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Context.--Spontaneous (nontraumatic) subdural hematomas have been reported yet have not been well studied. Objective.--To identify the neuropathologic features of acute spontaneous SDHs (ASSDHs) and their associated medical conditions. Design.--A retrospective study of 235 autopsy cases of SDH was conducted. Review of demographics, underlying medical conditions, and coagulation profile as well as gross and histopathologic examination of the brain and other organs were performed. Results.--Among the 32 cases of ASSDH, 5 cases (15.6%) had severe hemorrhage and 4 (12.5%) demonstrated brain herniation. Twenty-two cases (68.8%) had concurrent but nonconnecting subarachnoid hemorrhage or intraparenchymal hemorrhage. The most common underlying medical condition was thrombocytopenia (n = 21; 65.6%), followed by immunosuppression (n = 15; 46.9), bloodstream infections or sepsis (n = 12; 37.5%), hypertension (n = 13; 40.6%), and coronary artery disease (n = 12; 37.5%). Many patients with thrombocytopenia or immunosuppression had underlying malignancies, with leukemia being the most common type (n = 11; 34.4%). The use of circulatory devices or hemodialysis was noted in a significant portion of ASSDH cases. In terms of coagulation factors, most of our ASSDH patients had normal prothrombin time and activated partial thromboplastin time, but abnormal platelet count and D-dimer levels. Conclusions.--ASSDHs can be severe and are often associated with subarachnoid hemorrhage and/or intra-parenchymal hemorrhage. The causes of ASSDH are limited to certain underlying medical conditions that ultimately lead to bleeding tendency. Autopsies are helpful in determining the etiology. Given their association with abnormal platelet count, correcting platelet deficiencies is a potential preventive measure for ASSDHs. doi: 10.5858/arpa.2024-0003OA, Subdural hematomas (SDHs) are collections of blood between the dura mater and leptomeninges, typically due to shearing of bridging veins as a result of trauma. (1) SDHs can occur in [...]

Merkel cell carcinoma (MCC) is an aggressive, fast-growing, highly metastatic neuroendocrine skin cancer. The Merkel cell polyomavirus (MCPyV) is an oncogenic driver in the majority of MCC tumors. In this issue of the JCI, Hansen and authors report on their tracking of [CD8.sup.+] T cells reactive to MCPyV T antigen (T-Ag) in the peripheral blood of 26 patients with MCC who were undergoing frontline anti-programmed cell death protein-1 (anti-PD-1) immunotherapy. They discovered unique T cell epitopes and used the power of bar-coded tetramers to portray immune checkpoint inhibitor-induced immunogenicity as a predictor of clinical response. These findings provide the foundation for therapeutic possibilities for MCC, including vaccines and adoptive T cell- and T cell receptor-driven (TCR-driven) treatments., MCC is a rare and aggressive neuroendocrine tumor Merkel cell carcinoma (MCC) is an aggressive, fast-growing, highly metastatic neuroendocrine tumor. There are two pathways to the oncogenesis of MCC. One [...]

BACKGROUND. The tumor immune microenvironment can provide prognostic and therapeutic information. We aimed to develop noninvasive imaging biomarkers from computed tomography (CT) for comprehensive evaluation of immune context and investigate their associations with prognosis and immunotherapy response in gastric cancer (GC). METHODS. This study involved 2,600 patients with GC from 9 independent cohorts. We developed and validated 2 CT imaging biomarkers (lymphoid radiomics score [LRS] and myeloid radiomics score [MRS]) for evaluating the IHC-derived lymphoid and myeloid immune context respectively, and integrated them into a combined imaging biomarker [LRS/MRS: low(-) or high(+)] with 4 radiomics immune subtypes: 1 (-/-), 2 (+/-), 3 (-/+), and 4 (+/+). We further evaluated the imaging biomarkers' predictive values on prognosis and immunotherapy response. RESULTS. The developed imaging biomarkers (LRS and MRS) had a high accuracy in predicting lymphoid (AUC range: 0.765-0.773) and myeloid (AUC range: 0.736-0.750) immune context. Further, similar to the IHC-derived immune context, 2 imaging biomarkers (HR range: 0.240-0.761 for LRS; 1.301-4.012 for MRS) and the combined biomarker were independent predictors for disease-free and overall survival in the training and all validation cohorts (all P < 0.05). Additionally, patients with high LRS or low MRS may benefit more from immunotherapy (P < 0.001). Further, a highly heterogeneous outcome on objective response rate was observed in 4 imaging subtypes: 1 (-/-) with 27.3%, 2 (+/-) with 53.3%, 3 (-/+) with 10.2%, and 4 (+/+) with 30.0% (P < 0.0001). CONCLUSION. The noninvasive imaging biomarkers could accurately evaluate the immune context and provide information regarding prognosis and immunotherapy for GC., Introduction Recently, the tumor immune microenvironment (TIME) has attracted increasing research attention (1). A growing body of literature highlights its crucial role in cancer progression and therapeutic responses (1-3). In [...]

Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer- promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial- mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN- [gamma] and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance., Introduction Hemorrhage is omnipresent in solid cancers, occurring at macroscopic and microscopic levels due to invasive tumor growth, pathological vascularization, and therapy-induced or spontaneous necrosis. While traditionally perceived as a [...]