The mechanisms underlying adaptive resistance of melanoma to targeted therapies remain unclear. By combining ChIP sequencing with microarray-based gene profiling, we determined that ERBB3 is upregulated by FOXD3, a transcription factor that promotes resistance to RAF inhibitors in melanoma. Enhanced ERBB3 signaling promoted resistance to RAF pathway inhibitors in cultured melanoma cell lines and in mouse xenograft models. ERBB3 signaling was dependent on ERBB2; targeting ERBB2 with lapatinib in combination with the RAF inhibitor PLX4720 reduced tumor burden and extended latency of tumor regrowth in vivo versus PLX4720 alone. These results suggest that enhanced ERBB3 signaling may serve as a mechanism of adaptive resistance to RAF and MEK inhibitors in melanoma and that cotargeting this pathway may enhance the clinical efficacy and extend the therapeutic duration of RAF inhibitors.

Cutaneous involvement by an eosinophil-rich process (eosinophilic dermatosis) may be encountered in the setting of various hematologic malignancies, including mantle cell lymphoma, acute monocytic leukemia, acute lymphoblastic leukemia, large cell lymphoma, myelofibrosis and chronic lymphocytic leukemia (CLL). Of the various hematologic malignancies, eosinophilic dermatosis has been most frequently described in association with CLL. Published previously as insect bite-like reaction and eosinophilic dermatosis of myeloproliferative disease, this rare dermatitis presents as a pruritic, papular and occasionally vesicular eruption associated with an eosinophil-rich infiltrate histopathologically. Although clinical and histopathologic features are similar to insect bites, affected patients frequently deny a history of insect bites. We report a case of eosinophilic dermatosis of hematologic malignancy in a patient with known history of CLL.

Increase in the number of scattered atypical melanocytes with large hyperchromatic nuclei in a partial nail matrix may provide a diagnostic clue to subungual melanoma in situ in concert with its clinical suspicion.

Objective.A prospective observational study of mycophenolate mofetil (MMF) treatment in patients with diffuse progressive cutaneous systemic sclerosis (SSc) of recent onset.Methods.Twenty-five previously untreated consecutive patients with recent-onset (< 24 mo) diffuse progressive cutaneous SSc received MMF as the only disease-modifying therapy. Modified Rodnan skin score (mRSS) and affected body surface area (BSA) were compared from initiation of MMF to study end. Pulmonary function tests performed at the same institution before therapy and at study end were available in 15 patients. Histopathology and real-time PCR assessment of fibrosis-related gene expression were performed before and after treatment in skin biopsies from 3 patients.Results.At 18.2 ± 8.73 months of MMF therapy (median 2000 mg/day) the mRSS decreased from 24.56 ± 8.62 to 14.52 ± 10.9 (p = 0.0004) and the affected BSA from 36% ± 16% to 14% ± 13.3% (p = 0.00001). Pulmonary function tests remained stable from initiation of MMF to the end of the study. Skin histopathology showed a remarkable reduction in accumulation of fibrotic tissue. Real-time PCR of skin biopsies demonstrated a marked decrease in expression of fibrosis-related genes.Conclusion.Patients with diffuse progressive cutaneous SSc of recent onset treated with MMF experienced marked improvement in skin involvement and stabilization of pulmonary function. Skin biopsies from 3 patients demonstrated histopathological improvement and decreased expression of fibrosis-related genes.

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