Gastric Cancer最新文献

Background: Apatinib is a targeted therapy used in the treatment of advanced gastric cancer. However, many gastric cancer patients develop resistance to Apatinib, and the mechanisms underlying this resistance remain unclear. Previous studies have shown that Apatinib can induce ferroptosis in gastric cancer cells. More recent research suggests that polyunsaturated ether phospholipids are closely associated with tumor cell sensitivity to ferroptosis, and may represent key molecules involved in the resistance of tumor cells to ferroptosis.

Methods: We established Apatinib-resistant gastric cancer cell lines and assessed their tolerance to ferroptosis. We identified key enzymes responsible for the ferroptosis tolerance observed in drug-resistant cells using lipidomics and transcriptomics analysis. Molecular and biological experiments were conducted to elucidate the molecular mechanisms underlying Apatinib resistance mediated by ferroptosis tolerance in gastric cancer cells.

Results: Apatinib resistance is closely linked to ferroptosis resistance, which is driven by a reduction in the levels of polyunsaturated ether phospholipids-phospholipids that are particularly susceptible to oxidation and induce ferroptosis. The downregulation of key enzymes involved in polyunsaturated ether phospholipid synthesis, such as AGPS, mediates tolerance to both ferroptosis and Apatinib in gastric cancer cells, both in vitro and in vivo. Mechanistically, the expression of AGPS in tumor cells is regulated by the transcription factor ELK1. Drug-resistant cells acquire Apatinib tolerance by downregulating both ELK1 and AGPS expression.

Conclusions: Apatinib-resistant gastric cancer cells exhibit reduced expression of the transcription factor ELK1, which regulates the expression of AGPS. This reduction contributes to the resistance and malignancy of gastric cancer cells.

Background: The impact of neoadjuvant combined chemotherapy, immunotherapy, and targeted therapy on pathologic responses and survival outcomes in HER2-positive locally advanced gastric cancer remains unclear.

Patients and methods: In this single-arm, phase 2 trial, patients with HER2-positive resectable cT4 and/or N + M0 gastric or gastroesophageal junction (G/GEJ) adenocarcinoma received four cycles of neoadjuvant camrelizumab plus trastuzumab and CapOx, followed by D2 gastrectomy and four cycles of CapOx. The primary endpoint was pathological complete response (pCR, ypT0N0) rate.

Results: Twenty-five patients were enrolled and received neoadjuvant combination treatment. Of these patients, 11 (44%) were in cT3 and 14 (56%) in cT4a; all had positive nodal status. Of the 23 patients who underwent surgery, 5 (21.7%, 95% CI: 7.5-43.7) achieved pCR (ypT0N0), and 7 (30.4%, 95% CI: 13.2-52.9) achieved near pCR (ypT0). The R0 resection rate was 100%. During a median follow-up of 41.0 months, no patients with pCR had recurrence or death. In contrast, five of 18 patients with non-pCR had recurrence, and four of them died. The three-year disease-free survival rate was 78.3%. During neoadjuvant treatment, grade 3 adverse events were observed in 36% of patients, with no grade 4 or 5 adverse events reported. No treatment-related surgical delay or reoperation occurred.

Conclusion: Neoadjuvant camrelizumab plus trastuzumab and chemotherapy demonstrated favorable response and tolerable safety in HER2-positive G/GEJ adenocarcinoma.

A 73-year-old male patient presented with anemia and was diagnosed with unresectable advanced gastric cancer with distant lymph node metastases. The biopsy specimen showed a poorly differentiated adenocarcinoma. Immunohistochemistry was negative for human epidermal growth factor receptor 2, positive for claudin- 18, and revealed a preserved mismatch repair status. A regimen of capecitabine, oxaliplatin, and zolbetuximab was chosen as the primary chemotherapy regimen. On day 2, the patient started complaining of nausea and decreased appetite, and his symptoms gradually worsened. Esophagogastroduodenoscopy performed on day 11 revealed an erythematous and edematous mucosa with white secretions throughout the stomach. A histopathological examination revealed epithalaxia at the surface and severe inflammatory cell infiltration in the lamina propria. These endoscopic and histological findings indicated zolbetuximab-related gastritis. His symptoms improved three weeks after the discontinuation of chemotherapy. Endoscopic and pathological improvements of the gastritis were confirmed three months after the discontinuation of zolbetuximab. This report describes the first case of prolonged severe gastrointestinal symptoms with severe gastritis caused by zolbetuximab, as demonstrated by endoscopic and histopathological evidence.

Background: Large type 3 (≥ 8 cm) and type 4 gastric cancers (GCs) have poor prognoses and necessitate multidisciplinary treatment. A multi-institutional phase II study (OGSG1902) was conducted to assess the efficacy and safety of neoadjuvant chemotherapy (NAC) with docetaxel, oxaliplatin, and S-1 (DOS) in these patients.

