Introduction

Gastric cancers (GCs) are histologically classified into differentiated and undifferentiated types. Mixed histological type is considered more aggressive clinical behavior compared to pure histological type. However, no reports of large-scale prospective studies regarding the long-term prognosis of mixed histological type cured in patients by endoscopic resection (ER).

Aims & Methods

We aimed to determine the long-term prognosis of mixed histological-type GCs in patients cured by ER. We used data from the J-WEB EGC study, a nationwide, multicenter, prospective cohort that enrolled 9,715 patients with 10,926 lesions treated by ER between 2010 and 2012 across 41 institutions in Japan. For this analysis, we included patients classified as eCura A or B, according to the Japanese gastric cancer treatment guidelines, represent pathological criteria for curative resection following ER. eCura A included: differentiated-type, pT1a, without ulceration (UL0), negative horizontal and vertical margins (HM0, VM0) (A-1), and no lymphovascular invasion (Ly0, V0); differentiated-type, ≤30 mm, pT1a, with ulceration (UL1), HM0, VM0, Ly0, V0 (A-2); and undifferentiated-type, ≤20 mm, pT1a, UL0, HM0, VM0, Ly0, V0 (A-3). eCura B included differentiated-type, pT1b with submucosal invasion <500 μm, HM0, VM0, Ly0, and V0. We excluded patients with multiple lesion and those with lesions containing unusual type. Each patient was followed up for 5 years. The primary endpoints were 5-year overall survival (OS) and 5-year primary disease-specific survival (pDSS) to primary GC. Patients were divided into pure and histological types. OS and pDSS were assessed using the Kaplan–Meier method, and hazard ratios (HRs) for all-cause mortality was estimated using the Cox proportional hazards regression model with death as the event. After stratification into eCuraA-1, eCuraA-2, eCuraA-3, and eCura B, the 5-year OS and pDSS were compared between the pure and mixed histological types.

Results

A total of 7,242 patients with 8,187 GC lesions were classified as eCura A or B. After excluding 646 patients with multiple GC lesions and one patient with an GC lesion containing a neuroendocrine tumor component, 6,595 patients with a single GC lesion were included in the analysis. Of these, 6,434 were pure histological type and 161 mixed histological type. There was no difference in OS between pure and mixed histological types in all patients (92.5%, 95% confidence interval [CI]: 87.4–95.7 vs. 90.5%, 95% CI: 89.7–91.2; p = 0.415, respectively). Additionally, mixed histological type was not an independent factor in adjusted HRs for OS all-cause mortality (0.93, 95% CI: 0.52–1.64). The 5-year pDSS of the mixed histological-type GCs was significantly lower than that of the pure histological-type GCs (99.4%, 95% CI: 96.6–99.9 vs 99.96%, 95% CI: 99.9–100, p = 0.003, respectively). Among eCura A-2 patients, pDSS of the mixed histological-type GCs was significantly lower than that of the pure histological-type GCs (94.4%, 95% CI: 74.2–99.0 vs. 100%, 95% CI: 99.3–100; p < 0.001, respectively).

Conclusion

The long-term prognosis of curative ER patients, including those with mixed histological-type GCs, was favorable. However, the stratification analysis showed that mixed histological-type GCs in eCura A with ulcers was more likely to cause primary GC death than pure histological-type and might need careful surveillance.

Introduction

Spontaneous bacterial peritonitis(SBP) is the most common type of infection in patients with cirrhosis, with high mortality and recurrence rates^[1]. The intestinal immune barrier is an important link in blocking intestinal bacterial translocation^[2-3], but the mechanism of immune barrier changes in SBP in cirrhosis is unclear. The gut microbiota influences antitumor immunity by producing immunomodulatory metabolites^[4]. However, microbial consumption of multiple metabolites may also influence host immune responses^[5]. Here, we investigated the role of Stenotrophomonas maltophilia and its metabolites in the development of SBP.

