Recurrent Gastric Cancer Patients Research Articles

Development and validation of nomogram for predicting early recurrence after radical gastrectomy of gastric cancer

BackgroundAfter radical surgery, early detection of recurrence and metastasis is a crucial factor in enhancing the prognosis and survival of patients with gastric cancer (GC). Therefore, assessing the risk of recurrence in gastric cancer patients and determining the timing for postoperative recurrence is crucial.MethodsThe clinicopathological data of 521 patients with recurrent gastric cancer, who underwent radical gastrectomy at Zhejiang Cancer Hospital between January 2010 and January 2017, were retrospectively analyzed. These patients were randomly divided into two groups: a training group (n = 365) and a validation group (n = 156). In the training set, patients were further categorized into early recurrence (n = 263) and late recurrence (n = 102) groups based on a 2-year boundary. Comparative analyses of clinicopathological features and prognoses were conducted between these two groups. Subsequently, a nomogram for predicting early recurrence was developed and validated.ResultsIn this study, the developed nomogram incorporated age, serous infiltration, lymph node metastasis, recurrence mode, and the tumour marker CA19-9. In the training cohort, the area under the curve (AUC value) was 0.739 (95% CI, 0.682–0.798), with a corresponding C-index of 0.739. This nomogram was subsequently validated in an independent validation cohort, yielding an AUC of 0.743 (95% CI, 0.652–0.833) and a C-index of 0.743. Furthermore, independent risk factors for prognosis were identified, including age, absence of postoperative chemotherapy, early recurrence, lymph node metastasis, abdominal metastasis, and vascular cancer embolus.ConclusionIndependent risk factors for gastric cancer recurrence following radical surgery were utilized to construct a nomogram for predicting early relapse. This nomogram effectively assesses the risk of recurrence, aids in treatment decision-making and follow-up planning in clinical settings, and demonstrated strong performance in the validation cohort.

Utilizing serum metabolomics for assessing postoperative efficacy and monitoring recurrence in gastric cancer patients

Objective(1) This study aims to identify distinct serum metabolites in gastric cancer patients compared to healthy individuals, providing valuable insights into postoperative efficacy evaluation and monitoring of gastric cancer recurrence; (2) Methods: Serum samples were collected from 15 healthy individuals, 16 gastric cancer patients before surgery, 3 months after surgery, 6 months after surgery, and 15 gastric cancer recurrence patients. T-test and analysis of variance (ANOVA) were performed to screen 489 differential metabolites between the preoperative group and the healthy control group. Based on the level of the above metabolites in the recurrence, preoperative, three-month postoperative, and six-month postoperative groups, we further selected 18 significant differential metabolites by ANOVA and partial least squares discriminant analysis (PLS-DA). The result of hierarchical clustering analysis about the above metabolites showed that the samples were regrouped into the tumor-bearing group (comprising the original recurrence and preoperative groups) and the tumor-free group (comprising the original three-month postoperative and six-month postoperative groups). Based on the results of PLS-DA, 7 differential metabolites (VIP > 1.0) were further selected to distinguish the tumor-bearing group and the tumor-free group. Finally, the results of hierarchical clustering analysis showed that these 7 metabolites could well identify gastric cancer recurrence; (3) Results: Lysophosphatidic acids, triglycerides, lysine, and sphingosine-1-phosphate were significantly elevated in the three-month postoperative, six-month postoperative, and healthy control groups, compared to the preoperative and recurrence groups. Conversely, phosphatidylcholine, oxidized ceramide, and phosphatidylglycerol were significantly reduced in the three-month postoperative, six-month postoperative, and healthy control groups compared to the preoperative and recurrence groups. However, these substances did not show significant differences between the preoperative and recurrence groups, nor between the three-month postoperative, six-month postoperative, and healthy control groups; (4) Conclusions: Our findings demonstrate the presence of distinct metabolites in the serum of gastric cancer patients compared to healthy individuals. Lysophosphatidic acid, triglycerides, lysine, sphingosine-1-phosphate, phosphatidylcholine, oxidized ceramide, and phosphatidylglycerol hold potential as biomarkers for evaluating postoperative efficacy and monitoring recurrence in gastric cancer patients. These metabolites exhibit varying concentrations across different sample categories.

Defining nomograms for predicting prognosis of early and late recurrence in gastric cancer patients after radical gastrectomy.

