Gastric Cancer Therapy Research Articles

Efficacy and safety of anti-programmed death-1 antibody-based combination therapy in advanced or metastatic gastric or gastroesophageal junction cancer in Chinese patients: A real-world study.

Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed. In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.

Anchoring of hyaluronan glycocalyx to CD44 reduces sensitivity of HER2-positive gastric cancer cells to trastuzumab.

Trastuzumab is widely used in human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) therapy, but ubiquitous resistance limits its clinical application. In this study, we first showed that CD44 antigen is a significant predictor of overall survival for patients with HER2-positive GC. Next, we found that CD44 could be co-immunoprecipitated and co-localized with HER2 on the membrane of GC cells. By analyzing the interaction between CD44 and HER2, we identified that CD44 could upregulate HER2 protein by inhibiting its proteasome degradation. Notably, the overexpression of CD44 could decrease the sensitivity of HER2-positive GC cells to trastuzumab. Further mechanistic study showed that CD44 upregulation could induce its ligand, hyaluronan (HA), to deposit on the cancer cell surface, resulting in covering up the binding sites of trastuzumab to HER2. Removing the HA glycocalyx restored sensitivity of the cells to trastuzumab. Collectively, our findings suggested a role for CD44 in regulating trastuzumab sensitivity and provided novel insights into HER2-targeted therapy.

Self-assembled redox-responsive BRD4 siRNA nanoparticles: fomulation and its in vitro delivery in gastric cancer cells

With the development of newer biomarkers in the diagnosis of gastric cancer (GC), therapeutic targets are emerging and molecular-targeted therapy is in progress RNA interference has emerged as a promising method of gene targeting therapy. However, naked small interfering RNA (siRNA) is unstable and susceptible to degradation, so employing vectors for siRNA delivery is the focus of our research. Therefore, we developed LMWP modified PEG-SS-PEI to deliver siRNA targeting BRD4 (L-NPs/siBRD4) for GC therapy. L-NPs/siBRD4 were prepared by electrostatic interaction and characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The release characteristics, cellular uptake and intracellular localization were also investigated. The in vitro anticancer activity of the prepared nanoparticles was analysed by MTT, Transwell invasion and wound healing assay. Quantitative real time-polymerase chain reaction (qRT-PCR) and Western blot were used to detect the effect of gene silencing. The results showed that the optimal N/P was 30 and the prepared L-NPs/siBRD4 uniformly distributed in the system with a spherical and regular shape. L-NPs/siBRD4 exhibited an accelerated release in GSH-containing media from 12h to 24h. The uptake of L-NPs/siBRD4 was enhanced and mainly co-localized in the lysosomes. After 6h incubation, LMWP modified PEG-SS-PEI helped siRNA escape from the lysosomes and diffused into the cytoplasm. L-NPs/siBRD4 significantly inhibited the proliferation, migration and invasion of cells. This might be related with the silence of BRD4, then inhibition of PI3K/Akt and c-Myc. Our results demonstrate that L-NPs/siBRD4 are a novel delivery system with anticancer, which may provide a more effective strategy for GC treatment.

Relationship between the number of positive MSI markers and the efficacy of NIVO+IPI therapy in MSI-H gastric cancer: A subgroup analysis of NO LIMIT study (WJOG13320G/CA209-7W7).

386 Background: Although high instability of microsatellite lesion (MSI-H) is an established biomarker for response to immune checkpoint inhibitors, the relationship between the number of MSI markers and the efficacy of immune checkpoint inhibitors in MSI-H tumors has not been well elucidated. NO LIMIT (WJOG13320G/CA209-7W7) is a phase II trial of nivolumab plus low-dose ipilimumab (NIVO+IPI) for MSI-H advanced gastric or esophagogastric junction cancer (GC) in the first-line setting.1 Here, we investigated the relationship between the number of positive MSI markers and the efficacy of NIVO+IPI in NO LIMIT study. Methods: Eligible patients were unresectable advanced, recurrent, or metastatic GC with confirmed as MSI-H with the MSI-IVD Kit (FALCO), where two or more of the five MSI markers are defined as positive. Nivolumab (240 mg) biweekly and ipilimumab (1 mg/kg) every six weeks were given until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) assessed by a blinded independent central review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and the association between number of positive MSI markers and clinical efficacy (ORR, PFS, OS). The analysis was performed 18 weeks after the first dose in the last patient, with a median follow-up of 9 months (range, 4.0-18.0). Results: The breakdown of MSI markers in the 29 patients enrolled in NO LIMIT was as follows: BAT-26 (26/26, 100%), NR-21 (25/29, 86.2%), BAT-25 (25/29, 86.2%), MONO-27 (29/29, 100%), NR-24 (27/29, 89.4%). Since most of the cases were positive for all five of them (the number of cases with 2, 3, 4, and 5 positive markers was 2, 2, 1, and 24, respectively), we dichotomized cases into group A (all five positive) and group B (the others). Response rates in groups A vs. B were 62.5% (15/24) vs. 60.0% (3/5), respectively. There was no difference in PFS or OS between the two groups. Conclusions: The number of MSI markers is not related to the efficacy of NIVO+IPI in NO LIMIT study. Further follow-up is needed to confirm the relationship between survival. 1. Muro K, et al. ESMO Congress 2023. Clinical trial information: jRCT2080225304 . [Table: see text]

Real-world treatment patterns, testing patterns, and clinical outcomes of first-line (1L) therapy for metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (mGC/GEJC/EAC).

275 Background: GC/GEJC/EAC are among the leading causes of cancer-related morbidity and mortality worldwide. Nivolumab + fluoropyrimidine- + platinum-containing chemotherapy (NIVO+chemo) has demonstrated superior efficacy in patients with advanced non-HER2-positive (HER2-) GC/GEJC/EAC versus chemo alone in the CheckMate 649 trial. The objective of this study was to characterize real-world treatment and PD-L1 testing patterns in the 1L setting for mGC/GEJC/EAC since the FDA approval of NIVO+chemo on April 16, 2021. Methods: This retrospective observational study used the electronic medical record data from the ConcertAI Patient360 database. Adult patients with HER2- mGC/GEJC/EAC and 1L initiation date (index date) between April 16, 2021 and October 31, 2022 were included. PD-L1 testing patterns and 1L regimens were described overall and stratified by PD-L1 testing. The analyses of clinical outcomes are currently ongoing. Results: A total of 161 patients with mGC/GEJC/EAC met the inclusion criteria. The median age at index was 67.0 years, 76.4% were male, and the median follow-up time from index date was 6.7 months. 81 (50.3%) patients had evidence of receiving at least one PD-L1 test (median [interquartile range] time from first test to 1L initiation: 0.4 [-0.1, 1.0] months) among whom 28 (34.6%) had the first test documented after 1L initiation. Overall, 1L immunotherapy-based regimens were received by 63 (39.1%) patients, with NIVO+chemo being the most common (n = 47; 29.2%). 1L fluoropyrimidine- + platinum-containing chemotherapy and other chemotherapies were received by 51 (31.7%) and 42 (26.1%) patients, respectively. Among patients with evidence of PD-L1 testing, 31 (38.3%) received NIVO+chemo, and 37 (45.7%) received chemotherapy alone. Among those without evidence of PD-L1 testing, 56 (70.0%) received chemotherapy alone, and 16 (20.0%) received NIVO+chemo. Conclusions: These preliminary findings show an early uptake of NIVO+chemo in the advanced or metastatic GC/GEJC/EAC patient population. With a majority of PD-L1 untested patients receiving chemotherapy only as 1L therapy, there is an opportunity for these patients to potentially benefit from immuno-oncology containing regimens. Further analyses are needed to characterize the chemotherapy only treated patient population.

A phase II study of perioperative capecitabine plus oxaliplatin (CapeOx) therapy for advanced gastric cancer with multiple lymph node metastases (OGSG 1701).

