Treatment Of Advanced Gastric Cancer Research Articles

Research progress of perioperative immunotherapy for locally advanced gastric cancer

Gastric cancer is a highly heterogeneous disease, and its occurrence and development are the result of genetic factors, environmental factors, and host factors. As one of the main types of cancer in China, radical gastrectomy is the only chance for patients to be cured, but only 50% to 60% of initially diagnosed gastric cancer patients are suitable for radical gastrectomy, especially in locally advanced and advanced patients. The results of MAGIC and ACCORD07/FFCD9703 confirm the status of combination chemotherapy with fluorouracil as the standard of perioperative treatment for locally advanced gastric cancer. Gastric cancer is one of the most common diseases in China, with high heterogeneity and poor prognosis. Immunotherapy has always been a difficulty in medical research. However, the 5-year overall survival rate for gastric cancer patients remains low. Immunotherapy is effective in the first-line treatment of advanced gastric cancer. At the same time, immunotherapies such as immune checkpoint inhibitors, tumor vaccines, and cell therapy also show certain safety and effectiveness in the perioperative treatment of locally advanced gastric cancer patients. This paper reviews the research progress of immunotherapy in the perioperative treatment of locally advanced gastric cancer.

Polyene phosphatidylcholine enhances the therapeutic response of oxaliplatin in gastric cancer through Nrf2/HMOX1 mediated ferroptosis

Oxaliplatin (OXA)-based chemotherapy is one of the first-line treatments for advanced gastric cancer. However, the potential risk for chemotherapy-induced hepatic injury can hinder its effectiveness. Polyene phosphatidylcholine (PPC) is often used as a hepatoprotective agent to counter OXA-induced hepatic injury; however, its impact on the antitumour effectiveness of OXA remains uncertain. Our retrospective study examined 98 patients with stage IV gastric cancer to assess the impact of PPC on progression-free survival (PFS) and disease control rate (DCR). Furthermore, in vitro and in vivo assays were conducted to elucidate the combined biological effects of OXA and PPC (OXA+PPC) on gastric cancer. RNA sequencing, luciferase reporter assays, live/dead cell assays, immunofluorescence, and western blotting were used to identify the activated signalling pathways and downstream factors post OXA+PPC treatment. The findings indicated that PPC served as an independent prognostic factor, correlating with prolonged PFS and improved DCR in patients with gastric cancer. The combination of OXA and PPC significantly inhibited tumour cell growth both in vitro and in vivo. RNA sequencing revealed that OXA+PPC treatment amplified reactive oxygen species and ferroptosis signalling pathways. Mechanistically, OXA+PPC upregulated the expression of haem oxygenase-1 by promoting the nuclear migration of nuclear factor erythroid 2-related factor (Nrf2), thereby enhancing its transcriptional activity. Drug-molecule docking analysis demonstrated that PPC competitively bound to the peptide structural domains of both Nrf2 and Kelch-like ECH-associated protein 1 (KEAP1), accounting for the increased translocation of Nrf2. In conclusion, our study reveals the synergistic antitumour potential of PPC and OXA while protecting patients against hepatic injury. This suggests a promising combined treatment approach for patients with advanced gastric cancer.

Safety and efficacy of apatinib in combination with chemotherapy with or without immunotherapy versus chemotherapy alone as first-line treatment for advanced gastric cancer

