Targeted treatment of brainstem neurohistiocytosis guided by urinary cell-free DNA.
OBJECTIVE
To identify a treatment-responsiveBRAFV600Emutation in brainstem neurohistiocytosis, where no lesional tissue was readily obtainable, using a cell-free DNA approach.


METHODS
Cell-free DNA was extracted from urine and allele-specific PCR for theBRAFV600Emutation was performed. Response to conventional treatment (corticosteroids and interferon) and targeted treatment with a BRAF inhibitor was assessed by clinical evaluation, gadolinium-enhanced MRI brain scan, and serial testing of urinary cell-free DNA for mutant alleles.


RESULTS
BRAFV600Emutation could be readily identified in urinary cell-free DNA at an allele frequency of 4.2%. Treatment of Erdheim-Chester disease with corticosteroids and interferon was ineffective and associated with disease progression. Treatment with BRAF inhibitors was associated with clinical improvement and near-complete radiologic remission. Following 6 months of BRAF inhibitor therapy, no enhancing lesions could be detected in the brain and mutant alleles were cleared from the urine.


CONCLUSIONS
Analysis of urinary cell-free DNA using allele-specific PCR forBRAFV600Emutations allows rapid noninvasive identification of a highly treatment-responsive pathway, leading to clinical and radiologic remission of disease. Our case demonstrates that this assay may have a particular role in challenging neurohistiocytosis cases, where attempts at obtaining lesional tissue have failed or are not feasible.


METHODS
This study provides Class IV evidence. This is a single observation study without controls.
MRC Institute of Genetics and Molecular Medicine (D.H.) and Anne Rowling Neurology Clinic, Centre for Clinical Brain Sciences (D.H., P.F.), University of Edinburgh; and Human Dendritic Cell Laboratory (P.M., V.B., M.C.), Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne UK.
David
D
Hunt
MRC Institute of Genetics and Molecular Medicine (D.H.) and Anne Rowling Neurology Clinic, Centre for Clinical Brain Sciences (D.H., P.F.), University of Edinburgh; and Human Dendritic Cell Laboratory (P.M., V.B., M.C.), Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne UK.
Paul
P
Milne
MRC Institute of Genetics and Molecular Medicine (D.H.) and Anne Rowling Neurology Clinic, Centre for Clinical Brain Sciences (D.H., P.F.), University of Edinburgh; and Human Dendritic Cell Laboratory (P.M., V.B., M.C.), Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne UK.
Peter
P
Fernandes
MRC Institute of Genetics and Molecular Medicine (D.H.) and Anne Rowling Neurology Clinic, Centre for Clinical Brain Sciences (D.H., P.F.), University of Edinburgh; and Human Dendritic Cell Laboratory (P.M., V.B., M.C.), Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne UK.
Venetia
V
Bigley
MRC Institute of Genetics and Molecular Medicine (D.H.) and Anne Rowling Neurology Clinic, Centre for Clinical Brain Sciences (D.H., P.F.), University of Edinburgh; and Human Dendritic Cell Laboratory (P.M., V.B., M.C.), Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne UK.
Matthew
M
Collin