304 Background: Gastric cancer with paraaortic lymph node metastasis or bulky lymph node metastasis is difficult to undergo curative resection without preoperative chemotherapy. Even if curative resection can be performed, the prognosis is extremely poor. The purpose of this study was to evaluate the efficacy and safety of perioperative capecitabine plus oxaliplatin combined chemotherapy (CapeOx) for such advanced gastric cancer with multiple lymph node metastases. Methods: In this phase II trial, eligibility criteria were as follows; histologically proven gastric carcinoma; HER2 negative or unknown; with paraaortic lymph node metastases (#16a2/16b1) > 10 mm and/or bulky lymph node metastases located at celiac axis, common hepatic artery, splenic artery and/or upper mesenteric vein which make a huge bulk > 3.0 cm and/or multiple large bulks > 1.5 cm; without any other metastatic lesions; not a large (≥ 8 cm) type 3 or type 4 gastric cancer; and age between 20 and 80 years old. Treatment included three cycles of preoperative CapeOx (capecitabine; 2,000 mg/m2 for 14 days, oxaliplatin; 130 mg/m2 day 1) every 3 weeks, followed by five cycles of postoperative CapeOx after radical gastrectomy. The primary endpoint was response rate according to the RECIST v1.0. The planned sample size was 30 patients calculated on the hypothesis that the expected response rate was 65% and the threshold was 50%, with one-sided alpha of 0.05 and the power of 90%. Results: Thirty patients from 14 institutions were enrolled from September 2017 to June 2022. The number of patients with compete response, partial response, stable disease, progressive disease, and inevaluable were, 0, 20, 8, 1, and 1, respectively. The response rate was 66.7%, with the 90% confidence interval of 50.1 - 80.7% ( p = 0.049). The curative resection rate was 93.3%. The protocol treatment completion rate was 53.3%. The preoperative chemotherapy completion rate was 93.3%. The operation completion rate was 90.0%. The postoperative chemotherapy completion rate was 70.0%. The relative dose intensities were 94.8% for capecitabine and 95.2% for oxaliplatin on preoperative CapeOx, and 80.8% for capecitabine and 64.2% for oxaliplatin on postoperative CapeOx. The histological response rate (Grade ≥ 1b) was 66.7%. The adverse events of Grade ≥ 3 included neutropenia in 3.3%, anemia in 6.7%, and anorexia in 10% on preoperative CapeOx, and neutropenia in 23.8% and diarrhea in 9.5% on postoperative CapeOx. The final results of the survival analysis are yet to come. Conclusions: Perioperative CapeOx therapy for advanced gastric cancer with multiple lymph node metastasis showed favorable response rate, curative resection rate and acceptable adverse events, and was considered a promising treatment regimen. Clinical trial information: UMIN000028749 .

PD1 and CD39 expression on tumor infiltrating lymphocytes in patients with gastric cancer.

377 Background: Activation and clonal expansion of tumor antigen-specific T cells in cancer patients are crucial for immunotherapies. Recent reports indicate that CD39 is a marker to distinguish tumor-reactive CD8 T cell populations from bystander populations. In gastric cancer (GC), anti-CD39 antibody, anti-PD-1 antibody, and FOLFOX combination therapy may be effective therapy at AACR 2022. Methods: We retrospectively reviewed the data of 62 GC patients who underwent gastrectomy at our hospital (2017 - 2018) and examined their rejected specimen’s immune-microenvironment using immunohistochemistry. Then we prospectively enrolled 16 GC patients. Their tumor tissue and tumor-infiltrating lymphocytes (TILs) were extracted from surgical specimens, these fractions were subjected to the RNA-seq analysis ( n = 3), CD107a degranulation assay ( n = 7) and 3H-Thymidine incorporation assay ( n = 7). Results: The densities of CD39+CD8 TILs positively correlated with the densities of CD4 T cells and B-cells in GC tissues ( P = 0.01, < 0.01, respectively). Furthermore, higher densities of CD39+CD8 TILs in GC patients were associated with better overall survival ( P < 0.01). We classified TILs into four groups based on expression levels of the PD-1 and CD39. The proportion of CD39+CD8 T cells was significantly higher in GC tissues than their PBMCs ( n = 13) and non-cancerous tissues ( n = 4). CD39+PD-1+CD8 (DP) TILs in primary tumors were elevated expression of multiple inhibitory receptors such as LAG3, TIGIT and reduced expression of IL-2 by RNA-seq analysis. T cells expanded in vitro from DP-TILs ( n = 5) efficiently recognized autologous tumor cells in CD107a assay compared with other populations, and considered to be tumor-reactive T cells fraction. However, since these DP TILs in primary tumors show exhausted phenotypes, capacities to kill tumor are expected to be reduced in the tumor-microenvironment (TME). By adding ATP to the DP-TILs in vitro at the concentration reported in the TME, we observed reduction of cell proliferation by 3H-thymidene incorporation assay and of degranulation by CD107a assay, and we observed recovery of these changes by adding anti-CD39 inhibitory antibody. Conclusions: DP-TILs may have superior T cell receptors recognizing tumor-antigens and contribute to tumor eradication, especially when administrated anti-CD39 antibody.