Aims & Methods

We detected the bacterial composition of ascites and stool in patients with spontaneous bacterial peritonitis by 16S sequencing. The Stenotrophomonas maltophilia-SBP rat model was established by oral administration of carbon tetrachloride and Stenotrophomonas maltophilia. Metabolomics analysis was performed by liquid chromatography-mass spectrometry and single-cell sequencing was used to analyze changes in intestinal cell composition and gene expression. The biological functions of Stenotrophomonas maltophilia-conditioned medium and metabolites were determined in rat CD8⁺T cells.

Results

16S sequencing found that the abundance of Stenotrophomonas maltophilia in SBP ascites samples was high and positively correlated with inflammatory indicators. Among 1876 patients with cirrhosis and ascites, patients infected with Stenotrophomonas maltophilia had significantly increased levels of procalcitonin, C-reactive protein, ascites lactate dehydrogenase, and polymorphonuclear leucocytes count. Animal experiments showed that Stenotrophomonas maltophilia derived from human ascites can promote the occurrence of SBP in rats. Single-cell sequencing results showed that it significantly increased CD8⁺T cell exhaustion in the ileum and reduced memory T cells. Metabolomics analysis revealed that arginine was a significantly decreased metabolite in the supernatant of Stenotrophomonas maltophilia, and its downregulation was verified in rat serum and intestinal tissue. Mechanistically, Stenotrophomonas maltophilia degrades arginine through arginine decarboxylase, inhibits mTORC1 activity, thereby reducing CD8⁺T cell effector function and ultimately promoting the progression of SBP. Arginine supplementation significantly inhibited the formation of SBP and improved intestinal barrier function.

Conclusion

Stenotrophomonas maltophilia has been shown to promote SBP in rats by degrading arginine. Arginine supplementation is a potential preventive measure for SBP.

References

[1] Serper M, Tang H, Zhang S, et al. Clinical outcomes and care for spontaneous bacterial peritonitis: A national
cohort study. Hepatology. 2025.

• [2] Piano S, Singh V, Caraceni P, et al. Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide. Gastroenterology. 2019. 156(5): 1368-1380.e10.
• [3] Pabst O, Hornef MW, Schaap FG, Cerovic V, Clavel T, Bruns T. Gut-liver axis: barriers and functional circuits. Nat Rev Gastroenterol Hepatol. 2023. 20(7): 447-461.
• [4] Cong J, Liu P, Han Z, et al. Bile acids modified by the intestinal microbiota promote colorectal cancer growth by suppressing CD8(+) T cell effector functions. Immunity. 2024. 57(4): 876-889.e11.
• [5] Meza-Perez S, Liu M, Silva-Sanchez A, et al. Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine. Cell Host Microbe. 2024. 32(7): 1177-1191.e7.

Introduction

Endoscopic papillectomy (EP) is the preferable therapeutic strategy for non-invasive ampullary adenomas (AA), meaning limited to ampulla of Vater or sphincter of Oddi and with no invasion of the submucosa or further duodenal layers and no regional lymph node involvement, and with limited intraductal growth. To date, international guidelines recommend staging any AA with both MRI and EUS prior to EP, regardless of the size, the endoscopic appearance, and the grade of dysplasia. This implies a risk of superfluous examinations, especially for small non-deconstructed lesions.

Aims & Methods

The primary aim of this study is to evaluate the accordance rate between ERCP and EUS images in terms of AA intraductal growth definition. A monocentric, prospective, interventional study has been conducted including all consecutive patients referred to the Digestive and Interventional Endoscopy Unit of ASST Grande Ospedale Metropolitano Niguarda for endoscopic papillectomy from January 2024. Inclusion criteria was the availability of pre-EP staging MRI with no evidence of lymph node and metastatic involvement. All consecutive patients, prior to voluntary informed consent, underwent CE-EUS, which results have been blinded to ERCP endoscopist. Demographic, clinical, endoscopic and pathological data were collected.

