pyrimidinones and Nevus--Pigmented

Neurocutaneous melanosis (NCM) is a rare disorder characterised by giant or multiple melanocytic nevi and meningeal melanosis or melanoma. Onset of neurological symptoms is typically in children younger than 2 years and can be rapidly fatal. We present the case of a 13-year-old adopted girl presenting with numerous congenital melanocytic nevi and a seizure. She had no significant previous neurological history. Electroencephalogram showed epileptiform discharges over the right frontal region. MRI of the brain showed T1 hyperintensity in the bilateral amygdala and anterior temporal lobes with corresponding hyperintensity on T2 and fluid attenuated inversion recovery. There was no hydrocephalus. Along with the history of nevi, these imaging findings were concerning for NCM. The patient is being managed with levetiracetam and trametinib and shows no further neurological decline at 1-year follow-up, providing prognostic hope in this case of NCM.

Topics: Adolescent; Amygdala; Anticonvulsants; Electroencephalography; Female; Humans; Levetiracetam; Magnetic Resonance Imaging; Male; Melanosis; Mitogen-Activated Protein Kinase Kinases; Neurocutaneous Syndromes; Nevus, Pigmented; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Seizures; Temporal Lobe

Treatment of advanced melanoma with selective BRAF and MEK inhibitors is associated with a series of mucocutaneous side effects, among which morphological changes in preexisting nevi and the development of new melanocytic lesions, both benign and malignant. Objective was to describe the changes observed in melanocytic nevi under vemurafenib therapy, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma. The melanocytic lesions of a 51-year-old Caucasian male patient diagnosed with stage IV melanoma were monitored both clinically and dermoscopically throughout vemurafenib, followed by combined treatment with dabrafenib and trametinib. The 65 monitored nevi presented different behaviors under vemurafenib treatment: 18 reticular nevi, 9 reticular-homogenous nevi, 3 reticular-globular nevi, and 2 globular nevi showed a diffuse decrease in pigmentation. Ten reticular nevi remained unchanged, while the rest of the nevi, independent of the dermoscopic pattern, presented a gradual increase in pigmentation. On the other hand, under dabrafenib and trametinib treatment 57 of these nevi showed gradual decrease in pigmentation and central involution, while 7 reticular nevi and 1 globular nevus remained unchanged; none of the monitored nevi increased in pigmentation nor presented new globules following this combination therapy. Systematic total body skin examination is mandatory in patients receiving BRAF inhibitors. The divergent course of melanocytic nevi during vemurafenib vs. dabrafenib and trametinib therapy remains to be elucidated by further research.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Dermoscopy; Disease Progression; Follow-Up Studies; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoplasm Invasiveness; Nevus, Pigmented; Oximes; Pyridones; Pyrimidinones; Risk Assessment; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib

Congenital melanocytic nevus (CMN) syndrome represents a mosaic RASopathy, typically caused by postzygotic NRAS codon 61 mutations, which originate in ectodermal precursor cells and result in melanocyte deposits in the skin and central nervous system (CNS). Affected patients are prone to develop uniformly fatal melanomas in the skin and CNS. Here, we report the case of a 2.7-year-old male with CMN syndrome, diffuse leptomeningeal melanosis and CNS melanoma, who underwent experimental therapy with the DNA methyltransferase inhibitor azacitidine in combination with the mitogen-activated protein kinase (MEK) inhibitor trametinib with exceptional clinical and radiological response. Response to combination therapy appeared to be more durable than the treatment response observed in several other severely affected patients treated with trametinib for late-stage disease. Correspondingly, concomitant exposure to trametinib and azacitidine prevented development of trametinib resistance in NRAS-mutated human melanoma cells in vitro. Also, azacitidine was shown to inhibit growth and mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation of melanoma cells and act synergistically with trametinib to inhibit the growth of trametinib-resistant melanoma cells. These observations suggest that azacitidine enhances trametinib monotherapy and may represent a promising candidate drug for combination therapies to enhance the efficacy of MEK inhibitors in RAS-driven diseases.

Topics: Azacitidine; Child, Preschool; GTP Phosphohydrolases; Humans; Male; Melanoma; Membrane Proteins; Meningeal Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Nevus, Pigmented; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

Giant congenital nevi are melanocytic proliferations of the skin that may be complicated by melanoma, neurocutaneous melanocytosis, pain, pruritus, and disfigurement. Current treatment options include surgical resection and medical management of associated symptoms. There is limited efficacy in these modalities. No effective pharmacologic treatments are available for the treatment of these lesions. We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an

Topics: Antineoplastic Agents; Child; Female; Humans; Nevus, Pigmented; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome