Clear cell renal cell carcinoma (ccRCC) carries a high risk of recurrence, necessitating reliable prognostic biomarkers. This study evaluated the immunohistochemical expression, clinicopathological significance, and prognostic value of Musashi-1 (MSI1) and MTFR2 in ccRCC. Expression of MSI1 and MTFR2 was evaluated by immunohistochemistry in 124 ccRCC cases and paired non-neoplastic renal tissues. Associations with clinicopathological parameters and prognostic scoring models (SSIGN, UISS, SIS) were assessed, applying False Discovery Rate (FDR) procedures for multiple hypothesis testing. Progression-free survival (PFS) and disease-free survival (DFS) were analyzed using Kaplan-Meier curves, log-rank tests, and multivariate Cox regression models with multicollinearity diagnostics (VIF). Both MSI1 and MTFR2 were significantly upregulated in ccRCC compared to normal tissues (p < 0.001) and positively correlated with each other (r = 0.676, p < 0.001). High expression of either marker was significantly associated with adverse baseline features (larger tumour size, higher WHO/ISUP grade, advanced T-stage; q < 0.05) and higher-risk SSIGN, UISS, and SIS scores. Elevated MSI1 and MTFR2 predicted significantly shorter PFS and DFS (p < 0.001). Multivariate analysis confirmed T-stage, WHO/ISUP grade, MSI1, and MTFR2 as independent prognostic factors for PFS and DFS. The MSI1/MTFR2 axis represents strong independent prognostic signature in ccRCC and may enhance risk stratification while highlighting potential therapeutic targets.

The pathogenesis of cancer is characterized by the acceleration of tumor growth, inhibition of tumor suppression, genetic and epigenetic alteration, lubricative transformation and tumor microenvironment. Extramammary Paget's disease (EMPD) is a rare skin cancer that originates from apocrine glands in genital and axillary area. Although the pathogenesis of EMPD is still poorly understood, increasing evidence reveals that the mechanism of EMPD progression is regulated by the acquired ability of EMPD cells and tumor microenvironment. HER2/PI3K/AKT signaling and hormone receptor pathways are activated. Whereas tumor mutation burden is low, numerous driver genes such as ERBB2 and PIK3CA are detected. Tumor evolution in EMPD is characterized by high genetic intratumor heterogeneity with shared background factors. Tumor microenvironment in EMPD promotes immune evasion through the reduction of reduced CD4 + and CD8 + T cells and the increase of Treg cells and CD163 + macrophages. Enhanced Warburg effect and S. aureus contribute to the suppression of antitumor immunity. This review focuses on the mechanism of malignant progression in EMPD (hallmarks of EMPD).

Primary biliary cholangitis (PBC) is an autoimmune-related cholestatic liver disease predominantly affecting women, yet sex-specific differences in progression remain unclear. Multicenter retrospective analysis of 289 Japanese PBC patients compared sex disparities in demographics, laboratory parameters, histopathology, and prognostic scores. Males tended to be older at diagnosis, although this difference did not reach statistical significance. At diagnosis, significant laboratory differences were observed in total bilirubin and γGT, both higher in males (p < 0.05), consistent with a slightly higher ALBI score in males (p = 0.046), suggesting worse liver functional reserve. Males also had worse outcomes according to UK‑PBC Risk Scores and GLOBE score (p < 0.05). Histologically, at comparable bile duct loss, males tended to exhibit higher orcein‑positive granule deposition scores than females, suggesting chronic cholestasis resulting from bile duct loss tends to be more pronounced in males. Furthermore, positive correlations between fibrosis and bile duct loss, and between fibrosis and orcein‑positive granule deposition, were observed in females but not in males. Among mild‑fibrosis patients, males exhibited greater orcein-positive granule deposition. This study demonstrates sex differences in PBC progression and suggests that males may exhibit more pronounced chronic cholestatic changes, as reflected by greater orcein‑positive granule deposition, particularly in mild fibrosis.

