bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression profile of micro-RNA of lymphovascular invasive colon cancer.
Authors: Chen Zhongning , Fugere Tyler , Pandey Yadav
Published: May 2020

e16109

Background: Lymphovascular invasion (LVI) is an independent predictor of disease progression in patients with colorectal cancer, and is often associated with high tumor grade and advanced tumor stage. In concordance, micro-RNA(miRNA), which are small non-coding RNA that regulate post-transcriptional gene expression, have also recently been shown to be promising biomarkers to predict disease prognosis. The purpose of this study is to investigate [1] potential mechanism of tumor invasion by identifying miRNA that are differentially expressed with respect to LVI status, and [2] create a model to predict likelihood of SVI. Methods: Data was obtained from the TCGA database. Patients were selected based on biopsy proven diagnosis of adenocarcinoma of the colon. Patients were divided into based on the status of lymphovascular invasion (209 patients LVI negative, and 145 patients positive). A total of 130 miRNA were analyzed after filtering out miRNA expression counts < 10. The differential expression profile of the miRNA between the two groups were analyzed using a quasi-likelihood F test implemented by bioconductor package, edgeR. This package is well documented for analyzing RNA-seq data due to adjustment for biological variations and measuring error using a negative binomial distribution. After adjusting for gender, the expression of miRNA |Log2FC| > .3 and P value < 0.05 were obtained. A model was created using support vector machine (SVM) using miRNA that are differentially expressed. Results: Compared to negative LVI group, the positive LVI group has a miRNA profile with the down regulation of hsa-let-7f-1, hsa-let-7f-2, hsa-mir-200c, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-378a, hsa-mir-374a, hsa-mir-361, hsa-mir-128-1, and hsa-mir-200b, and up regulation of hsa-mir-142, hsa-mir-199b, hsa-mir-199a-1, and hsa-mir-199a-2. A support vector machine classifier with a predict power of 70% was created using the miRNA described as above. Conclusions: This miRNA expression profile unifies known pathways for LVI, such as over expression of myosin heavy chain 9 gene, or dysregulation of zinc finger E-box binding homeobox 1. They also act as biomarkers to predict the likelihood of LVI.
PD-L1 expression on tumor cells and tumor infiltrating immune cells in Chinese colorectal cancer patients.
Authors: Yang Jianjun , Xu Guanghui , Zheng Jiyang , Du Kunli , Zhou Wei , Wei Jiangpeng , Wang Haoyu , Yao Anliang , Zhao Fuyan , Cong Yuwei , Zhao Xiaochen , Bai Yuezong
Published: May 2020

e16111

Background: Nowadays, immune checkpoint inhibitors (ICIs) targeting programmed death-1/ligand-1 (PD-1/PD-L1) have been an alternative in cancer treatments. Previous biomarker analysis found that response to anti-PD1/PD-L1 was associated with PD-L1 expression on tumor cells and/or tumor infiltrating immune cells in some cancer types. Explorations of IMblaze370 study demonstrated better survival outcome in colorectal cancer (CRC) patients with positive PD-L1 expression compared with those with negative PD-L1 expression in the atezolizumab group. Our study investigated PD-L1 expression profile in Chinese CRC population. Methods: PD-L1 expression on tumor cells or tumor infiltrating immune cells in 816 CRC tumors between January 01, 2017 and December 02, 2019 in 3D Medicines database was assessed by immunohistochemistry assay (SP263 or 22C3). We defined percentage of PD-L1 expression on tumor cells as tumor proportion score (TPS) strong positive ≥50%, moderate positive ≥5% and < 50%, weak positive ≥1% and < 5%, and negative < 1%. Similarly, we defined percentage of PD-L1 expression on infiltrating immune cells as immune proportion score (IPS) strong positive ≥10%, moderate positive ≥5% and < 10%, weakly positive ≥1% and < 5%, and negative < 1%. In addition, MSI status was evaluated with targeted next-generation sequencing covering 100 MSI loci. Results: 12 (1.5%) individuals had TPS as strong positive, 63 (7.7%) as moderate positive, 95 (11.6%) as weak positive and 646 (79.2%) as negative. Meanwhile, TPS of patients were 55 (6.7%) for strong positive, 49 (6.0%) for moderate positive, 34 (4.2%) for weak positive and 678 (83.0%) for negative, respectively. 16.9% in Chinese CRC patients here were defined as positive PD-L1 expression (IPS ≥1%), which is lower than the positive proportion of CRC in IMblaze370 study (39.9% for IPS ≥1%, P < 0.0001). The PD-L1 expression on tumor cells and on tumor infiltrating immune cells showed minimal overlap. In detail, only 29 (3.6%) patients exhibited simultaneously TPS positive (≥1%) and IPS positive (≥1%). Furthermore, IPS was not associated with MSI status (P = 0.9153), while TPS showed an association with MSI-H (P < 0.0001). In detail, 45.5% of MSI-H CRC patients were TPS positive. Conclusions: Chinese CRC patients express PD-L1 with 20.8% TPS positive and 17.0% IPS positive, and TPS positive were related to MSI-H. When studying the connection between the efficacy of PD1/PD-L1 inhibitors and PD-L1 expression, TPS and IPS detection would be both considered to engage.
Effect of neoadjuvant chemotherapy and early chemotherapeutic response evaluation for low/intermediated-risk mid-low stage II/III rectal cancer: A prospective, open-label, single-arm, phase II trial.
Authors: Deng Xiangbing , Bi Liang , Wu Qingbin , He Du , Gou Hongfeng , Wu Bing , Yu Yongyang , Meng Wenjian , Meng Qiu , Wang Ziqiang
Published: May 2020

