Gastric Cancer最新文献

Background & aims: The role of histone lysine lactylation (Kla) in gastric cancer mesenchymal stromal cells (GCMSCs) remains elusive. This study aimed to investigate the potential lactyltransferase and the influence of histone Kla in GCMSCs.

Methods: Histone Kla levels in GCMSCs were characterized by cell immunofluorescence and Western blotting. The transcriptional regulation was validated via CUT&Tag sequencing coupled with qPCR analysis. Immunosuppressive effectors through Western blotting and multiplex immunohistochemistry (mIHC). β-alanine and AZD3965 were applied to inhibit histone Kla in vitro. Ultimately, β-alanine was selected for its ability to enhance the efficacy of anti-PD-1 therapy in NCG^PBMC tumor-bearing model.

Results: The primary GCMSCs exhibited higher histone Kla levels. Lactate treatment triggered the nuclear translocation of aminoacyl-tRNA synthetase 1 (AARS1), whose knockdown attenuated lactate-driven nuclear accumulation and suppressed histone Kla. CUT&Tag-qPCR analysis revealed lactate-induced Pan-Kla enrichment at the FAP promoter, driving extracellular matrix (ECM) receptor interaction pathways. Deeply, H4K8 lactylation (H4K8la) has been defined as the key regulatory role to promote FAP transcription, corroborated by mIHC mapping of their immune-excluded spatial organization. In NCG^PBMC tumor-bearing models, β-alanine synergized with anti-PD-1 therapy, enhancing tumor regression and augmenting CD8⁺ T cell effector functions.

Conclusions: We elucidate a Kla-dependent mechanism underlying GCMSCs-mediated ECM remodeling and immunosuppressive niche formation. The results provide novel insights into the epigenetic regulation of immunosuppressive TME.

Valvuloplastic esophagogastrostomy by a double flap technique has promise for preventing reflux after proximal gastrectomy. However, a short esophageal remnant sometimes strongly complicates the transhiatal procedure for alimentary tract reconstruction. We therefore developed secure robotic techniques for right transthoracic esophagogastrostomy by a double flap technique. To accomplish valvuloplastic esophagogastrostomy by this double flap technique in the right thorax of patients in the prone position, the esophagus and stomach were partially fixed before rotating these two organs to expose the anterior gastric wall side for anastomosis because it was invisible in the right thorax. However, this rotation process was complicated. Doubting that the required anastomosis that was conventionally created in the layout of the ventral esophagus and dorsal stomach in valvuloplastic esophagogastrostomy by a double flap technique protected against reflux, we have considered that, if the anastomosis is created at the posterior gastric wall, it may not be necessary to rotate the remnant esophagus and stomach. We herein describe a modified robotic procedure for right transthoracic valvuloplastic esophagogastrostomy incorporating a double flap technique. In this procedure, the anastomosis is created at the posterior remnant gastric wall under a natural operative view without re-arranging the anastomotic organs. This modified technique simplifies right transthoracic valvuloplastic esophagogastrostomy by a double flap technique without adversely influencing anti-acid reflux mechanisms.

Background: Undifferentiated-type gastric cancer (UGC) is more pathologically aggressive and progresses faster than differentiated-type gastric cancer (DGC). However, the impact of Helicobacter pylori (Hp) status on survival outcomes and clinicopathological features of UGC remains unclear.

Methods: This multi-center retrospective study analyzed 571 patients pathologically confirmed UGC from January 2011 to December 2021. Clinical and histopathological features and survival outcomes were compared between Hp-naïve undifferentiated-type gastric cancer (HpNUGC) and Hp-infected undifferentiated-type gastric cancer (HpIUGC).

Results: 571 patients including 283 HpNUGC (49.6%) and 288 HpIUGC (50.4%) were enrolled in survival analysis. The 5-year event-free survival (EFS) and 5-year overall survival (OS) rates were significantly lower in the HpNUGC group compared to the HpIUGC group (EFS: 46.3% vs. 64.3%, P < 0.001; OS: 54.3% vs. 67.7%, P < 0.001). Hp-naïve status was associated with a 57% higher risk of disease progression, recurrence, or death, collectively termed "events" in this study (HR 1.57; 95% CI 1.20-2.04), and a 50% higher risk of all-cause mortality (HR 1.50, 95% CI 1.12-2.00). The HpNUGC lesions demonstrated larger tumor diameters (P < 0.001), deeper invasion depths (P < 0.001), more frequent lymphatic metastasis (P = 0.003), more advanced disease stages (P = 0.002), and higher rates of positive incision margins (P = 0.049).

Conclusion: HpNUGC is associated with worse survival outcomes and exhibits more malignant pathological features compared to HpIUGC. Future prospective studies are needed to clarify the relationship between Hp status and the development and progression of UGC.

Background: Palliative resection for metastatic gastric cancer is not recommended in current practice guidelines; however, it is frequently performed based on clinical considerations. Prospective trials face challenges, necessitating large-scale retrospective analyses to provide clinical evidence.