SummaryThe specific first-line regimen for advanced gastric cancer (GC) is still controversial. The benefit of apatinib for first-line treatment of advanced GC remains unknown and needs to be further explored. Eighty-two patients with advanced GC treated in our institution from October 2017 to March 2023 were retrospectively reviewed. All individuals had her-2 negative GC and had received at least two cycles of first-line treatment, including 44 patients in the combination treatment group (apatinib in combination with chemotherapy with or without immunotherapy) and 38 patients in the simple chemotherapy group. We evaluated the efficacy and safety of apatinib in combination with chemotherapy with or without immunotherapy in the first-line treatment of advanced GC by comparing the efficacy, progression-free survival (PFS), and adverse events in two groups of patients. The median PFS of the simple chemotherapy group was 9.25 months (95% confidence interval (CI), 6.1–11.2 months), and that of the combination treatment group was 10.9 months (95% CI, 7.9–15.8 months), which was 1.65 months longer than the simple chemotherapy group. Statistically significant differences are shown (P = 0.022). The objective response rate (ORR) of the combination treatment group was 65.9%, and 36.8% in the simple chemotherapy group. Statistically significant differences are shown (P = 0.014). No serious (Grade IV) adverse events occurred in either group. Our study indicates that apatinib in combination with chemotherapy with or without immunotherapy as first-line treatment for advanced GC exhibits good anti-tumor activity and is well tolerated by patients.

Phase I trial of apatinib and paclitaxel+oxaliplatin+5-FU/levoleucovorin for treatment-naïve advanced gastric cancer.

Chinese guidelines recommend POF (paclitaxel, oxaliplatin, and 5-FU/levoleucovorin) as first-line treatment for advanced gastric cancer (AGC). Apatinib can augment the antitumor effect of paclitaxel, oxaliplatin, or fluorouracil in preclinical studies of AGC. A phase I clinical trial was conducted to evaluate the anticancer activity and maximum tolerated dose (MTD) of apatinib plus POF in treatment-naïve patients with AGC and to establish a recommended phase II dose. Participants received escalating doses of daily oral apatinib (250, 375, 500, 625, 750, and 850 mg) plus POF every 2 weeks using a conventional "3 + 3" study design. Among 21 treated patients, one experienced a dose-limiting toxicity (grade 3 skin ulceration at 850 mg). No MTD was reached. Apatinib 750 mg plus POF was recommended for phase II study. The most common grade 3-4 adverse events (AEs) were neutropenia (33.3%), mucositis (14.3%), and hand-foot syndrome (14.3%). Median progression-free and overall survival were 10.4 months (95% CI: 6.3, 14.6) and 18.4 months (95% CI: 9.8, 28.2), respectively. Apatinib up to 850 mg coadministered with POF was well tolerated with manageable AEs. The safety and anticancer activity of this regimen warrants its further investigation as first-line treatment for AGC in a larger study.

PD-1 inhibitor combined with albumin paclitaxel and apatinib as second-line treatment for patients with metastatic gastric cancer: a single-center, single-arm, phase II study

SummaryBackgroundImmune checkpoint inhibitors have been approved for first- and third-line treatment of advanced gastric cancer. However, pembrolizumab alone in the second line did not improve overall survival compared to chemotherapy in the KEYNOTE-061 study. In this study, we aimed to explore the efficacy and safety of a three-drug regimen of PD-1 inhibitor combined with albumin paclitaxel and apatinib (a VEGFR inhibitor) for the second-line treatment of patients with metastatic gastric cancer (mGC).MethodsThis was a single-center, single-arm, phase II clinical study. Patients with mGC with stable microsatellite and negative HER-2 expression who failed first-line chemotherapy were enrolled. The enrolled patients were treated with PD-1 inhibitor (selected according to patients’ requirements) in combination with albumin paclitaxel (125 mg/m2, intravenously, days 1 and 8, or 250 mg/m2, intravenously, day 1) and apatinib (250 or 500 mg, orally, days 1–21) every 3 weeks. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response, and adverse events (AEs).ResultsFrom July 11, 2019, to October 13, 2022, a total of 43 patients were enrolled, of whom 10 were PD-L1 negative, 11 were PD-L1 positive, and 22 had unknown PD-L1 expression. As of the data cutoff on April 1st, 2023, nine patients had partial response, 29 had stable disease, and five experienced progressive disease, with the ORR of 20.9% and DCR of 88.3%. The median PFS was 6.2 months (95% CI, 3.9–9.3), and the median OS was 10.1 months (95% CI, 7.5–14.1). All patients suffered from alopecia and neurotoxicity. The other main AEs of grade 1 or 2 were bone marrow suppression (N = 21, 48.8%), hand-foot reaction (N = 19, 44.2%), hypertension (N = 18, 41.9%), hypothyroidism (N = 11, 25.6%), gastrointestinal bleeding (N = 3, 7.0%), and liver function damage (N = 5, 11.6%). Two patients reported grade 3–4 immune-related liver damage.ConclusionSecond-line PD-1 inhibitor combined with albumin paclitaxel and apatinib showed certain efficacy and safety in patients with mGC.Trial registrationClinical trials, NCT04182724. Registered 27 November 2019; retrospectively registered, https://clinicaltrials.gov/study/NCT04182724

