Search

To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultraviolet radiation signature. Significantly mutated genes are BRAF, NRAS, NF1, NOTCH2, PTEN and TYRP1. Mutations and amplification of KIT are also common. Structural rearrangement and copy number signatures show that whole genome duplication, aneuploidy and complex rearrangements are common. Complex rearrangements occur recurrently and are associated with amplification of TERT, CDK4, MDM2, CCND1, PAK1 and GAB2, indicating potential therapeutic options.

Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors. Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2. Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8. SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas. TERT aberrations and ATRX mutations are associated with alterations in telomere length. Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.

Primary melanoma involving the anorectal region is rare, accounting for <1% of all melanomas in most Western countries. It characteristically presents at an advanced clinical stage and is associated with poor clinical outcomes. Preliminary reports suggest that response rates to immunotherapies in patients with advanced stage mucosal melanoma are much lower than in cutaneous (or acral) melanoma patients but reasons for this are unclear. Comprehensive characterisation of the immune microenvironment in anorectal melanoma has not previously been performed. A single-institution cohort of 43 primary anorectal melanoma patients was examined to describe clinicopathological features and characterise the immune microenvironment to provide insights into the behaviour of this rare melanoma subtype. The tumours displayed multiple adverse prognostic attributes including deep thickness (median 11.5 mm), ulceration (81%) and high mitotic rate (median 12/mm 2 ). The median overall survival was 24 months and the median recurrence-free survival was 9 months. Tumour-infiltrating lymphocytes (TILs) were absent or mild in most tumours (75%); PD-L1 positive staining (>1% of tumour cells) was present in 44% of cases, however in 86% of positive tumours the percentage of positive cells was ≤10%. Four tumours underwent whole genome sequencing; no ultraviolet signature was identified, and there was a lower mutational load but higher structural chromosomal variant load compared with cutaneous melanomas. Poor responses of anorectal melanomas to immunotherapy may be caused by lower immunogenicity of these tumours as characterised by low mutation burden (and therefore low neoantigenicity), low TILs infiltrates and low PD-L1 expression. Further investigation is required to determine whether TILs and PD-L1 expression predict response to immunotherapy in patients with mucosal melanoma., (Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Introduction: Wide surgical excision is the standard treatment for localized primary cutaneous melanomas, with a narrow histologic margin associated with an increased risk of local recurrence. The correlation between surgical and histologic margins is poorly documented in the literature., Methods: An audit was performed to (1) document the shrinkage of formalin-fixed specimens, and (2) use a precisely measured surgical margin in vivo to predict the histologic margin. For patients presenting for wide excision of melanomas and other malignant skin tumors, measured surgical margin, in vivo and ex vivo specimen width, and histologic margins after formalin fixation were recorded. The effects of clinicopathologic characteristics, including age, sex, body mass index (BMI), tumor type, anatomic site, and presence of visible tumor in predicting specimen shrinkage and histologic margin were assessed., Results: In total, 252 specimens were evaluated. When compared with measured width in vivo, the formalin-fixed specimens showed a mean shrinkage of 14% (R 2  = 0.98), regardless of patient age, sex, BMI, or site of the lesion. The measured surgical margin was not a strong predictor of the histologic margin, with a high degree of variability (R 2  = 0.55) not explained by patient factors, tumor subtype, or presence of visible tumor at the time of excision (p > 0.05)., Conclusions: A consistent 14% shrinkage rate of wide excision specimens was found across all patients and excision sites, and we propose a clinically useful 15% correction factor that will account for fixation and shrinkage of cutaneous excision specimens. Excision margins measured by the surgeon were a poor predictor of the histologic margins.

