Background: POLE-mutated endometrial carcinomas are associated with exceptionally favorable outcomes, forming the basis for treatment de-escalation in early-stage disease. Nevertheless, rare adverse clinical courses have been reported. This study describes an unusual case of late metastatic recurrence in a POLE-mutated tumor and provides a review of similar cases in the literature. Methods: We present a detailed clinical, radiological, pathological, and molecular description of a patient who developed metastatic recurrence 16 years after initial surgery. A systematic literature search was conducted to identify reports of recurrence, progression, or cancer-related death in POLE-mutated endometrial carcinoma, with extraction of recurrence patterns, genomic features, treatment, and outcomes. Results: The patient experienced sequential pulmonary, cerebral, and leptomeningeal metastases despite harboring a canonical POLE hotspot mutation, proficient mismatch repair status, wild-type TP53, no additional known driver mutation beyond PTEN alterations. The literature review identified a small number of similarly adverse cases. Reported recurrences were heterogeneous, though distant and occasionally central nervous system involvement were noted. Conclusions: While POLE-mutated tumors overall retain an excellent prognosis, rare cases may follow an atypical and aggressive course. Improved molecular annotation and integrated risk-stratification models are needed to better identify this minority of higher-risk patients.

Intracranial sarcomas can arise secondarily from primary brain tumors, including gliomas and meningiomas, either spontaneously or following radiotherapy. The current WHO classification recognizes sarcomatous transformation in several tumor entities; however, sarcomas arising from meningiomas remain poorly characterized and are regarded as a possible histological manifestation within the spectrum of anaplastic meningiomas. We analyzed nine matched meningioma-sarcoma pairs using integrated histopathological assessment and molecular profiling, including DNA methylation analysis, next-generation sequencing, copy number profiling, and proteomics. Although recurrent sarcomatous tumors were clonally related to their meningioma precursors-sharing identical NF2 alterations and overlapping chromosomal aberrations-they demonstrated pronounced divergence at the histological, immunophenotypic, and epigenetic levels. Importantly, sarcomatous transformation occurred in four cases without prior radiotherapy. Sarcomatous recurrences exhibited loss of meningothelial markers and acquired expression of cytokeratin and myogenic markers. DNA methylation profiling revealed a shift away from canonical meningioma signatures toward profiles resembling non-meningothelial mesenchymal tumors. Proteomic analysis showed consistent upregulation of SOX2 in sarcomatous tumors compared with their primary counterparts, suggesting acquisition of stem-like features during lineage divergence. Clinically, these tumors were associated with aggressive growth, early recurrence, and extracranial metastases, resembling malignant sarcomas more closely than anaplastic meningiomas. In addition, analysis of an institutional cohort of NF2-mutant intracranial tumors (n = 316) suggests that sarcomas with inactivating NF2 mutations may originate from meningiomas even in the absence of a clinically recognized precursor. Together, these findings suggest that sarcomatous transformation represents a rare evolutionary endpoint in NF2-mutant meningiomas, marked by clonal continuity but pronounced biological divergence. These results highlight limitations of morphology-based classification and emphasize the value of integrated molecular diagnostics in distinguishing these tumors from conventional high-grade meningiomas. Given their sarcoma-like behavior despite a meningioma ancestry, these tumors may not be adequately captured by current meningioma grading schemes.

Leptomeningeal disease (LMD) or leptomeningeal metastases (LM) occurs when tumor cells invade the leptomeningeal and cerebrospinal fluid (CSF) space. Melanoma is the most common cancer causing LMD (M-LMD). Its biology and pathophysiology are very poorly understood. Research efforts are being made to explore the mechanisms underlying the immune landscape and antitumor response in LMD. The significant advances in immunocellular and targeted therapies in unresectable or metastatic melanoma in the last decade have not translated to patients with LMD and the prognosis for these patients remains dismal. While several reviews in LMD have provided an overview including challenges in diagnosis and treatment, herein we highlight evidence-based findings with a focus on immunocellular and radiation therapies, as well as the challenges that we need to overcome to help breach the existing gap in research and treatments in M-LMD. This could potentially guide additional research avenues and a better understanding of the needs and challenges of M-LMD to find novel therapies and improve patient survival.

Anti-programmed cell death 1 (PD-1) antibody therapy is now widely used in various cancers. However, the role of the antibody Fc region in PD-1 directed immunotherapy is not well understood. Preclinical studies commonly use species-mismatched rat anti-mouse antibodies, which may not accurately reflect antibody-Fc gamma receptor (FcγR) interactions. Here, we used mouse anti-mouse PD-1 antibodies to investigate how the Fc region influences therapeutic efficacy for enhancing CD8 T cell responses using mouse models of chronic lymphocytic choriomeningitis virus infection and CT26 tumors. Treatment with these mouse anti-mouse PD-1 antibodies caused preferential depletion of PD-1+ virus-specific CD8 T cells in the liver, resulting in increased viral titers. These effects of mouse anti-PD-1 antibodies were Fc dependent since mutating the Fc region to block FcγR interaction prevented PD-1+ CD8 T cell depletion and resulted in effective immunotherapy. Using mice lacking activating FcγR III or inhibitory FcγR IIb, we found that depletion of PD-1+ CD8 T cells was mediated via activating FcγR III. Furthermore, we determined that phagocytic cells, not natural killer cells, were the in vivo effectors that mediated depletion of PD-1+ CD8 T cells. Similar depletion of tumor-specific CD8 T cells and reduced tumor control were observed in the CT26 model with Fc-intact mouse anti-mouse PD-1 treatment. These findings highlight potential negative effects of Fc-functional anti-PD-1 antibodies in therapies for liver cancer, liver metastases, and chronic hepatotropic viral infections. Conversely, FcγR-mediated depletion could benefit "agonistic" anti-PD-1 antibodies for treatment of autoimmunity. Our research emphasizes the importance of Fc region in tailoring PD-1 therapies for diverse clinical applications.