Methods: The PASS-META study group established a cohort of 983 patients with gastric cancer with surgically confirmed metastatic lesions treated at five major Korean institutions from 2014 to 2021, collecting 126 variables from preoperative, operative, and postoperative data through hospital records. The correlation between gastrectomy and survival outcomes was investigated using inverse probability of treatment weighting (IPTW) and standardization to estimate counterfactual outcomes.

Results: Machine learning-based imputation and statistical causal survival analysis revealed that gastrectomy was found to significantly improve survival in patients with limited peritoneal metastasis (P1 or P2; RR: 0.90, 95% CI 0.85-0.94), as well as in those with distant lymph node metastasis (dLN1; RR: 0.92, 95% CI 0.91-0.94) and hepatic metastasis (H1; RR: 0.92, 95% CI 0.82-1.00), suggesting a potential survival advantage across these subgroups. No survival benefit was observed in patients with severe peritoneal metastasis (P3). Among patients with P1-P2 metastasis, extensive lymph node dissection improved the 5-year survival rates compared with limited dissection, whereas minimally invasive surgery did not affect the survival outcome. Although gastrectomy increased the postoperative hospital stay and delayed the initiation of the first postoperative chemotherapy compared to patients without gastrectomy, it did not affect the total number of chemotherapy cycles.

Conclusion: This study suggests that gastrectomy offers a significant survival benefit to patients with surgically proven stage IV gastric cancer and limited peritoneal metastasis (P1/P2), distant lymph node (dLN1), or hepatic metastases (H1). Furthermore, specific surgical procedures such as extended lymph node dissection or minimally invasive surgery may be considered for patients undergoing gastrectomy.

Background: Leptomeningeal carcinomatosis (LMC) is a rare but highly lethal manifestation of gastric cancer. We sought to describe its clinical features and define prognostic factors in a large single-center cohort.

Methods: We retrospectively reviewed 86 patients diagnosed with LMC secondary to gastric cancer at Samsung Medical Center between 2008 and 2024.

Results: The median interval from primary gastric cancer diagnosis to LMC development was 12.0 months (range, 0-106). Common presenting symptoms included headache (73.3%), nausea/vomiting (55.8%), and dizziness (48.8%). Primary gastric cancers were predominantly Borrmann type III (48.2%) or type IV (38.8%) and had an undifferentiated-type (96.5%) histology. Intrathecal (IT) methotrexate-based chemotherapy was administered to 54 patients (62.8%), with or without radiotherapy or systemic chemotherapy. Cytological response was seen in 14/54 patients (25.9%) who received IT chemotherapy. Decompressive therapies, including Ommaya reservoir, external ventricular drainage (EVD) and ventriculoperitoneal (VP) shunt were performed in 71/86 patients (82.6%). The median overall survival from LMC diagnosis was 6.0 weeks (95% confidence interval [CI]: 3.7-8.3). In multivariable analysis, age ≥ 60 years (HR 1.8) and ECOG PS > 2 (HR 2.8) were independent adverse prognostic factors. Univariable subgroup analyses demonstrated prolonged survival with intrathecal chemotherapy (HR 0.5), systemic chemotherapy (HR 0.4), and decompressive procedures (HR 0.3), whereas radiotherapy showed no significant benefit.

Conclusions: The prognosis of gastric cancer patients with LMC remains extremely poor, and older age and poor performance status were independent adverse prognostic factors. As intrathecal chemotherapy, systemic chemotherapy, and decompressive therapies may improve survival, an individualized, multidisciplinary treatment approach is recommended.

Background: Helicobacter (H.) pylori is the major risk factor of gastric cancer (GC). We aimed to estimate the population attributable fraction (PAF) of GC and the number of new GC cases and deaths for GC attributable to H. pylori in different countries worldwide in 2022.

Methods: The PAF was estimated using country-specific pooled prevalence of H. pylori in the period 2000-2010 obtained through a systematic review and meta-analysis and a risk ratio of 5.9 for the association between H. pylori and GC. The absolute number of new GC cases and deaths for GC attributable to H. pylori was calculated using PAF and GC incidence and mortality reported by GLOBOCAN 2022.

Results: The PAF of GC due to H. pylori was calculated for 27 countries. The average PAF was 69.7% ranging from 40.7% in Malaysia to 82.3% in South Africa. The PAF was > 70% in all countries in the analysis in Africa, East Mediterranean region and Latin America, apart from Mexico, and in some countries in Western Pacific region (China, Japan and Korea) and Europe (Poland, Spain and Albania). The largest number of GC cases and deaths for GC attributable to H. pylori was estimated in China (GC: 252,850, deaths:184,666) and Japan (GC: 92,166, deaths: 31,809).

Conclusions: More than two-thirds of new GC cases in the countries in the analysis were attributable to H. pylori in 2022. Our estimates may contribute to better investigate cost-effectiveness of H. pylori screening strategies for GC prevention in different countries worldwide.