Infusional fluorouracil and weekly docetaxel as first-line therapy for gastric cancer with bone marrow metastasis and disseminated intravascular coagulation: A multi-center, phase II trial (Zhen Long).

337 Background: Gastric cancer (GC) with bone marrow metastasis (BMM) and disseminated intravascular coagulation (DIC) constitute a highly aggressive GC (HAGC) sub-type with distinctive features. The prognosis is poor and most HAGC patients die in weeks without effective treatment. Undue concerns about the myelosuppression mitigate against the application of cytotoxics in HAGC which is characterized by thrombocytopenia. Retrospective analysis showed low dose chemotherapy might relieve the DIC and bring with survival benefit but the standard of care (SOC) has not yet been established without a prospective study available. We completed a multi-center phase II trial evaluating the safety and efficacy of infusional fluorouracil and weekly docetaxel as first-line (1L) treatment for HAGC. Methods: This was a single-arm trial. A Simon's two-stage optimal design was applied. Eligible cases were: 18-75 years old, histologically confirmed GC, established BMM, overt DIC, platelet ≤ 50*109/L and Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 3. Fluorouracil 200mg/m2/d continuous infusion on days 1-21 and docetaxel 25mg/m2/d on days 1, 8, 15 were given every four weeks. Hematological response (HeR) was defined as the platelet restored to normal range. The primary end point was HeR rate. Secondary end points were time to HeR (TTHeR), one month mortality (OMM), overall survival (OS), adverse events (AEs) and quality of life (QoL). Results: From Jan 2021 to Sep 2022, 24 HAGC cases from three Chinese centers were enrolled (details shown in table below). 20 HeRs were achieved and the HeR rate was 83.3%. Median TTHeR was 13 days and OMM was 12.5%. Till the data cut-off date (Jul 31, 2023), 3 patients were still alive with a median follow-up of 403 days. The median OS was 242 days. Totally, twelve Grade 3 AEs were recorded in 7 (29.2%) patients, among which stomatitis (4, 16.7%) and aminotransferase elevation (3, 12.5%) were the most frequent. No drug-related grade 4 or 5 AEs were observed. QoL outcomes were significantly improved both during and after the treatment. Conclusions: Anti-cancer treatment is the key point to control DIC of HAGC. The Zhen Long regimen was well tolerated and showed promising efficacy in the 1L setting. It should be considered as the SOC in current practice, but further randomized trials are still needed. Clinical trial information: NCT04547153 . [Table: see text]

Enhanced Photodynamic Therapy Synergizing with Inhibition of Tumor Neutrophil Ferroptosis Boosts Anti-PD-1 Therapy of Gastric Cancer.

For tumor treatment, the ultimate goal in tumor therapy is to eliminate the primary tumor, manage potential metastases, and trigger an antitumor immune response, resulting in the complete clearance of all malignant cells. Tumor microenvironment (TME) refers to the local biological environment of solid tumors and has increasingly become an attractive target for cancer therapy. Neutrophils within TME of gastric cancer (GC) spontaneously undergo ferroptosis, and this process releases oxidized lipids that limit T cell activity. Enhanced photodynamic therapy (PDT) mediated by di-iodinated IR780 (Icy7) significantly increases the production of reactive oxygen species (ROS). Meanwhile, neutrophil ferroptosis can be triggered by increased ROS generation in the TME. In this study, a liposome encapsulating both ferroptosis inhibitor Liproxstatin-1 and modified photosensitizer Icy7, denoted LLI, significantly inhibits tumor growth of GC. LLI internalizes into MFC cells to generate ROS causing immunogenic cell death (ICD). Simultaneously, liposome-deliver Liproxstatin-1 effectively inhibits the ferroptosis of tumor neutrophils. LLI-based immunogenic PDT and neutrophil-targeting immunotherapy synergistically boost the anti-PD-1 treatment to elicit potent TME and systemic antitumor immune response with abscopal effects. In conclusion, LLI holds great potential for GC immunotherapy.

