The new paradigm of systemic therapies for metastatic melanoma.

New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.

Putative Intravascular Myofibroma Mimicking a Vascular Malformation With Phleboliths.

Myofibroma is a rare, benign myofibroblastic tumor that commonly presents at birth or in early infancy, usually as a painless, slow-growing, solitary, nodular mass. We present a case of a 40-year-old woman with a painful, solitary, myofibroma on the right elbow. The unique features of this case include age and gender of the patient, site, pain on presentation, tumor morphology, and putative intravascular nature of the tumor.

Acquired blue nevus of the nail bed.

Blue nevi are benign proliferations of melaninproducingdendritic melanocytes located in thedermis. These nevi tend to occur mostly on the skin,predominantly on the head and neck, dorsal aspectsof the distal extremities, and the sacral area, butcan also occasionally appear on mucosal surfaces.Blue nevi of the nail apparatus are uncommon. Themajority originate in the nail matrix where there is ahigher density of melanocytes. Herein we report ona 47-year-old man with a rare common blue nevus ofthe nail bed, an area with low melanocyte density. Athorough review of the English language literaturefound no documented cases of acquired blue nevioriginating in the nailbed of the toe.

Treatment of Moderate to Severe Pediatric Psoriasis: A Retrospective Case Series.

BACKGROUND: Psoriasis has an estimated prevalence of 0.5% to 2.0% in children. There is a paucity of data regarding the management and safety of treatments currently available for children with moderate to severe psoriasis. The aim of this study was to evaluate the treatment response and safety of systemic therapies used to manage moderate to severe pediatric psoriasis in a single referral center. Despite a small sample size, it was hypothesized that multiple therapeutics used for adult psoriasis would have a similar side-effect profile and positive disease response when used in a pediatric population. METHODS: A retrospective case series evaluated 51 children with moderate to severe psoriasis treated with systemic therapies for adverse event occurrence and for disease response using a 5-point Physician Global Assessment scale. RESULTS: Fifty-one patients, some of whom used multiple treatment options, produced 80 treatment data points. Adverse events were reported in 29 of these 80 treatments, with most being minor, subjective side effects. Overall, the most commonly reported side effect was fatigue, which was reported in 7.5% of treatments. Because of the small sample size, the data collected are limited and may not represent a comprehensive safety profile, nor do they allow comparison of efficacy between therapies. This case series found that biologic and immunomodulating therapies provide well-tolerated treatments with positive disease response for moderate to severe pediatric psoriasis. CONCLUSION: Although sample size and study design limit the data from this study, the study provides some guidance where little exists and helps to support the use of these treatments in this setting.

The Use of Methotrexate, Alone or in Combination With Other Therapies, for the Treatment of Palmoplantar Psoriasis.

Palmoplantar psoriasis is a chronic debilitating type of psoriasis. Treatment options for this disease are poorly studied. This chart review evaluated the use of methotrexate alone and in combination with 7 other systemic therapies in 48 patients with palmoplantar psoriasis. The findings demonstrate that methotrexate is a relatively well-tolerated and effective treatment for palmoplantar psoriasis, amenable as either monotherapy or in combination with other systemic agents.

A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response.

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17-producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade-responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17-induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

Self-supervised artificial intelligence predicts recurrence, metastasis and disease specific death from primary cutaneous squamous cell carcinoma at diagnosis.

Primary cutaneous squamous cell carcinoma (cSCC) is responsible for ~10,000 deaths annually in the United States. Stratification of risk of poor outcome (PO) including recurrence, metastasis and disease specific death (DSD) at initial biopsy would significantly impact clinical decision-making during the initial post operative period where intervention has been shown to be most effective. In this multi-institutional study, we developed a state-of-the-art self-supervised deep-learning approach with interpretability power and demonstrated its ability to predict poor outcomes of cSCCs at the time of initial biopsy. By highlighting histomorphological phenotypes, our approach demonstrates that poor differentiation and deep invasion correlate with poor prognosis. Our approach is particularly efficient at defining poor outcome risk in Brigham and Women's Hospital (BWH) T2a and American Joint Committee on Cancer (AJCC) T2 cSCCs. This bridges a significant gap in our ability to assess risk among T2a/T2 cSCCs and may be useful in defining patients at highest risk of poor outcome at the time of diagnosis. Early identification of highest-risk patients could signal implementation of more stringent surveillance, rigorous diagnostic work up and identify patients who might best respond to early postoperative adjunctive treatment.

HMGB1 Translocation After Ischemia in the Ovine Fetal Brain.

Inflammation contributes to the evolution of hypoxic-ischemic (HI) brain injury. High-mobility group box-1 (HMGB1) is a nuclear protein that is translocated from the nucleus and released after ischemia in adult rodents and thereby initiates inflammatory responses. However, there is very little information regarding the effects of HI on HMGB1 in immature brains. To investigate the effects of HI on HMGB1 in the term-equivalent fetal brain, ovine fetuses at 127 days gestation were studied after 30 minutes of carotid occlusion. Groups were sham-control and ischemia with 48 hours and ischemia with 72 hours of reperfusion. By immunohistochemistry, HMGB1 was found to be localized primarily in cell nuclei and partially in cytoplasmic compartments in the cerebral cortex of controls. Ischemia increased the area fraction of neuronal cells with cytoplasmic HMGB1 staining, and Western immunoblot revealed that cytosolic HMGB1 expression increased after ischemia (p < 0.05) and decreased in nuclei in ischemic versus the sham-control brains (p < 0.05). These data indicate that HMGB1 translocates from the nuclear to cytosolic compartments after ischemic brain injury in fetal sheep. This translocation may enable the action of HMGB1 as a proinflammatory cytokine that contributes to HI injury in the developing brain.