Comparative Analysis of Signet Ring and Non-Signet Ring Urachal Adenocarcinomas: A National Cancer Database Study.

Exosomal circUBR5 drives metastasis and chemoresistance in gastric signet-ring cell carcinoma by reprogramming cholesterol metabolism through the hsa-miR-1208/CYP19A1 axis and ACAT1 upregulation.

Cancer-specific mortality (CSM) rates in patients with rare histological prostate cancer subtypes after treatment with radical prostatectomy (RP) versus radiation therapy (RT) are largely unknown. Relying on the Surveillance, Epidemiology, and End Results database (2004-2020), we identified patients with five prostate cancer subtypes treated with RP or RT. Kaplan-Meier analyses and Cox regression models addressed CSM. Of 427,055 patients, 425,692 (99.68%) harbored acinar, 855 (0.20%) ductal, 324 (0.08%) mucinous, 54 (0.01%) signet ring cell adenocarcinoma, and 130 (0.03%) neuroendocrine carcinoma. Of those, 250,910 (59%), 592 (69%), 262 (81%), 34 (63%), and 34 (26%) were treated with RP, respectively. Five-year cancer-specific survival rates after RP versus RT were 99.2 versus 97.1% in acinar; 96.3 versus 87.1% in ductal; 98.7 versus 92.1% in mucinous; 97.0 versus 94.7% in signet ring cell; and 59.4 versus 20.5% in neuroendocrine carcinoma. In univariable Cox regression models, RP was associated with a lower CSM rate in acinar (hazard ratio [HR] 0.28; p < 0.001), ductal (HR 0.25; p < 0.001), and neuroendocrine (HR 0.36; p < 0.001), but not in mucinous (p = 0.052) and signet ring cell carcinoma (p = 0.8). After multivariable adjustment, RP remained an independent predictor of lower CSM in acinar (HR 0.35; p < 0.001), ductal (HR 0.30; p < 0.001), and neuroendocrine carcinoma (HR 0.53; p = 0.042). Higher CSM was recorded after RT in acinar, ductal, and neuroendocrine carcinoma. Conversely, no differences in CSM were identified when RP was compared with RT in mucinous and signet ring cell adenocarcinoma.

Abstract Background Breast cancer is the most frequently diagnosed malignancy among women, with invasive lobular carcinoma (ILC) comprising 15% of cases. ILC frequently harbors CDH1 mutations, resulting in the loss of E-cadherin as well as a dyscohesive growth pattern that hinders detection. Signet ring cell carcinoma of the breast, a rare but diagnostically significant variant with poor prognosis, can closely mimic primary gastric adenocarcinoma. Shared histomorphology, particularly in metastatic setting at diagnosis, predisposes to misclassification and consequent therapeutic misdirection. Case Presentation A 61-year-old woman presented to the emergency room with one-month of dysphagia, nausea, vomiting, and unintentional weight loss. Radiographic studies revealed abdominopelvic ascites, periportal lymphadenopathy, right adnexal enlargement, osseous lesions, and omental carcinomatosis. A biopsy of the gastric fundus was positive for invasive adenocarcinoma, diffuse type with signet ring features, supported by positive pan-cytokeratin AE1/AE3 staining. Further biopsy of an omental mass showed CK7 positivity and negativity for PAX8, CDX2, and CD20. Metastatic gastric adenocarcinoma was presumed, and capecitabine-oxaliplatin was commenced. Additional molecular profiling was completed, which revealed breast markers including ESR1, GATA 3, cytokeratin, and mammaglobin. A pathogenic loss of function variant in CDH1 was also detected. Further immunohistochemistry (IHC) on the omental specimen revealed ER 90%, PR 90%, and HER2 IHC 0. IHC of the omentum was also positive for GATA3, mammaglobin, and E-cadherin. These findings supported a diagnosis of metastatic lobular breast carcinoma with signet ring features. MRI breast did not identify a primary breast mass and there were no pathologic axillary lymph nodes. Following bilateral salpingo-oophorectomy, pathology for the right adnexal mass showed carcinoma of breast origin (ER 95%, PR 70% and HER2 IHC2+ and FISH negative). The treatment was switched to a first line aromatase inhibitor and CDK 4/6 inhibitor and the patient has since undergone multiple lines of therapy. Discussion Although breast cancer metastasizing to the stomach is rare—with an estimated incidence of just 0.04%—accurate diagnosis of primary origin of adenocarcinoma is vital due to the stark differences in management and outcomes. The clinical and morphological overlap between metastatic ILC with signet ring features and primary gastric carcinoma necessitates a high index of suspicion and thorough immunohistochemical analysis. ILC may metastasize in a diffuse pattern mimicking gastrointestinal malignancies and can present without an identifiable breast lesion. Literature has shown that ER, GCDFP-15, mammaglobin, and GATA3 are highly sensitive and specific for identifying breast origin, whereas CK20 and CDX2 are associated with gastrointestinal differentiation. Although not unique to breast tumors, CDH1 and PIK3CA alterations are detected in roughly 63-65% and 46% of invasive lobular carcinomas, respectively, versus only about 9.7% and 12% of gastric adenocarcinomas. Further studies are warranted to refine diagnostic algorithms that couple IHC with next-generation sequencing, clarifying when the addition of breast-specific markers is essential for definitive tumor origin assignment. Conclusion This case emphasizes the need for comprehensive diagnostic workup in atypical presentations and supports broader use of breast-specific IHC markers and molecular profiling in gastrointestinal biopsies with ambiguous or signet ring histology. Integrating markers such as ER, PR, GATA3, mammaglobin, and CDH1/PIK3CA profiling into a tiered diagnostic algorithm can prevent misclassification, facilitate timely therapy, and ultimately improve patient outcomes. Citation Format: J. Eckman, H. Jeon, S. Oh. When Signet Ring Cells Mislead: A Case of Metastatic Breast Cancer Presenting as Gastric Malignancy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-06-21.