Linc-ROR inhibits NK cell-killing activity by promoting RXRA ubiquitination and reducing MICB expression in gastric cancer patients.

Linc-ROR plays an important role in gastric cancer (GC) development and progression. This study sought to determine how the aberrant expression of Linc-ROR impacts GC progression and immune evasion, and to identify new targets for GC therapy. GC cells overexpressing Linc-ROR and GSAGS cells were cocultured with NK-92 cells, respectively, and Linc-ROR expression was determined using reverse transcription polymerase chain reaction. Linc-ROR overexpression experiments were used to measure the expression of MICB, a tumor protein that is recognized by natural killer (NK) cells. Bioinformatics analysis identified retinoid X receptor α (RXRA) and YY1 as MICB-specific transcription factors. Cotransfection and ubiquitinated drug experiments found that Linc-ROR promoted the ubiquitination and degradation of RXRA. Linc-ROR was upregulated in GC tissue and high expression was associated with tumor escape from NK-92 cell-mediated immunity. Linc-ROR overexpression inhibited the expression of MICB on the cell surface by degrading RXRA. These findings indicate that Linc-ROR promotes the binding of RXRA and E3 ligase UBE4B, reducing RXRA and MICB expression, and limiting NK cell-killing activity. Linc-ROR is a criticallong noncoding RNA with a tumor-promoting function in GC and thus may serve as a potential therapeutic target.

Development and evaluation of the Newstage system: integrating tumor regression grade and lymph node status for improved prognostication in neoadjuvant treatment of gastric cancer

BackgroundThe predictive correlation of tumor depth of invasion changes after neoadjuvant therapy, and the 8th American Joint Committee on Cancer (AJCC) ypTNM system for gastric cancer may not accurately predict patient prognosis following neoadjuvant therapy.MethodsA retrospective analysis was conducted on a total of 258 patients who underwent radical surgery for gastric cancer after neoadjuvant therapy. The Newstage system was established based on tumor regression grade and pathological lymph node status. The 3-year survival rates of patients classified by the Newstage system were compared with those classified by the AJCC ypTNM system.ResultsIn a cohort of 258 patients, the 3-year overall survival rates based on the Newstage system were: (I) 94.6%, (II) 79.3%, (III) 54.5%, and (IV) 30.2%. The Newstage system exhibited a lower Akaike information criterion value (902.57 vs. 912.03). Additionally, the area under the ROC curve (0.756 vs. 0.733) and the C-index (0.731 vs. 0.718) was higher than the AJCC ypTNM system. Furthermore, a multivariate analysis indicated that the Newstage system was an independent prognostic factor (p = 0.001).ConclusionThe Newstage system exhibits superior predictive performance in estimating survival rates for neoadjuvant therapy in gastric cancer. It also functions as an independent prognostic factor.

Retracted: Long Noncoding RNAs: New Regulators of Resistance to Systemic Therapies for Gastric Cancer.

[This retracts the article DOI: 10.1155/2021/8853269.].

CircPRDM5 inhibits the proliferation, migration, invasion, and glucose metabolism of gastric cancer cells by reducing GCNT4 expression in a miR-485-3p-dependent manner.

