Advanced Stage Gastric Cancer Research Articles

Pathological and Biological Significance of the Specific Glycan, TRA-1-60, on Aggressive Gastric Adenocarcinoma

The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was identified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid–ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody–drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.

Abstract 1179: A single-cell atlas of human gastric malignancy reveals CD8+ T cell rejuvenation as a mediator of immunotherapeutic response

Abstract Immune checkpoint inhibition (ICI) has emerged as a mainstream treatment for patients with advanced stage gastric cancer (GC). Cellular heterogeneity in the tumor microenvironment (TME) has a profound impact on the therapeutic responses to ICI. Here we characterize the kinetics of tumor-infiltrating immune populations in GC patients treated with anti-PD-1 using single-cell RNA and TCR sequencing (scRNA/TCR-seq), including primary tumors and metastases. Integrated with public GC scRNA-seq datasets, we construct the largest multi-omic atlas of GC cell states to date that captures the full trajectory of GC malignancy and comprises >320,000 cells derived from 73 samples. We demonstrate the rejuvenation of exhausted CD8+ T cells into a proliferative state marked by the loss of LAYN expression as a major mediator of ICI response in the TME. In parallel, we observe enhanced immunogenicity of cancer cells in post-ICI tumors, thus highlighting the coordination between tumor-intrinsic and microenvironmental factors elicited by ICI. Our study provides a valuable resource of investigating the tumor response to anti-PD-1 treatment and suggests novel strategies for combination therapy and patient stratification. Citation Format: Han Liang, Jian Chen, Yikai Luo, Muxing Kang, Wei Liu, Lie Wang. A single-cell atlas of human gastric malignancy reveals CD8+ T cell rejuvenation as a mediator of immunotherapeutic response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1179.

Claudin 18.2 as a novel therapeutic target.

Claudin 18.2, a tight-junction molecule predominantly found in the nonmalignant gastric epithelium, becomes accessible on the tumour cell surface during malignant transformation, thereby providing an appealing target for cancer therapy. Data from two phase III trials testing the anti-claudin 18.2 antibody zolbetuximab have established claudin 18.2-positive advanced-stage gastric cancers as an independent therapeutic subset that derives benefit from the addition of this agent to chemotherapy. This development has substantially increased the percentage of patients eligible for targeted therapy. Furthermore, newer treatments, such as high-affinity monoclonal antibodies, bispecific antibodies, chimeric antigen receptor T cells and antibody-drug conjugates capable of bystander killing effects, have shown considerable promise in patients with claudin 18.2-expressing gastric cancers. This new development has resulted from drug developers moving beyond traditional targets, such as driver gene alterations or growth factors. In this Review, we highlight the biological rationale and explore the clinical activity of therapies that target claudin 18.2 in patients with advanced-stage gastric cancer and explore the potential for expansion of claudin 18.2-targeted therapies to patients with other claudin 18.2-positive solid tumours.

Play the "combo fist" in the diagnosis and treatment of advanced gastric cancer

The incidence of gastric cancer ranks fifth among malignant tumors worldwide, with the fourth highest mortality rate. A noteworthy characteristic of our country is the high prevalence of advanced-stage patients of approximately 40%. Advanced-stage gastric cancer carries an unfavorable prognosis with median survival of around one year. Diagnosis methods for advanced-stage gastric cancer (such as laparoscopic exploration, molecular profiling, and artificial intelligence) are still being continuously improved, while chemotherapy remains the primary treatment. With the rapid development of medical science, the role of surgical intervention in advanced-stage gastric cancer is becoming increasingly prominent. Therefore, as gastric tumor surgeons, we should consider how to use a combination of treatments, including surgery, chemotherapy, targeted therapy, immunotherapy, and interventional therapy, based on different pathological stages and the heterogeneity of tumors. With a multidisciplinary approach involving experts from various fields, we can collectively improve the survival rate and quality of life for advanced-stage patients. This article provides a brief overview of the current advances in the diagnosis and treatment of advanced-stage gastric cancer, and discusses therapeutic decision primarily from the perspective of surgeons.