There are few studies on the predictive factors of early recurrence (ER) and late recurrence (LR) of advanced gastric cancer (GC) after curative surgery. Our study aims to explore the independent predictors influencing the prognosis between ER and LR in patients with advanced GC after curative intent surgery respectively. And we will further develop nomograms for prediction of post recurrence survival (PRS). Data of patients with GC who received radical gastrectomy was retrospectively collected. Recurrence was classified into ER and LR according to the 2 years after surgery as the cutoff value. Multivariate Cox regression analyses were used to explore significant predictors in our analysis. Then these significant predictors were integrated to construct nomograms. The 1-, 2- and 3-year probabilities of PRS in patients with ER were 30.00%, 16.36% and 11.82%, respectively. In contrast, the late group were 44.68%, 23.40%, and 23.30%, respectively. Low body mass index (hazard ratio [HR] = 0.86, P = .001), elevated monocytes count (HR = 4.54, P = .003) and neutrophil-lymphocyte ratio (HR = 1.03, P = .037) at the time of recurrence were risk factors of PRS after ER. Decreased hemoglobin (HR = 0.97, P = .008) and elevated neutrophil-lymphocyte ratio (HR = 1.06, P = .045) at the time of recurrence were risk factors of PRS after LR. The calibration curves for probability of 1-, 2-, and 3-year PRS showed excellent predictive effect. Internal validation concordance indexes of PRS were 0.722 and 0.671 for ER and LR respectively. In view of the different predictive factors of ER and LR of GC, the practical predictive model may help clinicians make reasonable decisions.

Reminiscence therapy-based care program alleviates anxiety and depression, as well as improves the quality of life in recurrent gastric cancer patients.

Reminiscence therapy is a non-drug method that eases psychological burden and enhances quality of life by memories and communications in cancer patients. This study aimed to evaluate influence of reminiscence therapy-based care program on anxiety, depression, and quality of life in recurrent gastric cancer patients. Totally, 96 recurrent gastric cancer patients were randomly assigned as 1:1 ratio into reminiscence therapy-based care group (N = 48) and usual care group (N = 48) to receive 12-week corresponding interventions. Besides, all patients were follow-up for 6 months. Hospital Anxiety and Depression Scales-anxiety score at 4th month (p = 0.031) and 6th month (p = 0.004), Hospital Anxiety and Depression Scales-depression score at 6th month (p = 0.018), and anxiety severity at 4th month (p = 0.041) and 6th month (p = 0.037) were lower in reminiscence therapy-based care group than in usual care group. Quality of Life Questionnaire-Core 30 global health status score at 2nd month (p = 0.048), 4th month (p = 0.036), and 6th month (p = 0.014), Quality of Life Questionnaire-Core 30 function score at 4th month (p = 0.014) and 6th month (p = 0.021) were higher, while Quality of Life Questionnaire-Core 30 symptoms score at 2nd month (p = 0.041) and 4th month (p = 0.035) were lower in reminiscence therapy-based care group than in usual care group. Furthermore, reminiscence therapy-based care was more effective on improving mental health and quality of life in recurrent gastric cancer patients with anxiety or depression at baseline than those without. Reminiscence therapy-based care serves as an effective intervention, which relieves anxiety and depression, and improves quality of life in recurrent gastric cancer patients.

Defining a Nomogram for Predicting Early Recurrence in Gastric Cancer Patients After Neoadjuvant Chemotherapy and Radical Gastrectomy

PurposeTo define and predict early recurrence (ER) in patients with gastric cancer (GC) who underwent radical gastrectomy after neoadjuvant chemotherapy (NAC). MethodsThe present study included 573 patients who underwent NAC followed by curative resection for GC between January 2014 and December 2019. The patients were randomly divided into the training (n = 382) and validation (n = 191) cohorts in a 2:1 ratio. The optimal cut-off value of recurrence-free survival for defining ER was determined based on post-recurrence survival (PRS). Risk factors for ER were identified by logistic regression. A nomogram was further constructed and evaluated. ResultsThe optimal cut-off value for defining ER was 12 months. Overall, 136 patients (23.7%) experienced ER and had significantly shorter median PRS (4 vs. 13 months, P < 0.001). In the training cohort, factors independently associated with ER included age (P = 0.026), Lauren classification (P < 0.001), preoperative carcinoembryonic antigen (P = 0.029), ypN staging (P < 0.001), major pathological regression (P = 0.004), and postoperative complications (P < 0.001). A nomogram integrating these factors exhibited higher predictive accuracy than the ypTNM stage alone in both the training and validation cohorts. Moreover, the nomogram enabled significant risk stratification in both cohorts; only the high-risk patients could benefit from adjuvant chemotherapy (ER rate: 53.9% vs. 85.7%, P = 0.007). ConclusionA nomogram involving preoperative factors can accurately predict the risk of ER and guide individualized treatment strategies for GC patients following NAC, which may assist in clinical decision-making.