Circular RNA (circRNA) plays a key part in the pathological process of gastric cancer (GC). The study is organized to analyze the function of circPRDM5 in GC cell tumor properties. Expression levels of circPRDM5, miR-485-3p, glucosaminyl (N-acetyl) transferase 4 (GCNT4), ki67, E-cadherin, N-cadherin, and hexokinase 2 (HK2) were analyzed by quantitative real-time polymerase chain reaction (PCR), Western blotting or immunohistochemistry assay. Cell proliferation was assessed by cell colony formation assay and 5-ethynyl-2'-deoxyuridine assay. Cell migration and invasion were investigated by transwell assay. Glycolysis was evaluated by the Seahorse XF Glycolysis Stress Test Kit. Dual-luciferase reporter assay and RNA pull-down assay were performed to identify the associations among circPRDM5, miR-485-3p, and GCNT4. Xenograft mouse model assay was conducted to determine the effects of circPRDM5 on tumor formation in vivo. CircPRDM5 and GCNT4 expression were downregulated, while miR-485-3p expression was upregulated in GC tissues and cells when compared with paracancerous tissues or human gastric epithelial cells. CircPRDM5 overexpression inhibited proliferation, migration, invasion, and glucose metabolism of GC cells; however, circPRDM5 depletion had the opposite effects. CircPRDM5 repressed tumor properties of GC cells in vivo. MiR-485-3p restoration relieved circPRDM5-induced effects in GC cells. GCNT4 overexpression remitted the promoting effects of miR-485-3p mimics on GC cell malignancy. CircPRDM5 acted as a sponge for miR-485-3p, and GCNT4 was identified as a target gene of miR-485-3p. Moreover, circPRDM5 regulated GCNT4 expression by interacting with miR-485-3p.CircPRDM5 acted as a miR-485-3p sponge to inhibit GC progression by increasing GCNT4 expression, proving a potential target for GC therapy.

Evaluations of Biomarkers CDX1 and CDX2 in Gastric Cancer Prognosis: A Meta-analysis.

CDX1 and CDX2 are homeobox-type transcription factors that are potential biomarkers and are associated with prognostic significance in intestinal-type gastric cancer early disease before lymph node metastasis is associated with better prognosis. In addition, the genes IDH 1 and IDH 2 previously known to be involved in brain cancer are implicated in cancer-related molecular signatures as a result new targeted personalized therapies may be possible. Our retrospective study determined the correlation between CDX markers and clinicopathologic data including survival in patients with gastric cancer. This study included studies from 1997 to December 2022 a meta-analysis to provide odds ratios (ORs) and relative risks (RRs). We discussed in detail the impact of IDH 1/2 on the prognosis of gastric cancer outcomes and potential therapeutic strategies. Our meta-analysis included 20 studies identifying 11,163 patients with gastric cancer. We found that CDX 1 overexpression was associated with better overall survival (pooled HR: 1.28) and CDX 2 expression and better 3-year survival (pooled HR: 1.64) and 5-year survival was the pooled HR was correlated 1 94 with both showing statistical correlation. Evidence suggests that IDH 1/2 mutations and CDX 1/2 overexpression are closely associated with metabolic abnormalities epigenetic changes and mutations evidence suggests the potential for novel targeted therapies in gastric cancer. CDX 1/2 overexpression is associated with a favorable prognosis in gastric cancer cases. Further studies are needed to explore the clinical significance of IDH 1/2 mutations and CDX 1/2 expression.

Integration of O2-economised tumour-targeted photosensitive magnetic nanomaterials in the diagnosis and therapy of gastric cancer.

Hypoxia in the tumour microenvironment is a major limiting factor in photodynamic therapy. The present study employed a novel O2-economised photosensitizer, ACSN, to effectively curtail oxygen consumption by impeding the aerobic respiration of tumour cells, thereby increasing the reactive oxygen species (ROS) production in photodynamic therapy. To enhance the efficacy of photodynamic therapy, the active targeting peptide iRGD was employed to facilitate drug accumulation in the tumour tissue. Therefore, we constructed a targeted drug platform, ACSN/Fe3O4@MSNs-iRGD, that integrates diagnosis and treatment. The drug exhibited excellent active targeting ability towards gastric cancer MGC-803 cells and can efficiently penetrate the mitochondria upon cellular internalisation. The photosensitizer ACSN, released from the drug, effectively suppressed mitochondrial aerobic respiration to conserve oxygen and exhibited robust ROS production upon laser excitation. The core-shell structure comprises Fe3O4, which offers excellent T2 dark contrast for real-time tumour monitoring through MRI imaging. By incorporating excellent photodynamic therapy and MRI imaging capabilities, this drug can serve as an effective platform for the integration of tumour diagnosis and treatment, thus addressing the limitations associated with conventional tumour therapies. It is anticipated that this approach will soon be clinically translated.