Impact of muscle mass loss on outcomes in advanced or metastatic gastric cancer patients receiving a second-line treatment.

Sarcopenia is a frequent disorder among cancer patients. It commonly leads to muscle mass wasting and poor clinical outcomes, even though it is rarely recognized and often undertreated. The relationship between skeletal muscle depletion and chemotherapy toxicity or postoperative complications is well known. The aim of the present study was to analyze the impact of sarcopenia on clinical outcomes of pretreated metastatic gastric cancer (GC) patients. 88 pretreated GC patients were retrospectively analyzed. Patients were divided into two groups according to their skeletal mass index (SMI): sarcopenic patients with low SMI (≤39 cm2/m2 for women and ≤55 cm2/m2 for men) and non-sarcopenic patients with normal/high SMI value. The two groups were compared according to outcomes and adverse events. Progression-free survival (PFS) was significantly higher in patients with normal/high SMI than in those with low SMI (6 vs. 3.5 months, respectively; HR 0.52). Similarly, the overall response rate (ORR) was higher in the subgroup with normal/high SMI (41% vs. 20%; p=0.02). Overall survival (OS) was not significantly different, but multivariate analysis demonstrated that both SMI and performance status were associated with OS. In the sarcopenic group, the patients treated in the second line with paclitaxel and ramucirumab regimen showed a better outcome profile. Overall, adverse events (AEs) were more frequent in the group of patients with low SMI (p<0.0001). Early recognition of sarcopenia may contribute to personalizing second or further lines of treatment in advanced GC and to weigh up the potential risk of serious toxicities.

The Efficacy and Safety of Nivolumab Plus mFOLFOX6 in Gastric Cancer with Severe Peritoneal Metastasis

(1) Background: Nivolumab plus chemotherapy is established as a first-line treatment for advanced gastric cancer (AGC). While mFOLFOX6 is commonly used for AGC with severe peritoneal metastasis, the efficacy of nivolumab combined with it remains uncertain. We evaluated the outcomes of nivolumab plus mFOLFOX6 for AGC with severe peritoneal metastasis in clinical practice. (2) Methods: This multicenter retrospective study was conducted between December 2021 and June 2023. We investigated AGC patients with massive ascites or inadequate oral intake due to severe peritoneal metastasis and who received nivolumab plus mFOLFOX6. (3) Results: Among 106 patients treated with nivolumab plus chemotherapy, 21 (19.8%) had severe peritoneal metastasis, with 14 receiving nivolumab plus mFOLFOX6. The median progression-free survival was 7.4 months (95%CI 1.9-10.1), and the median overall survival was 10.7 months (95%CI 5.3-NA), with four patients (28.5%) surviving more than 12 months. Improved ascites and oral intake were observed in 6/14 patients (42.8%) and 10/11 patients (90.9%), respectively. The major grade 3 or more adverse events included leukopenia (28.5%) and neutropenia (21.4%), with no severe immune-related adverse events reported. (4) Conclusions: The safety and moderate efficacy of nivolumab plus mFOLFOX6 were suggested even in AGC patients with severe peritoneal metastasis.

The correlation between systemic inflammatory markers and efficiency for advanced gastric cancer patients treated with ICIs combined with chemotherapy.

