Background: IgG4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder characterized by lymphoplasmacytic infiltrates enriched in IgG4-positive plasma cells, storiform fibrosis, and frequently elevated serum IgG4 levels. Classic forms, such as pancreaticobiliary or retroperitoneal involvement, are often recognized early, whereas atypical manifestations mimic malignancy or inflammatory conditions, leading to delayed or inappropriate treatment. Case Series: A 30-year-old man presented with hyperemesis, proptosis, and gait instability. He was found to have colonic stenosis, stomach thickening, pachymeningitis, and polyserositis. Gastroenteric histology and serology confirmed IgG4-RD. Steroids were ineffective, but rituximab produced sustained clinical and radiologic improvement. A 35-year-old woman developed jaundice and cholestasis with a perihilar mass highly suggestive of cholangiocarcinoma. Histopathology revealed IgG4-RD, and rituximab therapy led to marked clinical and serological improvement. A 64-year-old woman with a submandibular mass underwent sialoadenectomy, with histology confirming IgG4-RD; she remained asymptomatic without systemic treatment. Literature Review: A literature review highlighted the diagnostic challenges of atypical IgG4-RD. Gastrointestinal involvement is rare and often misclassified as inflammatory bowel disease. Isolated biliary disease frequently mimics cholangiocarcinoma, while salivary gland involvement may be misdiagnosed as neoplasia. Serum IgG4 levels >135 mg/dL and IgG4/IgG ratio >0.21 may support clinical suspicion, but histopathology remains indispensable for definitive diagnosis and for excluding malignancy. Steroid responsiveness is a hallmark, though relapses after tapering are common, often necessitating B-cell-directed therapy. Conclusions: IgG4-RD should be considered in patients with unexplained, relapsing, or steroid-responsive conditions. Early recognition, multidisciplinary collaboration, and integration of histopathology with clinical features are essential to avoid misdiagnosis and optimize management.

Antiphospholipid syndrome (APS) is a rare autoimmune disease characterized by thrombosis and obstetric complications. Extracellular vesicles (EVs) of either platelet and endothelial origin are recognized to be involved in the pathophysiology of the disease. This study aimed to evaluate the potential role of endothelial- and platelet-derived extracellular vesicles and the clinical features or progression of APS. We enrolled 22 patients diagnosed with APS and 18 age and sex-matched healthy controls. We determined APS-specific antibody positivity and clinical manifestations in APS affected patients, with a focus on neurological, cardiovascular, dermatological, hematological manifestations, and pregnancy-related complications. Platelet-poor plasma was collected from either patients and controls for the analysis of EVs by flow cytometry technology using monoclonal antibodies to specifically identify those derived from either platelets and/or endothelial cells. EVs of endothelial and platelet origins were overall significantly increased in patients as compared to healthy controls. Furthermore, a significant association was also observed between the number of extracellular vesicles and specific organ involvement, particularly central nervous system manifestations, hematological abnormalities, and obstetric complications. An elevated proportion of endothelial-derived EVs in APS and a reduction of resting endothelial cell-derived EVs were observed in APS-affected women with obstetric complications. Our findings highlight the involvement of endothelial cells and platelets in mirroring the activities of endothelial cells and platelets in APS. Additionally, extracellular vesicles may serve as potential predictors of organ involvement and disease-related damage.

Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by fibrosis, immune dysregulation, and vascular abnormalities. Extracellular vesicles (EVs), secreted by immune cells, have been implicated in modulating fibroblast activity and are actively involved in SSc pathogenesis. This study aims to determine whether lymphomonocytic-derived EVs influence fibroblast proliferation and collagen synthesis in SSc. Fibroblasts from healthy donors (HDFs) and SSc patients (SScHDFs) were exposed to EVs derived from Jurkat and U937 cell lines stimulated under pro-inflammatory conditions using tumor necrosis factor-α (TNFα) or phorbol 12-myristate 13-acetate + ionomycin (PMA + IONO). Proliferation was assessed using CCK-8 assays, while collagen production was quantified via ELISA. Our findings demonstrate that EVs derived from PMA + IONO-stimulated Jurkat and U937 cells significantly reduced fibroblast proliferation in a dose-dependent manner. Notably, SScHDFs exhibited lower baseline proliferation and a diminished overall response to EV treatment. Collagen production was markedly reduced in both fibroblast types following exposure to PMA + IONO-stimulated EVs, whereas TNFα-stimulated EVs affected only HDFs. These findings suggest that EVs from activated immune cells modulate fibroblast function in SSc, potentially contributing to disease pathogenesis. Further research is warranted to elucidate the molecular mechanisms underlying these effects and to explore the therapeutic potential of targeting EV-mediated signaling in SSc.

