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BACKGROUND/OBJECTIVES: Increased rates of histopathological misdiagnosis of melanoma have been associated with incisional punch more so than shave biopsy when compared with complete excisional biopsy. It is unknown how the increasing utilisation of shave biopsy may impact melanoma diagnosis. The extent to which the provision of clinical information to the pathologist may improve diagnostic accuracy remains unclear. This study assessed the impact of both initial biopsy technique and provision of adequate clinical information to pathologists on the accuracy of histopathological diagnosis of melanoma and disease progression. METHODS: We conducted a retrospective cohort with nested case-control study of all histopathological false-negative and false-positive melanoma diagnoses from January 2014 to May 2019 from the Victorian Melanoma Service electronic database. Cases were assessed for the initial biopsy type, provision of clinical information on pathology request forms and disease progression associated with false-negative diagnosis. RESULTS: Partial shave biopsy had higher odds of false-negative (OR 5.19, 95% CI 2.89-9.32; P < 0.001) and false-positive diagnoses (OR 1.95, 95% CI 1.45-2.63; P < 0.001) of melanoma when compared with elliptical excisional biopsy. These odds ratios were comparable with those found with incisional punch biopsy. Providing the suspected clinical diagnosis to pathologists also reduced the odds of false-negative diagnosis with melanoma progression by 3.8-fold (P = 0.02). CONCLUSION: The choice of initial biopsy technique and providing the suspected clinical diagnosis to pathologists are important for correct histopathological diagnosis of cutaneous melanoma and prevention of further disease progression.

Desmoplastic melanomas are uncommon. Their behaviour differs from that of other melanoma subtypes; therefore, management guidelines for non-desmoplastic melanomas may not be applicable. This review sought to examine all available evidence relating to the behaviour and management of desmoplastic melanomas, based on review of all relevant English-language publications, and to critically assess the recommendations for their management in current published melanoma management guidelines. Compared with other melanoma subtypes, patients with 'pure' desmoplastic melanomas (where ≥90% of the invasive melanoma is of desmoplastic melanoma subtype) have much lower rates of sentinel node positivity and distant metastasis. Local recurrence rates are higher for desmoplastic melanomas, but resection margins wider than those recommended for non-desmoplastic melanomas have not been shown to be of benefit. Adjuvant radiotherapy reduces the risk of local recurrence when a satisfactory histological clearance (≥8 mm) cannot be achieved. Of 29 published melanoma management guidelines identified, only 11 specified management for desmoplastic melanomas, while seven simply stated that the feature should be reported. Desmoplastic melanoma is a unique melanoma subtype with biology that differs from that of other melanoma subtypes. It requires specific management strategies but few current guidelines address these.

BACKGROUND/OBJECTIVES: Acral lentiginous melanoma (ALM) is a melanoma subtype associated with atypical locations on the hands and feet and advanced disease at diagnosis. There is a limited understanding of whether the survival is similar for nail, non-nail, lower limb and upper limb ALM patients. We therefore explored clinicopathologic characteristics and melanoma-specific survival of ALM patients according to tumour location. METHODS: A prospectively collected cohort study was performed of all primary invasive cutaneous acral lentiginous melanomas with known thickness and tumour location reviewed at a tertiary referral centre over 21 years. RESULTS: A total of 101 ALM patients were reviewed from 1994 until 2016. The majority of cases (82/101) occurred on the feet. Hand ALMs were thicker and more likely to be ulcerated than feet ALMs (P = 0.05 and 0.02, respectively); however, survival was not statistically different between these two groups (univariate HR 0.48 P = 0.11, 95% CI, 0.20-1.17; multivariate HR 0.67 P = 0.40, 95% CI, 0.27-1.69, respectively). Non-nail ALM patients had longer survival when compared to nail ALM on univariate analysis (HR 0.40, 95% CI, 0.17 to 0.90) which was accounted for by Breslow thickness and ulceration (multivariate HR 0.56, 95% CI, 0.24 to 1.34). CONCLUSIONS: The reduced melanoma-specific survival in nail ALM patients was likely due to their greater thickness and ulceration. Although hand ALMs are thicker and more frequently ulcerated, this is likely due to the higher proportion of nail ALMs present in this location.