Amphicrine carcinoma is a rare malignancy exhibiting both endocrine and exocrine differentiation within the same tumor cells. We report a case of a 70-year-old male who underwent screening upper endoscopy, which revealed a 15mm depressed lesion with a reddish elevated margin at the esophagogastric junction. Narrow-band imaging with magnification demonstrated an irregular, densely packed vascular pattern, suggesting malignancy. Endoscopic ultrasound indicated third-layer disruption, raising suspicion of submucosal invasion. Endoscopic resection was performed after informed consent. Histopathological analysis confirmed submucosal invasion and identified three tumor components: (1) an endocrine carcinoma component with a solid-nest structure, (2) a glandular component, and (3) a goblet cell-like signet ring cell carcinoma component. Immunohistochemistry revealed synaptophysin, INSM1, and CD56 positivity in all components, while MUC2 was expressed in the signet ring cell carcinoma component and partially in the others. The tumor exhibited a high Ki-67 labeling index, indicating aggressive proliferation. Based on these findings, the lesion was diagnosed as an endocrine carcinoma with an amphicrine carcinoma component. Additional surgery confirmed no residual tumor or lymph node metastasis. Given the rarity of amphicrine carcinoma and the limited understanding of its clinical behavior, further research is necessary to determine its prognosis and optimal management strategies.

Primary signet ring cell carcinoma (SRCC) of the bladder is an exceptionally rare and aggressive malignancy, accounting for only 0.12%–0.6% of all bladder cancers. This case report describes a 54‐year‐old female who presented with urinary incontinence and abdominal pain, initially misdiagnosed as a urinary tract infection. Imaging revealed suspicious bladder findings, and subsequent cystoscopy with transurethral resection identified SRCC, later confirmed by immunohistochemistry (PD‐L1 positive, CDX‐2/ER negative). Despite peritoneal carcinomatosis, the patient responded to cisplatin/gemcitabine chemotherapy and immunotherapy, demonstrating tumor shrinkage on follow‐up imaging. This case highlights the diagnostic challenges of SRCC due to its nonspecific symptoms and potential histological overlap with other metastatic gastrointestinal tumors. Early recognition and a multidisciplinary approach are critical for improving patient outcomes.