Immune checkpoint inhibitors (ICIs) have become an important therapeutic option for oral cancers; however, reliable biomarkers predicting treatment efficacy remain limited. In this study, we investigated the association between intratumoral immune cell subsets, regional lymph node (RLN) immune status, and clinical responses to ICIs in patients with recurrent oral cancer. Pretreatment tumor tissues and RLNs were analyzed by immunohistochemistry to evaluate tumor-infiltrating lymphocytes, including CD8[+], CD103[+], CD3[+], ICOS[+], and CD163[+] cells, as well as programmed death-ligand 1 (PD-L1) expression and CD169[+] sinus macrophages. Treatment responses were assessed according to RECIST version 1.1. Responders to ICIs exhibited higher densities of CD8[+] and CD103[+] T cells compared with non-responders, whereas no significant associations were observed for CD3[+], ICOS[+], CD163[+] cells, or PD-L1 expression. Elevated pretreatment serum C-reactive protein (CRP) levels were associated with poorer responses. CD169[+] sinus macrophages in RLNs did not correlate significantly with treatment efficacy or T-cell infiltration. These findings suggest that intratumoral effector and tissue-resident memory-like T-cell infiltration, together with systemic inflammatory status, may influence ICI efficacy in recurrent oral cancer, and could improve patient stratification for immunotherapy.

Lipids play diverse roles in cellular homeostasis, and dysregulation of lipid metabolism is implicated in a wide spectrum of diseases, including cancer. Ovarian cancer cells exhibit profound metabolic alterations that support autonomous proliferation under conditions of hypoxia and nutrient limitation. Although tumor angiogenesis occurs, insufficient and fragile neovasculature often limits nutrient supply, necessitating metabolic adaptation. Among these adaptations, lipid metabolic reprogramming has emerged as a critical feature that supports tumor growth, survival, invasion, and therapeutic resistance. Alterations in fatty acid synthesis, β-oxidation, lipid uptake, and inflammatory lipid metabolism collectively contribute to the malignant phenotype. This review summarizes current knowledge of lipid metabolic regulation in ovarian cancer, with particular emphasis on key enzymes and their regulatory mechanism and discusses potential implications for therapeutic targeting from a molecular and morphological perspective.

Zinc transporters, including ZIP6 (SLC39A6, also known as LIV-1) and ZIP10 (SLC39A10), are reportedly involved in breast cancer progression and metastasis. We aimed to clarify the association of the expression of zinc transporters with clinicopathological features and prognosis in breast cancer. We retrospectively included 200 patients who underwent surgery for invasive ductal carcinoma of the breast (invasive diameter ≥ 10 mm) at our institution between January 1, 2010 and June 30, 2023. Immunohistochemical staining for ZIP6 and ZIP10 was performed, and their expression levels were evaluated. Survival analyses were performed by stratifying patients into four groups based on combined ZIP6 and ZIP10 expression (high/low). We found that the expression levels of ZIP6 and ZIP10 showed a statistically significant positive correlation. Low ZIP6 expression was associated with aggressive clinicopathological features, including a higher Ki-67 labeling index, higher histological grade, and larger tumor size. Although survival differences did not reach statistical significance, combined evaluation of ZIP6 and ZIP10 expression revealed distinct survival tendencies among the expression groups. These findings suggest that combined assessment of ZIP6 and ZIP10 expression may provide additional prognostic information beyond ZIP6 expression alone. Future studies with larger cohorts and longer follow-up are warranted to validate these findings.

This paper discusses an EWSR1-SMAD3-rearranged fibroblastic tumor (ESFT) occurring in the wrist of a 5-year-old child and summarizes its clinicopathological features, immunohistochemical phenotype, and molecular characteristics to improve the accuracy of clinical diagnosis. A retrospective analysis was performed on the clinical manifestations, histopathology, immunohistochemical phenotype, and molecular characteristics of a 5-year-old patient with recurrent ESFT. Additionally, this paper presents a literature review of relevant studies on ESFT. Among the 21 cases of ESFT, including the present case, the disease primarily affects young and middle-aged adult females, with most tumors measuring 1-2 cm in diameter. It preferentially occurs in the soft tissues of the distal extremities-particularly the foot-and exhibits low-grade invasiveness. Histomorphologically, the tumor is composed of uniform spindle-shaped fibroblasts arranged in fascicular and interlacing patterns, with no prominent nucleoli or mitotic figures. A zonation pattern, focal microcalcification, and interstitial myxoid change are observed in some cases. Immunohistochemistry reveals diffuse, strong ERG expression in tumor cells; FISH molecular detection shows EWSR1 break-apart; and NGS results confirm EWSR1-SMAD3 rearrangement. ESFT is a benign neoplasm with a risk of local recurrence. It exhibits complex histomorphological features but demonstrates diffuse, strong immunoreactivity for ERG on immunohistochemistry and harbors characteristic genetic alterations.

Neutrophil extracellular traps (NETs) are web-like chromatin structures released by neutrophils that play dual roles in host defense and tissue injury. In liver diseases, NETs have emerged as key pathogenic mediators. This narrative review synthesizes current evidence on the involvement of NETs in alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis, hepatic ischemia-reperfusion injury (HIRI), hepatocellular carcinoma (HCC), and intrahepatic cholangiocarcinoma (iCCA). Mechanistically, NETs amplify sterile inflammation, promote hepatocyte death, activate hepatic stellate cells to drive fibrosis. NETs also promote malignant transformation, sustain an aggressive phenotype, attenuate immunotherapy responses, mediate resistance to targeted therapies, and contribute to poor prognosis in primary liver cancers. Preclinical studies targeting NET formation or degrading existing NETs have shown therapeutic benefits across these liver diseases. Despite promising results, clinical translation remains limited, with challenges including a lack of standardized biomarkers, optimal timing of intervention, and the need for liver-specific delivery. This review highlights NETs as a druggable target in liver diseases, and underscores future directions toward biomarker development and targeted therapies.

The lymphatic system in the liver has long been regarded as a passive transport route responsible for interstitial fluid drainage. However, recent research has redefined it as a "new frontier in hepatology," playing active and multifaceted roles in liver disease progression, ascites formation, and tumor immune responses. In malignancies such as liver cancer, lymphatic vessels function as conduits for lymph node metastasis, while simultaneously serving as pathways for tumor antigens and tumor-induced inflammatory cells, potentially contributing to the modulation of the immune microenvironment. This review first outlines the latest findings regarding the lymphatic system in non-neoplastic tissues. Next, we examine recent studies investigating the impact of lymphatic vessels on cancer progression. Furthermore, we focus specifically on the hepatic lymphatic system in both non-neoplastic and cancerous states. Finally, we conclude by discussing the potential role of hepatic lymphatic vessels in regulating the tumor microenvironment in liver cancer.

Accurate prognostic stratification of endometrial carcinoma (EC) remains challenging in resource-limited settings lacking molecular sequencing. We investigated whether immunohistochemical (IHC) assessment of combined L1CAM/β-catenin expression, integrated with mismatch repair (MMR) status and p53 expression, could refine prognostic risk stratification in EC in absence of POLE sequencing. A retrospective cohort study evaluated 140 surgically staged EC cases for L1CAM, β-catenin MMR, and p53 IHC expression with clinicopathological correlation. Survival analysis was performed on 111 cases (median follow up:38 months). L1CAM and β-catenin demonstrated mutually exclusive expression patterns (27.1% and 6.4% respectively; 66.5% double negative). L1CAM + tumors demonstrated significantly worse disease specific survival (DSS) (HR:4, 95%CI: 1.6-9.9) and disease-free survival (DFS) (HR:4.9, 95%CI: 2.2-11.4), compared to double-negative (64.5% vs 90.3% DSS, 41.9% vs 12.5% relapse rate). β-catenin alone didn't predict outcome but contributed to prognostic refinement when combined with L1CAM status. This prognostic gradient persisted in the pMMR/p53wt subgroup (L1CAM + mean DFS: 21.7 months vs double-negative: 69.6 months; p ≤ 0.001). The combined L1CAM/β-catenin IHC profile categorized patients into prognostically distinct categories and offers pragmatic prognostic refinement, particularly for pMMR/p53wt tumors in centers lacking POLE sequencing. This approach doesn't replace comprehensive molecular testing and requires prospective validation before clinical implementation.

Osteosarcoma has a poor prognosis and frequently metastasizes to the lungs. This study examined the role of transglutaminase 2 (TGM2), a ligand for adhesion G protein-coupled receptor 56 (GPR56), in lung metastasis of LM8 mouse osteosarcoma cells. Gβγ‑dependent ERK signaling mediated by GPR56 and the adhesion of GPR56-expressing LM8[MOCK] cells and GPR56‑deficient LM8[LOW] cells were analyzed using siRNA, western blotting, and cell staining. TGM2 and Ki67 expression in metastatic lung lesions was assessed by transplantation and immunohistochemistry. TGM2 enhanced endogenous ERK signaling in LM8[MOCK] cells. In the absence of TGM2, ERK signaling increased in LM8[LOW] cells but remained unchanged in LM8[HIGH] cells compared with LM8[MOCK] cells. In the presence of TGM2, ERK activity in LM8[LOW] cells resembled LM8[MOCK], whereas it was decreased in LM8[HIGH] cells. LM8[LOW] cells showed reduced adhesion, whereas LM8[HIGH] cells did not differ from LM8[MOCK] cells. Proliferation did not differ between LM8[LOW] cells and LM8[HIGH] cells. TGM2 was co‑expressed in CD31 + endothelial cells, and Ki67‑positive LM8 cells were observed along bronchi. These findings suggest that GPR56 promotes lung metastasis through TGM2‑mediated adhesion to pulmonary endothelial cells and enhanced ERK‑dependent proliferative signaling.