BACKGROUND/OBJECTIVES: There is evidence that cutaneous melanomas at different anatomic sites present with distinctive clinicopathologic features. We examined the anatomic distribution of cutaneous melanoma and its variation by patient characteristics, subtype and Breslow thickness, using high-resolution anatomic site data. METHODS: A cross-sectional study was performed of all primary cutaneous melanoma cases managed at a tertiary referral centre, analysing prospectively collected clinical data across 50 anatomic subsites. RESULTS: The study included 5141 in situ or invasive melanomas; most were invasive (76.2%), and the median Breslow thickness of invasive lesions was 1.0 mm. Superficial spreading (57.2%), lentigo maligna (20.8%) and nodular (12.2%) were the most common histopathological subtypes. Sun-exposed sites such as the female nose and cheek, the male ear, as well as the upper back in both sexes had the highest incidence of melanoma per unit area. When compared to the posterior forearm, the scalp, ear, preauricular, perioral, subungual and plantar sites had thicker invasive melanomas (each P < 0.05). The peri-auricular, ear and cheek had the highest incidence of nodular melanoma per unit area. There were subtype-, age- and sex-specific differences in melanoma anatomic distribution. CONCLUSION: Melanoma most commonly arises in sun-exposed facial areas, as well as the upper back. Increased thickness is found for melanoma in acral and many head and neck sites. Nodular melanoma is more likely to occur in head and neck sites including the peri-auricular area, ear and cheek. Clinicians should carefully assess these sites during skin examinations.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) is a diagnostic procedure developed in the 1990s. It is currently used to stage patients with primary cutaneous melanoma, provide prognostic information and guide management. The Australian Clinical Practice Guidelines state that SLNB should be considered for patients with cutaneous melanoma >1 mm in thickness (or >0.8 mm with high-risk pathology features). Until recently, sentinel lymph node (SLN) status was used to identify patients who might benefit from a completion lymph node dissection, a procedure that is no longer routinely recommended. SLN status is now also being used to identify patients who might benefit from systemic adjuvant therapies such as anti-programmed cell death 1 (PD1) checkpoint inhibitor immunotherapy or BRAF-directed molecular targeted therapy, treatments that have significantly improved relapse-free survival for patients with resected stage III melanoma and improved overall survival of patients with unresectable stage III and stage IV melanoma. Australian and international data indicate that approximately half of eligible patients receive an SLNB. METHODS AND ANALYSIS: This mixed-methods study seeks to understand the structural, contextual and cultural factors affecting implementation of the SLNB guidelines. Data collection will include: (1) cross-sectional questionnaires and semistructured interviews with general practitioners and dermatologists; (2) semistructured interviews with other healthcare professionals involved in the diagnosis and early definitive care of melanoma patients and key stakeholders including researchers, representatives of professional colleges, training organisations and consumer melanoma groups; and (3) documentary analysis of documents from government, health services and non-government organisations. Descriptive analyses and multivariable regression models will be used to examine factors related to SLNB practices and attitudes. Qualitative data will be analysed using

BACKGROUND: Pure desmoplastic melanoma (pDM) is an uncommon subtype of malignant melanoma with comparative high rates of local recurrence and low rates of sentinel lymph node positivity. The melanoma-specific survival (MSS) of pDM compared to other melanoma subtypes is unclear, with conflicting reports and lack of multivariable analyses. OBJECTIVES: We aimed to describe clinicopathological characteristics of a cohort of patients with pDM and to compare the MSS of pDM with superficial spreading melanoma (SSM). METHODS: A prospective cohort study was performed of all primary invasive cutaneous pDM with known tumour location and thickness reviewed at a tertiary referral centre over 21 years. RESULTS: A total of 119 primary cutaneous invasive pDMs from 3570 total invasive cutaneous melanomas were included. Compared to 2272 SSMs, and due largely to their greater average thickness, patients with pDM had worse MSS (unadjusted hazard ratio, HR, 2.56, 95% confidence interval, CI, 1.56-4.22). After adjustment for clinicopathologic factors (including thickness, ulceration, mitotic rate, age and sex), there was evidence that patients with pDM had an improved MSS (adjusted HR, 0.49; 95% CI, 0.28-0.87). Median thickness of head and neck pDM was greater than non-head and neck pDM (P < 0.001). There was reduced univariable MSS in head and neck pDM compared to the rest of the body. CONCLUSIONS: Decreased univariable MSS of patients with pDM compared to SSM was explained by the increased frequency of adverse clinicopathologic features at diagnosis, in particular the greater Breslow thickness of pDM. After adjustment, patients with pDM had half the chance of melanoma-specific death compared to SSM. Head and neck pDM were thicker at diagnosis compared to the rest of the body, which may account for its poorer survival compared to the rest of the body.