Melanoma incidence is increasing worldwide, and although drugs such as BRAF/MEK small-molecule inhibitors and immune checkpoint antibodies improve patient outcomes, most patients ultimately fail these therapies and alternative treatment strategies are urgently needed. DNAzymes have recently undergone clinical trials with signs of efficacy and no serious adverse events attributable to the DNAzyme. Here we investigated c-Jun expression in human primary and metastatic melanoma. We also explored the role of T cell immunity in DNAzyme inhibition of primary melanoma growth and the prevention of growth in non-treated tumors after the cessation of treatment in a mouse model. c-Jun was expressed in 80% of melanoma cells in human primary melanomas (n = 17) and in 83% of metastatic melanoma cells (n = 38). In contrast, c-Jun was expressed in only 11% of melanocytes in benign nevi (n = 24). Dz13, a DNAzyme targeting c-Jun/AP-1, suppressed both Dz13-injected and untreated B16F10 melanoma growth in the same mice, an abscopal effect relieved in each case by administration of anti-CD4/anti-CD8 antibodies. Dz13 increased levels of cleaved caspase-3 within the tumors. New, untreated melanomas grew poorly in mice previously treated with Dz13. Administration of anti-CD4/anti-CD8 antibodies ablated this inhibitory effect and the tumors grew rapidly. Dz13 inhibited c-Jun expression, reduced intratumoral vascularity (vascular lumina area defined by CD31 staining), and increased CD4 + cells within the tumors. This study provides the first demonstration of an abscopal effect of a DNAzyme on tumor growth and shows that Dz13 treatment prevents growth of subsequent new tumors in the same animal. Dz13 may be useful clinically as a therapeutic antitumor agent by preventing tumor relapse through adaptive immunity.

Tumor thickness is the strongest predictor of outcome for clinically localized melanoma. Therefore, accurate assessment is critical for appropriate staging, reliable estimation of prognosis, and management. When melanoma extends alongside skin adnexal structures more deeply than the main tumor mass (periadnexal extension), it is currently unknown whether the prognosis is more accurately reflected by the deepest point of periadnexal tumor extension or the main tumor mass. This study sought to address this question. Survival outcomes of 257 primary cutaneous melanoma patients with periadnexal extension diagnosed between 2005 and 2015 and managed at Melanoma Institute Australia were identified and compared with a control cohort of 514 patients who were matched for tumor thickness, sex, age, mitotic rate, ulceration status, and year of diagnosis but lacked periadnexal extension. The incidence of periadnexal extension at Melanoma Institute Australia was 1.5% (257/16,692 cutaneous melanomas diagnosed between 2005 and 2015). The patient characteristics between the 2 groups were otherwise very similar; median Breslow thickness was 0.9 mm for the periadnexal group and 1.0 mm for the control group. The median extension beyond the Breslow thickness in the tumors with periadnexal extension was 0.45 mm (mean, 0.4 mm). Median follow-up was 46 months for the periadnexal group and 44 months for the control group. Measures of clinical outcomes all showed trends for improved survival in the periadnexal extension group; these were melanoma-specific survival (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.44, 1.38), overall survival (HR, 0.91; 95% CI, 0.59, 1.41), disease-free survival (HR, 0.68; 95% CI, 0.45, 1.03), and distant disease-free survival (HR, 0.69; 95% CI, 0.4, 1.17), although none were statistically significant. There was a higher rate of sentinel lymph node (SLN) metastasis in the periadnexal group versus the control group in patients whose tumors were >1 mm thick (24/100=24% vs. 23/187=12.3%). Periadnexal extension was significantly associated with SLN metastasis on univariate logistic regression analysis (odds ratio [95% CI], 2.25 [1.20, 4.24], P=0.01). If the periadnexal extension had been included in the measurement of tumor thickness, 42.8% of patients would have been upstaged to a higher American Joint Committee on Cancer T category. The findings of this study indicate that periadnexal involvement that extends more deeply than the thickness of the main tumor mass increases the risk of SLN metastasis in tumours >1 mm thick, however, does not worsen clinical outcomes overall, and tumor thickness measurements should not include deeper foci of periadnexal tumor.

