Background: A higher number of tumor buds in the invasive front of colorectal cancer (CRC) specimens has been shown to contribute to a poor prognosis in CRC patients. Because macrophages (Mφs) have been demonstrated to alter the phenotype of cancer cells, we hypothesized that the phenotype of CRC cells in the tumor budding (TB) area might be changed by the interaction between CRC cells and Mφs. Methods: We assessed the expression of topoisomerase 1 in CRC cells to estimate the acquisition of chemoresistance in CRC. To demonstrate the tumor–stromal interaction between CRC cells and Mφs, we assessed two histological findings, the number of Mφs per single CRC cell and the proximity between CRC cells and Mφs by histological spatial analysis using HALO software. Results: The expression levels of topoisomerase 1 in CRC cells were decreased in deeper areas, especially in the TB area, compared to the surface area. Our histological spatial analysis revealed that 2.6 Mφs located within 60 μm of a single CRC cell were required to alter the phenotype of the CRC cell. Double-immunofluorescence staining revealed that higher Mφs were positive for interleukin-6 (IL-6) in the TB area and that AE1/AE3-positive CRC cells were also positive for phospho-STAT3 (pSTAT3) in the TB area; thus, the IL-6 receptor (IL-6R)/STAT3 signaling pathway in CRC cells was upregulated by IL-6 derived from neighboring Mφs. Conclusion: IL-6 secreted from the neighboring Mφs would alter the phenotype of CRC cells via IL-6R/STAT3 signaling pathway.

Despite recent advances in gastric cancer therapy, chemotherapy resistance and lack of methods for selecting combination regimens remain major problems. Organoids, which provide a culture system that more closely resembles tumor cell organization than traditional cell lines, can be established from surgical specimens with a high success rate and are widely used for drug sensitivity assays. In this study, we aimed to identify a novel biomarker for predicting multidrug resistance using gastric cancer organoids (GCOs). We evaluated 5‐fluorouracil or oxaliplatin‐resistant GCOs to find novel biomarkers that reflect multidrug resistance in gastric cancer. To examine the resistance mechanisms, RNA‐sequencing analysis and ex vivo drug sensitivity testing were performed. The association of biomarkers with patient prognosis and chemotherapy efficacy was evaluated using three original cohorts with a total of 230 cases. The results were also validated with two independent public cohorts and single‐cell RNA sequence data. Increased expression of peptidase inhibitor 3 (PI3) was detected in all 5‐fluorouracil or oxaliplatin‐resistant GCOs. Our findings suggest a potential association of PI3 expression with ribosome biosynthesis and RNA metabolism under organoid conditions. We also found that PI3 overexpression promoted 5‐fluorouracil/oxaliplatin/cisplatin resistance but not paclitaxel resistance. Immunohistochemical evaluation of PI3 expression revealed that the PI3‐positive gastric cancer group had a poorer outcome, especially in terms of time to recurrence. PI3 positivity was also an independent predictor of relapse after chemotherapy with DNA‐damaging agents. PI3 promotes DNA‐damaging drug resistance through multiple downstream regulations related to RNA and ribosomal metabolism. PI3 may be useful as a biomarker for the therapeutic selection of non‐DNA‐damaging agents. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH‐RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH‐RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH‐RA group. The percentage of distorted GCs was 13.3% in FTH‐RA group and 3.25% in FTH associated with MG (FTH‐MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH‐RA group. Positive indices of CD27⁺ cells and PD‐1⁺ cells per GC in FTH‐RA group were significantly higher than those in FTH‐MG group, though positive indices of CD68⁺ cells and CD163⁺ cells were similar. Myoid cell proliferation, as evaluated by α‐SMA, tenascin‐C, and l‐caldesmon expression, was significantly increased in the FTH‐RA group compared with the FTH‐MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH‐RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. PAF (platelet-activating factor), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases such as bronchial asthma and COPD. We focused on LPLAT9 (lysophospholipid acyltransferase 9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophages (AMs). LPLAT9 was predominant and upregulated in AMs, particularly monocyte-derived AMs, in patients with COPD. To identify the function of LPLAT9/PAF in AMs in the pathogenesis of COPD, we exposed systemic LPLAT9-knockout (LPALT9−/−) mice to cigarette smoke (CS). CS increased the number of AMs, especially the monocyte-derived fraction, which secreted MMP12 (matrix metalloprotease 12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophages and, subsequently, PAF synthesis in the lung. The LPLAT9−/− mouse lung showed reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AMs by increasing MCP1 (monocyte chemoattractant protein-1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9−/− mice compared with LPLAT9+/+ mice. Notably, these phenotypes were again worsened by LPLAT9+/+ bone marrow transplantation in LPALT9−/− mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AMs aggravated pulmonary emphysema via PAF-induced further accumulation of AMs. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD.

Background: Histiocytic sarcoma (HS) is a rare neoplasm showing morphological and immunophenotypic features of mature tissue histiocytes. We report a patient with nodal HS exhibiting prominent reactive eosinophilic infiltration. Case presentation: A 68-year-old man presented with intermittent left lower abdominal pain and weight loss over 3 months. A computed tomography scan revealed multiple abdominal nodules. Open biopsy of the mesenteric tumors was performed for definitive diagnosis. Histologically, the tumor was comprised of a diffuse noncohesive proliferation of pleomorphic large cells, including multinucleated cells. Neoplastic cells were positive for histiocytic markers (CD68, CD163, and LIGHT) and PD-L1 but lacked markers of Langerhans cells, follicular dendritic cells, and epithelial cells. Frequent reactive inflammatory cells were intermingled in the background. Interestingly, prominent eosinophilic infiltration was also noted. Spindle neoplastic cells were prone to be present around areas with little to no eosinophilic infiltration and exhibiting fibrosis and lymphatic vessel proliferation. Conversely, polygonal neoplastic cells were prone to be present around areas with relatively large amounts of eosinophilic infiltration without fibrosis or lymphatic vessel proliferation. Immunohistochemically, the tumor cells and reactive eosinophils expressed eotaxin-2 and eotaxin-3, respectively. Conclusion: We revealed that eotaxins induced the selective migration of eosinophils into tissues in this case. These eosinophils may affect the tumor remodeling and tumor biology characteristics of HS, such as fibrosis and lymphatic vessel proliferation.