e16133

Background: Neoadjuvant chemoradiotherapy (NCRT) is the standard of care for stage II/III rectal cancer (RC) for its local-control effect. As advancement in surgery, local relapse was no longer the primary cause of failures, especially in low/intermediated-risk stage II/III RCs, in which benefit of radiotherapy in local control wasn’t shown in our previous trial. Distant relapse has become the major form of recurrences, and occurs at an increased rate when chemotherapy was delayed. This trial explores the effect of neoadjuvant chemotherapy (NCT), and the possibility of early assessment of chemotherapeutic response in low/intermediated-risk stage II/III RCs. Methods: This prospective, single arm, phase II trial planned to enroll 60 low/intermediate-risk stage II/III mid-low RCs (low: cT3a-bN0-1M0 MRF(-); mid: cT3a-c or T4aN0-1M0). 4 cycles of CAPOX NCT were scheduled. Rectal MRI, transanal US, endoscopy, CT were examined prior to treatment and after every two cycles. The primary outcome was the clinicopathological response, defined as pathological TRG0-1, TRG2 without tumor length increase, or TRG3 with tumor length regression over 30%. This study was approved by the Ethics Committees of West China Hospital and registered at ClinicalTrials.gov (NCT03666442). Results: From Dec. 2017 to Oct. 2019, 61 eligible patients were enrolled. Two patients received 3 cycles and 2 had only 2 cycles of chemotherapy due to intolerable adverse effects; 57 cases finished 4 cycles. In pathological evaluation, 13 patients (21.3%) were complete response (pTRG0) with one positive node in one patient; 5 cases were pTRG1; 26 were pTRG2; 17 had no response (pTRG3). 48 cases (78.7%) were responders. In the ROC curve predicting the responder via the 2-cycle regression in tumor length, the AUC was 0.864 (95%CI (0.764,0.963), p < 0.001), and the best cutoff regression rate after 2 cycles NCT was 27%. With this cutoff, the sensitivity was 83.3%; specificity was 84.6%; accuracy was 83.6%; positive likelihood ratio was 5.42; negative likelihood ratio was 0.20. Conclusions: NCT achieve more favorable pCR and tumor response rate in low/intermediated-risk stage II/III RCs, comparing to previous studies. The tumor regression after 2 cycles NCT had good accuracy in diagnosing the chemotherapeutic response. This early assessed chemosensitivity may become another feature for tailored use of neoadjuvant treatments, further cohort study will be conducted. Clinical trial information: NCT03666442 .
In-hospital outcomes of splanchnic vein thrombosis including Budd Chiari syndrome associated with GI malignancies.
Authors: Handa Shivani , Gupta Kamesh , Khan Ahmad , Mehta Kathan , Kasi Anup
Published: May 2020

e16503

Background: Patients with gastrointestinal (GI) malignancies are at increased risk of developing splanchnic vein thrombosis (SVT). However, there is a dearth of information about the epidemiology of splanchnic vein thrombosis associated with specific GI malignancies. We sought to compare the differences in hospitalizations and mortality related to SVT among various GI malignancies. Methods: We included the top three discharge diagnoses to identify cases of splanchnic vein thrombosis (portal/mesenteric/hepatic and splenic vein thrombosis) along with a secondary diagnosis of a GI malignancy, namely esophagus, gastric, hepatic, colorectal, pancreatic and cholangiocarcinoma within the 2010-2014 Nationwide Inpatient Sample (NIS). Outcomes including mortality, hospitalization charges and length of stay were compared for different types of GI malignancies for SVT hospitalizations using the chi-square test. Complications related to SVT were also identified. Data was analyzed using STATA 15. Results: There were 320,804 total weighted admissions for SVT, of which 33,556 or 11.6% occurred in patients with GI malignancies. Hepatic cancer was the most common GI malignancy associated with SVT, responsible for 5.1% of all cases, followed by pancreatic cancer (2.76% cases). Hepatic vein thrombosis was the commonest type of SVT occurring in patients with GI malignancy. Hospitalizations for SVT in GI malignancies increased from 5743 in 2010 to 8415 in 2014, representing an increase of 46% over 5 years. On univariate analysis, patients with esophageal cancer and SVT had higher rates of cardiac arrest (3.5% vs 0.7% average for other cancers, p = 0.03), but there were no significant differences in rates of other complications studied including intracranial hemorrhage, requirement for blood transfusion, mechanical ventilation or variceal bleeding. Inpatient mortality rate for admission with SVT was the highest for esophageal cancer (21.1%), followed by gastric cancer (17%) against an average of 9.3% for all GI malignancies (p < 0.05).The median cost of an admission for a patient with SVT were highest for esophageal cancer $102,452, followed by colorectal cancer ($97,491) and the least for hepatic cancer ($67,007). Conclusions: We found that hospitalizations for splanchnic vein thrombosis in patients with GI related malignancies has been steadily increasing and represent a significant burden. Hospitalizations for SVT in esophageal, gastric and colorectal cancer patients bear poorer outcomes as compared to hepatic cancer.
Safety and preliminary antitumor activity of the transforming growth factor beta (TGF-β) receptor I kinase inhibitor, vactosertib, in combination with paclitaxel in patients with metastatic gastric adenocarcinoma.
Authors: Jung Minkyu , Lee Choong-Kun , Kim Hyo Song , Ock Chan-Young , Bum Bae Jin , Lee Jin , Kang Dong Woo , Hwang Sunjin , Kim Seong-Jin , Chung Hyun Cheol , Rha Sun Young
Published: May 2020

