細谷 好則

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.

BACKGROUND AND PURPOSE: The peritoneal cavity constitutes a unique immune microenvironment that critically influences the pathobiology of peritoneal metastasis (PM). This study aimed to clarify the mechanisms by which local immune alterations affect the efficacy of intraperitoneal (IP) chemotherapy for PM from gastric cancer (GC). METHOD: Peritoneal lavage or ascitic fluid was obtained from 42 patients with GC and PM treated with IP paclitaxel (PTX) in combination with systemic oxaliplatin and oral S-1. Serial samples from 31 patients were analyzed after 1-3 cycles of chemotherapy. Immune cell subsets were evaluated using multicolor flow cytometry with monoclonal antibodies, and the functional properties of peritoneal eosinophils were assessed using gene expression profiling and cytotoxicity assays. RESULTS: IP chemotherapy was associated with decreased CD4(+) T cells and increased CD11b(+) myeloid cells. Notably, many patients, particularly those with negative cytology (CY0), exhibited striking recruitment of CD66b(+) CD16(-) CD193(+) Siglec-F(+) eosinophils into the peritoneal cavity. Eosinophil expansion was correlated with improved clinical outcomes. Post-treatment eosinophils displayed an activated, partially degranulated phenotype with elevated CD11b and CD63 expression and distinct messenger RNA signatures compared with circulating eosinophils. Peritoneal eosinophils demonstrated the ability to induce apoptosis in GC cells. CONCLUSION: IP PTX promotes the recruitment and activation of eosinophils with potent antitumor activity in the peritoneal cavity. Early post-treatment abdominal eosinophilia is a robust prognostic biomarker and may represent a promising therapeutic target to enhance the efficacy of IP chemotherapy in patients with PM from GC.

BACKGROUND: Patients with advanced gastric cancer (GC) with peritoneal involvement have a dismal prognosis. Recent clinical trials have shown that anti-Claudin18.2 (CLDN18.2) antibody (zolbetuximab) enhances survival in patients with GC expressing high levels of CLDN18.2. However, the effectiveness of the zolbetuximab in patients with peritoneal metastases (PMs) remains unclear. In this study, we aimed to evaluate the expression of CLDN18.2 in disseminated lesions to assess the clinical utility of zolbetuximab in the treatment of GC with PM. METHODS: In 42 patients diagnosed with stage IV GC with PM, biopsy samples from the primary tumors and peritoneal metastatic nodules were collected and immunostained using the specific antibody (43-14A, Ventana). The expression of CLDN18.2 was comparatively evaluated based on staining intensity and the proportion of positive cells. RESULTS: Positive immunoreactivity of CLDN18.2 was observed in 37 (88%) of the primary tumors. Specifically, CLDN18.2 positivity was identified in 26 (62%) or 12 (29%) patients based on moderate to strong membrane staining in at least 40% or 75% of tumor cells, respectively. In comparison, the staining intensity in tumor cells was consistently reduced in PM across all patients. CLDN18.2 expression was absent in PM of 29 (69%) patients, while 3 (7.1%) cases were determined to be CLDN18.2-positive based on a cutoff value of 40% for high staining. This trend was particularly pronounced in cases with undifferentiated type and human epidermal growth factor receptor 2 (HER-2) negative primary tumors. CONCLUSIONS: Although CLDN18.2 expression in PM mirrored that in primary lesions, the levels were generally reduced. When zolbetuximab is used for GC patients with peritoneal involvement, it is preferable to assess the expression of CLDN18.2 in the disseminated lesions.

INTRODUCTION: The prevalence of obesity has increased markedly across the globe over the past several decades. In parallel, the number of metabolic surgeries has risen sharply in recent years, resulting in a growing incidence of concomitant surgical procedures. Obese individuals have an elevated risk of malignancy, partly due to the chronic inflammation associated with excess adipose tissue. A key clinical question arises: How should surgeons manage unexpected pathology identified during the preoperative evaluation of patients with morbid obesity? CASE PRESENTATION: A morbidly obese male patient with a body mass index of 50 underwent evaluation for laparoscopic sleeve gastrectomy (LSG). Preoperative CT and PET-CT revealed a 25-mm retroperitoneal mass adjacent to the left gastric artery. Given the elevated risk of malignancy in obese individuals, it was essential to rule out a malignant process before proceeding with LSG. Thus, we adopted a surgical strategy in which LSG would be performed only if the intraoperative frozen section confirmed the lesion to be benign. The retroperitoneal mass was resected laparoscopically and identified as a benign schwannoma on the intraoperative frozen section, allowing us to proceed with LSG as planned. Retroperitoneal schwannomas are rare and often difficult to diagnose preoperatively, which supports the rationale behind our surgical strategy. To our knowledge, this is the first reported case of concomitant LSG performed following the laparoscopic complete excision of a retroperitoneal schwannoma. CONCLUSIONS: Concomitant procedures performed alongside metabolic surgery may be a viable approach to reduce the overall surgical burden on patients. Given the increased risk of malignancy in morbidly obese individuals, a thorough preoperative evaluation for concomitant malignancies should be considered before bariatric surgery. When an unexpected abdominal pathology is identified on preoperative imaging in obese patients, the intraoperative frozen section analysis of the resected specimen can be a valuable tool to guide surgical decision-making regarding concomitant bariatric surgery.