Currently lacking research to explore the correlation between inflammatory markers and the efficacy of immune checkpoint inhibitors (ICIs) combined with chemotherapy in the treatment of advanced gastric cancer. This study is a retrospective study and included patients with advanced gastric cancer who receiving ICIs combined with chemotherapy from January 2020 to December 2022. We analysed the relationship between systemic inflammatory markers and the efficacy of ICIs combined chemotherapy and constructed a clinical prediction model. A nomogram was constructed based on the results of the bidirectional stepwise regression model. A total of 197 patients were enrolled in the training group, with a median follow-up period of time 26 months. Kaplan Meier analysis showed that the median OS of patients with low systemic immune-inflammatory index (SII) and low platelet to lymphocyte ratio (PLR) was superior to those with high SII and PLR. Univariate and multivariate Cox regression analysis showed that SII, NLR, PLR, and N stage as independent prognostic factors for OS. Adding SII to the conventional model improved the predictive ability of the 12-month OS. A total of 95 patients were included in the validation group, and external validation of the SII-based nomogram showed favourable predictive performance. Baseline SII, PLR, and N stage may serve as independent predictive factors for survival outcomes in advanced gastric cancer patients undergoing ICIs combined with chemotherapy. The SII-based nomogram can provide intuitive and accurate prognosis prediction of individual patients.

Efficacy and safety of trastuzumab deruxtecan and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer: A single-institution retrospective study.

265 Background: Despite the difficulty of directly comparing trastuzumab deruxtecan (T-DXd) and nivolumab as third- or later-line treatment for HER2-positive advanced gastric cancer (AGC) in randomized trials, discussions regarding optimal treatment strategies are desired. Methods: This single-institution retrospective study aimed to describe the real-world efficacy and safety of T-DXd and nivolumab as third- or later-line treatment for patients with HER2-positive AGC treated between March 2016 and May 2022. Results: Overall, 58 patients (median age, 64 years; 69% male) were eligible (T-DXd group, n = 20; nivolumab group, n = 38). Most had HER2 3+ (72%) and presented with metastatic disease at diagnosis (66%). Response rates in the 41 patients with measurable lesions were 50% and 15% in the T-DXd and nivolumab groups, respectively. The T-DXd and nivolumab groups had a median progression-free survival of 4.8 months (95% confidence interval [CI], 3.3–7.0) and 2.3 months (95% CI, 1.5–3.5), median overall survival of 10.8 months (95% CI, 6.9–23.8) and 11.7 months (95% CI, 7.6–17.1), and grade 3 or greater adverse event rates of 50% and 2%, respectively. Overall, 64% received subsequent treatment. Among 23 patients who received both regimens, the T-DXd–nivolumab and nivolumab–T-DXd groups had a median overall survival of 14.0 months (95% CI, 5.0–not reached) and 19.3 months (95% CI, 9.5–25.1), respectively. Conclusions: T-DXd and nivolumab had distinctive efficacy and toxicity profiles as third- or later-line treatment for HER2-positive AGC. Considering the distinct features of each regimen might help clinicians personalize the optimal treatment approaches for patients with HER2-positive AGC.

Preliminary results of surufatinib (Suru) plus standard chemotherapy (ChT) as second line (2L) treatment of advanced gastric cancer (aGC): A single-arm, phase 2 clinical trial.