e16505

Background: Recent studies demonstrated that TGF-β signaling attenuation in combination with paclitaxel inhibits epithelial-to-mesenchymal transition and cancer stem-like cells features, especially in diffuse type. We are reporting dose finding part in phase 1b study evaluating the combination of vactosertib, a highly selective and potent TGF-β inhibitor, with paclitaxel as a second line treatment in patients with metastatic gastric adenocarcinoma (GA). Methods: Eligible patients (pts) are ≥19 years old, have ECOG status ≤1, and have progressed on the first line treatment of metastatic GA treated with the combination therapy of fluoropyrimidine and platinum, or trastuzumab containing combination therapy in HER2-positive GA. The primary objective is to assess the safety and recommended phase 2 dose (RP2D) of vactosertib given 5 days on/2 days off in combination with weekly paclitaxel 80 mg/m2. Three dose levels of vactosertib (100, 200, and 300 mg BID) were tested. Results: As of Jan. 25, 2020, 12 pts were enrolled to the study (6, 3, and 3 pts in 100, 200, and 300 mg BID, respectively) and finished the safety evaluation. Median age was 50 (range, 39-65), 50% were male, and 75% had gastrectomy (4 pts with subtotal gastrectomy; 5 pts with total gastrectomy). At all cohorts, no dose limiting toxicity was observed. The most frequently reported treatment related adverse events (AEs) were anemia (50.0%), anorexia (41.6%), fatigue (33.3%), and urticaria (33.3%). AEs were mostly grade 1 or 2 and manageable. One case of grade 3 anorexia was reported as a treatment-related severe adverse event. Among 6 evaluable patients in 200/300 mg BID cohorts, the best responses to treatment were partial response in 1 patient; 57% decrease from baseline, 16.7% of overall response rate, and 83.3% of disease control rate at 12 weeks. Median progression free survival of the RP2D cohort has not been reached yet. Updated safety, PK, efficacy and biomarker data will be presented at the meeting. Conclusions: The combination of vactosertib plus paclitaxel has been well tolerated. The anti-tumor activity of this combination in patients with metastatic GA is now under exploration in the phase 2a part of the study. Clinical trial information: NCT03698825 .
Radiotherapy in localized gastric cancer management: To be or not to be?
Authors: Hussein Amany , Al Saleh Khaled , El-Sherify Mustafa , Nazmy Nashwa , Shete Jitendra
Published: May 2020

e16511

Background: Gastric adenocarcinoma still have dismal outcome in spite of the progress made in systemic treatment in last 2 decades. In localized disease, treatment outcome still suboptimal, with up to 88% suffer from recurrence/metastasis. Hence, improvement in radical initial treatment is mandatory. Recent trials showed survival benefit of adding radiotherapy (preoperative or adjuvant) with favorable toxicity profile when using current advances radiation techniques. Methods: We retrospectively analyzed impact of radiotherapy in management of localized gastric cancer in Kuwait. 87 adult patients with newly diagnosed gastric cancers were treated and followed up at Kuwait Cancer Control Center (KCCC) between 2009-2015, 12 were excluded due to inoperability. 13 patients were excluded as they had early disease and underwent only surgery. Finally, 62 patients were submitted in study 48 patient received radiotherapy (RT group) as part of treatment (44 postoperative, 3 postoperative after induction Chemotherapy, 1 preoperative). 14 patients did not receive radiotherapy (NRT group); five received perioperative chemotherapy, nine received postoperative chemotherapy). Survival analysis was done using Kaplan-Meier, and comparison was done according to clinicopathological features. Results: The median age at diagnosis was 55 (range 25-70). Men represented 65.5%. Asian were 17 patients and Caucasian were 70 patients. 68.9% were nonsmoker while 31% were smoker. Median follow up was 45 months (1-89). 2 year Overall survival in the NRT group was 50% while in RT group was 79.1%. 3 year OAS was 42.8% and 64.5% in NRT group and RT group respectively. Median overall survival for NRT group was 82 months. While for the RT group median survival was not reached at time of analysis with p value (0.025). 2 year DFS in NRT group was 50% while in RT group was 66.6%. 3 year DFS was 42.8% and 54.1% in NRT group and RT group respectively. Median DFS not reached in both groups p value (0.04). On correlation of prognostic clinicopathological features with benefits of adding radiotherapy it was noticed that high grade, positive margins statistically benefit more from local radiotherapy and had better local control. Distal tumours behave badly whether received radiotherapy or not. Interestingly benefit of adding radiotherapy was not significantly affected by nodal status. Conclusions: Radiotherapy should be part of management in postoperative locally advanced gastric cancer especially with high grade tumours and positive margins. However still ongoing trials to clear the role of radiotherapy in preoperative setting.
Precise early detection of gastric cancer and blood cell circuit.
Authors: Kshivets Oleg
Published: May 2020

e16512

Background: Significance of blood cell circuit in terms of early detection of gastric cancer (GC) was investigated. Methods: In trial (1975-2020) consecutive cases after surgery, monitored 136 GC patients (GCP) (m = 90, f = 46; distal gastrectomies = 95, proximal gastrectomies = 34, total gastrectomies = 7) with pathologic stage IA (tumor size = 1.81±0.70 cm; adenocarcinoma = 136; T1N0M0 = 136; G1 = 67, G2 = 26, G3 = 43, 5-year survival = 100%) and 120 healthy donors (HD) (m = 69, f = 51) were reviewed. Variables selected for study were input levels of blood cell circuit, sex, age, TNMG. Differences between groups were evaluated using discriminant analysis, clustering, nonlinear estimation, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing. Results: It was revealed that early detection of GC from HD (n = 256) significantly depended on: leucocytes (abs, total), segmented neutrophils (%, abs, total), lymphocytes (%), monocytes (%, abs, total), stick neutrophils (%, abs, total), eosinophils (%, abs, total) (P = 0.007-0.000). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships of early detection of GC and lymphocytes (rank = 1), segmented neutrophils (rank = 2), monocytes (3), stick neutrophils (4), leucocytes (5), eosinophils (6). Correct detection of early GCP was 100% by neural networks computing (error = 0.000; area under ROC curve = 1.0). Conclusions: Early detection of GC from HD significantly depended on blood cell circuit.
Limonoid compounds from Xylocarpus granatum and their anti-cancer activity against esophageal cancer cells.
Authors: Jing Li , Feng Li , Zhou Zhiguo , Shi Shuai , Deng Ruoying , Wang Zhicong , Liu Yibing
Published: May 2020