BACKGROUND: The recommended method for histopathological diagnosis of cutaneous melanoma is excisional biopsy, although partial biopsies (shave and punch) are often used. Following a partial biopsy, treatment guidelines recommend a narrow excisional biopsy to plan definitive management. There is limited evidence on the benefits of direct wide local excision (WLE) following diagnostic partial biopsies. METHODS: Retrospective cohort study of cutaneous melanoma cases, from two tertiary referral centres from January 2013 to December 2015. Demographic and histopathological data, including tumour thickness (T-stage) from initial biopsy and subsequent excisions, were collected. Logistic regression was used to examine histopathological T-staging between biopsy and subsequent excisions (upstaging). RESULTS: 2304 melanomas (2157 patients) were identified; 455 shave, 308 punch, 14 incisional and 1527 excisional biopsies. Out of 1527, 5 (<1%) excisional biopsies were upstaged from original biopsy T-stage to final WLE; compared to 28/455 (6%) for shave, 45/308 (15%) for punch and 2/14 (14%) for incisional biopsies. Histopathology upstaging were increased with punch (OR, 52.1; 95% CI, 20.5-132.4. P < 0.001) and shave biopsy (OR, 20.0; 95% CI, 7.7-52.0. P < 0.001) compared to excisional biopsy. Upstaging rates of 9.4% for desmoplastic (OR, 6.9; 95% CI, 2.4-19.7. P < 0.001) and 21.9% for acral lentiginous (OR, 18.4; 95% CI, 6.9-49.2. P < 0.001) melanomas were elevated compared to 1.4% for superficial spreading melanoma. CONCLUSIONS: In most cases, partial biopsy (particularly shave biopsy) can provide sufficient information to plan for definitive surgical melanoma management. Punch and incisional biopsies have elevated upstaging rates, a consideration in planning therapy. Partial biopsies of desmoplastic or acral lentiginous melanomas have high rates of upstaging and should have a complete excision prior to definitive treatment.

BACKGROUND: A proportion of patients develop recurrence following a tumour-negative sentinel lymph node biopsy (SLNB). This study aimed to explore whether melanoma patients with BRAF or NRAS mutant tumours have an increased risk of developing disease recurrence following a negative SLNB compared to patients with wild-type tumours. METHODS: Prospective cohort study of melanoma patients at three tertiary referral centres in Melbourne, who underwent SLNB. Clinical, pathological and molecular characteristics and recurrence data were prospectively recorded. Multivariate Cox proportional hazards regression models estimated the adjusted hazard ratio (aHR) and corresponding 95% confidence interval (CI) for the association between mutation status and development of recurrence following a negative-SLNB. RESULTS: Overall, 344/477 (72.1%) patients had a negative SLNB. Of these, 54 (15.7%) developed subsequent recurrence. The risk of disease recurrence following a negative SLNB was increased for patients with either a BRAF or NRAS mutant tumour compared to wild-type tumours (aHR 1.92, 95% CI: 1.02-3.60, p = 0.04). CONCLUSION: Melanoma patients with BRAF or NRAS mutant tumours had an increased risk compared to patients with BRAF/NRAS wild-type tumours of developing disease recurrence following a tumour-negative SLNB. The findings also confirm the importance of continued surveillance to monitor for disease recurrence among SLNB-negative patients.

Metastasis represents the end product of an elaborate biological process, which is determined by a complex interplay between metastatic tumour cells, host factors and homoeostatic mechanisms. Cutaneous melanoma can metastasize haematogenously or lymphogenously. The three predominant models that endeavour to explain the patterns of melanoma progression are the stepwise spread model, the simultaneous spread model and the model of differential spread. The time course to the development of metastases differs between the different metastatic routes. There are several clinical and histopathological risk factors for the different metastatic pathways. In particular, patient sex and the anatomical location of the primary tumour influence patterns of disease progression. There is limited existing evidence regarding the relationship between tumour mutation status, other diagnostic and prognostic biomarkers and the metastatic pathways of primary cutaneous melanoma. This knowledge gap needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies.