Abstract 4381: Predictive risk factors for cancer thrombosis in gastric cancer patients

Abstract Background Gastric cancer is strongly associated cancer thromboembolism. We aimed to identify the Khorana risk score (KRS) and other risk factors for cancer thromboembolism in patients with gastric cancer after gastrectomy. Methods We reviewed 610 gastric patients, who had undergone D2 radical gastrectomy between January 2005 and December 2017. Kaplan-Meier survival analysis and Cox regression models were used to evaluate for independent predictor of cumulative incidence of cancer thromboembolism and survival. Results The median follow up was 67.0 months. There were 35 (5.7%) caner thromboembolism. The cumulative incidences of thromboembolism were 6.1%, 3.1%, 3.3%, and 20.7% in stages I, II, III, IV. 181 (29.7%) patients were relapsed cancer and 159 (26.1%) patients were died. A high KRS (cumulative incidence 5.8%) was not associated with cancer thromboembolism compared to an intermediate KRS (cumulative 5.7%) (HR=1.005, 95% CI = 0.540-2.061, P= 0.876). After gastrectomy, recurrent cancer (cumulative incidence 9.9%) was associated with cancer thromboembolism compared to no recurrence (cumulative incidence 4.0%) (HR 3.713, 95% CI 1.879-7.335, P &amp;lt; 0.001). Conclusions Recurrent gastric cancer patients after gastrectomy were significantly increased cancer thromboembolism risk compared to no recurrent cancer patients. Among patients with gastric cancer after gastrectomy, KRS did not stratify the patients at high risk of cancer thromboembolism. Citation Format: Song Ee Park, Moon Ki Jung, In Gyu Hwang. Predictive risk factors for cancer thrombosis in gastric cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4381.

Clinical Implication of DNA Damage Response Genes in Advanced Gastric Cancer Stage IV and Recurrent Gastric Cancer Patients After Gastrectomy Treated Palliative Chemotherapy.

Purpose: This study aimed to investigate the relationship between DNA damage response (DDR)-related protein expression and the clinical outcomes of patients with gastric cancer stage IV and recurrent advanced gastric cancer patients after gastrectomy treated with palliative first-line chemotherapy. Materials and Methods: A total of 611 gastric cancer patients underwent D2 radical gastrectomy at Chung-Ang University Hospital between January 2005 and December 2017, of which 72 patients who received gastrectomy treatment with palliative chemotherapy were enrolled in this study. We performed the immunohistochemical assessment of MutL Homolog 1 (MLH1), MutS Homolog 2 (MSH2), at-rich interaction domain 1 (ARID1A), poly adenosine diphosphate-ribose polymerase 1 (PARP-1), breast cancer susceptibility gene 1 (BRCA1), and ataxia-telangiectasia mutated (ATM) using formalin-fixed paraffin-embedded samples. In addition, Kaplan-Meier survival analysis and Cox regression models were used to evaluate independent predictors of overall survival (OS) and progression-free survival (PFS). Results: Among the 72 patients studied, immunohistochemical staining analysis indicated deficient DNA mismatch repair (dMMR) in 19.4% of patients (n = 14). The most common DDR gene with suppressed expression was PARP-1 (n = 41, 56.9%), followed by ATM (n = 26, 36.1%), ARID1A (n = 10, 13.9%), MLH1 (n = 12, 16.7%), BRCA1 (n = 11, 15.3%), and MSH2 (n = 3, 4.2%). HER2 (n = 6, 8.3%) and PD-L1 (n = 3, 4.2%) were expressed in 72 patients. The dMMR group exhibited a significantly longer median OS than the MMR proficient (pMMR) group (19.9 months vs. 11.0 months; hazard ratio [HR] 0.474, 95% confidence interval [CI] = 0.239-0.937, P = 0.032). The dMMR group exhibited a significantly longer median PFS than the pMMR group (7.0 months vs. 5.1 months; HR= 0.498, 95% CI = 0.267-0.928, P = 0.028). Conclusions: Of stage IV gastric cancer and recurrent gastric cancer patients who underwent gastrectomy, the dMMR group had a better survival rate than the pMMR group. Although dMMR is a predictive factor for immunotherapy in advanced gastric cancer, further studies are needed to determine whether it is a prognostic factor for gastric cancer patients treated with palliative cytotoxic chemotherapy.