Big Data and Artificial Intelligence in Drug Discovery for Gastric Cancer: Current Applications and Future Perspectives.

Gastric cancer (GC) represents a significant global health burden, ranking as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Despite recent advancements in GC treatment, the five-year survival rate for advanced-stage GC patients remains low. Consequently, there is an urgent need to identify novel drug targets and develop effective therapies. However, traditional drug discovery approaches are associated with high costs, time-consuming processes, and a high failure rate, posing challenges in meeting this critical need. In recent years, there has been a rapid increase in the utilization of artificial intelligence (AI) algorithms and big data in drug discovery, particularly in cancer research. AI has the potential to improve the drug discovery process by analyzing vast and complex datasets from multiple sources, enabling the prediction of compound efficacy and toxicity, as well as the optimization of drug candidates. This review provides an overview of the latest AI algorithms and big data employed in drug discovery for GC. Additionally, we examine the various applications of AI in this field, with a specific focus on therapeutic discovery. Moreover, we discuss the challenges, limitations, and prospects of emerging AI methods, which hold significant promise for advancing GC research in the future.

The prognostic role of neutrophil/lymphocyte ratio and monocyte/lymphocyte ratio in advanced stage gastric cancer patients receiving chemotherapy: a single center experience

Objective: Several studies revealed that peripheral blood Neutrophil/Lymphocyte ratio (NLR) and Monocyte/Lymphocyte Ratio (MLR) were prognostic in various cancer types. However, there are no excessive information about the prognostic significance of NLR and MLR in patients with advanced gastric cancer. As a result, we examined whether NLR and/or MLR could be used as a prognostic marker to predict survival outcomes in patients with advanced gastric cancer receiving palliative chemotherapy.
 
 Method: We retrospectively analyzed 119 patients with gastric cancer receiving chemotherapy. We evaluated the relationship between potential prognostic factors and overall survival (OS) times using the Kaplan-Meier method and Cox regression survival modelling.
 
 Results: The median overall survival of the patients was 6.9 (2.1-41.6) months. In univariate analysis, NLR (p< 0.001), ECOG performance status (p< 0.001), presence of liver metastases (p< 0.001) and presence of peritoneal metastases (p< 0.001) were found to be associated with survival. The multivariate survival model showed the high NLR (HR=1.59, 95% CI 1.6-2.40, p= 0.026), the patients with ECOG performance score 2-3 (HR=2.91, 95% CI 1.60-5.27, p

The diagnostic and prognostic value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio on gastric cancer patients.

Gastric cancer (GC) is the remaining concern of cancer-associated health burden. Valuable predictive and prognostic indicators support the early diagnosis and improve outcome. Immune escape and inflammation are important cancer hallmarks. The prognostic and diagnostic value of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) was reported in some cancers. But these cheap and convenient indexes are far from clinical use. Thus, investigation the alteration of those index on GC is needed to impose the use of those indexes in clinic. The study recruited seventy-seven hospitalized patients newly diagnosed with GC and 90 healthy individuals. The clinical and preclinical data of participants were collected from Hospital Information Management system. This study were approved by the Ethical Committee, Vietnam Military Medical University. The data were analyzed on STATA version 14.0 and GraphPad Prism 8.0. The alteration of immunological system was reported by significantly higher white blood cell count, neutrophils, platelets, PLR, and NLR as well as decreased lymphocytes on GC, compared to healthy individuals. Those indexes were elevated on advanced stage GC, compared to early stage GC. Our receiver operating characteristic curve analysis showed the significant specificity and sensitivity of PLR (cutoff 135.0) and NLR (cutoff 2.0) on GC diagnosis with respective area under receiver operating characteristic curve of 84.74% and 85.17%, P < .0001. Besides, our results reported the tendency of increased PLR and NLR and short time from clinical signs to being diagnosed. PLR and NLR have significant specificity and sensitivity in diagnosis and prognosis of GC.