BACKGROUND: Cutaneous melanoma can metastasise haematogenously and/or lymphogenously to form satellite/in-transit, lymph node or distant metastasis. This study aimed to determine if BRAF and NRAS mutant and wild-type tumours differ in their site of first tumour metastasis and anatomical metastatic pathway. METHODS: Prospective cohort of patients with a histologically confirmed primary cutaneous melanoma at three tertiary referral centres in Melbourne, Australia from 2010 to 2015. Multinomial regression determined clinical, histological and mutational factors associated with the site of first metastasis and metastatic pathway. RESULTS: Of 1048 patients, 306 (29%) developed metastasis over a median 4.7 year follow-up period. 73 (24%), 192 (63%) and 41 (13%) developed distant, regional lymph node and satellite/in-transit metastasis as the first site of metastasis, respectively. BRAF mutation was associated with lymph node metastasis (adjusted RRR 2.46 95% CI 1.07-5.69, P=0.04) and sentinel lymph node positivity (adjusted odds ratio [aOR] OR 1.55, 95% CI 1.14-2.10, P=0.005). BRAF mutation and NRAS mutation were associated with increased odds of developing liver metastasis (aOR 3.09, 95% CI 1.49-6.42, P=0.003; aOR 3.17, 95% CI 1.32-7.58, P=0.01) and central nervous system (CNS) metastasis (aOR 4.65, 95% CI 2.23-9.69, P<0.001; aOR 4.03, 95% CI 1.72-9.44, P=0.001). NRAS mutation was associated with lung metastasis (aOR 2.44, 95% CI 1.21-4.93, P=0.01). CONCLUSIONS: BRAF mutation was found to be associated with lymph node metastasis as first metastasis and sentinel lymph node positivity. BRAF and NRAS mutations were associated with CNS and liver metastasis and NRAS mutation with lung metastasis. If these findings are validated in additional prospective studies, a role for heightened visceral organ surveillance may be warranted in patients with tumours harbouring these somatic mutations.

BACKGROUND/OBJECTIVES: Scalp melanoma has a worse prognosis than melanoma elsewhere, though the reasons for this are poorly understood. Current literature describing the clinicopathological associations of scalp melanoma is sparse. This study aims to compare clinical and histological features of scalp melanoma with other cutaneous head and neck melanomas (CHNM). METHODS: A cross-sectional study was performed of all primary CHNM cases seen by the Victorian Melanoma Service between 1994 and 2014, using prospectively recorded clinical data. Invasive and in situ melanomas were compared separately. RESULTS: Invasive scalp melanoma was associated with male sex (OR, 2.7; 95% CI, 1.9-3.9), increasing age (OR, 1.02 per year increase in age; 95% CI, 1.01-1.03), being first noticed by a person other than self, spouse/relative or doctor (OR, 2.9; 95% CI, 1.5-5.7), amelanosis (OR, 1.6; 95% CI, 1.1-2.3), and increased growth rate (OR, 1.14 per 1 mm/month growth rate increase; 95% CI, 1.04-1.26). Compared with other CHNM, scalp melanoma had greater median Breslow thickness (2.8 vs 1.2 mm) and was independently associated with satellite metastases (OR, 4.7; 95% CI, 1.9-11.5) and nodular subtype (OR, 1.8; 95% CI, 1.1-3.1). In situ scalp melanoma was associated with male sex, increasing age and solar keratoses. CONCLUSION: Scalp melanoma tends to occur in older men, is often rapidly growing and amelanotic, and is associated with high risk histological features. As it is likely to be overlooked, increased recognition of the atypical presentations of scalp melanoma is required.

© 2015 Macmillan Publishers Limited. All rights reserved. Stomatal conductance (g s) is a key land-surface attribute as it links transpiration, the dominant component of global land evapotranspiration, and photosynthesis, the driving force of the global carbon cycle. Despite the pivotal role of g s in predictions of global water and carbon cycle changes, a global-scale database and an associated globally applicable model of g s that allow predictions of stomatal behaviour are lacking. Here, we present a database of globally distributed g s obtained in the field for a wide range of plant functional types (PFTs) and biomes. We find that stomatal behaviour differs among PFTs according to their marginal carbon cost of water use, as predicted by the theory underpinning the optimal stomatal model and the leaf and wood economics spectrum. We also demonstrate a global relationship with climate. These findings provide a robust theoretical framework for understanding and predicting the behaviour of g s across biomes and across PFTs that can be applied to regional, continental and global-scale modelling of ecosystem productivity, energy balance and ecohydrological processes in a future changing climate.