Flavonoids and Gastric Cancer Therapy: From Signaling Pathway to Therapeutic Significance.

Gastric cancer (GC) is a prevalent gastrointestinal tumor characterized by high mortality and recurrence rates. Current treatments often have limitations, prompting researchers to explore novel anti-tumor substances and develop new drugs. Flavonoids, natural compounds with diverse biological activities, are gaining increasing attention in this regard. We searched from PubMed, Web of Science, SpringerLink and other databases to find the relevant literature in the last two decades. Using "gastric cancer", "stomach cancers", "flavonoid", "bioflavonoid", "2-Phenyl-Chromene" as keywords, were searched, then analyzed and summarized the mechanism of flavonoids in the treatment of GC. It was revealed that the anti-tumor mechanism of flavonoids involves inhibiting tumor growth, proliferation, invasion, and metastasis, as well as inducing cell death through various processes such as apoptosis, autophagy, ferroptosis, and pyroptosis. Additionally, combining flavonoids with other chemotherapeutic agents like 5-FU and platinum compounds can potentially reduce chemoresistance. Flavonoids have also demonstrated enhanced biological activity when used in combination with other natural products. Consequently, this review proposes innovative perspectives for the development of flavonoids as new anti-GC agents.

Gastric cancer secreted miR-214-3p inhibits the anti-angiogenesis effect of apatinib by suppressing ferroptosis in vascular endothelial cells.

Different from necrosis, apoptosis, autophagy and other forms of cell death, ferroptosis is a mechanism that catalyzes lipid peroxidation of polyunsaturated fatty acids under the action of iron divalent or lipoxygenase, leading to cell death. Apatinib is currently used in the third-line standard treatment of advanced gastric cancer, targeting the anti-angiogenesis pathway. However, Apatinib-mediated ferroptosis in vascular endothelial cells has not been reported yet. Tumor-secreted exosomes can be taken up into target cells to regulate tumor development, but the mechanism related to vascular endothelial cell ferroptosis has not yet been discovered. Here, we show that exosomes secreted by gastric cancer cells carry miR-214-3p into vascular endothelial cells and directly target zinc finger protein A20 to negatively regulate ACSL4, a key enzyme of lipid peroxidation during ferroptosis, thereby inhibiting ferroptosis in vascular endothelial cells and reducing the efficiency of Apatinib. In conclusion, inhibition of miR-214-3p can increase the sensitivity of vascular endothelial cells to Apatinib, thereby promoting the antiangiogenic effect of Apatinib, suggesting a potential combination therapy for advanced gastric cancer.

Research progress and future directions of immune checkpoint inhibitor combination therapy in advanced gastric cancer.

In recent years, with the continuous development of molecular immunology, immune checkpoint inhibitors (ICIs) have also been widely used in the treatment of gastric cancer, but they still face some challenges: The first is that only some people can benefit, the second is the treatment-related adverse events (TRAEs) that occur during treatment, and the third is the emergence of varying degrees of drug resistance with long-term use. How to overcome these challenges, combined therapy based on ICIs has become one of the important strategies. This article summarizes the clinical application of ICIs combined with chemotherapy, targeted therapy, radiotherapy, photodynamic therapy, thermotherapy, immune adjuvant, and dual immunotherapy and discusses the mechanism, and also summarizes the advantages and disadvantages of the current combination modalities and the potential research value. The aim of this study is to provide more and more optimized combination regimen for ICI combined therapy in patients with advanced gastric cancer and to provide reference for clinical and scientific research.

Immune checkpoint inhibitors or anti-claudin 18.2 antibodies? A network meta-analysis for the optimized first-line therapy of HER2-negative gastric cancer.