HOXA11 promotes lymphatic metastasis of gastric cancer via transcriptional activation of TGFβ1

Most gastric cancer (GC) patients with early stage often have no lymph node (LN) metastases, while LN metastases appear in the advanced stage. However, there are some patients who present with early stage LN metastases and no LN metastases in the advanced stage. To explore the deeper molecular mechanisms involved, we collected clinical samples from early and advanced stage GC with and without LN metastases, as well as metastatic lymph nodes. Herein, we identified a key target, HOXA11, that was upregulated in GC tissues and closely associated with lymphatic metastases. HOXA11 transcriptionally regulates TGFβ1 expression and activates the TGFβ1/Smad2 pathway, which not only promotes EMT development but also induces VEGF-C secretion and lymphangiogenesis. These findings provide a plausible mechanism for HOXA11-modulated tumor in lymphatic metastasis and suggest that HOXA11 may represent a potential therapeutic target for clinical intervention in LN-metastatic gastric cancer.

Transfer RNA-derived fragments as novel biomarkers of the onset and progression of gastric cancer.

Gastric cancer (GC) is a particularly malignant disease; thus, early diagnosis and treatment are especially important. Transfer RNA-derived small RNAs (tsRNAs) have been implicated in the onset and progression of various cancers. Therefore, the aim of this study was to explore the role of tRF-18-79MP9P04 (previously named tRF-5026a) in the onset and progression of GC. Expression levels of tRF-18-79MP9P04 were quantified in gastric mucosa specimens of healthy controls and plasma samples of patients with different stages of GC. The results showed that plasma levels of tRF-18-79MP9P04 were significantly decreased in the early and advanced stages of GC. The results of the nucleocytoplasmic separation assay found that tRF-18-79MP9P04 was localized in the nuclei of GC cells. High-throughput transcriptome sequencing identified genes regulated by tRF-18-79MP9P04 in GC cells, and the function of tRF-18-79MP9P04 was predicted by bioinformatics. Collectively, the findings of this study suggest that tRF-18-79MP9P04 would be useful as non-invasive biomarker for early diagnosis of GC and is related to cornification, the type I interferon signaling pathway, RNA polymerase II activities, and DNA binding.

Prognostic and predictive values of the grading system of lymph node status in patients with advanced-stage gastric cancer.

Lymph node metastasis is one of the most important prognostic factors of gastric cancer. However, the effect of germinal centers in lymph nodes on the prognosis of patients with gastric cancer has not been reported. This study aimed to investigate the contribution of germinal center generation to prognostic parameters and clinicopathological significance in gastric cancer. We retrospectively reviewed gastric cancer patients who underwent surgery from October 2012 to June 2022. We analyzed 5484 lymph nodes (210 patients) and calculated the lymph node metastasis rate (LNMR) and the proportion of non-metastatic lymph nodes containing three or more germinal centers (NML-GCP). Using a grading system that incorporated LNMR and NML-GCP. The tumors were classified into three groups based on this system, which was found to be significantly associated with prognosis. The TNM stage and grading system of lymph node status were independent risk factors for overall survival (OS) and disease-free survival (DFS). The 5-year OS rates for patients with advanced gastric cancer were 85.07% (n=50), 58.34% (n=42), and 24.44% (n=21) for Grades 1, 2, and 3, respectively (p<0.0001). The 5-year DFS rates were 65.32% (n=58), 40.85% (n=51), and 5.88% (n=34), respectively (p<0.0001). Patients with Grade 1 advanced gastric cancer had higher 5-year OS and DFS rates compared to those with Grade 2 or 3 in TNM stage II and III. Furthermore, the 5-year OS and DFS rates differed significantly among patients with different grades of advanced gastric cancer who received chemotherapy (p<0.0001). These findings suggest that the grading system may be valuable for predicting prognosis and guiding clinical management in patients with gastric cancer, and provides good prognostic stratification for OS and DFS in patients with TNM stage II and III.

Positive lymph node ratio as a prognostic factor for gastric cancer patients: Is it going to supersede positive lymph node number in guidelines?

