Uveal melanoma is a hard-to-treat arginine-dependent cancer secondary to argininosuccinate synthetase 1 (ASS1) loss with half of patients succumbing to liver-dominant metastases. Arginine deprivation with pegargiminase is a novel antimetabolite strategy for patients with uveal melanoma. We investigated the preclinical rationale for combining pegargiminase with melphalan, an alkylating agent approved recently for the treatment of hepatic-centric disease. Drug sensitivity of ASS1-deficient uveal melanoma cell lines was performed in 2D culture using proliferation and cytotoxicity assays, with analysis of cell death, cell cycle, DNA double-strand breaks, and interrogation of the molecular mechanism of action by RNA-seq. ADI-PEG20 and melphalan suppressed uveal melanoma cell line proliferation and triggered cytotoxicity, effects which were enhanced with the drug combination. ADI-PEG20 downregulated multiple genes of the Fanconi anemia pathway and synergized with melphalan to increase DNA double-strand breaks. Melphalan and pegargiminase is a rational new drug combination that warrants clinical testing in uveal melanoma.

Despite evidence that antibody drug conjugates (ADCs) are active in brain metastases, their role in primary central nervous system (CNS) tumors remains unclear. We report two adults with molecularly defined ependymoma - a MYCN-amplified spinal tumor with intracranial dissemination and a supratentorial ZFTA-RELA-fused tumor with multiple recurrences - who demonstrated radiographic response and/or durable clinical and metabolic stability with trastuzumab deruxtecan (T-DXd). HER2 expression was identified by immunohistochemistry in both tumors, consistent with prior systematic profiling of ADC targets in CNS tumors. Multiplexed imaging showed broad but heterogeneous HER2 expression across tumor states in both cases; in the MYCN-amplified tumor, this occurred alongside EGFR/MAPK-enriched proliferative niches, whereas the ZFTA-RELA tumor showed more diffuse organization without strong coupling of EGFR and proliferation. These findings provide early clinical evidence supporting HER2-directed ADCs in ependymoma and highlight the value of integrated molecular and spatial profiling in interpreting therapeutic response in rare CNS tumors.

Yolk sac tumors (YSTs) are highly malignant germ cell neoplasms, most commonly arising in the gonads. Intracranial involvement is exceptionally rare and typically affects the pineal or suprasellar regions. Metastatic YST presenting as a hemorrhagic brain lesion is an exceedingly unusual occurrence that poses significant diagnostic and therapeutic challenges. We report the case of a 26-year-old male who presented with rapidly progressive left-sided weakness and headache. Imaging revealed a right frontoparietal hemorrhagic mass with marked vasogenic edema and midline shift. The patient underwent urgent right frontal craniotomy and near-total tumor excision via a transsulcal approach. Postoperatively, neurological recovery was rapid, with near-complete motor improvement within days. Systemic evaluation revealed multiple pulmonary and para-aortic metastases and an enlarged right testis. Serum α-fetoprotein (AFP) was markedly elevated, and histopathological examination confirmed the diagnosis of YST. The patient received adjuvant chemotherapy, followed by radical orchidectomy and lymph node dissection, achieving normalization of AFP and full functional recovery at one year of follow-up. This case underscores the importance of considering germ cell tumors in the differential diagnosis of hemorrhagic brain lesions, particularly in young males. Early surgical intervention, combined with systemic chemotherapy, can lead to favorable neurological and oncologic outcomes even in such rare and aggressive presentations.

Glioblastoma (GBM) is the most common, aggressive and lethal primary tumor of Central Nervous System (CNS). Despite the standard of care and emerging treatment strategies, patient prognosis remains dismal. Over the past decade, immunotherapy has significantly improved outcomes in several tumors, and the clinical success observed in brain metastases (BM) from extracranial tumors has provided insights into CNS tumor immunobiology. However, immunotherapeutic approaches in GBM have so far yielded limited clinical benefit, underscoring the need to better understand the unique features of its tumor microenvironment (TME). This review compares the immunobiology of GBM and BM to elucidate potential mechanisms underlying immunotherapy failure in GBM. In addition, it explores the potential role of epigenetic drugs in reprogramming the GBM TME toward a more inflamed phenotype, thereby potentially enhancing immunogenicity and improving responsiveness to immunotherapy. Such strategies may offer a promising avenue to harness the immune system and inhibit GBM progression.

Recent advancements in melanoma treatment have reinvigorated hope among patients, significantly shifting the therapeutic landscape. A significant advancement in patient outcomes has been realised by applying first-line treatment strategies that include Immune Checkpoint Inhibitors (ICIs) and targeted therapies. Ipilimumab combined with nivolumab has demonstrated superior outcomes, earning a median overall survival surpassing 70 months. This notable success signifies a pivotal shift in the management of advanced melanoma, reflecting effective therapeutic strategies that clinicians can leverage. The advent of new ICIs, such as relatlimab, introduces additional complexities in decision-making for first-line therapy. Understanding the nuances of various treatments will empower physicians to make informed decisions. Several important characteristics, including brain metastases, PD-L1 expression, BRAF mutation status, performance status, and any previous adjuvant treatments, influence the treatment of advanced melanoma. These factors influence the choice of therapy and the potential efficacy in individual cases, underscoring the need for personalised treatment approaches. This review also sheds light on rare melanoma subtypes, particularly uveal melanoma. The FDA approval of tebentafusp and lifileucel has demonstrated potential in extending the survival time of patients with metastatic uveal melanoma. This progress highlights the importance of innovative therapies tailored to unique cancer profiles. By providing recent insights into these evolving treatment options, this review is an invaluable resource for clinicians. It aims to facilitate informed treatment decisions and enhance understanding of the multifaceted challenges in effectively managing advanced melanoma. As new therapies emerge, continuous education and adaptability will be key to optimising patient outcomes.

Brain metastases (BM) require a multidisciplinary treatment approach combining surgery, radiotherapy, and systemic therapy. While current guidelines recommend the analysis of established cancer driver genes in BM tissue, little is known about its real-life implementation and relevance on oncological treatment strategies. This retrospective multicenter study includes patients with BM from melanoma, lung and breast cancer operated between 2010 and 2022. Clinical records were evaluated for BM molecular analyses of predefined cancer drivers and their discordance to extracranial tumor sites, that is, ALK, BRAF, EGFR, KRAS, NTRK for lung, HER2, estrogen/progesterone receptor, BRCA1/2 for breast cancer and BRAF, KIT, NRAS among others for melanoma. Adjustment of systemic therapies based on BM molecular profiles was analyzed. Among 1431 BMs screened for availability of molecular analysis, molecular profiling was performed at least partially in 723 BMs (51%). In cases with matched extracranial tumor samples (n = 276), discordant alterations were found in 18% of lung, 4.7% of melanoma and 45% of breast cancer BMs. Molecular BM analyses informed systemic therapy adjustments in 13%-27% of patients depending on the primary tumor. Overall survival was significantly better in patients who underwent BM profiling, especially when operated in recensst years (median 19.3 vs. 9.9 months; p < 0.0001) and in patients with breast cancer who had a change in systemic therapies upon BM profiling (p = 0.0085). In conclusion, molecular profiling of BM allows selecting available treatment options for a substantial subset of patients. This study underscores the need for more systematic molecular testing in BM patients to guide systemic treatment decisions.