Multiple anti-programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors and zolbetuximab, an anti-claudin 18.2 antibody, have shown efficacy in the first-line treatment of HER2-negative gastric cancers. How to choose the best regimen remains an unsolved question. We aimed to conduct a comparative analysis of the therapeutic advantages between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers. Network meta-analysis was employed to systematically compare efficacy and safety data derived from various clinical trials. We included phase III randomized controlled trials in PubMed, Embase, Web of Science, Cochrane Library, and major conference abstracts. Network meta-analysis was used to compare the efficacy of each first-line therapeutic agent and to indirectly compare immunotherapy with anti-claudin-18.2-targeted therapy. Eight trials comprising a total of 6455 patients were included. For the overall survival (OS) analysis, no statistically significant differences were observed between pembrolizumab [hazard ratios (HR) = 1.00, 95% CI: 0.94-1.07], sintilimab (HR = 0.99, 95% CI: 0.89-1.09), sugemalimab (HR = 0.98, 95% CI: 0.87-1.10), tislelizumab (HR = 0.97, 95% CI: 0.87-1.09), zolbetuximab (HR = 0.98, 95% CI: 0.91-1.07), and nivolumab (HR = 1.00). For the progression-free survival (PFS) analysis, no statistically significant differences were observed between pembrolizumab (HR = 1.00, 95% CI: 0.93-1.06), sintilimab (HR = 0.91, 95% CI: 0.83-1.00), sugemalimab (HR = 0.92, 95% CI: 0.84-1.02), tislelizumab (HR = 0.93, 95% CI: 0.84-1.03), zolbetuximab (HR = 0.96, 95% CI: 0.88-1.05), and nivolumab (HR = 1.00). For the overall response rate analysis, all regimens presented similar effects on ORR. In addition, anti-claudin-18.2-targeted therapies presented similar OS (HR = 0.99, 95% CI: 0.95-1.04) and PFS (HR = 1.01, 95% CI: 0.91-1.12) compared to immunotherapy, although their toxicity profiles were distinct. Our network meta-analysis showed no significant difference in PFS, OS, or ORR between different checkpoint inhibitors or between immunotherapy and anti-claudin-18.2-targeted therapies in the first-line treatment of HER2-negative, unresectable, or metastatic gastric cancers.

Systemic immunoinflammatory index and prognostic nutrition index for predicting pathologic responses of patients with advanced gastric cancer after neoadjuvant therapy for advanced gastric cancer.

To investigate the value of prognostic nutrition index (PNI) and systemic immunoinflammatory index (SII) for predicting pathological responses of patients with advanced gastric cancer (GC) after neo-adjuvant chemotherapy (NACT). The clinicopathological data of 326 patients with advanced GC who received NACT in Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City) from January 2017 to December 2021 were retrospectively collected. The SII and PNI of patients were calculated. The receiver operating characteristics (ROC) curve was leveraged for getting the optimal cutoff values of SII and PNI. The pathological response of patients after NACT, as obtained from their postoperative pathological examinations, was evaluated based on the tumor regression grade (TRG) criteria. Multivariate regression analysis was employed for identifying factors that led to various pathological responses after NACT in advanced GC patients. The log-rank test was utilized for between-group comparison of patients' survival curves. The SII and PNI were 507.45 and 48.48 respectively, and their levels were divided into high and low groups. Pathological response (TRG 0-1) was observed in 66 cases (20.25%), while non-pathological response (TRG 2-3) was observed in 260 cases (79.75%). The results of multivariate logistic regression analysis showed that tumor diameter < 5 cm, ypT T0-T2, ypN N0, chemotherapy regimen XELOX (capecitabine combined with oxaliplatin), SII < 507.45 (P=0.002), PNI > 48.48 were all independent factors affecting the pathological responses of advanced GC patients after NACT (all P < 0.05). With SII and PNI being included, the AUC was 0.821 (95% CI: 0.765-0.876), and the specificity was 87.90% and the sensitivity was 64.20%. The Kaplan-Meier survival curve analysis showed that NACT patients with tumor diameter < 5 cm, ypT T0-T2, ypN N0, XELOX chemotherapy regimen, SII < 507.45 and SII ≥ 507.45 had a higher survival rate. (P < 0.001). Before treatment, tumor diameter < 5 cm, ypT T0-T2, ypN N0, chemotherapy regimen XELOX, SII < 507.45, PNI > 48.48 were all independent factors affecting the pathological response of advanced GC patients after NACT. Moreover, the inclusion of SII and PNI increased the accuracy of predicting the pathological response of patients after NACT.