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Background The presence of metastatic disease is one of the most important factors limiting survival in patients with uveal melanoma. Studies on proteins associated with metastatic mechanisms are sparse in the literature. Methods Enucleation samples from 15 patients with metastatic uveal melanoma (Group 1), liver metastasectomy samples from 8 patients with metastatic uveal melanoma (Group 2), and enucleation samples from 20 patients with non-metastatic uveal melanoma as controls (Group 3) were included in the study. Antibodies against heat shock protein 27 (HSP-27), BRCA1-associated protein-1 (BAP1), C-C chemokine receptor 7 (CCR7), B-Raf proto-oncogene serine/threonine-protein kinase V600E (BRAF V600E), and programmed death-ligand 1 (PD-L1) were used to detect immunoreactivity in each sample by immunohistochemical methods. Correlations between these expressed proteins and selected histopathological and clinical features, and metastatic process were investigated. Results The frequencies of HSP-27 (median score: Group 1: 8, Group 2: 12, Group 3: 4) and BRAF V600E expressions (number of samples: Group 1: 4 (26.7%), Group 2: 1 (12.5%), Group 3: 0 (0%)), and BAP1 expression loss (number of samples : Group 1: 12 (80%), Group 2: 8 (100%), Group 3: 9 (45%)) were higher in samples from patients with metastatic uveal melanoma (Group 1 + 2) than in those from patients with non-metastatic disease (Group 3) ( P = 0.001, P = 0.034, and P = 0.007, respectively). CCR7 expression (median score: Group 1: 0, Group 2: 2, Group 3: 3) was similar among these three groups ( P = 0.136). No samples exhibited PD-L1 expression ( P = 1.000). One-unit increases in the HSP-27 expression level and BAP1 expression loss were significantly related to 1.375- and 7.855-fold increases in the risk of metastasis, respectively ( P = 0.007 and P = 0.017). Conclusion HSP-27 and BAP1 are considered to be associated with metastasis, indicating these proteins as potential treatment targets in metastatic uveal melanoma.

Introduction: The discovery of immune checkpoint inhibitors has revolutionized metastatic renal cell carcinoma (RCC) treatment. However, in patients with RCC brain metastases, response rates are low and survival outcomes poor. To understand the tumor microenvironmental differences between primary kidney tumors, extracranial metastases, and brain metastases, we developed a detailed single-cell atlas of RCC brain metastases along with their matched extracranial and primary tumors. Methods: We performed single-nucleus RNA-seq on 27 samples (nearly 200,000 cells) from RCC patients; samples included 14 brain metastases, 8 matched primary kidney tumors, and 5 matched extracranial metastases. We performed multiplex IHC to validate selected transcriptomic findings. We used Nanostring CosMx 960-plex RNA spatial molecular imaging technique on selected samples to validate cellular interactions in a spatial context. Results: We established a multi-tissue single-cell atlas of RCC brain metastases by identifying 9 major and 37 minor malignant, immune, and stromal cell clusters. Brain metastases had higher neuronal and glial cells interacting with immune and tumor cells. Brain metastasis tumor cells were also transcriptomically reprogrammed to adapt to the brain microenvironment through enrichment of MYC targets, MTORC1 signaling, epithelial-mesenchymal transition, fatty-acid metabolism, oxidative phosphorylation, and reactive oxygen species pathways. Moreover, cell-to-cell communication and downstream target gene expression analyses showed that brain metastasis tumor cells expressed ligands and receptors that induce tumor cell proliferation in both autocrine and paracrine fashions. Among T-cell populations, we found fewer proliferating cytotoxic T lymphocytes in the brain than in other sites. Moreover, T cells in brain metastases expressed higher levels of several targetable inhibitory checkpoints than did extracranial metastases. In addition, we found that naïve/memory T cells in brain metastases were a favorable prognostic marker for overall survival after craniotomy. Our characterization of myeloid cell populations across the 3 disease sites found fewer dendritic cells and monocytes in the brain compared to other sites. Macrophages in brain metastases more highly expressed an M2 immunosuppressive gene signature than did those in primary RCC tumors. Conclusion: Our findings from the largest single-cell atlas of RCC brain metastases with matched primary and extracranial metastases suggest several unique targetable, immunosuppressive biological mechanisms in the brain microenvironment. These results provide a foundation for a deeper understanding of RCC brain metastasis biology and can serve as a resource for the scientific community to further explore therapeutically targetable tumor and immune-related mechanisms. Citation Format: Elshad Hasanov, Truong Nguyen Anh Lam, Jerome Lin, Patrick K. Reville, Merve Hasanov, Anna K. Casasent, David Shih, Sahin Hanalioglu, Mehmet Asim Bilen, Omar Alhalabi, Berrin Babaoglu, Baylar Baylarov, Adeboye O. Osunkoya, Lisa M. Norberg, Joy Gumin, Tuan M. Tran, Jianzhuo Li, Anh G. Hoang, Haidee D. Chancoco, Brittany C. Parker Kerrigan, Erika J. Thompson, Betty YS Kim, Dima Suki, Melike Mut, Figen Soylemezoglu, Giannicola Genovese, Kadir C. Akdemir, Hussain A. Tawbi, Nizar M. Tannir, Florencia McAllister, Michael A. Davies, Padmanee Sharma, Jason Huse, Frederick Lang, Nicholas Navin, Eric Jonasch. Single-cell and spatial transcriptomic mapping of human renal cell carcinoma brain metastases uncovers actionable immune-resistance targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5788.

ObjectiveOur understanding of IgG4‐RD and pachymeningitis has grown substantially, but the optimal approach for diagnosis, management, and long‐term outcomes is still an area of uncertainty.MethodsHUVAC is a database for IgG4‐RD patients, this database was retrospectively evaluated for pachymeningeal disease. Demographic, clinical, serological, imaging, histopathological data, and treatment details were re‐interpreted in patients with pachymeningitis.ResultsAmong 97 patients with IgG4‐RD, 6 (6.2%) had pachymeningitis. None of these patients had extracranial features, and also, in most of the patients, serum IgG4 levels were normal. Tentorium cerebelli and transverse sinus dura were the most commonly involved in the posterior fossa. During 18 months of median follow‐up on steroid+‐rituximab, none of them relapsed as pachymeningitis.ConclusionOur patients were mainly older males with sole neurological involvement. Non‐specific headache was the most common manifestation, and serum IgG4 levels were not useful for diagnosis. Typical radiology and tentorial thickening should suggest IgG4‐RD and prompt an early biopsy. Moreover, accompanying hypophysitis could also be a clue. With steroids+ rituximab treatment, no relapse related to meningeal involvement was seen in long‐term follow‐up.