Intracranial metastases (IM) are far more common than primary malignant brain tumors, yet remain understudied, representing an important unmet clinical need. Although patients with IM have historically been excluded from clinical trials, thus limiting assessment of intracranial treatment efficacy, their inclusion is increasing; however, patients with suspected leptomeningeal metastatic disease (LMD) remain commonly excluded, likely due to poorer prognosis and anticipated limited treatment response. Despite established treatment response criteria for confirmed LMD, there is limited guidance on how LMD should be diagnosed or excluded in broader IM trials, creating substantial risk for variability and misclassification. This article addresses the gap by proposing MRI-based criteria for classifying IM appearances with respect to LMD suspicion, focusing on the exclusion of LMD, illustrated with real patient examples. IM-related MRI findings are categorized into three groups: (a) imaging consistent with LMD, not requiring cerebrospinal spinal fluid confirmation; (b) equivocal findings warranting further evaluation with cerebrospinal fluid analysis or spinal MRI; and (c) imaging with low suspicion for LMD. Common pitfalls, mimics, and recommended next steps for equivocal findings are discussed. Keywords: Intracranial Metastasis, Leptomeningeal Metastatic Disease, MRI © RSNA, 2026.

The prolonged survival of lung cancer patients is accompanied by an increasing incidence of leptomeningeal metastases (LM). Patients with LM have a poor prognosis, significantly impacting their quality of life and overall survival. Recent studies have shown that while intrathecal pemetrexed (IP) can improve symptoms and confer a survival benefit in non-small cell lung cancer (NSCLC) patients with LM, drug resistance remains a significant challenge. As for systemic therapy, intravenous bevacizumab combined with chemotherapy has demonstrated clinical benefits in NSCLC patients. However, clinical data on intrathecal bevacizumab remain scarce. Therefore, this study aims to preliminarily explore the efficacy and safety of intrathecal pemetrexed and bevacizumab in the treatment of NSCLC patients with LM.

Leptomeningeal disease (LMD) is a devastating manifestation of advanced cancer, marked by rapid neurological decline and limited treatment options. Immune profiling in central nervous system (CNS) neoplasms, including LMD, is critical for understanding disease biology and guiding therapy. Here, we use single-cell RNA and T cell receptor (TCR) sequencing of cerebrospinal fluid (CSF) from patients with CNS lymphoma (CNSL), brain metastases (BrMs), and glioblastoma (GB), alongside deep TCR sequencing of blood and spatial transcriptomics of brain lesions. We uncover distinct, disease-specific CSF immune landscapes: CNSL-associated LMD shows clonal T cell expansion, while BrMs and GB are enriched in blood-derived and resident-like myeloid cells. Spatial analysis confirms transcriptional similarities between CSF and tumor microenvironments. Longitudinal sampling reveals dynamic immune changes and emerging resistant clones. These findings establish the CSF as an immune-active compartment reflecting disease-specific features and highlight the value of CSF liquid biopsy for immune monitoring and therapeutic stratification in LMD.

Metastases from meningioma are very rare and occur predominantly in WHO grade II and III tumors, with the lungs being the most common site. The increasing use of 68Ga-DOTA-peptides PET/CT has improved the detection of primary and secondary tumor sites. This imaging modality, evaluating the tumor expression of somatostatin receptors (SSTR), not only refines the diagnostic accuracy but also can guide a subsequent peptide receptor radionuclide therapy (PRRT). We report a case of meningioma brain tumor becoming refractory after initial neurosurgery and stereotactic radiotherapy. Meningioma has progressed to lung metastases displaying high expression of SSTR, and hence suitable for PRRT.

A 66-year-old man with metastatic castration-resistant prostate adenocarcinoma experienced a rising PSA after multiple systemic therapies and radiation therapy to the cervical and thoracic spine for bone metastases. F-18 piflufolastat (Pylarify) PSMA PET/CT demonstrated widespread metastases, involving bones, lungs, mediastinal and hilar lymph nodes, liver, and intracranial and intraspinal sites. He subsequently developed worsening neurological symptoms. Brain MRI fused with PSMA PET revealed numerous radiotracer-avid scattered leptomeningeal enhancing foci intracranially. Cervical spine MRI fused with PSMA PET demonstrated multifocal radiotracer-avid intradural, extramedullary enhancing lesions. Biopsy of cervical intradural lesions confirmed metastatic prostate carcinoma.