Results

To date, a total of 20 patients have been enrolled (M 49%, median age 58 years [38-71]); they were referred to EP mainly after an incidental diagnosis (50% of the cases) during EGDS (45% of the cases) or EUS (25% of the cases). No cases of FAP among them was included. Median AA diameter was 20 mm [15-28.8], mostly Paris 0-Is (50%) and 0-IIa (45%) lesions, mainly with a non-LST behaviour (60%) and a non-deconstructed mucosal pit pattern (Kudo IIIL, 62.5%). At EUS, 5 (25%) presented a >5mm main pancreatic duct (MPD) dilation, and 10 (50%) a common bile duct (CBD) dilation, with a median CBD diameter of 12 mm [8-15]; CBD intraductal involvement was reported in 5 cases (for a median extension of 3 mm [2.5-9.3]), while DPP in 1 (with a 3 mm extension). Previous cholecystectomy was performed in 6 (30%) cases, and previous sphincterotomy in 3 (15%). Concordance with cholangiografic ERCP images was of 19/20 (95%) cases: in 1 case EUS revealed a small CBD involvement, not confirmed at ERCP and at subsequent histology on the R0 specimen. All AA were resected thorough endocut hot snare polypectomy, mainly (60%) en-bloc. After EP, 18 (90%) cases underwent concomitant biliary and pancreatic plastic stenting, and 13 (65%) mechanical and injectional hemostasis. Reported AEs were 2 cases of bleeding, 2 pancreatitis and 1 cholangitis, all managed endoscopically. At specimen histology, 14 (70%) cases were low-grade dysplasia adenomas, 3 (15%) high-grade, and 1 (5%) adenocarcinoma (which underwent surgery), with 5/19 (26.3%) cases of R1/R2. 6/19 (31.6%) cases (all the R1/R2 and 1 R0) presented a residual adenoma at 2-months-follow-up: all of them were treated with Habib ablation with negative histological controls after a median of 2 procedures. After a 5.4 months median follow-up time, only 1 recurrence was reported, successfully treated endoscopically.

Conclusion

According to our limited experience, pre-EP EUS did not provide any additional nor incisive information for the therapeutic management of any-size AA without lymph node and metastatic involvement. Further data from this ongoing prospective study and hopefully from RCT will help identify a specific subgroup of AA which would effectively benefit from CE-EUS/MRI staging prior to EP, thus sparing unnecessary examinations.

Introduction

Rectal adenocarcinoma with mucinous components is a relatively infrequent kind of rectal cancer which exhibits two different histotypes: mucinous adenocarcinoma and signet-ring cell carcinoma. When compared to classic adenocarcinoma, these subtypes are associated with a younger age of presentation and a worse prognosis.

Aims & Methods

The aim of this study was to analyse the features of the mucosal immune microenvironment pattern of rectal carcinomas with intra- or extra-cellular mucinous components.
Patients enrolled for IMMUNOREACT 1 and 2 trials (NCT04915326 and NCT04917263, respectively) further analysed based on the subtype of cancer, comparing not otherwise specified (NOS) adenocarcinomas with rectal adenocarcinomas with mucinous components. A panel of immune markers was investigated at immunochemistry: CD3, CD4, CD8, CD8β, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80. Flow cytometry was used to determine the proportion of epithelial cells expressing CD80, CD86, CD40, HLA ABC or HLA DR and the proportion of activated CD8+ T cells, CD4+ Th1 cells, and Treg. Non parametric tests were used.

Results

In this cohort, 9 patients had an adenocarcinoma with mucinous components, while 115 had a NOS adenocarcinoma. Rectal adenocarcinomas with mucinous components had a higher proportion of CD4+CD25+ T cells (activated T helpers) in healthy mucosa surrounding rectal cancer (p=0.006) and a higher proportion of CD8+ T cells (cytotoxic lymphocytes) in cancer tissue (p=0.027) than NOS adenocarcinomas.

Conclusion

Rectal adenocarcinomas with mucinous components are a distinct subtype of adenocarcinoma and their peritumoral immune microenvironment is associated with an impaired cytotoxic infiltration and a higher activation of T helpers. These findings may suggest these subtype of rectal cancer cells may be favoured by a less active immunesurveillace that can easily escaped explaining the association of these cancer subtypes with poorer outcomes.

