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In a recent multicenter survey of 311 patients treated at 23 academic North American centers, the PFS was 10.9 months and the OS was 21.9 months. Intensive induction improved PFS but not OS [15]. Autologous stem cell transplantation did not improve outcomes in patients who achieve complete remission [15]. Role of targeted agents in DHL is currently being explored and preclinical and clinical studies are underway testing PI3K inhibitors, Aurora kinase inhibitors, and BCL-2 inhibitors [16�C18]. Phase II trial (NCT02272686) of Bruton's tyrosine kinase inhibitor (ibrutinib) after stem cell transplantation is also being considered [19]. Another phase I/II trial (NCT02213913) is also evaluating the role of lenalidomide when added to DA-R-EPOCH in patients with DHL [20]. The idea of evaluating therapeutic synergism using new targeted agents and traditional cytotoxic agents seems very exciting and promising. Only randomized trials could see more shed more light on this. In summary Tolosa-Hunt syndrome is a rare clinical presentation and mandates thorough diagnostic workup to identify other causes that simulate it. In our patient, initial impression of Tolosa-Hunt syndrome, which was made based on clinical presentation and MRI findings, was soon realized to be secondary to lymphomatous infiltration from DHL which preceded systemic relapse as evidenced by FDG Quinapyramine PET/CT scan. Lastly, in regard to DHL management, we recommended aggressive induction chemotherapy and participation in clinical trials when available and eligible. Conflict of Interests The authors declare that there is no conflict of interests regarding the publication of this paper.A 59-year-old male patient with no significant history of autoimmune disease presented to clinic with bleeding from a mole in the right forearm. Biopsy and mutation testing identified melanoma with BRAFV600E mutation. PET/CT showed four FDG avid soft tissue nodules in the subcutaneous tissues of chest and back, abdominal MS-275 manufacturer mesentery, and right retroperitoneum. Excisional biopsy from right axillary lymph node was positive for melanin A staining and showed extracapsular invasion, confirming the diagnosis of stage M1c metastatic melanoma. Therefore, patient received 4 cycles of ipilimumab (3?mg/kg) treatment every 3 weeks without significant adverse reaction except skin rash on the infusion site. Twelve weeks after the last cycle of ipilimumab treatment, the patient presented to ED with acute onset chest pain and shortness of breath which started 1 day prior to the presentation. Vital sign showed BP 97/55?mmHg, HR 106 beats/min, RR 20 breaths/min, and O2 saturation 99% while breathing room air and temperature 36.9��C. Physical examination revealed distant heart sound and 5?cm of jugular venous distension. Electrocardiogram showed low QRS voltage and T wave inversion on V1�CV4 leads, and troponin I was negative.