title: A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma.
abstract: BACKGROUND
  Combination therapy with BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib significantly improves progression-free survival of patients with BRAF V600-positive metastatic melanoma, but their use can be associated with life-threatening toxicities. We report the case of a patient receiving dabrafenib and trametinib for metastatic melanoma who developed intracranial hemorrhage while on therapy. Combination therapy with dabrafenib and trametinib improves progression-free survival of patients with BRAF V600-positive metastatic melanoma. Nevertheless, it is associated with an increased incidence and severity of any hemorrhagic event. To the best of our knowledge, this is the first report of intracranial hemorrhage with pathological confirmation.
  
  
  METHODS
  We present the case of a 48-year-old man with metastatic melanoma of unknown primary site. He had metastases to the right clavicle, brain, liver, adrenal gland, and the right lower quadrant of the abdomen. He progressed on treatment with alpha-interferon. He was found to have a 4.5-cm mass in the left frontotemporal lobe and underwent gross total resection followed by adjuvant CyberKnife stereotactic irradiation. He was subsequently started on ipilimumab. Treatment was stopped due to kidney injury. He was then placed on dabrafenib and trametinib. He returned for follow-up complaining of severe headache and developed an episode of seizure. MRI showed a large area of edema at the left frontal lobe with midline shift. Emergency craniotomy was performed. Intracranial hemorrhage was found intra-operatively. Pathology from surgery did not find tumor cells, reported as organizing hemorrhage and necrosis with surrounding gliosis; immunohistochemistry for S100 and HMB45 were negative.
  
  
  CONCLUSIONS
  This case demonstrates the life-threatening adverse effects that can be seen with the newer targeted biological therapies. It is therefore crucial to maintain a high index of suspicion when patients on this combination therapy present with new neurologic symptoms.
authors.affiliation: Department of Internal Medicine, University of Miami, Miami, USA.
authors.forename: Le Min
authors.initials: le M
authors.lastname: Lee
authors.affiliation: Department of Hematology and Oncology, University of Miami, Miami, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Feun
authors.affiliation: Department of Pathology, University of Miami, Miami, USA.
authors.forename: Yaohong
authors.initials: Y
authors.lastname: Tan
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects; D003399:Craniotomy; D003937:Diagnosis, Differential; D004359:Drug Therapy, Combination; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects* / Q000627:therapeutic use; D020300:Intracranial Hemorrhages / Q000139:chemically induced* / Q000175:diagnosis / Q000601:surgery; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000009:adverse effects* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000009:adverse effects* / Q000627:therapeutic use; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C561627:dabrafenib