Aims: Early recognition and accurate diagnosis underpins melanoma survival. Identifying early melanomas arising in association with pre-existing lesions is often challenging. Clinically suspicious foci, however small, must be identified and examined histologically. This study assessed the accuracy of punch biopsy 'scoring' of suspicious foci in excised atypical pigmented skin lesions to identify early melanomas., Methods and Results: Forty-one excised pigmented skin lesions with a clinically/dermoscopically focal area of concern for melanoma, with the suspicious focus marked prior to excision with a punch biopsy 'score' (a partial incision into the skin surface), were analysed. Melanoma was diagnosed in nine of 41 cases (22%). In eight of nine cases (89%) the melanoma was associated with a naevus, and in seven of nine (88%) cases the melanoma was identified preferentially by the scored focus. In six of nine cases (67%), the melanoma was entirely encompassed by the scored focus. In one case of melanoma in situ, the diagnostic material was identified only on further levelling through the scored focus. In 28 of 32 of non-melanoma cases (88%), the scored focus identified either diagnostic features of a particular lesion or pathological features that correlated with the clinical impression of change/atypia including altered architecture or distribution of pigmentation, features of irritation or regression., Conclusions: The 'punch scoring technique' allows direct clinicopathological correlation and facilitates early melanoma diagnosis by focusing attention on clinically suspicious areas. Furthermore, it does not require special expertise in ex-vivo clinical techniques for implementation. Nevertheless, in some cases examination of the lesion beyond the scored focus is also necessary to make a diagnosis of melanoma., (© 2017 John Wiley & Sons Ltd.)

Cultural differences in spatial perception have been little investigated, which gives rise to the impression that spatial cognitive processes might be universal. Contrary to this idea, we demonstrate cultural differences in spatial volume perception of computer generated rooms between Germans and South Koreans. We used a psychophysical task in which participants had to judge whether a rectangular room was larger or smaller than a square room of reference. We systematically varied the room rectangularity (depth to width aspect ratio) and the viewpoint (middle of the short wall vs. long wall) from which the room was viewed. South Koreans were significantly less biased by room rectangularity and viewpoint than their German counterparts. These results are in line with previous notions of general cognitive processing strategies being more context dependent in East Asian societies than Western ones. We point to the necessity of considering culturally-specific cognitive processing strategies in visual spatial cognition research.

Objective: To evaluate whether prescribed benzodiazepines affect one's risk of suicide., Data Sources: A PubMed search of English-language publications from database inception until October 11, 2016, was conducted using the terms benzodiazepine and suicide. References and related articles were also searched to yield additional publications., Study Selection/data Extraction: Studies were included if they addressed the relationship between suicidal behavior and the prescribed use of either specific benzodiazepines or benzodiazepines as a class. A total of 17 studies were included in this review., Results: The majority of studies found that benzodiazepines were associated with increased suicide risk. This finding was consistent across various populations and different types of research, including a placebo-controlled crossover trial, a laboratory model of suicidal behavior, case-control studies regarding completed suicides on inpatient units, and large naturalistic studies., Conclusions: Benzodiazepines appear to cause an overall increase in the risk of attempting or completing suicide. Possible mechanisms of prosuicidal effects may include increases in impulsivity or aggression, rebound or withdrawal symptoms, and toxicity in overdose., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

We describe a case involving bizarre paranoid delusions following implantation of a sacral nerve stimulator, and review the literature regarding psychotic symptoms related to surgical implants. A 64-year-old female developed bizarre paranoid delusions regarding a sacral nerve stimulator that had been implanted two years previously for dysfunctional voiding. The patient believed that the wires from the sacral nerve electrodes had grown up her spine and were affecting her vision as well as controlling her thoughts. The delusions developed in the setting of profound anxiety and feelings of loss after the death of her mother. The patient initially demanded that the implant be removed emergently. The delusions gradually abated as she adjusted to the loss of her mother. Fortunately the symptoms abated entirely with supportive care. We suspect that given the frequency of surgical implants that the association with delusional thoughts might be much higher than suggested by a literature review.