353 Background: Limited options are available for aGC patients who have failed first line (1L) systemic treatment, and single-agent ChT with paclitaxel (Pac) or irinotecan (Iri) remains the mainstay. Recent studies have suggested improved efficacy with the combination of ChT and antiangiogenic agents in the 2L setting. Suru is a tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1 and CSF-1R. This trial is aimed to evaluate the efficacy and safety of Suru plus Pac or Iri as 2L treatment for aGC. Methods: This single-arm, single center, phase 2 trial was designed to enroll up to 35 histologically confirmed HER2-negative aGC patients with evaluable disease who failed 1L ChT with or without immunotherapy (IO). Eligible patients were administered 21-day cycles of Suru (250mg, po, qd) plus Pac (150mg/m2, iv, d1) or Iri (125mg/m2, iv, d1, d8) per investigator choice for 6 cycles, followed by Suru (250mg, po, qd) maintenance if no disease progression (PD), until intolerable toxicity, PD, or death. The primary endpoint was ORR (per RECIST v1.1), and secondary endpoints included DCR, PFS, OS, and safety. Results: As of Sep 11, 2023, 15 patients were enrolled, and 6 patients remained on treatment. The median follow-up time was 5.77 (95% CI: 3.37~10.13) months. Among all 15 patients, the median age was 66 (range: 33-76) years, 14 (93.3%) were male, and 14 (93.3%) had an ECOG PS of 1. Ten (66.7%) patients had received prior anti-PD-1 antibodies, and all 15 patients received Pac as the standard ChT. All 15 patients were evaluable for tumor response, with 5 PR, 9 SD, and 1 PD as their best overall response (BOR). The ORR and DCR were 33.3% and 93.3%, respectively. The median PFS was 5.23 months, while the OS data was immature yet. The ORR, DCR and PFS seemed comparable between patients with and without prior IO. In terms of safety, the combined treatment was generally well tolerated, treatment-related Grade 3/4 adverse events included neutropenia (6, 40%), leukopenia (1, 6.7%), lymphopenia (1, 6.7%), and proteinuria (1, 6.7%). There were no treatment-related serious adverse events or treatment-related deaths. Conclusions: These results suggested promising anti-tumor activity and a manageable safety profile of Suru plus standard ChT in 2L treatment of aGC. The trial is still ongoing, and more data will be disclosed in the future. Clinical trial information: ChiCTR2200063336 . [Table: see text]

Impact of adding nivolumab to first-line chemotherapy in patients with advanced gastric cancer.

334 Background: Nivolumab plus chemotherapy (Nivo-Chemo) is the standard treatment for advanced gastric cancer based on the results of CheckMate 649 trial and ATTRACTION-4 trial. However, real-world data on the efficacy of Nivo-Chemo are limited. This study aimed to assess the efficacy of Nivo-Chemo in the clinical practice setting by comparing it to chemotherapy alone. Methods: We retrospectively reviewed the medical records of patients with advanced gastric cancer who received palliative chemotherapy in our hospital between 2017 and 2023. The inclusion criteria were as follows: age ≥ 20 years; histologically confirmed advanced unresectable or recurrent gastric/gastro-esophageal junction adenocarcinoma; HER2 negative or unknown; and no prior treatment. Patients were divided into two groups based on their first-line treatment: the Nivo-Chemo group and chemotherapy alone (Chemo) group. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were assessed. Results: Of 78 patients, 52 patients were in the Chemo group and 26 patients were in the Nivo-Chemo group. Median age were 69 years (range 30–83) and 67 years (range 39–76) in the Chemo group and Nivo-Chemo group. Eastern Cooperative Oncology Group performance status (ECOG PS) was 0/1/2 in 18/27/7 patients (35%/52%/13%) in the Chemo group and in 17/8/1 patients (65%/31%/4%) in the Nivo-Chemo group. Histological type (Intestinal type/diffuse type) was 19/33 (37%/63%) in the Chemo group and 8/18 (31%/69%) in the Nivo-Chemo group. Combined positive score (CPS) was assessed in 21 patients in the Nivo-Chemo group. The CPS &lt;1/1-5/&gt;5 was in 3/10/8 (12%/38%/31%). In the Chemo group, 28 patients (54%) received anti-PD-1 monotherapy after progression of first-line chemotherapy. The median PFS was 5.7 months in the Chemo group and 6.0 months in the Nivo-Chemo group (HR 0.88, 95% CI 0.50-1.55, p = 0.66). The median OS was 15.0 months in the Chemo group and 18.6 months in the Nivo-Chemo group (HR 0.76, 95% CI 0.37-1.53, p = 0.44). The ORR was 50% in the Chemo group and 54% in the Nivo-Chemo group, while the DCR was 63% and 69%, respectively. Conclusions: In clinical practice, the addition of nivolumab to chemotherapy tended to provide a survival benefit compared to chemotherapy alone.