.SignificanceStomach (gastric) cancer survival depends significantly on the stage in which it is detected, and surveillance with white light endoscopy exhibits poor contrast between gastric cancer and healthy tissue, especially at early stages. Early gastric cancer can exhibit changes in epithelial microstructure, including loss of regular gastric pit structure and collagen alterations which increase tissue stiffness.AimTo improve contrast between early cancer and normal tissue, we investigate the use of optical coherence tomography (OCT) and elastography (OCE) to visualize changes in tissue structure and stiffness consistent with gastric cancer.ApproachImages of eight samples of ex vivo human stomach tissue from three patients were collected with a benchtop OCT system. OCT was performed for qualitative visualization of tissue structure. OCE was then performed on 17 regions of interest using a simplified optical palpation method to extract relative stiffness measurements. A transparent silicone reference layer was placed on the tissue, and axial compression was applied. The resulting deformation (strain) of the reference layer was measured, and the corresponding stress applied to the sample surface was extracted from the characteristic stress-strain curve of the reference material. Spatially resolved stress measurements were mapped and overlaid on en face OCT images. Tissue classification was confirmed by pathology.ResultsOCT image volumes showed more distinct gastric pit and tissue layer structure, as well as less optical attenuation, in normal tissue compared to gastric metaplasia and focal signet ring cell carcinoma (SRCC). Exemplary OCE-derived stress maps showed a trend of increasing measured stress with progression of precancer (metaplasia and dysplasia) and SRCC, suggesting increased tissue stiffness.ConclusionsThis proof-of-concept study provides evidence that OCT and OCE may be capable of visualizing differences in tissue structure and stiffness between normal, metaplastic, dysplastic, and early cancerous gastric tissue, potentially providing the basis for improved screening tools with higher sensitivity.

Tumor microenvironment-driven ST6Gal-Ⅰ activation promotes aggressiveness in gastric signet-ring cell carcinoma via ITGβ1/FAK/Paxillin signaling.

Advanced T stage and nodal disease are independently associated with worse cancer-specific survival in stage IV colorectal cancer: A SEER-based survival analysis.

When Looks Deceive: Signet Ring Cell Carcinoma Masquerading as Solitary Pinpoint Gastric Erosion

The clinical benefit of PD-1/PD-L1-based immunotherapy in gastric signet ring cell carcinoma (GSRCC) remains unclear. This study evaluated the efficacy of first-line immunotherapy in advanced GSRCC. This single-center retrospective cohort study assessed the clinical response of patients with advanced GC diagnosed from November 2019 to January 2025 after receiving first-line immunotherapy combined with chemotherapy and/or target therapy, concurrently comparing therapeutic outcomes in GSRCC and non-GSRCC cohorts. This study included 230 patients, with objective response rate (ORR) achieving 43.9%. Among the 150 non-GSRCC patients, the ORR was 50.7%, compared to 31.3% in the 80 GSRCC patients. Non-GSRCC patients had longer median progression-free survival (PFS: 10.0 vs 7.9 months; p = 0.002) and overall survival (OS: 17.4 vs 15.3 months; p = 0.039). Peritoneal metastasis was independently associated with rapid progression and poor survival (HR 2.63, 95% CI 1.52-5.53; p = 0.001). Among GSRCC patients, those with peritoneal metastasis had significantly shorter PFS (6.6 vs 13.6 months; p < 0.001) and OS (11.0 vs 19.4 months; p = 0.001). The findings suggest that GSRCC is associated with resistance to immunotherapy in advanced GC. Furthermore, peritoneal metastasis is significantly associated with poor prognosis in GSRCC patients.

A 43-year-old man with a family history of gastric cancer had undergone endoscopic submucosal dissection (ESD) for a signet-ring cell carcinoma (SRCC) lesion. Five years later, a recurrent SRCC lesion was treated with a second ESD. Two months later, multiple recurrent SRCC lesions were again detected. Immunohistochemical staining revealed reduced E-cadherin expression. Genetic testing for CDH1 identified an R732Q missense mutation. The patient subsequently underwent total gastrectomy, which identified 22 intramucosal SRCC lesions. Notably, the most distal carcinoma was located in the duodenal bulb and appeared to arise from mucosa containing gastric fundic glands, gastric foveolar epithelium, CD10-positive cells, MUC2-positive cells, and Brunner's glands, suggesting origin from ectopic gastric mucosa in the duodenum. To our knowledge, this is the first reported case of SRCC arising from ectopic gastric mucosa in patients with hereditary diffuse gastric cancer. Screening for ectopic gastric mucosa may be warranted in patients with CDH1 mutations.