The elongation of a figure or object can induce a perceptual bias regarding its area or volume estimation. This bias is notable in Piagetian experiments in which participants tend to consider elongated cylinders to contain more liquid than shorter cylinders of equal volume. We investigated whether similar perceptual biases could be found in volume judgments of surrounding indoor spaces and whether those judgments were viewpoint dependent. Participants compared a variety of computer-generated rectangular rooms with a square room in a psychophysical task. We found that the elongation bias in figures or objects was also present in volume comparison judgments of indoor spaces. Further, the direction of the bias (larger or smaller) depended on the observer's viewpoint. Similar results were obtained from a monoscopic computer display (Experiment 1) and stereoscopic head-mounted display with head tracking (Experiment 2). We used generalized linear mixed-effect models to model participants' volume judgments using a function of room depth and width. A good fit to the data was found when applying weight on the depth relative to the width, suggesting that participants' judgments were biased by egocentric properties of the space. We discuss how biases in comparative volume judgments of rooms might reflect the use of simplified strategies, such as anchoring on one salient dimension of the space.

Accurate knowledge about size and shape of the body derived from somatosensation is important to locate one's own body in space. The internal representation of these body metrics (body model) has been assessed by contrasting the distortions of participants' body estimates across two types of tasks (localization task vs. template matching task). Here, we examined to which extent this contrast is linked to the human body. We compared participants' shape estimates of their own hand and non-corporeal objects (rake, post-it pad, CD-box) between a localization task and a template matching task. While most items were perceived accurately in the visual template matching task, they appeared to be distorted in the localization task. All items' distortions were characterized by larger length underestimation compared to width. This pattern of distortion was maintained across orientation for the rake item only, suggesting that the biases measured on the rake were bound to an item-centric reference frame. This was previously assumed to be the case only for the hand. Although similar results can be found between non-corporeal items and the hand, the hand appears significantly more distorted than other items in the localization task. Therefore, we conclude that the magnitude of the distortions measured in the localization task is specific to the hand. Our results are in line with the idea that the localization task for the hand measures contributions of both an implicit body model that is not utilized in landmark localization with objects and other factors that are common to objects and the hand.

Humans can recognize emotions expressed through body motion with high accuracy even when the stimuli are impoverished. However, most of the research on body motion has relied on exaggerated displays of emotions. In this paper we present two experiments where we investigated whether emotional body expressions could be recognized when they were recorded during natural narration. Our actors were free to use their entire body, face, and voice to express emotions, but our resulting visual stimuli used only the upper body motion trajectories in the form of animated stick figures. Observers were asked to perform an emotion recognition task on short motion sequences using a large and balanced set of emotions (amusement, joy, pride, relief, surprise, anger, disgust, fear, sadness, shame, and neutral). Even with only upper body motion available, our results show recognition accuracy significantly above chance level and high consistency rates among observers. In our first experiment, that used more classic emotion induction setup, all emotions were well recognized. In the second study that employed narrations, four basic emotion categories (joy, anger, fear, and sadness), three non-basic emotion categories (amusement, pride, and shame) and the "neutral" category were recognized above chance. Interestingly, especially in the second experiment, observers showed a bias toward anger when recognizing the motion sequences for emotions. We discovered that similarities between motion sequences across the emotions along such properties as mean motion speed, number of peaks in the motion trajectory and mean motion span can explain a large percent of the variation in observers' responses. Overall, our results show that upper body motion is informative for emotion recognition in narrative scenarios.

In neurology and psychiatry the detailed study of illusory own body perceptions has suggested close links between bodily processing and self-consciousness. One such illusory own body perception is heautoscopy where patients have the sensation of being reduplicated and to exist at two or even more locations. In previous experiments, using a video head-mounted display, self-location and self-identification were manipulated by applying conflicting visuo-tactile information. Yet the experienced singularity of the self was not affected, i.e., participants did not experience having multiple bodies or selves. In two experiments presented in this paper, we investigated self-location and self-identification while participants saw two virtual bodies (video-generated in study 1 and 3D computer generated in study 2) that were stroked either synchronously or asynchronously with their own body. In both experiments, we report that self-identification with two virtual bodies was stronger during synchronous stroking. Furthermore, in the video generated setup with synchronous stroking participants reported a greater feeling of having multiple bodies than in the control conditions. In study 1, but not in study 2, we report that self-location - measured by anterior posterior drift - was significantly shifted towards the two bodies in the synchronous condition only. Self-identification with two bodies, the sensation of having multiple bodies, and the changes in self-location show that the experienced singularity of the self can be studied experimentally. We discuss our data with respect to ownership for supernumerary hands and heautoscopy. We finally compare the effects of the video and 3D computer generated head-mounted display technology and discuss the possible benefits of using either technology to induce changes in illusory self-identification with a virtual body.