Identification of metabolism-related genes for predicting peritoneal metastasis in patients with gastric cancer

ObjectiveThe reprogramming of metabolism is an important factor in the metastatic process of cancer. In our study, we intended to investigate the predictive value of metabolism-related genes (MRGs) in recurrent gastric cancer (GC) patients with peritoneal metastasis.MethodsThe sequencing data of mRNA of GC patients were obtained from Asian Cancer Research Group (ACRG) and the GEO databases (GSE53276). The differentially expressed MRGs (DE-MRGs) between a cell line without peritoneal metastasis (HSC60) and one with peritoneal metastasis (60As6) were analyzed with the Limma package. According to the LASSO regression, eight MRGs were identified as crucially related to peritoneal seeding recurrence in patients. Then, disease free survival related genes were screened using Cox regression, and a promising prognostic model was constructed based on 8 MRGs. We trained and verified it in two independent cohort.ResultsWe confirmed 713 DE-MRGs and the enriched pathways. Pathway analysis found that the MRG-related pathways were related to tumor metabolism development. With the help of Kaplan–Meier analysis, we found that the group with higher risk scores had worse rates of peritoneal seeding recurrence than the group with lower scores in the cohorts.ConclusionsThis study developed an eight-gene signature correlated with metabolism that could predict peritoneal seeding recurrence for GC patients. This signature could be a promising prognostic model, providing better strategy in treatment.

120P Clinical implication of DNA damage response gene in advanced gastric cancer stage IV and recurrent gastric cancer patients after gastrectomy treated palliative chemotherapy

This study aimed to investigate the relationship between DNA damage response (DDR)-related protein expression and clinical outcomes of patients with in gastric cancer stage IV and recurrent advanced gastric cancer patients after gastrectomy treated palliative 1st line chemotherapy.

The Efficacy and Safety of Sintilimab Combined With Nab-Paclitaxel as a Second-Line Treatment for Advanced or Metastatic Gastric Cancer and Gastroesophageal Junction Cancer.

BackgroundUnresectable advanced or recurrent gastric cancer patients have a poor prognosis. PD-1 monotherapy regimen and PD-1 combined chemotherapy regimen have become the standard third- and first-line treatment for advanced gastric cancer, respectively. However, the status of immune checkpoint inhibitors in the second-line treatment for advanced gastric cancer has not been established. The combination of chemotherapy and anti-PD-1 antibody has been demonstrated to have a synergistic effect. In this study, we aimed to evaluate the efficacy and safety of sintilimab combined with nab-paclitaxel in the second-line treatment for advanced gastric cancer (GC)/gastroesophageal junction (GEJ) cancer patients.Patients and MethodsWe retrospectively analyzed patients with advanced GC/GEJ cancer that progressed after first-line systemic therapies with sintilimab combined with nab-paclitaxel from April 1, 2019 to December 31, 2021. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety.ResultsThirty-nine patients were enrolled and eligible for response assessment. Complete response (CR) was not observed, 15 patients achieved partial response (PR), 16 patients had stable disease (SD) and 9 patients had progressive disease (PD). The ORR and DCR were 15 (38.5%) and 31 (79.5%), respectively. Median PFS was 5.4 months (95%CI: 3.072-7.728). PFSs between different subgroups were analyzed. The results showed that gender, age, Human epidermal growth factor receptors 2 (HER2) status, PD-L1 expression, primary tumor site and chemotherapy cycles had no significant effect on PFS. Most of the adverse events (AEs) were of grade 1-2 and manageable. The common treatment-related adverse events of grade 3 or 4 included anemia (12.8%), neutropenia (12.8%), leukopenia (10.3%), hand-foot syndrome (7.7%), thrombocytopenia (7.7%). The potential immune-related adverse events (irAEs) were grade 1 pneumonia (1 pts [2.6%]) and grade 4 hepatitis (1 pts [2.6%]). There were no treatment-related deaths.ConclusionThese results indicate that sintilimab combined with nab-paclitaxel exhibits good anti-tumor activity and an acceptable safety profile as a second-line treatment for advanced or metastatic gastric cancer. These results warrant further investigation and evaluation to identify patients who can benefit more from the combined treatment strategy.

Preoperative Folate Receptor-Positive Circulating Tumor Cells Are Associated With Occult Peritoneal Metastasis and Early Recurrence in Gastric Cancer Patients: A Prospective Cohort Study.