Colorectal cancer (CRC) is among the most common carcinomas globally and a leading cause of cancer-related mortality. In Pakistan, it is the fifth most diagnosed malignancy and the fourth leading cause of cancer death. A significant number of patients present at advanced stages, limiting curative treatment options. Peritoneal metastasis is a recognized route of disease spread in CRC, following hepatic and pulmonary metastasis. While peritoneal washing cytology (PWC) is an established prognostic tool in gastric and gynecological cancers, its role in CRC remains unclear and underutilized. This study aimed to evaluate the association of peritoneal fluid cytology with tumor stage, histological subtype, and tumor differentiation in patients with CRC in a Pakistani population, with the secondary goal of evaluating its prognostic significance and potential therapeutic implications. We conducted a prospective observational study at the GI and HPB Department of SIUT Hospital, Karachi, from July to September 2025. A total of 83 patients aged 18-80 years with biopsy-proven colorectal adenocarcinoma, meeting specific inclusion criteria, were enrolled. Peritoneal lavage was performed intraoperatively before tumor manipulation, and cytological analysis of the fluid was conducted using standardized techniques. Cytology was deemed positive if malignant or atypical cells were identified. Statistical analysis was performed using SPSS version 26, with significance set at p < 0.05. Among the 83 patients, 71.1% were male, with a mean age of 41.3 ± 14.9 years. Rectal cancer was more prevalent (69.9%) compared to colonic cancer (28.8%). Signet-ring cell carcinoma was the most common histological subtype, found in 60.9% of patients, followed by mucinous adenocarcinoma (39.1%). Poorly differentiated tumors were observed in 43.3% of cases. Peritoneal cytology was positive in 14 patients (16.9%). Positive cytology was significantly associated with signet-ring cell carcinoma (p = 0.037) and advanced tumor stages, particularly stage IIIC (p = 0.0025). Stage IIIB also showed a trend toward significance (p = 0.380). Peritoneal fluid cytology was found to correlate with aggressive tumor histology and advanced staging in CRC, suggesting its potential as a prognostic marker. While not currently part of routine staging protocols for CRC, positive peritoneal cytology could identify patients at higher risk for recurrence and poor outcomes. These patients may benefit from intensified treatment approaches, including consideration for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), as well as closer postoperative surveillance. Larger multicenter studies with long-term follow-up are warranted to confirm these findings and to explore the therapeutic implications of cytology-positive status in CRC. Hasan SR, Muhammad S, Khan S, et al. Colorectal Cancer: Correlating the Role of Peritoneal Fluid Cytology to Tumor Biology and Stage: A Prospective Study from Pakistan. Euroasian J Hepato-Gastroenterol 2025;15(2):141-145.

Gastric signet-ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer characterized by unique biological features, leading to low rates of early diagnosis, poor prognosis, and limited response to chemotherapy and immunotherapy. Effective targeted therapies for GSRCC remain scarce. Given these treatment challenges and the potential efficacy of antibody-drug conjugates (ADCs) in clinical settings, this study focuses on identifying novel ADCs with significant potential to improve the treatment outcomes of GSRCC. We conducted a comprehensive bioinformatics analysis of GSRCC using multi-omics data (including transcriptomics and proteomics) and identified the poliovirus receptor (PVR) as a potential therapeutic target for GSRCC. We selected deruxtecan (DXd) as an effective carrier for developing an ADC targeting GSRCC. The synthesized PVR monoclonal antibody-DXd complex (PVR-DXd) has a drug-to-antibody ratio (DAR) of 4. PVR-DXd demonstrated potent antitumor activity in a human GSRCC xenograft model, effectively eliminating tumors while sparing normal tissue, highlighting its potential as a novel and impactful targeted therapy for this aggressive subtype of gastric signet ring cell carcinoma. This preliminary study supports the further development of PVR-DXd as a candidate therapy for advanced GSRCC.