e16516

Background: We aimed to study the anti-cancer effects of limonoid compounds that were isolated and purified from Xylocarpus granatum fruits on human esophageal cancer cells. A structure-activity relationship experiment was designed to identify the functional moiety of limonoid compounds identified as being critical for its anti-cancer activity. Methods: Esophageal cancer Eca109 cells were treated with limonoid compounds. Cell proliferation was determined by the MTT assay in vitro and cellular apoptosis by flow cytometry and Western Immunolotting. Results: Four linonoid compounds strongly inhibited the cellular proliferation of Eca109 cells. Xylogranatin C was the strongest inhibitor, whose inhibitory effect was comparable to that of the well-known chemotherapeutic agent, cisplatin. Furthermore, xylogranatin C might induce Eca109 cell apoptosis through joint effects on multiple pathways, including the death receptor and endoplasmic reticulum pathways. Additionally, xylogranatin C suppressed tumor cell proliferation by up-regulating miR-203a expression in Eca109 cells. Conclusions: Inhibitory effects of xylogranatin C were more potent than cisplatin. Xylogranatin C induced Eca109 cellular apoptosis and exerted anti-tumor activity. Xylogranatin C might have induced Eca109 cellular apoptosis via joint effects on multiple pathways, including the death receptor and mitochondria-dependent signaling pathways. Additionally, xylogranatin C suppressed tumor cell proliferation by up-regulating miR-203a expression in Eca109 cells.
ACTL6A to drive gastric cancer progression through induction of glutathione synthesis.
Authors: Fang Lekun , Yang Ziqing , Zou Shaomin , Xie Yunling
Published: May 2020

e16521

Background: Actin-like 6A (ACTL6A), an actin-like protein, is a member of ATP-dependent SWI/SNF like BAF chromatin remodeling complexes. Previous reports revealed that ACTL6A was involved in varying cellular processes including chromatin remodeling, transcriptional regulation, vesicular transport, and nuclear migration. Nevertheless, its role and mechanism in Gastric Cancer (GC), the second leading causes of cancer-related death worldwide, has not been reported. To explore it, we found that ACTL6A inhibits ferroptosis of GC cells via regulating glutathione (GSH) metabolism. Ferroptosis is a regulated form of cell death driven by accumulation of lipid-based reactive oxygen species (ROS). Methods: GC cell line snu638 was used for studies. Firstly, silencing ACTL6A in snu638 with shRNA, cell proliferation was measured by counting cell confluence in incucyte. Overlapping the Gene Set Enrichment Analysis (GSEA) results of RNA-sequencing and two databases, we found that ACTL6A is positively correlated with GSH metabolism, which can be validated by real time-PCR. Next, cells were treated with ferrostatin-1 (fer-1), a ferroptosis inhibitor, to check if ACTL6A can inhibit ferroptosis. Finally, 13C-glucose and 13C-glutamine were used for tracing the metabolites in snu638, which were measured by LC-MS system. Results: Suppression of ACTL6A significantly inhibits GC cell growth. In our RNA-sequence results, ACTL6A is positively correlated with GSH metabolism, which is also enrich in two GC databases. ROS level was increased after ACTL6A knockdown. Since ROS plays an important role in ferroptosis, we found that fer-1 can rescue cell death caused by suppression of ACTL6A. When tracing with 13C-glucose, total GSH and 13C incorporation from 13C-glucose in the m+2 and m+4 isotopomer of GSH is reduced when ACTL6A is depleted, while total contribution of U-13C glucose to serine, glycine and glutamate have no significant changes. When tracing with 13C-glutamine, m+5 fractional contributions of 13C-glutamine to γ-glutamyl-cysteine and GSH are decreased when silencing ACTL6A. These results reveal that ACTL6A promotes de novo GSH synthesis. Conclusions: ACTL6A acts as an oncogene in GC via regulating GSH metabolism, and ferroptosis is inhibited for increasing GSH by ACTL6A, which highlights the importance of ACTL6A in GC metabolism and tumorigenesis. Therefore, ACTL6A could be a potential diagnosis marker or target gene of chemotherapy for GC.
High intra-tumor heterogeneity observed in esophageal squamous cell carcinoma.
Authors: Xue Jun , Li Yingqiang , Mu Tianhao , Chen Shifu
Published: May 2020

e16522

Background: Intra-tumor heterogeneity (ITH) is a critical factor in the metastasis of esophageal squamous cell carcinoma (ESCC). Analysis of ITH facilitates better diagnosis and medication. Cosine distance similarity reflects the directional relationship of each vector to analyze ITH better. Methods: Whole Exome Sequencing (WES) data of 185 tumor regions and 39 normal esophageal tissues from 39 patients were collected from NCBI database. We found highly variable SNPs in the East Asian populations from ExAC, GenomAD and other databases, and calculated the cosine distance of the SNPs between each tumor sample with the corresponding paracancerous sample. Sliding windows were incrementally advanced along the genome. Results: All 39 samples exhibited spatial ITH. Significant long distances were observed in patients with metastatic lymph nodes, and the homologous samples of the patients were roughly identical. In contrast, the sliding windows of different samples presented a distinctly heterogeneous scene. Conclusions: The cosine distance is suitable for the similarity calculation of high-dimensional vectors. The similarity of different samples can be calculated by using mutation sites as vectors. The cosine distance can be used to present further information and graph composition, compared with digital information. In the future, different samples can be clustered based on cosine distance by recruiting more samples and machine learning.
Resting memory CD4+ T cells and plasma cells in gastric cancer may be potential immune biomarkers.
Authors: Chen Jingde , Zhang Bei , Zhou Yifan , Zhao Xiaochen , Bai Yuezong
Published: May 2020