BackgroundThe aim of this study is to explore the clinical feasibility of detecting folate receptor-positive circulating tumor cells (FR+ CTCs) for predicting peritoneal metastasis and short-term outcome in gastric cancer patients.MethodsThis is a prospective, single-center, observational study. We applied ligand-targeted enzyme-linked polymerization method to detect preoperative FR+ CTC levels in peripheral blood. We evaluated the diagnostic value of FR+ CTCs and other biomarkers in predicting peritoneal metastasis. Prognostic factors for recurrence-free survival (RFS) were investigated in univariate and multivariate analyses.ResultsA total of 132 patients with gastric cancer and 9 patients with benign disease were recruited. Gastric cancer patients had a significantly higher CTC level compared to that of patients with benign disease (p < 0.01). Combined model including CTC level and other biomarkers presented high sensitivity (100%) and moderate specificity (59.3%) in predicting peritoneal metastasis. Univariate analysis revealed that decreased serum prealbumin, decreased peripheral lymphocyte count, FR+ CTCs, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and lymph node metastasis were significantly associated with shorter RFS. FR+ CTC level [≥12.6 folate units (FU)/3 ml, hazard ratio (HR) = 6.957, p = 0.005] and CA19-9 (>34 ng/ml, HR = 3.855, p = 0.037) were independent prognostic factors in multivariate analysis.ConclusionsOur findings for the first time suggested the diagnostic value of preoperative CTC levels in predicting peritoneal metastasis in gastric cancer. Moreover, the FR+ CTC level could be a novel and promising prognostic factor for the recurrence of gastric cancer in patients who underwent surgery.Clinical Trial RegistrationChinese Clinic Trial Registry, identifier ChiCTR2100050514.

Integrated analysis of 1804 samples of six centers to construct and validate a robust immune-related prognostic signature associated with stromal cell abundance in tumor microenvironment for gastric cancer

BackgroundStromal cells in tumor microenvironment could promote immune escape through a variety of mechanisms, but there are lacking research in the field of gastric cancer (GC).MethodsWe identified differential expressed immune-related genes (DEIRGs) between the high- and low-stromal cell abundance GC samples in The Cancer Genome Atlas and GSE84437 datasets. A risk score was constructed basing on univariate cox regression analysis, LASSO regression analysis, and multivariate cox regression analysis in the training cohort (n=772). The median value of the risk score was used to classify patients into groups with high and low risk. We conducted external validation of the prognostic signature in four independent cohorts (GSE26253, n=432; GSE62254, n=300; GSE15459, n=191; GSE26901, n=109) from the Gene Expression Omnibus (GEO) database. The immune cell infiltration was quantified by the CIBERSORT method.ResultsThe risk score contained 6 genes (AKT3, APOD, FAM19A5, LTBP3, NOV, and NOX4) showed good performance in predicting 5-year overall survival (OS) rate and 5-year recurrence-free survival (RFS) rate of GC patients. The risk death and recurrence of GC patients growing with the increasing risk score. The patients were clustered into three subtypes according to the infiltration of 22 kinds of immune cells quantified by the CIBERSORT method. The proportion of cluster A with the worst prognosis in the high-risk group was significantly higher than that in the low-risk group; the risk score of cluster C subtype with the best prognosis was significantly lower than that of the other two subtypes.ConclusionThis study established and validated a robust prognostic model for gastric cancer by integrated analysis 1804 samples of six centers, and its mechanism was explored in combination with immune cell infiltration characterization.

Anxiety and depression in recurrent gastric cancer: Their prevalence and independent risk factors analyses.

Various anxiety and depression-related risk factors have been reported in cancer patients. However, little is known about the anxiety and depression-related risk factors in recurrent gastric cancer patients. Therefore, our aim was to investigate the prevalence and risk factors for anxiety and depression in recurrent gastric cancer patients.Totally 82 recurrent gastric cancer patients were consecutively recruited, and their clinical features were collected from hospital's electronic medical records. Besides, 80 newly diagnosed gastric cancer patients and 80 healthy controls were enrolled. Their anxiety and depression status was assessed using Hospital Anxiety and Depression Scale (HADS).The HADS-anxiety score (9.1 ± 3.4, 7.2 ± 3.0, 4.8 ± 2.7, respectively) and the percentage of anxiety patients (52.4%, 33.8%, 11.3%, respectively) were increased in recurrent gastric cancer patients compared to newly diagnosed gastric cancer patients and healthy controls; Also, the HADS-depression score (7.9 ± 3.1, 6.7 ± 2.6, 4.1 ± 2.8, respectively) and the percentage of depression patients (41.5%, 25.0%, 8.8%, respectively) had similar trends. Forward stepwise multivariate logistic regression revealed that age ≥60 years, diabetes, tumor-node-metastasis (TNM) stage at diagnosis, shorter time to recurrence and distant metastasis at recurrence were independent risk factors for anxiety occurrence, whereas age ≥60 years, diabetes, tumor location at diagnosis (cardia vs gastric antrum) and shorter time to recurrence were independent risk factors for depression occurrence.The prevalence of anxiety and depression is such high, and their relevant risk factors include age ≥60 years, diabetes and shorter time to recurrence in recurrent gastric cancer patients.