BackgroundThe incidence of early-onset colorectal cancer is increasing. The rate of early diagnosis and screening is low, and the prognosis is poor. This study aims to compare the clinical and pathological characteristics of colorectal cancer patients under age stratification, so as to improve the awareness of prevention in different populations and provide the basis for treatment strategies.MethodsThis retrospective cross-sectional study included patients who underwent electronic colonoscopy and were diagnosed with colorectal cancer by pathology in Qilu Hospital of Shandong University from July 2017 to June 2020. Their clinical and pathological data were statistically analyzed according to <40 years, 40–50 years and >50 years groups.Results850 patients were included (40 <40 years, 108 40–50 years, and 702 >50 years). The proportions of comorbidities (7.5% vs 26.8% vs 55.4%, p=0.006) and medical history were higher (12.5% vs 11.1% vs 17.1%, p=0.163) in the >50 years group; the proportion of family history was higher in the <40 years group (10.0% vs 9.3% vs 3.8%, p=0.015). All patients in the age group under 40 years had symptoms (100% vs 96.3% vs 93.4%, p=0.161), while some patients in the other two groups did not. The incidence of left-sided colon was higher in the <40 years group (37.5% vs 25.0% vs 23.1%, p=0.392); the incidence of right-sided colon was higher in the 40–50 and >50 years group (10.0% vs 25.9% vs 21.9%, p=0.392). Low-grade (7.5% vs 5.6% vs 5.4%, p=0.057), mucinous adenocarcinoma (15.0% vs 9.3% vs 3.6%, p=0.002) and signet ring cell carcinoma (5.0% vs 0.9% vs 0.3%, p=0.002) were more common in the <40 years group. Late-stage tumors were more common in the <50 years group (65.0% vs 51.9% vs 46.6%, p<0.01); early-stage tumors were more common in the >50 years group (35.0% vs 48.2% vs 53.4%, p<0.01).ConclusionThere are more family history in early-onset colorectal cancer patients, with various symptoms, mucinous adenocarcinoma and signet ring cell carcinoma, poor tumor differentiation and late stage. Young adults with symptoms should undergo colonoscopy actively. For patients <40 years, genetic testing should be performed.

In recent years, several studies have described the clinicopathological characteristics of Helicobacter pylori (H. pylori) -uninfected gastric cancer. This entity is now recognized as one of the major topics in gastric cancer research and clinical practice. Currently, H. pylori-uninfected gastric epithelial neoplasms (HpUGENs; excluding adenocarcinomas of the esophagogastric junction and gastric neuroendocrine tumors) are classified into seven subtypes in our research results: raspberry-type gastric epithelial neoplasm (GEN; foveolar-type adenoma), whitish flat elevated-type GEN (GEN with gastric phenotype), gastric adenocarcinoma of fundic-gland type (GA-FG), gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM), other GEN with a gastric phenotype (complex type of GEN with gastric phenotype), GEN with an intestinal or gastrointestinal mixed phenotype arising in the pyloric gland region, and signet-ring cell carcinoma (SRCC). This study outlines our analysis of current cases, detailing the endoscopic and clinicopathological characteristics of HpUGENs, and provides practical insights for their endoscopic and pathological diagnosis. Since many of these neoplasms histologically show low-grade atypia, they are sometimes diagnosed as gastric adenoma or gastric dysplasia rather than adenocarcinoma in the World Health Organization classification, highlighting the need for standardized histopathological diagnostic criteria of gastric epithelial neoplasms with low-grade atypia. Moreover, as no clinical practice guidelines have yet been established for HpUGENs, future research should aim to elucidate the relationship between early and advanced lesions, perform comprehensive analyses of H. pylori-uninfected advanced gastric cancer, and conduct molecular biological studies to achieve a better understanding of the entire disease spectrum and to establish evidence-based clinical guidelines.