Objective: Discontinuities in health insurance coverage may make it difficult for individuals early in psychosis to receive the services that are critical in determining long-term outcome. This study reports on the rates and continuity of insurance coverage among a cohort of early-psychosis patients enrolled in Specialized Treatment Early in Psychosis (STEP) at the Connecticut Mental Health Center., Methods: Insurance status at baseline, six months, and 12 months was collected from 82 participants from a combination of self-reports, clinical chart review, clinician reports, and a database maintained by the state Department of Social Services., Results: A total of 34 participants did not know whether they had health insurance or did not appear for follow-up assessments at six and 12 months. Among the remaining 48 participants, at baseline 18 had private insurance, 13 had public insurance, and 16 had no insurance. By the 12-month assessment, 13 (72%) privately insured and five (38%) publicly insured participants had lost coverage; less than one-third of the 48 participants (N=14) maintained continuous coverage., Conclusions: Specialty services for individuals experiencing early psychosis should address the difficulty of maintaining health insurance coverage during a period of illness in which continuity of care is critical to recovery.

Background: When we talk to one another face-to-face, body gestures accompany our speech. Motion tracking technology enables us to include body gestures in avatar-mediated communication, by mapping one's movements onto one's own 3D avatar in real time, so the avatar is self-animated. We conducted two experiments to investigate (a) whether head-mounted display virtual reality is useful for researching the influence of body gestures in communication; and (b) whether body gestures are used to help in communicating the meaning of a word. Participants worked in pairs and played a communication game, where one person had to describe the meanings of words to the other., Principal Findings: In experiment 1, participants used significantly more hand gestures and successfully described significantly more words when nonverbal communication was available to both participants (i.e. both describing and guessing avatars were self-animated, compared with both avatars in a static neutral pose). Participants 'passed' (gave up describing) significantly more words when they were talking to a static avatar (no nonverbal feedback available). In experiment 2, participants' performance was significantly worse when they were talking to an avatar with a prerecorded listening animation, compared with an avatar animated by their partners' real movements. In both experiments participants used significantly more hand gestures when they played the game in the real world., Conclusions: Taken together, the studies show how (a) virtual reality can be used to systematically study the influence of body gestures; (b) it is important that nonverbal communication is bidirectional (real nonverbal feedback in addition to nonverbal communication from the describing participant); and (c) there are differences in the amount of body gestures that participants use with and without the head-mounted display, and we discuss possible explanations for this and ideas for future investigation.

Background: This review aims to compare the effectiveness of linezolid to vancomycin for the treatment of Methicillin Resistant Staphylococcus Aureus (MRSA) skin and soft tissue infections (SSTIs) in inpatients., Methods: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and reference lists were searched in March 2007. We included randomized controlled trials that looked at inpatients treated with linezolid versus vancomycin for the treatment of hospital-acquired MRSA SSTIs. Outcome measures were clinical cure (resolution of symptoms and signs) and microbiological cure (eradication of MRSA on wound culture). The validity of the included trials was assessed. The results were combined in meta-analyses, the robustness of which was tested in sensitivity analyses., Results: Four trials were included in this review: three for clinical outcomes (174 participants) and three for microbiological outcomes (439 participants). For clinical outcomes there were non-significant trends in favour of linezolid (RR 0.34; 95% CI 0.04, 2.89; P = 0.32). For microbiological outcomes there was weak evidence of linezolid outperforming vancomycin (RR 0.55; 95% CI 0.30, 1.01; P = 0.05). Sensitivity analyses did not change the conclusions taken from the main analysis., Conclusion: With the current available data no difference could be detected between the two treatments, but a trend towards higher effectiveness of linezolid was observed. More data will be required to determine if linezolid is superior to vancomycin for the treatment of MRSA SSTIs. Further systematic reviews are needed to look at other outcomes (length of hospital stay, safety and tolerability, cost-effectiveness) and at MRSA infections at other sites.