Real world prevalence of biomarkers for treatment of advanced gastric cancer or gastroesophageal junction cancer in a cohort of Colombian patients.

402 Background: Gastric cancer (GC) is the leading cause of cancer-related deaths in Colombia, GLOBOCAN estimated 6.451 deaths in 2022. Development of immune checkpoint inhibitors and HER2 target therapy with chemotherapy had improved overall survival in advanced setting, but we do not have data about the prevalence of biomarkers used for selection of these patients in Colombia or Latin-America. Our aim is to describe the prevalence of biomarkers used currently for selection of treatment in a real-world multicenter cohort of advanced gastric and gastroesophageal junction (GEJ) cancer. Methods: We did a retrospective observational multicenter study of patients with advanced GC/GEJ cancer treated at three reference cancer centers in Bogota, Colombia between January 1, 2023 and July 31, 2023. We reviewed medical history and pathology reports looking for the prevalence of biomarkers used for selection of first line systemic therapy. Ventana 4B5 for HER2 IHQ evaluation and Dako 22C3 for PDL1 expression by CPS were used. MMR proteins were evaluated by IHQ nuclear expression. Results: 101 patients with advanced GC/GEJ were included. The median age was 61 years (range 18-83), 53,5% of patients were men, 92.1% were gastric cancer and 87,1% were de novo stage IV. Signet ring cells were found in 40%, peritoneal carcinomatosis was documented in 59% and 75,2% were distal tumors (no cardias or GEJ involvement). PDL1 positivity, defined as CPS ≥1 was found in 30.6%, using CPS ≥ 5 cutoff just 22.7% of them were positive. HER2 positivity and MMR deficiency were found in the same proportion of patients 5%. Among young patients (&lt; 50 years) 80% had diffuse histology, 30% were CPS ≥5. HER2 status and PDL1 testing was unknown in 21% and 29% respectively. Conclusions: Among these real-world patients, both HER2 and PDL1 positivity was lower than reported in other regions. Higher incidence of distal tumors, signet ring cells and diffuse histology could explain this difference. Correlation of PDL1 positivity between 22C3 and 28.8 was unknown in our population. Our study remarks the high medical need for investigation of biomarkers and developing of prospective studies for correlation and other targets like Claudins and FGFR2b.[Table: see text]

Tislelizumab combined with POFI (irinotecan, paclitaxel, oxaliplatin and 5-FU/levoleucovorin) as first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC): Preliminary results of a single-arm, open-label phase I/II trial (SYLT-023).

331 Background: Tislelizumab is a humanised IgG4 monoclonal antibody with high affinity and binding specificity for PD-1. Combined with fluoropyrimidine + platinum (XELOX or FP), it is approved in China as first-line treatment of advanced gastric cancer (AGC). Both irinotecan and paclitaxel have also shown antitumor activity in advanced gastric/gastroesophageal junction adenocarcinoma. In this phase I/II study, we explore the safety, tolerability, and efficacy of tislelizumab + irinotecan, paclitaxel, oxaliplatin and 5-FU (POFI) as first-line treatment of HER-2 negative, pMMR AGC. Methods: In a phase I dose finding study using a standard 3+3 design, subjects received four escalating dose levels (dl) of irinotecan/paclitaxel (mg/m2): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tislelizumab 200 mg plus oxaliplatin 85 mg/m2, levoleucovorin 200 mg/m2, and 5-FU 2400 mg/m2 for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D). Results: Fifteen subjects with treatment naïve AGC were enrolled (3 each in dl #1, dl #2, and dl #3 and 6 in dl #4). The median age was 65 years (range 36-72); 80% were male. Two subjects (13.3%) were diagnosed with gastroesophageal junction cancer, 9 (60%) had poorly differentiated disease, and 5 (33.3%) had liver metastasis. PD-L1 CPS scores were: 5 (n=5); 1 (n=1); and 0 (n=9). All subjects were evaluated for dose-limiting toxicity (DLT). One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. All subjects had ≥1 treatment-related adverse event (TRAE) and 10 (66.7%) had ≥1 grade 3-4 TRAE per NCI CTC-AE 5.0. The most frequent grade 3-4 TRAEs were neutropenia (n=8; 53.3%), anemia (n=2; 13.3%), and increased glutamyl transpeptidase (n=2 pts; 13.3%). Confirmed objective response rate in 13 subjects with measurable disease was 100% (1 complete response [CR], 12 partial responses [PR]) per RECIST 1.1. Of the 2 subjects with non-measurable disease, one was a CR and the other was non-CR/non-PD. Survival data are immature. Conclusions: Tislelizumab+POFI was well tolerated and showed preliminary antitumor activity. A phase II study at the RP2D is ongoing. Clinical trial information: NCT05319639 .