The mortality rate in gastric cancer during pregnancy is very high, which dictates the need to research and improve the methods of early diagnosis of malignancies, as well as studying the pathogenesis of malignant tumors in pregnant women. We report a lethal case of gastric cancer in a pregnant woman. The findings of the autopsy, histological, histochemical and immunohistochemical examinations verified gastric signet ring cells carcinoma with multiple metastases and infiltration of the placental intervillous space. The possible pathogenesis of cancer with changes in the hormonal background occurring in pregnant women is discussed. Understanding the endocrine mechanisms of carcinoma pathogenesis will be useful for developing new therapies for gastric cancer.

847 Background: The biological behavior of appendiceal epithelial neoplasms (AENs) depends on histological subtype and grade. Due to their rarity, previous molecular analyses have grouped diverse biological types together. We aimed to examine genomic and outcomes differences among distinct biological subgroups of appendiceal cancer. Methods: Tempus Lens was used to analyze de-identified clinical genomic, and transcriptomic information for patients (pts) diagnosed with AENs (N=807): mucinous adenocarcinomas (MA) (N=282), non-mucinous adenocarcinomas (NMA) (N = 311), signet-ring cell carcinoma (SRC) (N=46), and goblet cell adenocarcinoma (GCA) (N = 168). Pts were stratified by GNAS/KRAS co-mutations (mut) (N=151) or wild-type (wt) (N=231). RNA-seq data were normalized and quantified as transcripts per million (TPM) and reported as log2(TPM+1). Immune infiltration was estimated via quanTIseq and enrichment via single sample gene set enrichment analysis (ssGSEA). Real-world overall survival (rwOS) was defined as the time from sample collection to death or loss to follow up. Median OS (mOS) was estimated using Kaplan-Meier curves and compared using log-rank tests. Results: Across the cohort, median age was 63 years; 87% were Stage IV with grade distribution of 18% G1, 34% G2, 48% G3; 54% were female; 79% were White, 10% Black, 2% Asian, 8% other and 9% Hispanic ethnicity. Most common mutations across histologies are shown in the table. In MA and NMA, the most common KRAS alterations were 37% and 25% G12D, 20% and 14% G12V, 7% and 6% G13D, and 5% and 4% G12C. GNAS / KRAS -mut was present in 38% MA, 14% NMA and 7% SRC. Grade 2 MA was genomically more like G1 than G3 with KRAS and GNAS rates for G1/2/3 of 90%/83%/46% and 64%/41%/17%, respectively. In MA pts, mOS was shorter for G3 compared to G2 and G1, respectively (13.2m vs 28.8m vs 25.9m, p=0.002). Although, immune cell infiltration was similar between MA and NMA pts; pts with GNAS/KRAS-mut showed higher levels of M1 macrophages (p&lt;0.05), higher enrichment in the tertiary lymphoid structure signature (p&lt;0.001) and lower levels of M2 macrophages (p&lt;0.0001) and NK cells (p&lt;0.0001) compared to wt pts. mOS was improved in GNAS/KRAS-mut (N=307) pts compared to wt pts (20.5m vs 16m, p=0.008). Conclusions: AENs show unique DNA alterations by histological subtype. Grade 2 MA closely resembles G1, not G3, in survival and genomics, supporting a three-tier grading system over a high-grade (G2/G3) grouping. KRAS G12D represented 37% of KRAS mutations, and pts with KRAS/GNAS co-mutations had better survival and a favorable immune profile, supporting further immunotherapy research in low-grade MA. Most common mutations across histological subtypes. MA NMA GCA SRC KRAS *** 75% 55% 14% 20% TP53 *** 44% 59% 34% 17% SMAD4 24% 26% 15% 30% GNAS *** 41% 15% 8% 7% APC *** 8% 23% 2% 4% RHOA *** 0.5% 3% 8% 4% KDM6A * 2% 3% 4% 15% PIK3CA 7% 14% 4% 11% ***p&lt;0.001; *p&lt;0.05.

