Establishment of gastric signet ring cell carcinoma organoid for the therapeutic drug testing.
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ABSTRACT:
SUBMITTER: Li G
PROVIDER: S-EPMC8748936 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent advances in the epidemiology, pathology, molecular mechanisms, and combined modality therapy (CMT) fields have shown that gastric signet ring cell carcinoma (GSRC) should be considered a distinct cancerous entity. Clinical management of this cancer is challenging, with chemoradioresistance and poor outcomes in advanced stages. Pathological and molecular sets of GSRC demonstrate different features of poor cohesion and differentiation according to the WHO, Japanese Gastric Cancer Association, and Laurén classifications. These features also result in poor response to adjuvant and neoadjuvant chemoradiotherapy. Certain studies of GSRC showed the disputed effectiveness of hyperthermic intraperitoneal chemotherapy and immunotherapy. Our aim was to discuss how an improved understanding of these therapeutic benefits may provide better treatment selection for patients, and therefore improve survival. The challenges in the new understanding of GSRC in routine practice and pathology, and the current limitations of treatment will also be discussed.
| S-EPMC7478370 | biostudies-literature
Project description:BackgroundAdvanced gastric signet-ring cell carcinoma (SRCC) is a specific type of malignant gastric cancer (GC) with distinct poorer survival. Claudin18.2 (CLDN18.2) is a promising neo-biomarker for the treatment of GC. Clinical trials of CLDN18.2-targeted antibody and T cell-based immunotherapy providing promising prospects for the treatment of GC. The effect of antibody therapy depended on the expression rate of CLDN18.2 has been found in clinical trials. This study aimed to determine the prevalence and the therapeutic value of CLDN18.2 in advanced gastric SRCC.MethodsExpression of CLDN18.2 in 105 formalin-fixed, paraffin-embedded (FFPE) tumor tissues was detected by immunohistochemistry (IHC) and evaluated according to FAST criteria. Next-generation sequencing (NGS) using 416 pan-cancer genes panel was performed to characterize the genomic landscape in 61 advanced gastric SRCC patients. Fisher's exact test was used to determine gene differences in different CLDN18.2 expression levels.ResultsA total number of 105 advanced gastric SRCC samples were analyzed, of which 95.2% (100/105) were positive stained. Moderate-to-strong CLDN18.2 expression was observed in 64.8% (68/105) of all samples. In particularly, 21.0% (22/105) samples had positive staining in more than 90% tumor cells. No significance was found between CLDN18.2 expression and overall survival (OS). NGS results showed that single nucleotide variations (SNVs) could be frequently found in TP53 (26.2%), CDH1 (19.7%), MED12 (18.0%), PKHD1 (18.0%) and ARID1A (11.5%), besides, copy number variations (CNVs) were rich in NOTCH1 (18.0%) and FLT4 (9.8%) in SRCC samples. Moreover, SNVs in GRIN2A was found in 20% of the patients who had CLDN18.2 staining in <40% of tumor cells (P=0.043), indicating CLDN18.2 expression might be related to the aberration of GRIN2A in advanced gastric SRCC.ConclusionsThe highly expressed CLDN18.2 among advanced gastric SRCC patients that we found certified the value of CLDN18.2-targeted therapy in this specific type of GC. In addition, Analyses between CLDN18.2 expression and genetic abnormalities provided novel therapeutic options for advanced gastric SRCC.
| S-EPMC7807267 | biostudies-literature
Project description:BackgroundThe aim of our study was to develop a nomogram model to predict overall survival (OS) and cancer-specific survival (CSS) in patients with gastric signet ring cell carcinoma (GSRC).MethodsGSRC patients from 2004 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database and randomly assigned to the training and validation sets. Multivariate Cox regression analyses screened for OS and CSS independent risk factors and nomograms were constructed.ResultsA total of 7,149 eligible GSRC patients were identified, including 4,766 in the training set and 2,383 in the validation set. Multivariate Cox regression analysis showed that gender, marital status, race, AJCC stage, TNM stage, surgery and chemotherapy were independent risk factors for both OS and CSS. Based on the results of the multivariate Cox regression analysis, prognostic nomograms were constructed for OS and CSS. In the training set, the C-index was 0.754 (95% CI = 0.746-0.762) for the OS nomogram and 0.762 (95% CI: 0.753-0.771) for the CSS nomogram. In the internal validation, the C-index for the OS nomogram was 0.758 (95% CI: 0.746-0.770), while the C-index for the CSS nomogram was 0.762 (95% CI: 0.749-0.775). Compared with TNM stage and SEER stage, the nomogram had better predictive ability. In addition, the calibration curves also showed good consistency between the predicted and actual 3-year and 5-year OS and CSS.ConclusionThe nomogram can effectively predict OS and CSS in patients with GSRC, which may help clinicians to personalize prognostic assessments and clinical decisions.
