orco mutant mosquitoes lose strong preference for humans and are not repelled by volatile DEET.

Female mosquitoes of some species are generalists and will blood-feed on a variety of vertebrate hosts, whereas others display marked host preference. Anopheles gambiae and Aedes aegypti have evolved a strong preference for humans, making them dangerously efficient vectors of malaria and Dengue haemorrhagic fever. Specific host odours probably drive this strong preference because other attractive cues, including body heat and exhaled carbon dioxide (CO2), are common to all warm-blooded hosts. Insects sense odours via several chemosensory receptor families, including the odorant receptors (ORs), membrane proteins that form heteromeric odour-gated ion channels comprising a variable ligand-selective subunit and an obligate co-receptor called Orco (ref. 6). Here we use zinc-finger nucleases to generate targeted mutations in the orco gene of A. aegypti to examine the contribution of Orco and the odorant receptor pathway to mosquito host selection and sensitivity to the insect repellent DEET (N,N-diethyl-meta-toluamide). orco mutant olfactory sensory neurons have greatly reduced spontaneous activity and lack odour-evoked responses. Behaviourally, orco mutant mosquitoes have severely reduced attraction to honey, an odour cue related to floral nectar, and do not respond to human scent in the absence of CO2. However, in the presence of CO2, female orco mutant mosquitoes retain strong attraction to both human and animal hosts, but no longer strongly prefer humans. orco mutant females are attracted to human hosts even in the presence of DEET, but are repelled upon contact, indicating that olfactory- and contact-mediated effects of DEET are mechanistically distinct. We conclude that the odorant receptor pathway is crucial for an anthropophilic vector mosquito to discriminate human from non-human hosts and to be effectively repelled by volatile DEET.

Treatment Outcomes for Metastatic Melanoma of Unknown Primary in the New Era: A Single-Institution Study and Review of the Literature.

BACKGROUND: Metastatic melanoma of unknown primary (MUP) is uncommon, biologically ill defined, and clinically understudied. MUP outcomes are seldom reported in clinical trials. In this study, we analyze responses of MUP patients treated with systemic therapy in an attempt to inform treatment guidelines for this unique population. METHODS: New York University (NYU)'s prospective melanoma database was searched for MUP patients treated with systemic therapy. PubMed and Google Scholar were searched for MUP patients treated with immunotherapy or targeted therapy reported in the literature, and their response and survival data were compared to the MUP patient data from NYU. Both groups' response data were compared to those reported for melanoma of known primary (MKP). RESULTS: The MUP patients treated at NYU had better outcomes on immunotherapy but worse on targeted therapy than the MUP patients in the literature. The NYU MUP patients and those in the literature had worse outcomes than the majority-MKP populations in 10 clinical trial reports. CONCLUSIONS: Our study suggests that MUP patients might have poorer outcomes on systemic therapy as compared to MKP patients. Our cohort was small and limited data were available, highlighting the need for increased reporting of MUP outcomes and multi-institutional efforts to understand the mechanism behind the observed differences.

Outcomes in Melanoma Patients Treated with BRAF/MEK-Directed Therapy or Immune Checkpoint Inhibition Stratified by Clinical Trial versus Standard of Care.

OBJECTIVES: Since 2011, metastatic melanoma treatment has evolved with commercial approval of BRAF- and MEK-targeted therapy and CTLA-4- and PD-1-blocking antibodies (immune checkpoint inhibitors, ICI). While novel therapies have demonstrated improved prognosis in clinical trials, few studies have examined the evolution of prognosis and toxicity of these drugs among an unselected population. We assess whether survival and toxicity reported in trials, which typically exclude most patients with brain metastases and poor performance status, are recapitulated within a commercial access population. METHODS: 182 patients diagnosed with stage IV melanoma from July 2006 to December 2013 and treated with BRAF- and/or MEK-targeted therapy or ICI were prospectively studied. Outcomes and clinicopathologic differences between trial and commercial cohorts were assessed. RESULTS: Patients receiving commercial therapy (vs. on trial) had poorer prognostic features (i.e., brain metastases) and lower median overall survival (mOS) when assessed across all treatments (9.2 vs. 17.5 months, p = 0.0027). While toxicity within trial and commercial cohorts did not differ, patients who experienced toxicity had increased mOS (p < 0.001), irrespective of stratification by trial status or therapy. CONCLUSION: Metastatic melanoma patients receiving commercial treatment may represent a different clinical population with poor prognostic features compared to trial patients. Toxicity may prognosticate treatment benefit.