361 Background: Neoadjuvant chemoimmunotherapy is revolutionizing the treatment landscape for solid tumors. However, a subset of patients exhibited limited therapeutic response. Metabolomic profiling of non-responding patients revealed aberrant polyol pathway activation, with sorbitol accumulation identified as a novel immune-modulatory mechanism. To address this challenge , we initiated a randomized controlled trial evaluating the safety and efficacy of chemoimmunotherapy combined with a sorbitol-restricted diet in locally advanced gastric cancer (LAGC) patients. Methods: Key inclusion criteria were: age ≥ 18 years; histologically confirmed gastric cancer with locally advanced disease as defined by the AJCC 8th Edition; and no prior systemic anticancer therapy. Eligible patients were randomized 1:1 to receive either neoadjuvant chemoimmunotherapy (3-week cycles of SOX plus PD-1 antibody tislelizumab) combined with sorbitol-supplemented diet (2 g per dose, three times daily during treatment weeks； intervention group), or neoadjuvant chemoimmunotherapy (control group). The primary endpoint was the major pathological response (MPR) rate. Secondary endpoints included pathological complete response (pCR) rate, disease control rate (DCR), and R0 resection rate. Exploratory endpoints included treatment-related adverse events (TRAEs), progression-free survival (PFS), and overall survival (OS). Clinical trial registration: NCT06826079. Results: This interim analysis included the first 26 patients (13 per arm) of a planned 86-patient cohort. Demographic characteristics were comparable between groups, with the investigational arm comprising 8 males and 5 females (mean age 59 years, range 45-72) and the control arm 9 males and 4 females (mean age 56 years, range 48-68). Gastric signet ring cell carcinoma (GSRCC), prevalence showed a numerical trend favoring the investigational arm (46.2% vs 30.8%, p=0.42). Both groups demonstrated identical pCR rates (23.1%, 3/13 per arm), but the investigational arm exhibited superior MPR rates (61.5% vs 38.5%, p=0.039) and significantly higher ypN0 status achievement (76.9% vs 38.5%, p=0.012), with the GSRCC subgroup showing similar trends (MPR: 50% vs 25%; ypN0: 67.7% vs 25%). Both groups maintained 100% R0 resection and DCR rate. Safety profiles were comparable, with any-grade TRAEs occurring in 53.8% (7/13) of the investigational arm and 46.2% (6/13) of controls, and grade ≥3 TRAEs in 15.4% (2/13) per arm. Diarrhea was predominant in the investigational group, while leukopenia was most frequent in controls. Conclusions: This interim analysis demonstrates that the addition of a sorbitol-supplemented diet to neoadjuvant chemoimmunotherapy significantly enhances therapeutic efficacy in LAGC patients while maintaining a comparable safety profile. Clinical trial information: NCT06826079 .

Leptomeningeal carcinomatosis (LMC) from gastric cancer is rare but carries a poor prognosis, and its risk factors and clinical presentation remain unclear. Among 3850 patients treated with palliative chemotherapy, those with pathologically or cytologically confirmed LMC were included. Responsiveness to intrathecal methotrexate (IT-MTX) was defined as a malignant cell count < 1/μL on ≥ 2 consecutive cerebrospinal fluid analyses. Survival outcomes were compared across subgroups with different clinical presentations. During a median follow-up of 13.7months, LMC was diagnosed in 0.8% (32/3850) of patients. At the time of LMC diagnosis, 27 patients were undergoing palliative systemic chemotherapy, 4 were diagnosed with recurrence following curative surgery, and 1 was diagnosed with the initial presentation of metastatic gastric cancer. Multivariate logistic regression analysis revealed that signet ring cell carcinoma (SRC) and/or poorly differentiated adenocarcinoma (PD) was the most relevant risk factor for LMC (adjusted odds ratio 4.78; p = 0.036). Thirty patients received IT-MTX, with responders (n = 23) showing longer overall survival (OS) than non-responders (n = 7) (p = 0.004). Among the 29 patients with available data on extracranial disease control, those with controlled extracranial disease at LMC diagnosis (n = 19) demonstrated significantly better OS following IT-MTX than those with progressive extracranial disease (n = 10) (p = 0.023). SRC and/or PD is a key risk factor for LMC, which often arises despite controlled extracranial disease, necessitating early evaluation for neurologic symptoms. Survival outcomes depend on IT-MTX response and the status of extracranial disease.