e16523

Background: Previous studies revealed the CD8+T cells deeply involved in tumor progress and reaction to immunotherapy. Now we used expression data and in silicon algorithm to analyze immune cell composition in gastric cancer and explored other subsets of immune cells that may be the potential immune biomarkers. Methods: CIBERSORT quantified 22 immune cell subtypes using four GEO gastric cancer cohorts (GSE15459, GSE26253, GSE29272, GSE57303) and TCGA-STAD, TCGA-PAAD gene expression data, and only CIBERSORT P- value of < 0.05 were included in the survival analysis. Immune cell high was defined as ≥median cells proportion individually and were computed for survival analysis and hazard ratios. Wilcox test was applied to analyze the differences between normal and tumor tissues. Log-rank Mantel-Cox test was applied to compare the survival curves between the patient groups. Statistical analyses were conducted using R v3.3.2. Results: Unsupervised hierarchical analysis of four GEO gastric tumor cohort using 22 immune cells proportions identifies three subclasses. In the subclass with the best overall survival performance, we found enriched resting CD4 T memory cells. Then in TCGA-STAD (P = 0.03) and TCGA-PAAD (P = 0.03) cohort, we observed that normal tissue obtained higher fraction of resting CD4 T memory cells than tumor. On the other hand, in patients who administrated chemotherapy in TCGA-STAD, by comparing immune cell high and low subgroup, we found that plasma cells (P = 0.02), T cells CD8(P = 0.03) were associated with improved overall survival. while, neutrophils(P = 0.05), NK cells resting(P = 0.04), were correlated with decreased overall survival. Also we proved one similar result in GEO cohort, that plasma cells-high (above median) subgroup provided increased overall survival (P = 0.04, HR = 0.76). In contrast, other three immune cells were not significantly associated with survival benefits. Conclusions: Together, these results indicated that memory CD4 T cells and plasma cells infiltration in gastric cancer have important clinical meanings and may be potential immune biomarkers. The continued integration of observations from a variety of experimental models will be required to further understand and utilize the full potential of immune cells.
The IL-6/STAT3 signaling pathway mediated by radiotherapy regulates the expression of PD-L1 and affects the biological functions of esophageal cancer cells.
Authors: Zhou Yichen , Zhu Honglei , Pang Xuezhou , Shen Yang , He Yu , Ma Daiyuan ,   ASCO Authors' Group
Published: May 2020

e16531

Background: The mechanism by which radiotherapy regulates PD-L1 expression and affects the biological behavior of esophageal cancer cells is not clear.The IL-6 /STAT3 signaling pathway may be involved. Methods: After irradiation of different doses to the esophageal cancer cell lines (Eca109, KYSE150, and TE1), RT-PCR and Western blotting were used to detect PD-L1, STAT3 and P-STAT3, ELISA was performed to examine the effects on IL-6, CCK-8 assays were used to test the effects on the proliferation. After the optimal dose radiation, Transwell assays were used to detect the invasion and proliferation of cell clones, and cell cycle changes were detected by flow cytometry. Results: The mRNA and the protein expression of PD-L1 in the cancer cell lines was significantly higher than in the normal esophageal cell line HET-1A(P < 0.01). The PD-L1 mRNA levels first increased and then decreased, which peaked 12 hours after 3,6,9,12Gy irradiation and was significantly higher than in nonirradiated cells (P < 0.05). PD-L1 protein expression first increased and then decreased, which peaked 48 hours after 6 Gy irradiation (P < 0.05). P-STAT3 protein expression first increased and then decreased after 6Gy irradiation (P < 0.05), that the expression in Eca109 peaked 48 hours but in KYSE150 and TE1 peaked 24 hours (P < 0.05). IL-6 protein expression peaked 12 hours and decreased gradually after irradiation (P < 0.05). The proliferation levels of the the cancer cell lines decreased after irradiation, and the inhibitory force increased with the increase in dose and time after radiotherapy (P < 0.05). The clone formation ability of the cancer cell lines was inhibited to varying degrees 14 days after irradiation with 6 Gy(P < 0.05). After 48 hours irradiation with 6 Gy, and the invasion ability of the cancer cell lines was lower than that of the nonirradiated cell lines (P < 0.05), and the proportion of cells in G2/M phase was higher in exposed cells than in nonexposed cells (P < 0.05), while the proportion of cells in S phase did not change significantly. Conclusions: PD-L1, IL-6 and STAT3 protein expression in the esophageal cancer cell lines first increased and then decreased consistency after irradiation, radiotherapy could regulate PD-L1 expression through the IL-6/STAT3 signaling pathway and affect the biological functions of esophageal cancer.
Glutathione system in the blood of gastric cancer patients with various tumor histotypes and prevalence of the disease.
Authors: Goroshinskaya Irina A. , Surikova Ekaterina I. , Frantsiyants Elena M. , Nemashkalova Ludmila A. , Kachesova Polina S. , Chudilova Anastasiya V. , Medvedeva Dar'ja E. , Maslov Andrey A. , Malinin Sergey A. , Kit Oleg I. , Fomenko Yuriy A. , Petrov Dmitry S.
Published: May 2020