Gastric malignancies constitute the sixth most common cancer with regards to incidence and have the fifth most mortality rates. Extended lymph-node dissection is the surgical modality of choice while treating advanced stage gastric cancer. It is yet a topic of debate, whether or not the amount of positive lymph nodes after a pathological examination following the surgical intervention is of prognostic value. In this study, it is aimed to evaluate the prognostic significance of positive lymph nodes following the surgery. A total of 193 patients who underwent curative gastrectomy between January 2011 and December 2015 have been considered for a retrospective data collection. The cases with R1-R2 resections, palliative or emergent surgeries are excluded. Metastatic to total number of lymph nodes, corresponded a ratio which was analyzed in this survey and practiced as a predictive parameter of disease outcome. This survey includes 138 male (71.5%) and 55 female (28.5%) patients treated between 2011 and 2015 in our clinic. The survey follow-up duration of the cases range between 0, 2, and 72 months, corresponding an average of 23.24 ± 16.99 months. We calculated cutoff value of 0.09 with, sensitivity is 76.32% for positive to total number of lymph nodes ratio, whereas specivity applies for 64.10%, positive predictive value for 58% and negative predictive value for 80.6%. Positive lymph node ratio has a prognostic value in terms of predicting the prognosis of the patients with gastric adenocarcinoma following a curative gastrectomy. This might in long term contribute to the prognostic analysis of patients if integrated in the current staging system.

MSC-NPRA loop drives fatty acid oxidation to promote stemness and chemoresistance of gastric cancer

Cisplatin (CDDP)-based chemotherapy is the preferred treatment strategy for advanced stage gastric cancer (GC) patients. Despite the efficacy of chemotherapy, the development of chemoresistance negatively affects the prognosis of GC and the underlying mechanism remains poorly understood. Accumulated evidence suggests that mesenchymal stem cells (MSCs) play important roles in drug resistance. The chemoresistance and stemness of GC cells were observed by colony formation, CCK-8, sphere formation and flow cytometry assays. Cell lines and animal models were utilized to investigate related functions. Western blot, quantitative real-time PCR (qRT-PCR) and co-immunoprecipitation were used to explore related pathways. The results showed that MSCs improved the stemness and chemoresistance of GC cells and accounted for the poor prognosis of GC. Natriuretic peptide receptor A (NPRA) was upregulated in GC cells cocultured with MSCs and knockdown of NPRA reversed the MSC-induced stemness and chemoresistance. At the same time, MSCs could be recruited to GC by NPRA, which formed a loop. In addition, NPRA facilitated stemness and chemoresistance through fatty acid oxidation (FAO). Mechanistically, NPRA protected Mfn2 against protein degradation and promoted its mitochondrial localization, which consequently improved FAO. Furthermore, inhibition of FAO with etomoxir (ETX) attenuated MSC-induced CDDP resistance in vivo. In conclusion, MSC-induced NPRA promoted stemness and chemoresistance by upregulating Mfn2 and improving FAO. These findings help us understand the role of NPRA in the prognosis and chemotherapy of GC. NPRA may be a promising target to overcome chemoresistance.

Comparison of Two Chemotherapy Regimens After First-Line Treatment for HER2-Negative Metastatic Gastric Cancer.

Metastatic stage gastric cancer is a disease with a poor prognosis and the likelihood of achieving a cure in these patients is low. Treatment response to subsequent-line treatments is poor. We aimed to investigate the effectiveness of the folinic acid, fluorouracil and irinotecan (FOLFIRI) and paclitaxel+carboplatin regimens, which are used in subsequent lines of therapy in advanced-stage gastric cancer. This study included 40 patients who have metastatic stage gastric cancer and received FOLFIRI or paclitaxel+carboplatin therapy in subsequent lines of therapy between 2017 and 2022. The data of the patients were analyzed retrospectively. At diagnosis median age was 51 (23-88) years. The tumor was localized in the gastroesophageal junction in eight (20%) patients and in other gastric locations in 32 (80%) patients. At diagnosis, 75% (n=30) of the patients presented with the disease in the metastatic stage, while 25% (n=10) presented with stage II-III disease. Regarding the treatments received in the second and further lines of therapy, 18 (45%) patients received paclitaxel+carboplatin and 22 (55%) patients received a FOLFIRI regimen. Of these treatments, 67.5% (n=27) were given as the second line and 32.5% (n=13) were given as third-line therapy. The objective response rate (ORR) was 45.5% in the FOLFIRI arm compared to 16.7% in the paclitaxel+carboplatin arm (p=0.05). Both treatment arms had a median progression-free survival (PFS) of three months (p=0.82). The median overall survival (OS) time was seven months in the FOLFIRI arm compared to eight months in the paclitaxel+carboplatin arm (p=0.71). Side effects were similar between both treatment arms. This study determined that FOLFIRI and paclitaxel+carboplatin treatments have similar OS, PFS, and side effect profiles in subsequentline treatment of gastric cancer. The FOLFIRI treatment regimen yielded a higher ORR.