EMMPRIN in extracellular vesicles from peritoneal mesothelial cells stimulates the invasion activity of diffuse-type gastric cancer cells.

Peritoneal metastasis of gastric cancer (GC) results in extremely poor prognoses. The peritoneal cavity is covered by a monolayer of peritoneal mesothelial cells (PMCs). Interactions between GC cells and PMCs might play a pivotal role in peritoneal metastasis. Extracellular vesicles (EVs) correlate with intercellular communication. Although intercellular communication between cancer cells and PMCs might be associated with the peritoneal metastatic process, the role of EVs from PMCs remains unclear. We investigated the effects of EVs from PMCs on GC cells. Three GC cell lines (OCUM-12, NUGC-3, and MKN74) and four mesothelial cell lines were used. The effects of EVs derived from the PMCs on the invasion and migration of GC cells were evaluated by Matrigel invasion assay. Factors contained in the PMC EVs were analyzed; extra-cellular matrix metalloproteinase inducer (EMMPRIN) was detected in the EVs. The effects of an EMMPRIN inhibitor on the invasion-stimulating activity of EVs were examined. The EMMPRIN expressions of 110GCs were evaluated by immunohistochemistry. PMC EVs significantly promoted the invasion of diffuse-type GC cells, i.e., OCUM-12 and NUGC-3cells. EMMPRIN in the EVs stimulated the invasion of OCUM-12 and NUGC-3cells. The invasion-stimulating activity of PMC EVs was inhibited by the EMMPRIN inhibitor. A high EMMPRIN expression in PMCs was significantly associated with worse cancer-specific survival and peritoneal-recurrence-free survival. EMMPRIN in EVs from PMCs might stimulate the malignant progression of diffuse-type GC. EMMPRIN might be a useful prognostic marker of recurrence in GC patients.

LINC00963/miR-4458 regulates the effect of oxaliplatin in gastric cancer by mediating autophagic flux through targeting of ATG16L1

Oxaliplatin resistance is the greatest obstacle to the management of local recurrence in gastric cancer patients after surgery. Accumulating evidence has suggested that inhibiting autophagy may be a novel approach for reversing resistance to oxaliplatin treatment. In this manuscript, we aimed to investigate the role of LINC00963 in regulating autophagy and oxaliplatin resistance. qRT-PCR, immunochemistry staining, and western blotting were used to detect gene expression. Plasmids were used to up- and downregulate the expression of LINC00963 and miR-4458. A caspase 3/7 activity kit and flow cytometry were used to detect the apoptosis rate. CCK8 and Transwell assays were used to test cell proliferation and migration, respectively. Transmission electron microscopy and a dual fluorescent lentivirus autophagy system were used to evaluate autophagic flux. Dual luciferase reporter gene assays and RNA pulldown assays were used to evaluate the potential crosstalk. LINC00963 was highly expressed in gastric cancer patients and cell lines. In addition, high LINC00963 expression was found to be associated with poor prognosis and local recurrence in gastric cancer patients, indicating that LINC00963 might be involved in oxaliplatin resistance. Moreover, we found that LINC00963 was aberrantly highly expressed in oxaliplatin-resistant SGC-7901 (SGC-7901-R) cells and promoted proliferation and migration and reduced the apoptosis rate in SGC-7901-R cells. Furthermore, among all potential target microRNAs, miR-4458 was found to be negatively regulated by LINC00963 both in vivo and in vitro. In addition, miR-4458 overexpression led to impaired proliferation and migration and enhanced cell apoptosis and G1 arrest in SGC-7901-R cells. Further RNA pulldown and dual luciferase reporter gene assays indicated the interaction between LINC00963 and miR-4458. Moreover, we found enhanced autophagic flux in SGC-7901-R cells compared with SGC-7901 cells; in addition, an inhibitor of autophagy induced apoptosis in SGC-7901-R cells. Then, we found that downregulation of LINC00963 expression and upregulation of miR-4458 expression significantly suppressed autophagic flux in SGC-7901-R cells. Based on starBase V3.0 and dual luciferase reporter gene assays, we predicted and confirmed that ATG16L1 might be the target of miR-4458 to regulate autophagy. In conclusion, LINC00963 and miR-4458 are potential biomarkers for predicting the overall survival of gastric cancer patients. Moreover, targeting LINC00963 to inhibit autophagic flux sensitizes gastric cancer cells to oxaliplatin treatment, suggesting that it is a potential novel therapeutic target for improving oxaliplatin sensitivity.