| S-EPMC8258759 | biostudies-literature
Project description:BackgroundNomograms were established to predict the survival for gastric signet ring cell carcinoma (GSRC) in young and middle-aged adults. Material and Methods. Eligible patients with GSRC from 2004 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database and then divided into a training and a testing cohort in proportion. Independent prognostic factors were picked by univariate and multivariate Cox regression analysis to set up nomograms. The predictive effect and clinical value of nomograms were evaluated by the concordance index (C-index), calibration curves, and receiver operating characteristic curve (ROC).ResultsA total of 1686 GSRC patients were subsumed into this case for analysis, including a training (n = 1180) and a testing cohort (n = 506). Independent risk factors related to overall survival (OS) and cancer-specific survival (CSS) comprised of race, TNM stage, tumor size, number of positive lymph nodes (PLNE), and chemotherapy. For OS, the C-indexes of the training and testing cohorts were 0.737 and 0.752, while for CSS, C-indexes were, respectively, 0.749 and 0.751. These revealed that nomograms accurately predicted OS and CSS. Calibration curves and ROC demonstrated the apparent superiority of nomograms.ConclusionWe built a well-understood and comprehensive prognostic assessment model for GSRC, which provided an individualized survival prediction in the form of a quantitative score that can be considered for clinical practice.
| S-EPMC8016563 | biostudies-literature
Project description:While the incidence of gastric cancer (GC) in general has decreased worldwide in recent decades, the incidence of diffuse cancer historically comprising poorly cohesive cells-GC (PCC-GC) and including signet ring cell cancer is rising. Literature concerning PCC-GC is scarce and unclear, mostly due to a large variety of historically used definitions and classifications. Compared to other histological subtypes of GC, PCC-GC is nevertheless characterized by a distinct set of epidemiological, histological and clinical features which require a specific diagnostic and therapeutic approach. The aim of this review was to provide an update on the definition, classification and therapeutic strategies of PCC-GC. We focus on the updated histological definition of PCC-GC, along with its implications on future treatment strategies and study design. Also, specific considerations in the diagnostic management are discussed. Finally, the impact of some recent developments in the therapeutic management of GC in general such as the recently validated taxane-based regimens (5-Fluorouracil, leucovorin, oxaliplatin and docetaxel), the use of hyperthermic intraperitoneal chemotherapy as well as pressurized intraperitoneal aerosol chemotherapy and targeted therapy have been reviewed in depth for their relative importance for PCC-GC in particular.
| S-EPMC9412924 | biostudies-literature
Project description:Purpose:To identify the potential therapeutic role of postoperative radiotherapy (RT) in patients with locally advanced (stage II and stage III) gastric signet ring cell carcinoma (SRC). Materials and methods:Patients with locally advanced gastric SRC from the Surveillance, Epidemiology, and End Results program database between 2004 and 2012 were included in our study. Univariate and multivariate Cox proportional models were performed, and survival curves were generated to evaluate the prognostic effect of postoperative RT and surgery alone on SRC patients. Propensity score matching (PSM) was used to avoid selection bias among the study cohorts. Results:We found that patients with postoperative RT had better probability of survival compared with those who did not receive RT (overall survival [OS], P<0.001; cancer-specific survival [CSS], P<0.001). After PSM, analysis of both overall and CSS showed that patients who underwent postoperative RT had better prognosis than those receiving surgery alone in the matched cohort (OS, P=0.00079; CSS, P=0.0036). Multivariate Cox proportional model indicated that postoperative RT had better effect on prognosis compared with surgery alone with respect to both overall (hazard ratio [HR], 0.716; 95% confidence interval [95% CI], 0.590-0.87; P=0.001) and CSS (HR, 0.713; 95% CI, 0.570-0.890; P=0.003). Conclusions:Postoperative RT had better prognosis compared with surgery alone for both overall and CSS for patients with locally advanced gastric SRC.
| S-EPMC6928086 | biostudies-literature
Project description:Signet-ring cell carcinoma (SRC) in advanced gastric cancer (GC) is often associated with more invasiveness and a worse prognosis than other cell types. The genetic alterations associated with gastric carcinogenesis in SRC are still unclear. In this study, 441 GC patients receiving curative surgery for GC between 2005 and 2013 were enrolled. The clinicopathological characteristics and genetic alterations of GC patients with and without SRC were compared. Among the 441 GC patients, 181 had SRC. For early GC, patients with SRC had more tumors located in the middle and lower stomach, more infiltrating tumors and better overall survival (OS) rates than those without SRC. For advanced GC, patients with SRC had more scirrhous type tumors, more PIK3CA amplifications, fewer microsatellite instability-high (MSI-H) tumors, more peritoneal recurrences and worse 5-year OS rates than those without SRC. For advanced GC with SRC, patients with peritoneal recurrence tended to have PD-L1 expression. For advanced GC without SRC, patients with liver metastasis tended to have PD-L1 expression, PI3K/AKT pathway mutations, TP53 mutations and MSI-H tumors. For advanced GC, PD-L1 expression was associated with peritoneal recurrence in SRC tumors, while non-SRC tumors with liver metastasis were likely to have PI3K/AKT pathway mutations, TP53 mutations and PD-L1 expression; immunotherapy and targeted therapy may be beneficial for these patients.