Is it possible that advanced-stage gastric cancer patients can be cured by surgery alone?: Erratum.

Is it possible that advanced-stage gastric cancer patients can be cured by surgery alone?: Erratum.

Survival benefits of perioperative chemoradiotherapy versus chemotherapy for advanced stage gastric cancer based on directed acyclic graphs.

The overall survival benefits of perioperative chemotherapy (PCT) and perioperative chemoradiotherapy (PCRT) for patients with locally advanced gastric cancer (GC) have not been fully explored. The aim of this study was to compare the benefits of PCT and PCRT in GC patients and determine the factors affecting survival rate using directed acyclic graphs (DAGs). The data of 1,442 patients with stage II-IV GC who received PCT or PCRT from 2000 to 2018 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. First, the least absolute shrinkage and selection operator (LASSO) was used to identify possible influencing factors for overall survival. Second, the variables that were selected by LASSO were then used in univariate and Cox regression analyses. Third, corrective analyses for confounding factors were selected based on DAGs that show the possible association between advanced GC patients and outcomes and evaluate the prognosis. Patients who received PCRT had longer overall survival than those who received PCT treatment (P = 0.015). The median length of overall survival of the PCRT group was 36.5 (15.0 - 53.0) months longer than that of the PCT group (34.6 (16.0 - 48.0) months). PCRT is more likely to benefit patients who are aged ≤ 65, male, white, and have regional tumors (P<0.05). The multivariate Cox regression model showed that male sex, widowed status, signet ring cell carcinoma, and lung metastases were independent risk factors for a poor prognosis. According to DAG, age, race, and Lauren type may be confounding factors that affect the prognosis of advanced GC. Compared to PCT, PCRT has more survival benefits for patients with locally advanced GC, and ongoing investigations are needed to better determine the optimal treatment. Furthermore, DAGs are a useful tool for contending with confounding and selection biases to ensure the proper implementation of high-quality research.

Understanding The Regulatory Role of USP32 and SHMT2 in The Progression of Gastric Cancer.

Gastric cancer is the fifth most common neoplasm and the fourth reason for mortality globally. Incidence rates are highly variable and dependent on risk factors, epidemiologic and carcinogenesis patterns. Previous studies reported that Helicobacter pylori (H. pylori) infection is one the strongest known risk factor for gastric cancer. USP32 is a deubiquitinating enzyme identified as a potential factor associated with tumor progression and a key player in cancer development. On the other hand, SHMT2 is involved in serine-glycine metabolism to support cancer cell proliferation. Both USP32 and SHMT2 are reported to be upregulated in many cancer types, including gastric cancer, but its complete mechanism is not fully explored yet. The present study explored possible mechanism of action of USP32 and SHMT2 in the progression of gastric cancer. In this experimental study, Capsaicin (0.3 g/kg/day) and H. pylori infection combination was used to successfully initiate gastric cancer conditions in mice. It was followed by 40 and 70 days of treatment to establish initial and advanced conditions of gastric cancer. Histopathology confirmed formation of signet ring cell and initiation of cellular proliferation in the initial gastric cancer. More proliferative cells were also observed. In addition, tissue hardening was confirmed in the advanced stage of gastric cancer. USP32 and SHMT2 showed progressive upregulated expression, as gastric cancer progress. Immunohistologically, it showed signals in abnormal cells and high-intensity signals in the advanced stage of cancer. In USP32 silenced tissue, expression of SHMT2 was completely blocked and reverted cancer development as evident with less abnormal cell in initial gastric cancer. Reduction of SHMT2 level to one-fourth was observed in the advanced gastric cancer stages of USP32 silenced tissue. USP32 had a direct role in regulating SHMT2 expression, which attracted therapeutic target for future treatment.