Background: Corpus atrophic gastritis (CAG) requires endoscopic-histological surveillance due to the risk of developing gastric neoplastic lesions (GNL). This study aimed to identify variables associated with GNL development at long-term follow-up using a Fisher score-based feature-ranking-approach coupled with a One-Class Support-Vector-Machine (SVM) model.

Methods: A dataset containing 30 clinical, endoscopic, and histological variables from consecutive CAG patients (2001-2023) adhering to a surveillance-program was considered. GNL presence at the longest available follow-up was recorded. Gastric biopsies and histological evaluations followed the updated-Sydney-system. A Fisher score-based feature ranking method and a One-Class SVM were employed to select key variables linked to GNL development, and then validated with synthetically generated data.

Results: Overall, 355 CAG patients were initially considered. Of these, 36 were excluded due to the presence of GNL at baseline gastroscopy, and 216 for missing data. Thus, a total of 103 patients were considered and grouped into: CAG patients with [22 patients (F 68.1%), median-age 68(35-83) years] and without GNL at follow-up [81 patients (F 72.8%) median-age 59(26-84) years]. After a median follow-up of 60(12-192) months, 13 epithelial GNL (gastric adenocarcinoma or high/low-grade dysplasia) and nine type-1 gastric-neuroendocrine-tumors (T1gNET) were recorded. Parietal-cell-antibodies and pepsinogen-I < 30 μg/l were associated with epithelial GNL and T1gNET. Antral inflammation and age > 60 were linked to epithelial GNL, while anti-thyroperoxidase-antibodies, smoking, and dyspeptic-symptoms were linked to T1gNET. Low-dose aspirin and H. pylori eradication therapy showed inverse associations with epithelial GNL and T1gNET, respectively.

Conclusions: This is the first study in which an AI-model simultaneously considers clinical, endoscopic, and histological features from a dataset of CAG patients, showing the potential to identify variables associated with GNL development.

Background: Immune checkpoint inhibitors (ICI) are pivotal in cancer treatment. However, not all patients are responsive to current ICI therapies, and new targets are needed. Thus, the HLA-G/ILT2 pathway emerges as one such potential ICI. The present study aimed to analyze the implications of this pathway in cytotoxic T cells from patients with gastric adenocarcinoma.

Methods: Peripheral blood mononuclear cells (PBMCs), and tissue infiltrating lymphocytes were obtained from 16 patients with gastric adenocarcinoma. PBMCs from 17 healthy subjects were used as controls. Cells were subjected to flow cytometry on the one hand and stimulation (assessed by IFNγ production) and proliferation assays, in the presence or absence of HLA-G, on the other.

Results: Despite lower CD3 + counts (p = 0.0036), CD3 + CD8 + ILT2 + (ILT2 + Tc) cells are overrepresented in patients, compared to control subjects (p < 0.0001). These ILT2 + Tc exhibit enhanced anti T-cell receptor (TCR)-stimulated IFNγ production, compared to its counterparts ILT2- Tc (p = 0.0039), which was impaired by the presence of HLA-G (p = 0.0002). Proliferative responses of Tc were significantly reduced by HLA-G (p < 0.0001) after 5 days of stimulation. Finally, simultaneously PD1 and ILT2 staining revealed differential expression patterns between patients.

Conclusions: CD8 + T cells expressing ILT2 are overrepresented in patients with gastric adenocarcinoma, independent of PD-1 expression, and appear particularly susceptible to functional suppression in the presence of HLA-G-positive tumors. These findings highlight the immunomodulatory role of HLA-G in the tumor microenvironment and support its relevance as a potential target for personalized immunotherapeutic strategies.

Background: We aimed to reveal the outcomes of endoscopic resection (ER) for locally recurrent early gastric cancer (LRGC) after ER using the data obtained in a Japanese multicenter prospective cohort study of ER for early gastric cancer (EGC) using Web registry (J-WEB/EGC).

Methods: Short-term and long-term outcomes were compared between 125 LRGCs (119 patients) and 9387 primary EGCs of naive stomach (8455 patients) enrolled in this study at 41 centers between July 2010 and June 2012. We calculated 5-year overall survival rates (OS) and disease-specific survival rates (DSS) for LRGC, divided ERs into curative and noncurative resections, and calculated hazard ratios (HR) for all-cause mortality with Cox regression analysis.

Results: For LRGCs and primary EGCs, median resection times were 100 and 77 min (p<0.0001), en-bloc resection rates were 97.6% and 99.5% (p<0.05), and R0 resection rates were 86.4% and 93.3% (p<0.05), respectively. There were no significant differences for adverse events between LRGC and primary EGC. Five-year OS and DSS for LRGC cases were 89.9% and 100%. Compared to curatively resected primary EGC cases, HR for all-cause mortality of curatively resected LRGC, noncuratively resected primary EGC and noncuratively resected LRGC cases were 0.58 (95% CI 0.24-1.41), 1.46 (1.25-1.7) and 3.02 (1.43-6.36), respectively.

Conclusions: A curative ER for LRGC offers the same long-term prognosis as primary EGC. ER for LRGC can offer a secure and radical treatment.