Methods: Patients with large type 3 or type 4 GC without distant metastasis, except for positive peritoneal cytology (CY), were enrolled. Patients received three courses of neoadjuvant DOS therapy (docetaxel 40 mg/m² and oxaliplatin 100 mg/m² on day 1 via intravenous infusion, and S-1 80 mg/m² orally for 14 days, repeated every 3 weeks) followed by gastrectomy. After R0 resection, adjuvant docetaxel/S-1 therapy was administered for 1 year.

Results: From October 2019 to February 2022, 48 patients were enrolled. NAC was completed in 91.7% of patients. The R0 resection rate was 89.6%. The pathological response rate (Grade 1b-3) was 66.7%. Among patients with measurable lesions, the response rate was 50.0%. The CY-negative conversion rate was 80.0%, and the protocol completion rate was 45.8%. Grade 3 or 4 adverse events during NAC, including neutropenia and appetite loss, occurred in 37.5% of patients. Major postoperative complications (Clavien-Dindo Grade IIIa or higher) were observed in 2.1% of patients.

Conclusions: NAC with DOS for large type 3 or type 4 GC followed by gastrectomy demonstrated promising efficacy, high pathological response rates, and an acceptable toxicity profile. Further evaluation of long-term survival outcomes is ongoing.

Background: This study compared plasma cell-free DNA (cfDNA) and tumor tissue DNA (ttDNA) to explore the clinical applicability of cfDNA in patients with metastatic gastric cancer (mGC) receiving palliative second-line paclitaxel + ramucirumab treatment.

Methods: Targeted sequencing of 106 genes was conducted using germline DNA and cfDNA at baseline (baseline-cfDNA) and progressive disease (PD-cfDNA). The results were compared with those of ttDNA-based cancer panel data.

Results: Of 76 consecutive patients, 46 (27 males; median age 57.5 [range, 32-73] years) who had all three samples were included. Combined analysis of ttDNA and baseline-cfDNA revealed that TP53 (58.7%) was the most frequently mutated gene, followed by CDH1 (26.1%), KRAS (21.7%), and APC (13.0%). For these genes, the sensitivity and positive predictive value of baseline-cfDNA over ttDNA were 71.8% and 51.9%, respectively. When baseline-cfDNA and PD-cfDNA results were combined, 34 patients (73.9%) were found to have additional mutations compared with ttDNA results alone. PD-cfDNA analysis revealed 14 novel pathogenic mutations in ten patients (21.7%). At baseline, patients with a high circulating tumor DNA fraction concentration showed a significantly shorter progression-free survival (PFS) (P = 0.016) in univariable and multivariable analyses. High maximal variant allele frequency (VAF) (P = 0.022), high sum of VAF (P = 0.028), and high TP53 VAF (P = 0.022) were associated with worse PFS in univariable analysis.

Conclusions: Although cfDNA alone cannot replace ttDNA entirely, cfDNA analysis revealed additional mutations. Notably, PD-cfDNA analysis revealed novel pathogenic mutations that emerged during treatment. Moreover, the baseline circulating tumor DNA fraction concentration and VAF values were associated with longer PFS.

Background: Cachexia is a common complication in advanced gastric cancer (AGC). Eicosapentaenoic acid (EPA) may ameliorate cachexia. This single-arm, phase II study assessed the potential benefit of an oral nutritional supplement containing EPA (ONS-EPA) for cachexia in AGC patients.

Methods: Chemotherapy-naive AGC patients with cachexia, defined by serum albumin < 3.5 g/dl and C-reactive protein ≥ 0.5 mg/dl, were included. Patients received an EPA-enriched supplement (Prosure^®, 1.056 g EPA/pack) twice daily during first-line chemotherapy. The primary endpoint was time to treatment failure (TTF) in patients adhering to ≥ 25% of the planned ONS-EPA dose in the first two weeks (per-protocol set, PPS). Secondary analyses evaluated adherence impact on treatment outcomes.

Results: Of 72 enrolled patients, 65 were evaluated. Median adherence was 42.8%. Median TTF in the PPS group was 4.8 months (95% CI 3.6-5.5), below the pre-set 4-month threshold. The PPS group had a higher proportion of patients who improved their nutritional and inflammatory status during treatment, along with better TTF and overall survival (OS) compared to those with poor adherence. Adjusted median TTF was 4.6 vs. 2.5 months (hazard ratio: 0.56; 95% CI 0.28-1.12, p = 0.105).

Conclusions: Although the primary endpoint was not achieved, the study suggests that ONS-EPA may benefit AGC patients with cachexia.

Background: Loss of appetite following gastric cancer surgery, particularly total gastrectomy, significantly impacts patient quality of life due to the removal of the ghrelin-secreting region. We developed appetite-preserving gastrectomy (APG), a modified total gastrectomy that preserves this region.

Methods: Ten consecutive patients with esophagogastric junction cancer who were indicated for total gastrectomy and underwent APG between April 2023 and April 2024 were evaluated for early surgical outcomes, appetite, and changes in weight and body composition.