References

1. Nitsche U, Friess H, Agha A, Angele M, Eckel R, Heitland W, Jauch KW, Krenz D, Nüssler NC, Rau HG, Ruppert R, Schubert-Fritschle G, Wilhelm D, Werner J, Engel J. Prognosis of mucinous and signet-ring cell colorectal cancer in a population-based cohort. J Cancer Res Clin Oncol. 2016 Nov;142(11):2357-66. doi: 10.1007/s00432-016-2224-2. Epub 2016 Aug 29. PMID: 27573386.
2. Hyngstrom JR, Hu CY, Xing Y, You YN, Feig BW, Skibber JM, Rodriguez-Bigas MA, Cormier JN, Chang GJ. Clinicopathology and outcomes for mucinous and signet ring colorectal adenocarcinoma: analysis from the National Cancer Data Base. Ann Surg Oncol. 2012 Sep;19(9):2814-21. doi: 10.1245/s10434-012-2321-7. Epub 2012 Apr 4. PMID: 22476818; PMCID: PMC3688065.

Clinical Case Summary

A 62-year-old woman with hypothyroidism and multiple sclerosis presented to our care to underwent outpatient esophagogastroduodenoscopy (EGD) after one episode of hematemesis, which had occurred 20 days earlier following the use of Naproxen (440 mg/day) for low back pain. Proton pump inhibitor (PPI) therapy had been initiated afterward. EGD revealed a 20 mm ulcer in the gastric body with an adherent clot. Upon gastric distension, oozing bleeding from the ulcer was observed and treated with adrenaline injection and endoscopic clips. Diffuse oozing from the gastric mucosa and multiple suction-related hematomas were also noted. The patient was hospitalized and started on high-dose intravenous PPI therapy and fasting. H. pylori serology was negative. Physical exam showed hepatomegaly and lower limb edema. Lab tests revealed elevated cholestatic enzymes, proteinuria, leukocytosis, hypoalbuminemia, mild anemia, and a monoclonal spike on serum protein electrophoresis. Abdominal ultrasound confirmed hepatomegaly. Autoimmune, viral, and metabolic liver diseases were excluded. Liver magnetic resonance raised suspicion of a storage disorder. Liver biopsy confirmed AL-type amyloid deposits. A follow-up EGD was performed, in absence of further GI bleeding, to obtain gastric biopsies. It showed a 1 cm ulcer with an adherent clot in the fundus. Again, insufflation triggered diffuse oozing from the ulcer and gastric mucosa with suction-related hematomas. Histology confirmed amyloid deposits. Suspecting multiple myeloma, immunofixation identified Bence-Jones proteinuria and hypergammaglobulinemia. Spinal MRI showed vertebral collapse at D12–L1; cardiac MRI excluded cardiac involvement. MM with secondary AL amyloidosis was diagnosed. Treatment with targeted therapy led to symptom resolution.This case highlights the importance of considering rare systemic diseases in atypical GI bleeding, especially when triggered by minimal stimuli such as gastric distension.

References

1. Histological images of liver and stomach with amyloid deposits.
2. Endoscopic images of gastrointestinal bleeding manifestations in patients with gastric amyloidosis

Introduction

Assessment of liver fibrosis is a key element in the management of patients with hepatitis B virus (HBV) infection, whether in the active, inactive, or occult phase. Among the non-invasive tools currently available, the FIB-4 score, based on biological parameters and FibroScan, using vibration-controlled transient elastography (VCTE) are widely used.

Aims & Methods

This retrospective, descriptive, and analytical study was conducted in a university hospital between 2017 and 2025. All patients followed for chronic HBV infection in the department of hepatogastroenterology were included. Clinical and biological data, along with fibrosis assessment results (FIB-4 score and FibroScan), were collected from patients medical records. The aim of this study was to compare the diagnostic performance and concordance of these two modalities in assessing liver fibrosis in a heterogeneous population of HBV-infected patients.