e16534

Background: The role of oxidative stress in tumor growth and the multifaceted functional significance of glutathione have led to an interest in studying the components of the glutathione-dependent system in gastric cancer (GC), which occupies a leading position in cancer incidence and mortality. The aim of this work was to study the functioning of the glutathione system in the red blood cells of patients with gastric cancer in a comparative aspect depending on the histotype of the tumor and the prevalence of the disease. Methods: The study included 89 patients with GC divided into 6 groups depending on the histotype of the tumor. Separately, the results of the study were analyzed in patients with T4 status according to TNM and in patients with stage IV cancer. The content of reduced glutathione and the activity of glutathione-dependent enzymes were studied by conventional spectrophotometric methods in the red blood cells of patients. Statistical processing of the results was performed using the Statistika 6.0 program with Student’s t-test for two independent groups. Results: An increase in the content of glutathione in patients with GC compared with the group without oncopathology was revealed. The maximum increase was observed in patients with low-grade adenocarcinoma - by 42.5%, while in signet ring cell cancer (SRCC) there was only a tendency to increase by 17.8%. Glutathione reductase activity was reduced in adenocarcinoma by 23.4-26.2% and did not change in SRCC. The activity of the antioxidant enzymes glutathione peroxidase and glutathione transferase was increased in all groups and especially in SRCC - by 76% and 23-29%, respectively. In patients with T4 status and at stage 4 of the process, lower activity of the studied glutathione-dependent enzymes was revealed compared with all other groups of patients. Conclusions: The data indicate a greater functional potential of the glutathione system in SRCC. A significant increase in the activity of glutathione transferase with a sufficiently high level of reduced glutathione contributes to the development of treatment resistance in patients with SRCC.
Irinotecan with or without capecitabine as a beyond 2nd line regime for esophago-gastric adenocarcinomas.
Authors: Hapuarachi Sonal Brindley , Dawod Mohammed , Weaver Jamie , Shaheen Fadhel , Khan Adeel , Hubner Richard , Waddell Tom , Mansoor Wasat
Published: May 2020

e16545

Background: Purpose: The aim of this retrospective study was to assess the efficacy and toxicity of irinotecan +/- capecitabine for patients with metastatic esophago-gastric (EG) adenocarcinomas previously treated with at least two chemotherapy regimens including platinum-based, fluoropyramidines and taxanes. Introduction: Treatment for metastatic EG cancer beyond 2nd line remains controversial. Recently, the TAGS phase III trial (Shitara et al., 2018) showed overall survival benefit with Trifluridine/tipiracil of 2.1 months compared to placebo as a third line. Apatinib is also approved for use as third line in China (Li et al., 2013). Based on minimal evidence (Kang et al., 2013), irinotecan in combination with capecitabine is used in the UK. We performed a retrospective study to assess the efficacy and toxicity of irinotecan as a beyond 2nd line regime in metastatic EG adenocarcinomas in one of Europe’s largest cancer centres, The Christie. Methods: Data was collected retrospectively from all metastatic EG adenocarcinoma patients who were treated with irinotecan +/- capecitabine as a beyond 2nd line palliative treatment at the Christie Hospital from January 2014 to December 2019. Irinotecan was either given 2 or 3 weekly at dose of 180 mg/m² with or without capecitabine 800 mg/m². Response rate (RR) was calculated according to RECIST version 1.1, overall survival measured and toxicity data collected. Results: Fifty-six patients received irinotecan as beyond 2nd line palliative chemotherapy. Out of the thirty-seven patients with measurable disease on their scans, the overall response rate was 8.1% and the disease control rate was 51.4% as per RECIST 1.1. Median overall survival was 5 months (95% CI 4.2-5.8). The presence of grade 3-4 toxicities was 16% (9 patients) and included neutropenia, fatigue, nausea and diarrhea. On average, 3.7 cycles were administered, 32% (18 patients) required dose reductions, mainly secondary to grade 2 diarrhea and fatigue. Conclusions: Irinotecan in combination with capecitabine is efficacious as a beyond 2nd line regime in metastatic EG with an acceptable toxicity profile with a limited role in patients with resistant disease to first line platinum-based chemotherapies with fluoropyramidines.
Tepotinib inhibits the epithelial-mesenchymal transition and tumor growth of gastric cancers via increasing GSK3β, ECAD, MUC5AC, and MUC6.
Authors: Zang Dae Young , Sohn Sung-Hwa , Kim Bohyun , Sul Hee Jung , Jeong Jinhui , Kim Bum Jun , Kim Hyeong Su
Published: May 2020

e16562

Background: Aberrant expression of mucins can promote the epithelial-mesenchymal transition (EMT), which leads to enhanced tumorigenesis. Carcinogenesis-related pathways involving c-MET and beta-catenin involve mucins. This study characterized expressions of MET, MUC5AC, MUC5B, and MUC6 EMT signaling in human gastric cancer (GC) cell lines, and further characterized the differential susceptibility of these cell lines to tepotinib. Methods: We assessed the antitumor activity of tepotinib in GC cell lines. The effect of tepotinib on cell viability (IC50), apoptotic cell death, the EMT, and c-MET and beta-catenin signaling were evaluated by MTS assay, flow cytometry, western blotting, and qRT-PCR. Antitumor efficacy was assessed in MKN45 xenograft mice. Results: Tepotinib treatment showed dose-dependent growth inhibition of c-MET-amplified SNU620, MKN45, and KATO III cells with concomitant induction of apoptosis, but tepotinib treatment did not have an effect on c-MET-reduced MKN28 and AGS cells. Tepotinib treatment also significantly reduced expressions of phospho-c-MET, total c-MET, phospho-ERK, total ERK, beta-catenin, and c-Myc protein in SNU620 and MKN45 cells. In contrast, this drug was only slightly active against KATO III cells. Notably, tepotinib significantly reduced the expressions of EMT promotion genes such as MMP7, COX-2, WNT1, MUC5B, and c-Myc in c-MET-expressed GC cells, and increased expressions of EMT suppression genes such as MUC5AC, MUC6, GSK3beta, and ECAD. In a murine xenograft model, tumor volumes were significantly reduced in the tepotinib-treated group, when administered by daily oral gavage at a dose of 10mg/kg/day. Histologically, tepotinib induced more necrosis than in the control group. Conclusions: These data show the possibility that tepotinib may have therapeutic effects in c-MET-amplified GC, suggesting that clinical studies need to confirm the therapeutic effect.
The impact of neoadjuvant and/or adjuvant treatment modalities in resectable gastric cancer (rGC).
Authors: Ng Camille , Kim Sungjin , Guan Michelle , Hendifar Andrew Eugene , Kim Haesoo , Liu Jar-Yee , Mehta Sejal , Placencio-Hickok Veronica , Gangi Alexandra , Klempner Samuel J , Burch Miguel , Chao Joseph , Cho May Thet , Kamrava Mitchell , Atkins Katelyn Mae , Gong Jun
Published: May 2020

