲ( P= 0.662)(our study did not enrolled stage IV patients).When patients were classified into 4 groups according to the T classification, the plasma fibrinogen level gradually increased with increasing depth of cancer invasion (one way ANOVA; P= 0.002). Yet, when the patients who have lymph nodes metastasis classified according to the N classification, the differences among them did not have statistically significance ( P= 0.333). Multivariate analysis revealed that hyperfibrinogenemia had an independent association with advanced cancer (odds ratio,2.686(1.012-7.125); P= 0.047), lymph node metastasis (odds ratio,2.012 (1.012-3.125); P= 0.035) and tumor size(odds ratio,1.949 (1.099-3.454); P= 0.022). Our study aslo suggested that the patients with hyperfibrinogenemia before surgery showed a significantly lower survival rate (Log-Rank test; P< 0.001), hyperfibrinogenemia was a independent predictor on the overall survival, which could predict worse clinical outcome. Conclusions: Hyperfibrinogenemia may be considered a useful biomarker to predict advanced tumor, lymph node metastasis and large tumor size and can be a good predictor of worse clinical outcome.
Clinical and molecular features of responders to PD-1 blockade for patients with microsatellite instability high or mismatch repair deficient advanced gastrointestinal tumors.
Authors: Chida Keigo , Kawazoe Akihito , Kawazu Masahito , Nakamura Yoshiaki , Suzuki Toshihiro , Kitano Shigehisa , Nakatsura Tetsuya , Kuwata Takeshi , Shitara Kohei , Ikeda Masafumi , Yoshino Takayuki 
Published: May 2020

e16550 Background: An anti-PD-1 inhibitor pembrolizumab showed a durable response for patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors. However, clinical and molecular features of responders to PD-1 blockade for MSI-H/dMMR advanced gastrointestinal (GI) tumors are not well understood. Methods: Patients with MSI-H/dMMR GI tumors who received anti‒PD-1 monotherapy were enrolled in this study. PD-L1 expression in tumor cells or immune cells as well as combined positive score (CPS) were assessed using the PDL1 IHC 22C3 pharmDx assay. Cancer genome alterations were evaluated by a next generation sequencing-based panel with Oncomine Comprehensive Assay for tumor tissue samples or Guardant360 ctDNA Assay for plasma samples. Results: A total of 43 patients with gastric cancer (n = 19), colorectal cancer (n = 16), cholangiocarcinoma (n = 4), small intestine cancer (n = 2) and pancreatic cancer (n = 2) were analyzed in this study. All patients had measurable lesions and objective response was observed in 20 patients (46%). Objective response rate (ORR) was significantly higher in patients with ECOG PS of 0 than in those with PS of 1 or 2 (64% vs. 22%, p = 0.01) and PD-L1+ in tumor cells than in those with PD-L1- in tumor cells (67% vs. 32%, p = 0.03). ORR was similar according to PD-L1 CPS; 45% in CPS < 1, 47% in CPS ≥1 and 56% in CPS ≥10, respectively. ORR was numerically lower in patients with PTEN mutation than in those with PTEN wild type (29% vs. 56%). Also, durable response rate (objective response lasting continuously ≥6 months) was significantly lower in patients with PTEN mutation than in those with PTEN wild type (0% vs. 52%, p = 0.03). In the overall population, median progression-free survival (PFS) was 10.0 months (95% CI, 4.0-not reached). In univariate analysis, PS (1 or 2 vs. 0) was the strongest clinical factor associated with PFS (3.9 months vs. not reached, HR 3.9; 95% CI 1.7-9.2, p = 0.002). After adjusted by PS, PTEN mutation was only molecular factor associated with shorter PFS (3.4 vs. 24.5 months, HR 3.0; 95% CI 1.1-8.4, p = 0.03). Conclusions: Some clinical and molecular factors were associated with response to PD-1 blockade for MSI-H/dMMR advanced GI tumors. Updated biomarker analysis with whole exome sequencing and multiplex IHC will be presented.
Association of HLA class I genotype with outcomes of gastrointestinal cancer patients with immunotherapy.
Authors: Lu Zhihao , Shen Lin , Zhang Henghui , Jiao Xi , Wang Yujiao , Zhang Lei , Qian Juanjuan , Chen Huan , Yang Ying , Wu Lijia , Liu Chang , Gong Jifang , Li Jian , Zhang Xiaotian , Wang Xicheng , Peng Zhi , QI Changsong , Wang Zhenghang , Li Yanyan 
Published: May 2020