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.

Effectiveness and Safety of Chinese Herbal Injections Combined with SOX Chemotherapy Regimens for Advanced Gastric Cancer: a Bayesian Network Meta-Analysis.

Background: Randomized controlled trials (RCTs) have demonstrated that combining Chinese herbal injections (CHIs) with oxaliplatin plus tegafur (SOX) chemotherapy regimens improves clinical effectiveness and reduces adverse reactions in patients with advanced gastric cancer (AGC). These RCTs highlight the potential applications of CHIs and their impact on AGC patient prognosis. However, there is insufficient comparative evidence on the clinical effectiveness and safety of different CHIs when combined with SOX. Therefore, we performed a network meta-analysis to rank the clinical effectiveness and safety of different CHIs when combined with SOX chemotherapy regimens. This study aimed to provide evidence for selecting appropriate CHIs in the treatment of patients with AGC. Methods: We searched eight databases from their inception until March 2023. Surface Under the Cumulative Ranking Curve (SUCRA) probability values were used to rank the treatment measures, and the Confidence in Network Meta-Analysis (CINeMA) software assessed the grading of evidence. Results: A total of 51 RCTs involving 3,703 AGC patients were identified. Huachansu injections + SOX demonstrated the highest clinical effectiveness (SUCRA: 78.17%), significantly reducing the incidence of leukopenia (93.35%), thrombocytopenia (80.19%), and nausea and vomiting (95.15%). Shenfu injections + SOX improved Karnofsky's Performance Status (75.59%) and showed a significant reduction in peripheral neurotoxicity incidence (88.26%). Aidi injections + SOX were most effective in reducing the incidence of liver function damage (75.16%). According to CINeMA, most confidence rating results were classified as "low". Conclusion: The combination of CHIs and SOX shows promising effects in the treatment of AGC compared to SOX alone. Huachansu and Shenfu injections offer the greatest overall advantage among the CHIs, while Aidi injections are optimal for reducing the incidence of liver damage. However, further rigorous RCTs with larger sample sizes and additional pharmacological studies are necessary to reinforce these findings.

ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis.

The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1α, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.

Immunotherapy and combined treatment in gastric cancer

Gastric Carcinoma (GC) ranks as the fifth inducing cause for cancer incidence, and its the fourth inducing reason for cancer-related mortality. Traditional treatments, which involve a combination of chemotherapy and surgical resection, often yield unfavorable prognoses for gastric cancer patients, especially for those with advanced stages or metastases. Immunotherapy has recently emerged as the significant focus in the treatment of advanced gastric cancer, particularly for patients with MSI-H/dMMR. Medications targeting PD-1, such as nivolumab and Keytruda, have gained marketing approval in recent years. Additionally, some biomarkers like HER2, FGFR, and VEGF have shown positive efficacy in clinical research. However, resistance to immunotherapy remains a significant challenge, and the effectiveness of these pharmaceuticals often lasts only about a year for patients suffering advanced gastric cancer. Consequently, theres a need to explore new immune checkpoint inhibitors and discover novel combination therapy approaches. This review is aimed at introducing several latest immune checkpoint inhibitors currently in clinical phases or in pre-clinical stages, alongside innovative combination strategies for treating gastric cancer.