| S-EPMC7463705 | biostudies-literature
Project description:BackgroundThere is no consistent evidence about the appropriate treatment strategies for gastric signet ring cell carcinoma (GSRC) to improve prognosis. We conducted a population-based study to examine the effects of combined modality therapies on survival outcomes using the Surveillance, Epidemiology, and End Results (SEER) data.MethodsAnalyses included stage II-III primary GSRC patients who were diagnosed between 2006 and 2016. Therapies were categorized as gastrectomy group, adjuvant chemotherapy (CT) group, neoadjuvant radiotherapy (RT) group, and adjuvant chemoradiotherapy (CRT) group. Survival analyses were conducted by Kaplan-Meier method and Cox proportional hazards models and subgrouped by gender, tumor site, stage at diagnosis, and number of lymph nodes removed.ResultsOf the 1717 cases of stage II-III primary GSRC, the mean (SD) age was 59.6 (13.3) years, and over a half were male (52.8%). A total of 39.9% patients received adjuvant CRT and the 5-year overall survival (OS) rate was 34.6%. The median OS of patients treated with adjuvant CRT was significantly longer than that of the gastrectomy group (33 months vs 24 months, aHR = 0.71, 95% CI: 0.59, 0.84). Although the crude model showed a significant association between adjuvant CT and total survival (cHR = 0.81, 95% CI: 0.68, 0.96), the effect measure turned null in the multivariable and sub-group analysis. We did not find the significant effect of neoadjuvant RT.ConclusionsIn this study, GSRC patients with stage II-III experienced improved overall survival after receiving adjuvant CRT, which provides several treatment implications. More clinical trials will be needed to verify the conclusion derived from this study.
| S-EPMC7520351 | biostudies-literature
Project description:BackgroundGastric signet ring cell carcinoma (SRCC) is an aggressive gastric adenocarcinoma with a poor prognosis when diagnosed at an advanced stage. As alternative medicine, two natural supplements (ascorbate (AA) and sodium alpha lipoate (LA)) have been shown to inhibit various cancers with mild side effects.MethodsThese two natural supplements and a series of combinations (AA&LA, AA+LA and LA + AA) were incubated with non-SRCC cells (GPM-1), patient-derived gastric origin SRCC (GPM-2), gastric-origin SRCCs (HSC-39 and KATO-3), human pancreatic (MIA PaCa-2) and ovarian (SKOV-3) cells for evaluating their therapeutic effects. Moreover, these treatments were applied in 3D-cultured organoids to reveal the feasibility of these approaches for in vivo study.ResultsAnalyzing their antioxidant capabilities and dose-response curves, we observed that all four gastric cell lines, including three patient-derived cell lines were sensitive to ascorbate (~ 10 mM). The influence of ascorbate incubation time was studied, with a 16-h incubation found to be optimal for in vitro studies. Moreover, a simultaneous combination of AA and LA (AA&LA) did not significantly inhibit cell proliferation, while prior LA treatment increased the growth inhibition of AA therapy (LA + AA). Anti-cancer efficacy of AA was further confirmed in 3D-cultured SRCC (KATO-3) organoids.ConclusionsThis study highlights the potential of AA and LA + AA in treating gastric origin SRCC, and demonstrates the influence of order in which the drugs are administered.
| S-EPMC8903574 | biostudies-literature
Project description:BACKGROUND:Gastric signet ring cell carcinoma (GSRCC) is one of the most malignant tumors. It has the features of high invasiveness, rapid progression, and resistance to chemotherapy. However, systematic analyses of mRNAs have not yet been performed for GSRCC. AIM:To identify key mRNAs and signaling pathways in GSRCC. METHODS:A transcriptome analysis of two GSRCC and two non-GSRCC samples was performed in this study. Differentially expressed mRNAs and pathways were identified based on the KEGG and PANTHER pathway annotations. The interactive relationships among the differential genes were mapped with the STRING database. Quantitative real-time polymerase chain reaction was used to validate the key gene expression in GSRCC. RESULTS:About 1162 differential genes (using a 2-fold cutoff, P < 0.05) were identified in GSRCC compared with non-GSRCC. The enriched KEGG and PANTHER pathways for the differential genes included immune response pathways, metabolic pathways, and metastasis-associated pathways. Ten genes (MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA6, MUC13, GUCA2A, FFAR4, REG1A, and REG1B) were identified as hub genes in the protein-protein interaction network. The expression levels of five genes (MAGEA2, MAGEA3, MAGEA4, MAGEA6, and REG1B) showed potential clinical value. CONCLUSION:We have identified the potential key genes and pathways in GSRCC, and these hub genes and pathways could be diagnostic markers and therapeutic targets for GSRCC.
| S-EPMC7052547 | biostudies-literature