Results

A total of 100 HBV-infected patients were included, consisting of 54 males (54%) and 46 females (46%), with a median age of 55 years [42.5; 60]. Among them, 70% of patients had an active chronic hepatitis B (n=70), 29% were in the inactive phase (n=29), and 1 patient had an occult HBV infection.
Regarding comorbidities, 14% had arterial hypertension, 13% had metabolic dysfunction-associated steatotic liver disease (MASLD), and 5% had type 2 diabetes mellitus. Alcohol consumption was reported in 4% (n=4), and 5% were smokers (n=5). A family history of liver disease was documented in 12% of cases (n=12).
Concerning virological parameters, HBe antigen was positive in 13% (n=13) and negative in 87% (n=87). HBV DNA levels were <2,000 IU/mL in 48% of patients (n=48), between 2,000 and 20,000 IU/mL in 25% (n=25), and >20,000 IU/mL in 27% (n=27).
Evaluation of liver fibrosis using both the FIB-4 score and FibroScan revealed that 40% of patients had a FIB-4 score >3.25, indicating advanced fibrosis, while 60% had a score <1.45, suggesting minimal fibrosis. These findings were consistent with those obtained by FibroScan. To assess the diagnostic performance of the FIB-4 score in detecting advanced fibrosis (F3–F4) according to FibroScan, a receiver operating characteristic (ROC) analysis was conducted. The FIB-4 score demonstrated an area under the curve (AUC) of 0.96 using a cutoff value of 1.96, with a sensitivity of 93.75%, specificity of 84.52%, and a negative predictive value (NPV) of 98.61%.

Conclusion

The FIB-4 score demonstrated excellent diagnostic accuracy for identifying advanced liver fibrosis in patients with HBV infection, with a performance comparable to that of FibroScan. Given its simplicity, accessibility, and cost-effectiveness, the FIB-4 index represents a reliable first-line tool for fibrosis screening, particularly in settings where elastography is unavailable or limited.

Introduction

Emerging experimental and clinical data suggest that the gut microbiome can significantly influence the antitumor efficacy of key chemotherapy agents, including 5-fluorouracil, oxaliplatin, and docetaxel. These agents form the backbone of the neoadjuvant chemotherapy (NAC) regimen, FLOT, which is widely used for the treatment of locally advanced gastric cancer (GC). However, despite growing evidence from preclinical models, clinical studies investigating the direct association between gut microbiome composition and the response to NAC in GC patients remain scarce.

Aims & Methods

This study aims to address this gap in knowledge by exploring the relationship between the gut microbiome and therapeutic outcomes in this clinical context. In this longitudinal observational study, we explored the association between pre-treatment fecal microbiome composition analyzed via 16S rRNA gene sequencing and histological tumor regression, as assessed by the Becker score, in GC patients undergoing NAC with the FLOT regimen, followed by gastrectomy.

Results

Among the 38 enrolled patients, 19 (50%) achieved a Becker score of 1–2 and were classified as ‘Responders,’ while the other 19 (50%) were classified as ‘Non-responders’. Responders exhibited a higher abundance of Parabacteroides distasonis, Alistipes sp. AL-1, and Bacteroides plebeius. A combined biomarker of these species demonstrated robust predictive accuracy for a favorable response to NAC, with sensitivity of 89%, specificity of 63%, and an AUC of 0.8 (95% CI: 0.66–0.94). In contrast, non-responders showed a predominance of bacterial genera, including Ruminococcaceae UCG-014, Ruminococcus 1, Ruminococcaceae UCG-005, and the [Eubacterium] eligens group. The combined biomarker of these genera demonstrated excellent predictive performance for poor NAC response, with sensitivity of 89%, specificity of 95%, and an AUC of 0.93 (95% CI: 0.85–1.0).

Conclusion

The results of our study support the hypothesis that the pre-treatment gut microbiome composition can serve as a reliable biomarker for predicting both positive and negative responses to NAC in GC patients. By identifying specific microbial signatures associated with chemotherapy outcomes, this research provides critical insights into how microbiome-based strategies might enhance personalized treatment regimens for GC. Future studies are needed to validate these findings and explore potential therapeutic interventions targeting the microbiome to improve clinical outcomes in GC patients.