e16551 Background: Chowell et al. showed that HLA (human leukocyte antigen) class I (HLA-I) heterozygosity may avail to survival benefit from immune checkpoint blockade (ICB) in advanced cancer patients. Among their cohorts of melanoma patients, patients with the HLA-B44 supertype had improved survival, while the individuals with HLA-B62 supertype had worse outcome. However, these observations were not supported by another study of NSCLC patients treated with immune checkpoint inhibitors (ICIs). Now whether HLA-I genotype can serve as predictive marker for ICB treatment of other malignancies such as gastrointestinal cancer remains unclear. Methods: Tumor tissue samples before immunotherapy as well as related clinical data were collected from 91 Chinese gastrointestinal cancer patients receiving anti-PD-1/PD-L1 inhibitors and/or anti-CTLA-4 antibodies. Genomic features of tumor specimens were characterized by whole exome sequencing (WES) and HLA-I genotyping of normal DNA from peripheral blood cells were performed using WES data. Tumor immune microenvironment signatures were examined by RNA-sequencing targeting 395 immune related genes. Results: We observed that the individuals with HLA-B62 supertype (n = 15) had a significantly shorter PFS (median PFS, 1.83 months versus 3.53 months; HR, 2.3; 95% CI, 1.03-5.0; p= 0.009) than that of those without HLA-B62 supertype (n = 35) in a subgroup of patients with microsatellite stability (MSS, n = 50) and it was not so in other patients with microsatellite instability-high (MSI-H, n = 17) or unknown MSI status (n = 24). Moreover, the patients with B62 supertype and TP53 mutations (n = 15) exhibited more markedly shortened PFS (mPFS, 1.8 months versus 5.57 months; HR, 3.9; 95% CI, 1.5-9.6; p< 0.0001) and OS (mOS, 4.2 months versus 17.3 months; HR, 4.5; 95% CI, 1.5-13.2; p< 0.0001) compared to those patients with non-B62 supertype and TP53 wildtype (n = 26). Furthermore, gene expression levels of certain immune activation related pathways or markers (IFN-γ signature, cytolytic marker, etc.) in the patients with B62 supertype and without B44 supertype (n = 23) were statistically lower ( p< 0.05) than in those patients without B62 supertype (n = 62). Chi-square test revealed no correlation between HLA-B62 supertype and TP53 mutation, MSI status, tumor mutation burden (TMB) or PD-L1 expression. Conclusions: HLA-B62 supertype in combination with TP53 mutations may define a subset of gastrointestinal cancer patients who probably fail to benefit from ICIs, especially in MSS patients.
The dynamic change of cancer genome and T-cell receptor repertoire of an early gastric cancer cohort.
Authors: Li Zhuoran , Bai Jing , Wu Xi , Zhou Weixun , Xu Yaping , Yang Ling , Yang Aiming 
Published: May 2020

e16553 Background: The dynamics of the cancer genome and T-cell receptor (TCR) repertoire are largely unclear during the development of gastric cancer, especially in the early stage. In this study, we studied the characteristics of genome and tumor microenvironment changes chronologically in 15 early gastric cancer (EGC) patients and illustrated their influence on carcinogenesis. Methods: 75 gastric tissues including precancerous lesions, cancer lesions and paired reference gastric samples, and 29 peripheral blood samples were obtained chronologically from 15 patients. All the lesions were categorized into 3 groups according to its pathology type (group1: inflammation or intestinal metaplasia, group 2: low-grade dysplasia (LGD), group 3: EGC). Deep sequencing of whole-exome and CDR3 chain of TCR of each sample was performed. Tumor mutation burden (TMB), TCR repertoire diversity and clonality were evaluated based on the sequencing data. Results: Heterogeneity existed in cancer genome and TCR repertoire among different patients. During carcinogenesis, TMB increased at first and then decreased, reaching its peak at LGD, which was different from what we have known from other advanced cancer. A detailed analysis showed that only part of the driver gene mutations maintained in this process. Compared with T cells infiltrated in reference samples, tumor-infiltrating T cells shared more clones with peripheral blood T cells. Diversity and clonality of TCR repertoire didn’t show significant change with the development of cancer (Shannon index: group 1 = 6.32, group 2 = 6.06, group 3 = 6.09, p = 0.836; Clonality: group 1 = 0.19, group 2 = 0.19, group 3 = 0.17, p = 0.374). Some CDR3 clones appeared in early-stage and maintained during the carcinogenesis process. Conclusions: Our research is the first to analyze the cancer genome and TCR repertoire changes from both the spatial and temporal perspectives during the development of early gastric cancer. Somatic mutations appeared in the very early stage of gastric cancer and may induce the immune microenvironment changes in gastric mucosa.
TP53 mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with anti-angiogenic or standard chemotherapy regimens.
Authors: Fischer Nicholas William , Graziano Francesco , Bagaloni Irene , Di Bartolomeo Maria , Lonardi Sara , Vincenzi Bruno , Fornaro Lorenzo , Ongaro Elena , Aprile Giuseppe , Bisonni Renato , Prisciandaro Michele , Gariépy Jean , Loupakis Fotios , Sarti Donatella , Del Prete Michela , Catalano Vincenzo , Magnani Mauro , Ruzzo Annamaria 
Published: May 2020

