A man in his late 20s was diagnosed with BRAF V600E-mutated cutaneous melanoma of the left knee (T3a) and underwent wide local excision. One year later, he had a solitary local recurrence resected and received 12 months of adjuvant dabrafenib and trametinib. Seven months after completion of adjuvant therapy, he developed headaches and a right visual field deficit. Magnetic resonance imaging (MRI) revealed a solitary left occipital enhancing lesion. Subtotal resection confirmed melanoma brain metastasis (MBM), and he initiated adjuvant ipilimumab/nivolumab, complicated by Clostridiodies difficile colitis and subsequent immune-related colitis requiring corticosteroids and vedolizumab. Postoperative radiotherapy (RT) was completed. Six months later, he underwent stereotactic radiosurgery (SRS) to a new left putamen lesion (hereinafter referred to as basal ganglia lesion). Nivolumab was resumed but discontinued because of severe inflammatory arthritis requiring immunosuppression. The patient presented to our institution 6 months later. Positron emission tomography/computed tomography identified a new right thigh metastasis. MRI revealed apparent enlargement of the left occipital and basal ganglia lesions (Figure 1). Ipilimumab/nivolumab treatment was reinitiated but was complicated 3 months later by worsening right hemiparesis and hemianopia in the setting of hemorrhagic changes in both lesions. Stereotactic biopsy of the occipital lesion confirmed radiation necrosis. He subsequently developed acute worsening of right hemiparesis, and a lacunar infarct, attributed to mass effect on the lenticulostriate vessels, was identified. Given his biopsy-proven radiation necrosis and complete response of the right thigh metastasis, with no other systemic disease identified at the time, immunotherapy was discontinued (the last dose was received 3–4 weeks before biopsy). Axial brain magnetic resonance images demonstrating two intracranial lesions in a patient with metastatic melanoma. From left to right: T2 fluid-attenuated inversion recovery, postcontrast T1-weighted, and susceptibility-weighted imaging. A hemorrhagic left basal ganglion lesion is seen with surrounding vasogenic edema, heterogeneous contrast enhancement, and susceptibility artifact consistent with blood products. A second lesion in the left occipital lobe shows postsurgical changes with peripheral enhancement and adjacent edema. Imaging features reflect a combination of treated brain metastases, radiation effects, and hemorrhagic progression. Three months after the biopsy, resection of the enlarging occipital lesion was performed in the setting of worsening hemianopia and again confirmed radiation necrosis. One month later, the basal ganglia lesion showed further hemorrhagic progression and enlarging nodular enhancement with worsening edema, headaches, and aphasia. Surgical re-resection was not recommended. Multidisciplinary review concluded that, although radiation necrosis could not be excluded, a focal nodular region of enhancement raised concern for active tumor progression. Given diagnostic uncertainty and the need for rapid intracranial disease control, the team initiated encorafenib/binimetinib as the systemic therapy most likely to produce a prompt response and help distinguish tumor progression from radiation necrosis. Imaging 4 weeks later revealed reduced lesion size and edema. Over the following months, he was doing well clinically with only mild symptom burden and was able to work full time. After 7 months on targeted therapy, MRI revealed asymptomatic progression in the basal ganglia and a new occipital lesion, which was treated with hypofractionated stereotactic radiotherapy (SRT; 3800 centigrays in 10 fractions). During this course of radiation, he developed worsening headaches, and high-dose corticosteroids were initiated for symptomatic management. Four months after the patient completed radiation, radiographic basal ganglia progression was again noted. At that time, he remained on high-dose steroids and was overall feeling fairly well; although, by this time, he had stopped working because of fatigue and neurocognitive difficulties. Laser interstitial thermal therapy (LITT) of the basal ganglia lesion was performed for suspected tumor progression with symptomatic improvement in executive function, aphasia, and abulia. Three months later, systemic relapse was identified on positron emission tomography/computed tomography, which demonstrated a new, fluorodeoxyglucose-avid, left lower-lobe pulmonary nodule, a left retroperitoneal nodule, and focal uptake in the right tibia. Encorafenib/binimetinib was continued, and nivolumab/relatlimab was added after new cerebral enhancement and biopsy-confirmed retroperitoneal disease were established. This combination—dual mitogen-activated protein kinase inhibition together with dual immune checkpoint blockade—is not standard practice because of a lack of prospective evidence for improved efficacy and the potential for increased toxicity.1-3 After multidisciplinary discussion reflecting the patient's rapidly evolving disease, limited remaining therapeutic options, and motivation, the decision was made to proceed with treatment despite the anticipated risks and uncertain benefit. At the time of initiating nivolumab/relatlimab, he had successfully tapered dexamethasone to 2 mg daily. Imaging revealed reduced edema and lesion size on steroid taper. Approximately 4 months later, new intralesional hemorrhage occurred in the left basal ganglia lesion, temporally associated with the use of nonsteroidal noninflammatory drugs. Short-interval MRI demonstrated further lesion enlargement with worsening hemorrhage, edema, and midline shift. At the time, he suffered from worsening right hemiparesis as well as insomnia, fatigue, generalized malaise, and nausea/vomiting. Given continued clinical and radiographic progression despite maximal therapy, he was transitioned to hospice care and died approximately 3 years and 4 months after his initial diagnosis of intracranial disease (Figure 2). Longitudinal clinical course and treatment timeline. The schematic illustrates key intracranial and systemic disease milestones over time, including surgical interventions, radiotherapy, systemic therapies, and radiographic outcomes. Representative axial postcontrast brain MRI images are shown alongside major clinical events. LITT indicates laser interstitial thermal therapy; mo, month; MRI, magnetic resonance imaging; postop, postoperative RT, radiotherapy; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy. Despite representing only approximately 1% of all cancers, melanoma is the third most common cause of brain metastases after lung and breast cancers.4-6 Brain metastases are a major contributor to morbidity and mortality in advanced melanoma and often define the disease course in affected individuals.7, 8 Although central nervous system (CNS) involvement is most often observed in the context of widespread metastatic disease, up to 20% of patients may present with isolated brain lesions.9, 10 The interval from primary diagnosis to detection of brain metastases varies widely, with some cases occurring many years later.11, 12 Neurologic complications are common and often severe in patients with metastatic melanoma. 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