Figure 4.
Trametinib treatment resolved histiocytic lesions, and downregulated inflammatory gene expression. (A) Images of indurated skin lesions of patient H1. Top: before tocilizumab treatment; bottom: during tocilizumab treatment. (B) Magnetic resonance imaging (MRI) of left maxillary sinus tumor (patient H1). Top left: coronal T1-weighted fat suppressed with contrast material administration shows an enhancing soft tissue mass in the left maxillary sinus (arrow). Top right: axial T2-weighted images shows that the mass (arrow) is mostly hyperintense. Bottom left: a follow-up MRI performed after 28 months of trametinib treatment. Axial T2-weighted fat saturated image shows complete resolution of the finding (arrow). Bottom right: graph depicting tumor volume (cubic centimeters) as calculated according to MRIs. (C) Image of the skin of patient H1 during trametinib treatment. (D) Graphs depicting longitudinal measurements of inflammatory markers (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), hemoglobin (HB), and albumin (ALB) levels during clinical follow-up of patient H1. CRP (upper left panel; dotted red line delineates upper norm of 0.5 mg/dL), ESR (lower left panel; dotted red line delineates upper norm of 20 mm/h), HB (upper left panel; the dotted red line delineates lower norm of 11.4 g/dL), ALB (lower right panel; the dotted red line delineates lower norm of line 3.8 g/dL). Treatment periods are highlighted in red (methotrexate), green (tocilizumab), and blue (trametinib). (E) Flow cytometry analysis of classical (CD14high CD16−) and nonclassical (CD14dim CD16+) monocyte subset distribution of patient H1 during trametinib treatment. The dot plot depicts percentages of classical (top) and nonclassical (bottom) monocytes of total monocytes, based on flow cytometry analysis. Values of controls and patients with H syndrome as depicted in Figure 2B. (F) Volcano plots showing the differentially expressed genes in classical monocytes. Negative FC represents genes that were downregulated during therapy, and positive FC represents genes that were upregulated during therapy. FDR, false discovery rate.

Trametinib treatment resolved histiocytic lesions, and downregulated inflammatory gene expression. (A) Images of indurated skin lesions of patient H1. Top: before tocilizumab treatment; bottom: during tocilizumab treatment. (B) Magnetic resonance imaging (MRI) of left maxillary sinus tumor (patient H1). Top left: coronal T1-weighted fat suppressed with contrast material administration shows an enhancing soft tissue mass in the left maxillary sinus (arrow). Top right: axial T2-weighted images shows that the mass (arrow) is mostly hyperintense. Bottom left: a follow-up MRI performed after 28 months of trametinib treatment. Axial T2-weighted fat saturated image shows complete resolution of the finding (arrow). Bottom right: graph depicting tumor volume (cubic centimeters) as calculated according to MRIs. (C) Image of the skin of patient H1 during trametinib treatment. (D) Graphs depicting longitudinal measurements of inflammatory markers (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]), hemoglobin (HB), and albumin (ALB) levels during clinical follow-up of patient H1. CRP (upper left panel; dotted red line delineates upper norm of 0.5 mg/dL), ESR (lower left panel; dotted red line delineates upper norm of 20 mm/h), HB (upper left panel; the dotted red line delineates lower norm of 11.4 g/dL), ALB (lower right panel; the dotted red line delineates lower norm of line 3.8 g/dL). Treatment periods are highlighted in red (methotrexate), green (tocilizumab), and blue (trametinib). (E) Flow cytometry analysis of classical (CD14high CD16−) and nonclassical (CD14dim CD16+) monocyte subset distribution of patient H1 during trametinib treatment. The dot plot depicts percentages of classical (top) and nonclassical (bottom) monocytes of total monocytes, based on flow cytometry analysis. Values of controls and patients with H syndrome as depicted in Figure 2B. (F) Volcano plots showing the differentially expressed genes in classical monocytes. Negative FC represents genes that were downregulated during therapy, and positive FC represents genes that were upregulated during therapy. FDR, false discovery rate.

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