e16571 Background: Current data support the angiogenic potential of cancer cells with mutant p53 and VEGF-A up-regulation in solid tumors. These findings have renewed interest in the p53 role as a predictive/prognostic factor in cancer therapy. We investigated TP53 mutations in gastric adenocarcinoma (GA) samples of metastatic patients (pts) who underwent anti-angiogenic Paclitaxel-Ramucirumab (PR) therapy. The analysis was also performed in a control group of pts who received first-line chemotherapy (CT) with platinum derivates and fluoropyrimidines. Methods: TP53 mutations were identified by next-generation sequencing in 110 GA primary tumors of two retrospective metastatic series including 48 pts who were treated with second-line PR and 62 pts who received first-line CT with Cisplatin or Oxaliplatin plus 5-Fluorouracil or Capecitabine. Detected TP53 mutations were classified for TP53 mutant-specific residual transcriptional activity scores ( TP53 RTAS) (Fischer NW et al JCI Insight 2018). TP53 RTAS results were used for stratifying pts in survival analyses. Primary end-point was overall survival (OS). Results: In the PR group, TP53 mutations were detected in 29 out of 48 tumor samples (60.4%) with 10 having TP53 RTAS 0%-to-<1%. In the CT group, TP53 mutations were found in 40 out of 62 tumor samples (64.5%) with 11 having TP53 RTAS 0%-to-<1%. In the PR group, the 10 cases with a TP53 mutation causing no residual or minimal activity ( TP53 RTAS 0%-to-<1%) showed better OS in comparison with pts in the remaining groups (wild-type and TP53 RTAS > 1%). This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval 0.17-0.85, p = 0.02). An opposite effect was seen in the CT group with the worst OS in carriers of TP53 RTAS 0%-to-<1% mutations (Hazard Ratio = 2.64, 95% confidence interval 1.17-5.95, p = 0.02). Notably, in the whole group of 110 pts, TP53 mutations (any type) occurred more frequently in the intestinal-type GA group (p = 0.02). Conclusions: Additional studies are warranted to explore the favorable role of TP53 mutations in cancer pts undergoing anti-angiogenic therapies. TP53 mutations frequently occur in GA and these findings would lead to novel tailored therapy strategies in this lethal disease.
Safety Run-In Phase (SRP) cohorts 1 and 2 of the IMMUNIB trial (AIO-HEP-0218/ass): An open-label, single-arm phase II study evaluating safety and efficacy of immunotherapy with PD-L1/L2 inhibition (nivolumab) in combination with receptor tyrosine kinase inhibition (lenvatinib) in advanced stage hepatocellular carcinoma (HCC).
Authors: Mueller Daniel Wilhelm , Siegler Gabriele Margareta , de Toni Enrico , Lindig Udo , Siebler Jurgen , Walker Martin , Al-Batran Salah-Eddin , Vogel Arndt 
Published: May 2020

e16601 Background: Immuno-oncology (I-O) drug nivolumab binds to T-cell PD-1 receptor and overcomes tumor induced inhibition of T-cell proliferation and cytokine release caused by PD-L1/L2 interaction. It so enhances the immune system’s natural tumor erasing capacity. In combination with selective targeting of oncogenic signaling pathways by receptor tyrosine kinase inhibitor (TKI) lenvatinib, a markedly improved response rate is expected in patients suffering from advanced stage HCC. Methods: This investigator-initiated phase II trial is designed as a signal generating, single-armed trial. 50 patients are planned in total. Primary endpoints are efficacy (objective response rate acc. to investigator assessed RECIST 1.1) and safety of combination treatment. The trial comprises two successive Safety Run-in Phase (SRP) cohorts, each consisting of 3 consecutively recruited patients, to evaluate safety of defined dose level 0: 240 mg nivolumab i.v. q2w along with 12 mg (≥ 60 kg bw) respectively 8 mg ( < 60 kg bw) lenvatinib p.o. qd. This abstract focuses on safety data from SRP cohort 1 and 2 (6 patients) in which all AEs were evaluated after patients received 2 cycles of IMP in dose level 0. In total, 10 patients have been enrolled into the trial up to now. Results: Summarized over both SRP cohorts, no dose limiting toxicities (DLTs) i.e. selected grade 4 events occurred in the six evaluated patients. 2 SAEs (abdominal infection; not IMP-related; grade 3 / fever; IMP-related; grade 1) and 21 AEs have been documented in 6 patients (most common AEs: hypertension [3x (14%); IMP-related], pain [3x (14%) (flank; extremity; unspecified); not IMP-related] - in total 12 AEs IMP-related and 9 AEs not IMP-related). No grade 5 AE, one grade 4 AE (AST increase; IMP-related) and three grade 3 AEs (Abdominal infection and hepatic encephalopathy; not IMP-related / ALT increase; IMP-related) in two patients have been reported. All other AEs were of grades 1 or 2. No patient discontinued treatment during SRP. Conclusions: Combination treatment with nivolumab 240 mg and lenvatinib 12/8 mg was assessed as safe and well tolerated from the data obtained from 6 patients in two cohorts, each received two combination cycles. Regular recruitment was thus opened in January 2020 and is planned to be completed in Q3/2020. Clinical trial information: NCT03841201 .