e16564

Background: In rGC ( > cT2), we investigated the impact of various neoadjuvant and/or adjuvant treatment modalities on pathologic complete response (pCR), surgical margins, and overall survival (OS). Methods: The National Cancer Database (NCDB) was interrogated to identify rGC patients (pts) between 2004-2015. Gastric adenocarcinoma cases that were cT2-T4b, any N, M0 and underwent definitive surgery were included. We analyzed the association of 9 treatment groups: neoadjuvant chemoradiation only (nCRT), neoadjuvant chemo only (nCT), adjuvant chemo only (aCT), adjuvant chemoradiation only (aCRT), neoadjuvant chemo and adjuvant radiation (nCTaRT), received any chemo at all (any CT), received any chemoradiation at all (any CRT), received any radiation at all (any RT), and no perioperative therapy (NT) across 3 endpoints: pCR, margin status, and OS using logistic regression and Cox proportional hazards models with adjustment for baseline characteristics. Results: From 183,204 GC cases screened, a total 3061 pts were available with a median follow-up of 41.6 mos and median OS of 29.0 mos. On multivariable analyses, nCRT was associated with the greatest odds of having a pCR (odds ratio or OR 59.6, 95% confidence interval (CI) 10.6-334.1, p < 0.001) with NT as the reference. Having received any RT (OR 0.42, 0.10-1.86), nCRT (OR 0.68, 0.33-1.37), or nCT (OR 0.83, 0.60-1.15) was associated with the lowest odds for having positive surgical margins although none reached p < 0.05. For OS, having received any CT (hazard ratio or HR 0.41, 0.35-0.48) was associated with the lowest risk of death followed by nCRT (HR 0.48, 0.35-0.66), aCT (HR 0.52, 0.43-0.62), aCRT (HR 0.55, 0.48-0.63), any CRT (HR 0.61, 0.41-0.91), nCT (HR 0.62, 0.54-0.71), and nCTaRT (HR 0.67, 0.52-0.87, all p < 0.05). Median OS was greatest in pts treated with any CT (53.9 mos) followed by nCRT (39.1 mos) and aCT (36.1 mos) with 2-year OS rates being 65.6% (95% CI 61.3-69.5%), 63.6% (52.3-73.0%), and 59.7% (54.2-64.7%), respectively. Conclusions: Although nCRT had a high pCR rate, receipt of any CT (neoadjuvant and/or adjuvant) afforded the greatest OS in this modality-by-modality comparison in a large cohort of rGC pts.
Tumor response score with neoadjuvant FLOT versus FOLFOX in gastric cancer patients: Results from a United States-based cohort.
Authors: De Andrade James Pereira , Ahn Hye Seong , Chao Joseph , Melstrom Laleh Golkar , Paz Isaac Benjamin , Fong Yuman , Lee Byrne , Woo Yanghee
Published: May 2020

e16573

Background: A recent RCT comparing FLOT and ECF regimens for locally advanced gastric cancer found FLOT to be superior in pathologic complete response (PCR) rates: 16% versus 6%. We evaluated patients who underwent resection after FLOT and FOLFOX in a diverse US population. Methods: Patients diagnosed with gastric adenocarcinoma at a single institution who underwent preoperative chemotherapy either with FLOT or FOLFOX between 2017 and 2019 were evaluated for pathologic response. Results: Fifty-nine patients underwent gastrectomy for adenocarcinoma. Of these, 59% underwent neoadjuvant chemotherapy: FLOT 20 patients, FOLFOX 12 patients, ECF 1 patient, other regimen 2 patients. Racial/ethnic background of patients were 20% non-Hispanic white, 23% Hispanic/Latino, 40% Asian, 6% black, and 6% other. Three patients (8.6%) had PCR, two received FLOT and one FOLFOX. Four patients had a near complete response (tumor regression score 1), all of whom received FLOT. In total, 16 of 20 patients who received FLOT had at least a partial response whereas only 5 of 12 patients who received FOLFOX had any tumor response (p = 0.027). Among all patients receiving neoadjuvant chemotherapy, 66% had poorly differentiated tumors. Only 1 of these patients experiencing a complete or near complete response compared to 50% of patients with non-poorly differentiated tumors (p = 0.001). Conclusions: In an ethnically diverse US population, tumor regression rates were improved with FLOT when compared to FOLFOX. For medically appropriate patients, strong consideration should be given for FLOT in the neoadjuvant setting.
Immunogenomic classification of gastric cancer based on the tumor microenvironments expression of PD-L1 and CD8+ T-cell infiltration.
Authors: Chen Yu , Chen Gang , Xiong Jia-ni , Lan Bin , Gao Xuan , Jun Liu , Lin Jin , Xu Yaping , Guan Yan-Fang , Chen Ling , Chen Li-zhu , Xia Xuefeng , Guo Zengqing
Published: May 2020