Macrophages enhance cisplatin resistance in gastric cancer through the transfer of circTEX2.

Cisplatin-based chemotherapy is often used in advanced gastric cancer (GC) treatment, yet resistance to cisplatin may lead to treatment failure. Mechanisms underlying cisplatin resistance remain unclear. Recent evidence highlighted the role of macrophages in cancer chemoresistance. Macrophage-derived exosomes were shown to facilitate intercellular communication. Here, we investigated the cisplatin resistance mechanism based on macrophage-derived exosomes in gastric cancer. Cell growth and apoptosis detection experiments revealed that M2-polarized macrophages increased the resistance of GC cells to cisplatin. qRT-PCR, RNAase R assay, actinomycin D assay and cell nucleo-cytoplasmic separation experiments confirmed the existence of circTEX2 in macrophage cytoplasm, with a higher expression level in M2 macrophages than that in M1 macrophages. Further experiments showed that circTEX2 acted as microRNA sponges for miR-145 and regulated the expression of ATP Binding Cassette Subfamily C Member 1 (ABCC1). Inhibition of the circTEX2/miR-145/ABCC1 axis blocked the cisplatin resistance of gastric cancer induced by M2 macrophages, as evidenced by invitro and invivo experiments. In conclusion, our research suggests that the exosomal transfer of M2 macrophage-derived circTEX2 enhances cisplatin resistance in gastric cancer through miR-145/ABCC1. Additionally, communication between macrophages and cancer cells via exosomes may be a promising therapeutic target for the treatment of cisplatin-resistant gastric cancer.

Retracted: Clinical Efficacy of Modified Yiwei Shengyang Decoction Combined with FOLFOX4 Chemotherapy Regimen in the Treatment of Advanced Gastric Cancer and Its Effect on Tumor Marker Levels.

[This retracts the article DOI: 10.1155/2022/6234032.].

Convenient method to improve efficiency of lymph node examination after gastrectomy with D2 lymphadenectomy for gastric cancer

BackgroundThe D2 procedure has been accepted as the standard treatment for advanced gastric cancer (GC) in East Asia. Determination of the number of lymph nodes (LNs) after gastrectomy may influence the pathological stage assessment of lymph node metastasis, significantly influencing prognostic evaluations and formulation of chemotherapy regimens.MethodsBetween January 2020 and January 2022, the medical files of 312 patients with clinical stage T0-4aN0-3M0 gastric cancer were reviewed retrospectively, and the patients were assigned to the normal group (lymph nodes were examined roughly), manual group (lymph nodes were manually examined meticulously), and device group (lymph nodes were examined by device). The clinical and pathologic characteristics, number of lymph nodes harvested, and the time required for lymph node examination was compared.ResultsA total of 312 gastric cancer patients (mean age 65.8 ± 10.3 years, 85 females and 227 males) underwent gastrectomy with curative intent at our department. Sex, age, body mass index (BMI), tumor size, clinical TNM stage, and pathologic TNM stage in the three groups showed no statistically significant differences (P > 0.05). The mean number of harvested lymph nodes in the normal, manual, and device group was 24.2, 36.6 and 35.2, respectively, which showed significant differences (P < 0.0001). The mean number of positive lymph nodes in the normal, manual, and device group was 3.5, 3.9 and 3.9, respectively (P = 0.99). The mean time consumption in device group was 15 min while the time consumption in manual group was 52.3 min, which showed a significant difference (P < 0.0001).ConclusionThis improved lymph node examination method offers a simple approach that is worth promoting, and it can improve the number of harvested lymph nodes efficiently.