Purpose In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored. Patients and Methods In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety. Results Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event. Conclusion Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

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Recently, we have discovered an endogenous cholinergic pathway for angiogenesis mediated by endothelial nicotinic acetylcholine receptors (nAChRs). Since angiogenesis plays a major role in wound repair, we hypothesized that activation of nAChRs with nicotine would accelerate wound healing in a murine excisional wound model. In genetically diabetic and control mice full-thickness skin wounds (0.8 cm) were created on the dorsum and topically treated over 7 days with either vehicle (phosphate-buffered saline, PBS) or nicotine (10 ؊8 mol/L, 10 ؊9 mol/L; each, n ‫؍‬ 5). Wound size was measured over 14 days followed by resection, histological analysis, and quantitation of vascularity. In diabetic animals an agonist (epibatidine, 10 ؊10 mol/L) or antagonist (hexamethonium, 10 ؊4 mol/L) of nAChRs as well as the positive control basic fibroblast growth factor (bFGF, 25 g/kg) were also tested. To further study the role of endothelial nAChRs in angiogenesis, we used an ex vivo vascular explant model. In diabetic mice wound healing was markedly impaired. Nicotine significantly accelerated wound healing as assessed by closure rate and histological score. The effects of nicotine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium. Histomorphometry revealed increased neovascularization in animals treated with nicotine. Furthermore, capillary-like sprouting from vascular explants was significantly enhanced by nicotine. In conclusion, agonist-induced stimulation of nAChRs accelerates wound healing in diabetic mice by promoting angiogenesis. We have discovered a cholinergic pathway for angiogenesis that is involved in wound healing, and which is a potential target for therapeutic angiogenesis.

The diagnosis of myeloid leukemia cutis can be difficult, particularly in the context of an initial skin biopsy with a malignant hematopoietic neoplasm. We studied the immunohistochemical characteristics of 33 cases of myeloid leukemia cutis diagnosed at Stanford University Medical Center, Stanford, CA, 1996-2007, and compared them with the corresponding bone marrow blast immunophenotype and World Health Organization classification (2008). In the skin, CD43 marked 97% of cases (32/33), myeloperoxidase marked 42% (14/33), CD68 marked 94% (31/33), CD163 marked 25% (7/28), and CD56 marked 47% (14/30). CD34 and CD117 were predominantly negative. In 19 cases in which myeloperoxidase was negative, all marked with CD68 and CD43. The flow cytometric immunophenotype of the leukemic blasts in the bone marrow was discordant with the immunohistochemical profile in the skin in all cases, showing loss or gain of at least 1 antigen. Given the immunophenotypic differences between skin and bone marrow blasts, we provide an updated immunohistochemical approach to the diagnosis of myeloid leukemia cutis.