Histone deacetylases (HDACs) and lysine demethylases (KDMs) are key epigenetic enzymes regulating chromatin structure and gene transcription. Aberrant expression of those epigenetic modifiers has been extensively documented in cancer, but their role in hepatocellular carcinoma (HCC) is yet undefined. In this study, we aimed to analyze the expression of specific components of HDACs and KDMs in the liver tissue of HCC patients and evaluate the possible association with clinical outcome. Fifty-four patients with HCC of nonviral etiology were enrolled and followed-up for clinical and biochemical parameters after curative surgery. Gene expression of HDAC11 , KDM5D , KDM6B , and KDM8 was assessed in HCC tissues and homologous non-neoplastic liver tissues by RealTime q-PCR. For a subset of patients, total HDAC enzymatic activity in nuclear extracts from liver tissues was assessed. HDAC11 was upregulated in 32 and downregulated in 19 HCC samples. In contrast, KDMs genes resulted mostly downregulated in HCC. Kaplan-Meier survival analysis revealed that patients with HDAC11 upregulation had a significantly higher mortality rate than those with HDAC11 downregulation ( p = 0.041). Furthermore, Cox regression analysis showed that HDAC11 expression was a predictor of mortality with a hazard ratio (HR) of 2.29 (95% CI, 1.01–5.22; p = 0.04). This mortality risk even increased when adjusted for age, sex, C-reactive protein, creatinine, albumin, alpha fetoprotein, lipid parameters, microvascular invasion and tumor differentiation degree. These findings highlight a possible prognostic role for HDAC11 in HCC and suggest to consider the potential of targeting histone-modifying enzymes for future therapeutic strategy.

Background and Clinical Significance: Metaplastic breast carcinoma (MBC) is a rare type of breast tumor with various subtypes. MBCs are typically high-grade and exhibit a particularly aggressive behavior, with a significant propensity for recurrence and specific chemoresistance, especially in neoadjuvant settings. One of its high-grade variants is the metaplastic carcinoma with heterologous mesenchymal differentiation (MCHMD). At present, the literature regarding the genetic predisposition of MBC and its connection with BRCA2 is limited. Hence, we present a rare case of a 51-year-old patient with a germline BRCA2 pathogenic variant affected by MCHMD. Case presentation: A 51-year-old Caucasian woman with a family history of breast cancer noticed a lump in her right breast. A needle biopsy of the mass resulted in a diagnosis of poorly differentiated (G3) invasive ductal carcinoma, associated with a dominant component of pleomorphic carcinoma with osteoclast-like cells. After surgery, the pathological report diagnosed a metaplastic carcinoma of the breast with heterologous mesenchymal differentiation (MCHMD) according to the WHO 2019 classification. Genetic testing revealed the presence of the pathogenic variant c.9676del of the BRCA2 gene. Conclusions: We report, to the best of our knowledge, the first case of a BRCA2 mutation in a woman with metaplastic carcinoma of the breast with heterologous mesenchymal differentiation.

Antibodies directed against platelet factor 4 (PF4) are increasingly recognized as key mediators of immunothrombosis. In heparin-induced thrombocytopenia (HIT), these antibodies emerge following exposure to the polyanion heparin, whereas in vaccine-induced immune thrombocytopenia and thrombosis (VITT), they arise in response to vector-based vaccination or (adeno)viral infections. In both settings, anti-PF4 antibodies promote platelet activation and enhance inflammatory and thrombotic processes. PF4 itself has also been implicated in atherosclerosis and cardiovascular disease (CVD), although clinical studies investigating this link have yielded inconsistent results. We review the current knowledge on the roles of PF4 and anti-PF4 antibodies in atherosclerosis and CVD and discuss preclinical and clinical evidence for their relevance in the perioperative setting, for disease progression and antiplatelet therapy.