Combined blue nevus-smooth muscle hamartoma: a series of 12 cases.

BACKGROUND: One of the most common types of combined melanocytic nevus is that of a blue nevus with ordinary melanocytic nevus. Blue nevi have also been described in association with non-melanocytic cell types, such as those of neural or mesenchymal derivation. Although there are rare descriptions in the literature of blue nevi with myomatous structures, the specific association of combined blue nevi with smooth muscle hyperplasia has not been reported METHODS: We review the clinicopathological features of 12 cases of combined blue nevi with smooth muscle hyperplasia. RESULTS: The majority of these lesions occurred on the back of middle-aged patients and were clinically interpreted as melanocytic nevi or melanoma. Histopathologic examination revealed a combined population of 'common' and blue nevus melanocytes with accompanying smooth muscle hyperplasia. In addition to a lentiginous proliferation of melanocytes at the dermal-epidermal junction with variable basilar hyperpigmentation, there were varying degrees of epidermal acanthosis and follicular induction (three cases). CONCLUSION: We present an unusual hamartoma with features of combined blue nevus and smooth muscle hyperplasia, which has not been previously described.

Reticulated Hyperpigmentation as a Sign of Lichen Planopilaris.

INTRODUCTION: Reticulated hyperpigmentation is a relatively uncommon dermatologic pattern. It is used to describe brown-colored skin lesions that manifest in a lacy or net-like distribution. When a clinician encounters a patient with reticulated hyperpigmentation, its location is often the most helpful feature in establishing a differential diagnosis. As this pattern is rarely observed on the scalp, this site is currently not included in the diagnostic approach. CASE PRESENTATION: In this report, we present a case of lichen planopilaris (LPP) in a black man who presented with reticulated hyperpigmentation over the scalp. CONCLUSION: We suggest that it may be warranted to add LPP to the differential diagnosis of reticulated hyperpigmentation, especially when arising on the scalp of darker skinned individuals.

A Novel Atypical Presentation of Frontal Fibrosing Alopecia Involving the Frontoparietal Scalp.

Frontal fibrosing alopecia (FFA) is a progressive scarring alopecia of unknown etiology that classically presents with a band of hair loss along the frontotemporal scalp. We report a case of FFA involving a band of alopecia along the frontotemporal scalp extending into 2 symmetrical triangles along the parietal scalp reminiscent of the Greek letter upsilon (υ). Trichoscopy demonstrated loss of follicular ostia and peripilar casts. Histology demonstrated altered follicular architecture with decreased follicular density and focal perifollicular fibrosis with a lichenoid infiltrate. Both the trichoscopy and histology support a diagnosis of FFA.

Scedosporium apiospermum infections and the role of combination antifungal therapy and GM-CSF: A case report and review of the literature.

Scedosporium apiospermum, a ubiquitous environmental mold, is increasingly reported as causing invasive fungal disease in immunocompromised hosts. It poses a therapeutic challenge due to its intrinsic resistance to traditional antifungals and ability to recur despite demonstrating susceptibility. We present an immunocompromised patient with a cutaneous S. apiospermum infection that disseminated despite treatment with voriconazole, the drug of choice. Adding echinocandins and GM-CSF provided partial recovery, indicating a potential synergistic role of dual-antifungal and immunotherapeutic agents.