CircPTK2 inhibits the tumorigenesis and metastasis of gastric cancer by sponging miR-134-5p and activating CELF2/PTEN signaling

BackgroundCircRNAs are a new subset of noncoding RNAs formed by covalent closed loops and play crucial roles in the regulation of cancer gene expression. However, the roles and underlying mechanisms of circRNAs in gastric cancer (GC) remain indistinct. This study aimed to explore the role and mechanism of hsa_circ_0006421 (circPTK2) in GC. MethodsThe differential expression of circRNAs between GC tissues and adjacent normal tissues were identified by a circRNA expression profiling. Associations of circPTK2 or miR-134-5p expression with clinicopathological characteristics and prognosis of GC patients were analyzed by chi-square of Fisher’s exact tests and Kaplan-Meier analysis. CCK8, colony formation, EdU assays and animal models were performed to assess the effects of circPTK2 on proliferation and invasion of GC cells. CircPTK2-specific probes were used to purify the RNA pulled down from the circPTK2, and enrichment of circPTK2 and miR-134-5p was detected by qRT-PCR. The effects of circPTK2 on miR-134-5p expression and CELF2/PTEN signaling were examined by qRT-PCR and Western blotting analysis. ResultsLow expression of circPTK2 and high expression of miR-134-5p were related to the poor survival, and high expression of miR-134-5p was related to the tumor recurrence in GC patients. Overexpressing circPTK2 suppressed the proliferation, colony formation, DNA synthesis and cell invasion as well as xenograft tumor growth and lung metastasis in vitro and in vivo, whereas silencing circPTK2 had the opposite effects. Moreover, circPTK2 was negatively correlated and co-localized with miR-134-5p in the cytoplasm of GC tissue cells. circPTK2 bound to and sponged miR-134-5p in GC cells, and miR-134-5p facilitated cell growth and invasion but attenuated circPTK2 induced tumor suppressive effects and CELF2/PTEN signaling activation in GC cells. ConclusionscircPTK2 functions as a tumor suppressor in GC by sponging miR-134-5p and activating the CELF2/PTEN axis.

A Case Study on Modeling the Time to Recurrence of Gastric Cancer Patients.

Gastric cancer is a malignant tumor of the stomach and it is one of the leading causes of death worldwide. The study aimed to model the time to first recurrence of gastric cancer patients at the Tikur Anbesa specialized hospital. The data for this study were gastric cancer patients followed up from January 1, 2013 to February 29, 2020 at Tikur Anbesa Specialized Hospital, Oncology Center, Addis Ababa. We used Weibull, log-logistic and lognormal as baseline hazard functions with the gamma and the inverse Gaussian frailty distributions. Data analyzed with the statistical software R. The median recurrence time of the patients was about 23.96 months with a maximum recurrence time of 60.81 months, of which about 61.2% had first recurrences of gastric cancer. The clustering effect is significant in modeling the time to recurrence of gastric cancer. According to the result of the log-logistic inverse Gaussian frailty model, the sex of the patient, the tumor size, smoking habit, the treatment carried out, the vascular invasion, the stage of the disease, the helicobacter pylori infection and the histological type were the significant prognostic factors at 5% level of significance. Inverse Gaussian frailty model is the model that best describes the time to recurrence of the gastric cancer data set. Gender of the patients, tumor size, treatment taken, vascular invasion, disease stage, helicobacter pylori infection and histological type were the determining prognostic factors. This requires measures to improve patient health and prevent relapse based on significant risk factors, and particular attention should be paid to patients with such factors.

A multicenter phase II study of S-1 plus ramucirumab as first-line treatment in elderly patients with advanced/recurrent gastric cancer (KSCC1701).

