佐田 尚宏

BACKGROUND: Recent studies reveal that during trogocytosis plasma membranes are frequently transferred upon cell-to-cell contact, and that this phenomenon plays an important role in the modulation of anti-tumor immune response. However, the accompanying physiological roles in the tumor microenvironment are poorly understood. METHODS & RESULTS: Human gastric cancer cell line OCUM-1 was co-cultured with T cells whose plasma membrane was stained with PKH26. Flow-cytometric analysis revealed that OCUM-1 was positive for PKH26 at one hour and the positive rate increased over time. The acquisition of PKH26 was dependent on cell-to-cell contact and suppressed when T cells were fixed. OCUM-1 came to express various immunological synapse molecules after 10 hours of co-culture (positive rate, CD45:73.6±7.9%, CD3: 35.5±10.1%, CD4: 15.3±14.7%, CD8: 7.7±2.4%, CD11a: 8.1±4.3%, CD11b: 3.4±1.9%). We focused on CD11a which belongs to β2 integrins and aids immune cell adherence to endothelial cells. After co-culture with activated T cells (LAK), the expression level of CD11a on OCUM-1 was accelerated (with T cells: 19.1±13.4%, with LAK: 75.2±11.8%) and the adhesion rate on endothelial cells increased in a CD11a dependent manner (adhesion rate, single-culture: 2.0±0.64%, co-culture: 6.3±2.0%, co-culture (pre-treat with CD11a antibody): 2.3±1.4%, n=10, single-culture vs co-culture, p<0.0001; co-culture vs pre-treat with CD11a antibody, p<0.0001). CONCLUSION: These results suggest that acquisition of CD11a from T cells by trogocytosis enables cancer cells to increase adhesive properties towards endothelial cells, which may result in intravenous metastasis promotion.

Intra-ampullary papillary-tubular neoplasms (IAPNs) are rare precursor lesions of the ampulla of Vater, with a high propensity for progression to invasive carcinoma. Synchronous primary malignancies of the biliary tract are uncommon, and their occurrence in the absence of congenital anomalies such as pancreaticobiliary maljunction (PBM) has not been well documented. We report a case of an IAPN coexisting with a synchronous gallbladder carcinoma in a patient without identifiable predisposing anomalies. A 70-year-old woman with a history of interstitial pneumonia, acute pancreatitis, and mixed connective tissue disease on chronic steroids was under surveillance for branch-duct intraductal papillary mucinous neoplasm of the pancreatic body. Follow-up contrast-enhanced computed tomography revealed a 14-mm enhancing mass at the ampulla of Vater, with upstream dilation of both the pancreatic and bile ducts. Endoscopic evaluation and biopsy confirmed adenocarcinoma, and she underwent pancreaticoduodenectomy. A Grade B bile leak complicated postoperative recovery, which was managed conservatively; she was discharged on postoperative day 28. Histology demonstrated a 20 × 17 mm IAPN confined to the ampullary bile duct without invasion of adjacent ducts, and immunophenotyping confirmed a gastric/pancreatobiliary phenotype. Incidentally, a separate 32 × 30 mm gallbladder fundus tumor was identified and diagnosed as primary gallbladder carcinoma invading only the muscular layer (pT1b, pN0). Resection margins were negative, and no adjuvant therapy was administered due to comorbid pulmonary disease. This case underscores the importance of thorough preoperative evaluation of the gallbladder in patients with ampullary neoplasms, even in the absence of known biliary tract anomalies. Recognition of synchronous malignancies may alter surgical planning and improve outcomes. Vigilant imaging, including targeted ultrasonography, should be incorporated into the preoperative workup for ampullary lesions to detect occult gallbladder carcinoma.

Background: Liquid biopsy using bodily fluids enables noninvasive acquisition of diverse tumor-derived molecules for comprehensive characterization of tumor profiles. Metabolomic analysis, in particular, may accurately reflect disease pathogenesis and holds promise for clinical diagnostic applications. Objective: This study explored metabolic alterations associated with pancreatic ductal adenocarcinoma (PDAC) using non-targeted metabolomic analysis of pancreatic juice to construct a preliminary diagnostic model based on selected metabolites. Methods: Pancreatic juice samples were collected intraoperatively and postoperatively from patients undergoing pancreaticoduodenectomy for PDAC (n = 11) and from those who had non-PDAC diseases, including benign conditions such as chronic pancreatitis and non-pancreatic malignancies such as distal bile duct adenocarcinoma and ampullary adenocarcinoma (n = 14). Non-targeted metabolomic analysis was performed using LC-QTOF-MS. Data were processed using MS-DIAL and MetaboAnalyst, and components showing intergroup differences were selected via PLS-DA. A diagnostic model was constructed using logistic regression based on annotated metabolites. Results: PLS-DA identified 56 discriminative components, of which 19 were successfully annotated. One metabolite was notably increased and 22 were relatively decreased in pancreatic juice of patients with PDAC. Among known metabolites that tended to decrease were isocitric acid, citric acid, and several oxidized fatty acids. A tentative logistic regression-based diagnostic model using these selected metabolites showed moderate discriminative performance. Citric acid was included in the final three-variable model, suggesting its potential as a candidate marker for PDAC discrimination. Conclusions: Pancreatic juice reflects PDAC-associated metabolic changes and may contain candidate diagnostic biomarkers. Metabolites annotated in this study may have potential as novel markers, and further studies on unknown components could help advance PDAC diagnosis and treatment.