e16578

Background: Previous data has shown that a positive response to immunotherapy usually relies on active interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). The aim of this study was to classify gastric cancer (GC) subsets based on the TME immune status according to the expression of PD-L1 and infiltration of CD8+ T cells. Methods: One hundred and eighty-six tumor tissue from gastric cancer patients with a curative D2 gastrectomy were examined for evaluating PD-L1 and CD8+ T cells status using histopathologic analysis. The molecular characteristics of 289 GC samples in TCGA network were further analyzed to distinguish the genetic features of four immune subtypes depending on the presence of PD-L1/CD8+T cell. Results: GC samples were categorized into four types, type I (CD8+/PD-L1+, 60.3%), II (CD8-/PD-L1-, 11.8%), III (CD8-/PD-L1+, 0%), and IV (CD8+/PD-L1-, 27.9%), basing on PD-L1/CD8 expression. The PD-L1 expressing level was geographically associated with the intensity of CD8+ T cell infiltration which was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.003 and p = 0.006). Distinct patterns of genetic profile were described in four types of GC from TCGA database. Type I and III which PD-L1 were overly expressed had comparatively higher MSI and TMB, with EBV mainly enriched in Type I, whereas CIN was more likely to occur in PD-L1 aberrant types II and IV. SNV analysis illustrated higher gene mutations in oncogenes (PIK3CA and ERBB2), and in DNA damage repair related pathway, such as PRKDC, ATM, and SWI/SNF complexes (e.g. ARID1A) in Type I. However, TP53 mutations tend to enrich in Type II and IV. Similar results were obtained by transcriptome analysis. Conclusions: The genetic features of four immune subtypes proof that PD-L1 and CD8+ T cells status are reasonable immunogenomic classification of gastric cancer. SNV analysis prompts a potential mechanism for effectiveness of immunotherapy in Type I patients. Overall, the results may be useful for the development of clinical treatments for the blockade of immune checkpoints.
The mutational pattern of homologous recombination (HR) related genes and its relevance to response to immunotherapy in gastric cancer.
Authors: Fan Yue , Ying HaiFeng , Wu Xueying , Mao Beibei , Zhang Henghui
Published: May 2020

e16579

Background: Although therapeutic strategies based on immune checkpoint inhibitors (ICIs) have been introduced for gastric cancer (GC), there is still a pressing need to find potential predictive therapeutic biomarkers beyond PD-L1 expression to help patients to derive more benefit from these therapies. Homologous recombination deficiency (HRD) could modify tumor immune microenvironment by increasing the presence of tumor-infiltrating lymphocytes (TILs) indicating that HRD might be a biomarker of immunotherapies. Our aim was to analyze the mutational pattern of HR related genes in a large Chinese GC cohort and its relevance to tumor immune profile and clinical response to immunotherapy. Methods: A panel of 543 cancer related genes was used to analyze the genomic profiling of Genecast cohort which is consisted of 484 Chinese patients with GC. The correlation between HR-gene mutations and tumor immunity or clinical outcome using two GC genomics datasets (TCGA and MSK-GC) by the bioinformatic approach. Results: Fifty-one of 484 (10.54%) patients had at least one somatic mutation in HR-gene, ATM (16/484, 3.31%), ATRX (14/484, 2.89%), and ATR (13/484, 2.69%) were among the top mutated HR-gene in Genecast cohort. Mutations in HR-gene are associated with elevated TMB, enhanced immune activity, and microsatellite instability (MSI) status. In MSK-GC cohort, including a total of 49 patients who had stomach adenocarcinoma (STAD) or gastroesophageal junction adenocarcinoma (GEJ) and treated with ICIs, HR-mut GC (n = 12) had a significantly better OS than HR-wt GC (n = 37) (log-rank test, P = 0.034). Conclusions: Our data suggests that detection of somatic mutations of HR-gene could expand the proportion of patients who might get benefit from immune checkpoint blockade therapy response.
Variability in multimodality treatment influences survival in non-metastatic gastric cancer patients.
Authors: Hoang Tuyen , Dayyani Farshid , Alfaro Ariceli , Huynh Jasmine , Ji Jingran , Ko Andrew H. , Cho May Thet , Hiyama Darryl
Published: May 2020

e16588

Background: While gastric cancer is a leading cause of cancer-related mortality in Eastern Europe and Asia, it is less common in the United States. Recommendations regarding optimal treatment of non-metastatic gastric cancer (nmGC) with regard to type and extent of surgery, choice and sequence of chemotherapeutic agents, and use of radiation therapy vary somewhat depending on geographic location. To determine how variability in treatment practices affects patient outcomes, we conducted a retrospective study to evaluate clinical outcomes in nmGC patients treated at four high-volume academic institutions. Methods: California Cancer Registry of demographic and clinical data were collected for nmGC patients who underwent surgery with curative intent from 2010-2018. We conducted chart reviews of the patients’ electronic health records to validate clinical factors and outcomes. We performed multivariable Cox regressions to determine prognostic factors for outcomes. Results: Demographics of study cohort (n = 326): mean age 66 years; 64% male; 44% Caucasian, 35% Asian, 16% Latino. Tumor stage: 48% loco-regional (pT4 or pN1+) versus 52% localized (pT1-3, pN0). Histology: 47% intestinal, 30% diffuse, 8% mixed, 15% unknown. Surgery: number of recovered lymph nodes varied from 0 to 60 in any tumor stage. Chemotherapy: 20% neoadjuvant, 25% adjuvant, 16% perioperative, 39% none. Multimodality therapy: 44% surgery only, 31% chemotherapy, 25% chemotherapy and radiation. With a median follow-up after surgery of 6 years, 24% of patients developed recurrence and 40% had died. Compared to open surgery, laparoscopic surgeries was associated with lower lymph node recovery (median = 15 vs 19, p = .0042), which in turn was associated with a significant decrease in overall 5-year survival after adjusted for tumor stage (hazard ratio HR = 1.9, p = .0012). Timing of chemotherapy and addition of radiation therapy to chemotherapy did not confer further improvements in survival. In contrast, greater lymph node recovery plus chemotherapy were associated with improved survival in patients with loco-regional tumors (HR = 0.3, p = .0020). Conclusions: This study highlights major practice differences in the management of nmGC across providers and institutions. Further efforts should be made to standardize the use of chemotherapy and adequate recovery and assessment of lymph nodes in this patient population.