4043 Background: Elderly patients are often intolerable in the combination with cytotoxic agents. Therapy with S-1 alone is a key option for initial chemotherapy for Japanese elderly patients with unresectable gastric cancer in clinical practice. However, there are some cases in which the antitumor effects with S-1 alone are insufficient. We aimed to investigate the efficacy and safety of S-1 plus ramucirumab therapy to elderly patients with advanced/recurrent gastric cancer. Methods: Patients aged 70 years and older with previously untreated unresectable or recurrent gastric cancer patients were included in Japan. They received S-1 therapy (40-60 mg twice daily for 28 days, every 6 weeks) plus ramucirumab therapy (8 mg/kg, every 2 weeks) until disease progression. The primary endpoint was the one-year survival rate and null hypothesis of one-year survival was set as 40%, which is the lower bound of the 95% confidence interval in previously reported studies on S-1 therapy. The secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), and safety. Results: Between September 2017 and November 2019, 48 patients were enrolled in this study. The characteristics of patients were male/female: 34/14, median age: 77.5 years (range: 71-87), and PS (0/1): 20/28. The one-year survival rate was 65.2% (95% confidence interval 49.8-78.6%), which means this trial met the primary endpoint. The median OS and PFS were 16.4 months (95%CI:12.0–20.7) and 5.8 months (95%CI:4.0–7.2), respectively. The best RR (CR+PR) was 60.9%. The frequent grade 3 or grade 4 adverse events were neutropenia (27.7%), anorexia (23.4%), anemia (19.1%), hypertension (14.9%), leucopenia (12.8%) and hypoalbuminemia (12.8%). Conclusions: Based on the observed efficacy and safety, S-1 plus ramucirumab is an appropriate first-line treatment for elderly patients with advanced/recurrent gastric cancer. Clinical trial information: UMIN000028309.

Prognostic impact of CEA/CA19-9 at the time of recurrence in patients with gastric cancer.

We evaluated the clinical impact of the carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) values at the time of recurrence in gastric cancer patients. Among 790 patients with R0 resected gastric cancer without neoadjuvant therapy between 2004 and 2017, 89 recurrence cases were retrospectively evaluated. The clinical impact of CEA and CA19-9 values on recurrence sites and post-recurrent prognosis were evaluated using univariate and multivariate analyses. The positive rates of CEA and CA19-9 at recurrence were significantly higher than the preoperative positive rates (CEA, 56% vs 24%; CA19-9, 37% vs 15%). Although CA19-9-positive patients at recurrence exhibited a poor survival, the difference was not significant. The positive rates of CEA at liver or lymph node recurrence were significantly higher than the preoperative positive rates. The positive rate of CA19-9 at peritoneal recurrence was significantly higher than the preoperative positive rate. CA19-9-positive patients at recurrence exhibited worse prognosis than CA19-9-negative patients, although the difference was not significant. At lymph node recurrence, CA19-9-positive patients exhibited a significantly worse survival than CA19-9-negative patients. In recurrent gastric cancer, the positive status of CA19-9 at recurrence might have a negative prognostic impact after recurrence; particularly, in patients with lymph node recurrence.

A machine learning-based predictor for the identification of the recurrence of patients with gastric cancer after operation

To explore the predictive performance of machine learning on the recurrence of patients with gastric cancer after the operation. The available data is divided into two parts. In particular, the first part is used as a training set (such as 80% of the original data), and the second part is used as a test set (the remaining 20% of the data). And we use fivefold cross-validation. The weight of recurrence factors shows the top four factors are BMI, Operation time, WGT and age in order. In training group:among the 5 machine learning models, the accuracy of gbm was 0.891, followed by gbm algorithm was 0.876; The AUC values of the five machine learning algorithms are from high to low as forest (0.962), gbm (0.922), GradientBoosting (0.898), DecisionTree (0.790) and Logistic (0.748). And the precision of the forest is the highest 0.957, followed by the GradientBoosting algorithm (0.878). At the same time, in the test group is as follows: the highest accuracy of Logistic was 0.801, followed by forest algorithm and gbm; the AUC values of the five algorithms are forest (0.795), GradientBoosting (0.774), DecisionTree (0.773), Logistic (0.771) and gbm (0.771), from high to low. Among the five machine learning algorithms, the highest precision rate of Logistic is 1.000, followed by the gbm (0.487). Machine learning can predict the recurrence of gastric cancer patients after an operation. Besides, the first four factors affecting postoperative recurrence of gastric cancer were BMI, Operation time, WGT and age.