Multiple myeloma (MM) is a malignant plasma cell neoplasm characterized by marked biological heterogeneity and complex metabolic reprogramming. Although dysregulated lipid metabolism has been implicated in MM, its morphological correlations and clinical significance remain unclear. The present study evaluated cytoplasmic vacuoles in peripheral blood smears and analyzed their associations with the prognosis and stage of MM. Additionally, lipid droplet formation and the expression of key cholesterol regulatory molecules among MM cell lines were examined via molecular and biochemical approaches. Intracytoplasmic vacuoles were more frequently observed at advanced Revised International Staging System stages of MM, although no significant difference in overall survival was observed. MM cell lines exhibited prominent lipid droplet accumulation and upregulated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) and scavenger receptor class B type I (SR-BI) expression. The pharmacological inhibition of SR-BI suppressed MM cell proliferation and induced apoptotic cell death, whereas the inhibition of ACAT-1 had only a modest effect. Ultrastructural analysis revealed marked cytoplasmic vacuolization following SR-BI inhibition. These findings indicate that altered cholesterol metabolism is closely associated with cytoplasmic vacuolization in MM cells, suggesting that SR-BI plays a critical role in MM cell survival. Therefore, targeting the cholesterol trafficking pathways may represent a potential therapeutic strategy in MM.

Ulcerative colitis is a chronic inflammatory bowel disease characterized by persistent inflammation of the colon. The extensive and persistent mucosal damage associated with ulcerative colitis (UC) can contribute to carcinogenesis, thereby underscoring the significant clinical interest in identifying an in situ marker. p53-binding protein (53BP1) is a DNA damage response (DDR) molecule that localizes at sites of double-strand breaks. Herein, we investigated the in situ DDR in UC by evaluating 53BP1 immunofluorescence. Our study revealed a significant increase in abnormal 53BP1 foci, defined as three or more foci and/or foci larger than 1 µm within the nucleus, in patients with UC compared to controls. Furthermore, the presence of abnormal 53BP1 foci in UC correlated with the severity of symptoms, endoscopic gradings, serological and histopathological inflammation. Of note, 53BP1 foci were observed in the colon mucosa of patients in remission, indicating that 53BP1 is a sensitive DDR marker. In addition, large 53BP1 foci, indicative of a severe DDR, were more prevalent in patients with colitic cancer than in controls. In conclusion, our findings suggest that 53BP1 may serve as a in situ marker reflecting the extent of the DDR in UC.

This study aimed to assess the effect of a combination of osteoblasts and octacalcium phosphate collagen composite (OCP/Col) on bone regeneration. In oral and maxillofacial surgery, OCP/Col has been clinically used as artificial bone. Although OCP/Col was reported to promote osteoblast differentiation, few studies have reported on its use in combination with cell transplantation. Moreover, its effects are not fully clarified. Therefore, we evaluated the osteogenic properties of a combination of OCP/Col and osteoblasts. We found that osteoblasts cultured in OCP/Col differentiated toward osteolineage, expressing several osteoblast markers. In animal experiments, the cell transplantation group showed promotion of osteoblast differentiation and stromal formation in the tissues compared with the OCP/Col group. These findings indicate that combining osteoblasts and OCP/Col would be beneficial for bone regeneration therapy.

The APC (adenomatous polyposis coli) gene, which was first discovered as a colorectal cancer suppressor gene, is highly expressed in the nervous system. The Apc gene/Apc protein is deeply involved in brain development and morphogenesis. In the postnatal brain, Apc/Apc is involved in synaptic transmission, axon growth, and intracellular transport. Apc/Apc expressed in glial cells is involved in glial cell differentiation and neural circuit formation through glial cell functions. Reports from disease model animals and familial adenomatous polyposis (FAP) patients suggest that APC may be involved in the onset of autism, cognitive impairment, and schizophrenia.