Fibrinogen-to-Lymphocyte Ratio Was an Independent Predictor of Lymph Node Metastasis in Patients with Clinically Node-Negative Advanced-Stage Gastric Cancer.

Various hematological indicators have been reported to predict lymph node metastasis (LNM) in gastric cancer (GC) patients, but the relationship between FLR and LNM has not been studied. Therefore, the aim of this study was to evaluate the role of preoperative fibrinogen-to-lymphocyte ratio (FLR) in predicting LNM in patients with clinically node-negative (cN0) advanced gastric cancer (AGC). We retrospectively reviewed 571 eligible patients with primary AGC adenocarcinoma who underwent radical gastrectomy (discoverycohort). Patients were divided into high and low FLR groups according to the optimal cutoff value determined by Youden index. FLR is an independent predictor of LNM determined by logistic regression and validated in the validation cohort of 207 patients. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of FLR for LNM. The nonlinear relationship between FLR and LNM risk was assessed using restricted cubic spline. Sensitivity analyses were performed according to FLR quartiles to further assess the robustness of the results. The nomogram was built based on FLR and clinicopathological characteristics, and was evaluated by calibration curves, ROC curve analysis and decision curve analysis. In the discoverycohort, the area under the curve (AUC) value for FLR to predict LNM was 0.592. There is a linear relationship between the FLR value and the risk of LNM, and the risk of LNM increased with FLR value. High FLR level is an independent risk factor for LNM, and the results of sensitivity analysis robust this finding. The nomogram for individual risk assessment performed well. Furthermore, we verified the FLR was an independent predictor of LNM in the validation cohort. FLR was an independent predictor of LNM in patients with cN0 AGC.

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

Indications, Safety, Efficacy and Survival Benefit of Intraperitoneal Chemotherapy in Patients With Advanced Gastric Cancer.

Advanced gastric cancer remains a significant concern for the medical community mostly due to the locoregional extension of the disease. Most commonly, stomach neoplasms are resectable, but not curable, due to the elevated percentage of peritoneal dissemination after gastrectomy and extensive lymph node dissection. Locoregional intraperitoneal chemotherapy plays a pivotal role in overall survival and prognosis of patients with advanced gastric cancer and shows a high probability of peritoneal dissemination after gastrectomy. In this review, we aimed to collect and present literature data concerning intraperitoneal chemotherapy in advanced stages of gastric cancer as well as evaluate the safety and survival benefit of the procedure. We conducted a survey including all randomized controlled trials and clinical trials that were published in the last 30 years. The keywords used were: advanced gastric cancer, intraperitoneal chemotherapy and peritoneal carcinomatosis. We searched for clinical trials in Pubmed, Embase databases and the Cochrane library. Inclusion criteria were: patients with advanced gastric cancer with no macroscopical signs of peritoneal dissemination, who were treated with D2 gastrectomy and received one or more cycles of intraperitoneal chemotherapy. The final review included 20 articles. The safety of intraperitoneal chemotherapy, as well as the survival benefit of patients were evaluated. The majority of articles denoted that intraperitoneal chemotherapy is a safe procedure without severe or lethal complications. The majority of complications were hematological while non-hematologic complications were also noted. A survival benefit with statistically significant results (p<0.05) was observed in 6 out of 10 randomized controlled trials. Intraperitoneal chemotherapy for advanced gastric cancer is a safe procedure with promising results regarding survival benefit and prognosis. Further patient evaluation is required in order to standardize the type of chemotherapeutic agent and the sufficient dose and cycles for the most appropriate results.

Differentially Expressed Genes and Signaling Pathways Potentially Involved in Primary Resistance to Chemo-Immunotherapy in Advanced-Stage Gastric Cancer Patients.

Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3′ massive analysis of cDNA ends (3′MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-β-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/β-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.