Results: There were no postoperative complications of grade II or higher (Clavien-Dindo classification). Appetite, assessed using the Simplified Nutritional Appetite Questionnaire, showed no significant impairment at 3 months (14.5 points, P = 0.82) and 6 months (15 points, P = 0.44) postoperatively compared with preoperative values. Oral calorie intake was maintained at 3 months (1675 kcal, P = 0.97) and 6 months (1675 kcal, P = 0.22) postoperatively compared with preoperative levels. The patients' body weight decreased by 9.2% at 6 months postoperatively compared with preoperative values, but their lean body mass remained stable. Although a significant decrease in the blood Ghrelin levels was observed postoperatively, 53% and 60.4% of the preoperative levels was maintained at one month and 6 months, respectively.

Conclusions: APG is a safe procedure that preserves the residual stomach as an endocrine organ, maintains ghrelin secretion and appetite, and prevents muscle loss. However, further trials are required to compare the efficacy of APG with total gastrectomy in preventing postoperative appetite loss.

Gastric cancer is the fifth most common cancer worldwide and leptomeningeal carcinomatosis (LM) occurs in 0.06% of gastric cancers. As such, trials are difficult to power and quantitative analyses difficult to standardize. We composed a review and analysis of 47 recent cases to be used as a comprehensive resource for an oncologist faced with managing this highly morbid, rapidly fatal disease. Gold-standard of diagnosis of LM is through cerebral spinal fluid (CSF) cytology; MRI is the preferred imaging modality to identify LM. However, repeated lumbar punctures and imaging studies are often required to establish diagnosis. Negative results do not rule out LM. Treatment includes radiation and intrathecal chemotherapy, most commonly with methotrexate. Systemic treatment with chemotherapy and immunotherapy is also used. Median survival was 2 months. Intrathecal methotrexate was most commonly dosed at 10-12 mg and treatment continued till symptom resolution, serial lumbar punctures with negative cytology, decrease and stabilization of CSF carcinoembryonic antigen (CEA) levels, progression of disease, or poor functional status. The maximum survival was 12 months. The results of this review indicate that suspicion for leptomeningeal disease should be high in any patient with gastric malignancy or with symptoms consistent with malignancy. Treatment on a biweekly to bi-monthly basis and the addition of systemic therapy to intrathecal therapy should be studied in a matched prospective manner. And in the absence of this information, treatment with at least intrathecal chemotherapy and radiation therapy should be considered in those with a performance status conducive to continued treatment.

Peritoneal metastasis is a critical step in the progression of gastric cancer (GC), yet its underlying mechanisms remain poorly understood. Here, we identify FERMT2, a member of the Kindlin protein family, as a key regulator of anoikis resistance (AR) and peritoneal metastasis in GC. FERMT2 expression increases in a suspension-time-dependent manner and is associated with higher pathological grade, advanced clinical stage, and poorer prognosis. Functional studies in vitro and in vivo demonstrate that FERMT2 promotes AR and facilitates peritoneal metastasis. Mechanistically, FERMT2 suppresses the ubiquitination of SOX2, thereby enhancing its stability and up-regulating FN1 transcription. Furthermore, we report that TGFβ-RI expression also increases in a suspension-time-dependent manner, forming a positive feedback loop with FERMT2 via TGFβ-1/TGFβ-RI signaling. This feedback loop drives extracellular fibronectin matrix deposition, strengthens cell-matrix interactions, and supports AR. These findings establish FERMT2 as a pivotal mediator of peritoneal metastasis in GC, offering insights into its potential as a therapeutic target.

Gastric cancer (GC) has a poor prognosis and high mortality because it is often diagnosed at an advanced stage. Targeted therapeutics are considered an important class for advanced GC treatment. However, the fewer effective therapeutic targets and the poor coverage of the GC population limit the use of GC targeted therapies. Recent research suggests that the AXL receptor tyrosine kinase (AXL) plays an vital role in the survival and proliferation of GC cells, and blocking AXL pathway may be an effective strategy for targeted therapies. On the other hand, the affibody molecule, with its small size and faster penetration of tissue, has great potential in tumor imaging and targeted therapy. In this study, we report the novel AXL-binding affibody molecules (Z_AXL:239) screened by a phage-displayed peptide library. The Z_AXL:239 could specifically bind and interact with AXL proteins in vitro and in vivo, as demonstrated by surface plasmon resonance, co-immunoprecipitation, immuno-fluorescence co-localization, and near infrared fluorescent imaging. In addition, Z_AXL:239 affibody molecules could significantly inhibit the proliferative activity and induce apoptosis of AXL-positive GC cells by decreasing the phosphorylation levels of the PI3K/AKT1 and MEK/ERK pathway, leading to the suppression of the downstream nuclear protein c-myc. Moreover, Z_AXL:239 was found to have significant anti-tumor effects in AXL-positive GC transplantation tumor nude mouse models. In brief, we provide strong evidence that the novel Z_AXL:239 affibody molecules have great potential as a potent tumor-specific molecular imaging and targeted therapeutic agents for GC.