Activating mutations in the GTPase RAC1 are a recurrent event in cutaneous melanoma. We investigated the clinical and pathological associations of RAC1(P29S) in a cohort of 814 primary cutaneous melanomas with known BRAF and NRAS mutation status. The RAC1(P29S) mutation had a prevalence of 3.3% and was associated with increased thickness (OR=1.6 P = 0.001), increased mitotic rate (OR=1.3 P = 0.03), ulceration (OR=2.4 P = 0.04), nodular subtype (OR=3.4 P = 0.004), and nodal disease at diagnosis (OR=3.3 P = 0.006). BRAF mutant tumors were also associated with nodal metastases (OR=1.9 P = 0.004), despite being thinner at diagnosis than BRAF WT (median 1.2 mm versus 1.6 mm, P < 0.001). Immunohistochemical analysis of 51 melanomas revealed that 47% were immunoreactive for RAC1. Melanomas were more likely to show RAC1 immunoreactivity if they were BRAF mutant (OR=5.2 P = 0.01). RAC1 may therefore be important in regulating the early migration of BRAF mutant tumors. RAC1 mutations are infrequent in primary melanomas but may accelerate disease progression.

Brain-computer interface (BCI) technology aims to help individuals with disability to control assistive devices and reanimate paralyzed limbs. Our study investigated the feasibility of an electrocorticography (ECoG)-based BCI system in an individual with tetraplegia caused by C4 level spinal cord injury. ECoG signals were recorded with a high-density 32-electrode grid over the hand and arm area of the left sensorimotor cortex. The participant was able to voluntarily activate his sensorimotor cortex using attempted movements, with distinct cortical activity patterns for different segments of the upper limb. Using only brain activity, the participant achieved robust control of 3D cursor movement. The ECoG grid was explanted 28 days post-implantation with no adverse effect. This study demonstrates that ECoG signals recorded from the sensorimotor cortex can be used for real-time device control in paralyzed individuals.

Familial amyloidotic polyneuropathy (FAP) is a lethal genetic disorder that affects the peripheral and autonomic nervous systems, heart, gastro-intestinal (GI) tract, and soft tissues. Disease progression is increasingly reported following liver transplantation, the only proven treatment for FAP. Small molecule thyroxine mimetics stabilize transthyretin, inhibiting FAP amyloid fibril formation under stringent in vitro conditions. We report on the progress of an international, randomized placebo-controlled study designed to determine the effect of diflunisal, a thyroxine mimetic, on neurologic disease progression in patients with active FAP. Our experience to date indicates diflunisal is well tolerated by this study cohort and that neurologic disease advances more rapidly in FAP than it does in diabetes mellitus. Background: Transthyretin-related familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant genetic disorder that predominantly affects the peripheral nervous system. FAP amyloid fibrils result from the misfolding of transthyretin, a transport protein predominantly produced by the liver. Although liver transplantation effectively treats patients with certain FAP mutations and limited disease, reports increasingly document progressive amyloid deposition following transplantation [1,2]. Alternative treatments are needed. In vitro investigations and a phase I clinical trial have demonstrated that thyroxine and small molecule mimetics, e.g. diflunisal, inhibit tetrameric transthyretin dissociation and suppress amyloid fibril formation [3,4]. Methods: To examine the effect of diflunisal on disease progression in FAP, we designed a randomized, placebo controlled, double blind, multicenter international study employing the validated diabetic (DM) polyneuropathy metric, Neurologic Impairment Score + 7 attributes (NIS+7®), as the primary endpoint. A two-point change in NIS+7 correlates with clinically detectable progression of peripheral neur

This paper demonstrates a synergy-based brain-machine interface that uses low-dimensional command signals to control a high dimensional virtual hand. First, temporal postural synergies were extracted from the angular velocities of finger joints of five healthy subjects when they performed hand movements that were similar to activities of daily living. Two synergies inspired from the extracted synergies, namely, two-finger pinch and whole-hand grasp, were used in real-time brain control, where a virtual hand with 10 degrees of freedom was controlled to grasp or pinch virtual objects. These two synergies were controlled by electrocorticographic (ECoG) signals recorded from two electrodes of an electrode array that spanned motor and speech areas of an individual with intractable epilepsy, thus demonstrating closed loop control of a synergy-based brain-machine interface. © 2006 IEEE.

This paper presents Craniux, an open-access, open-source software framework for brain-machine interface (BMI) research. Developed in LabVIEW, a high-level graphical programming environment, Craniux offers both out-of-the-box functionality and a modular BMI software framework that is easily extendable. Specifically, it allows researchers to take advantage of multiple features inherent to the LabVIEW environment for on-the-fly data visualization, parallel processing, multithreading, and data saving. This paper introduces the basic features and system architecture of Craniux and describes the validation of the system under real-time BMI operation using simulated and real electrocorticographic (ECoG) signals. Our results indicate that Craniux is able to operate consistently in real time, enabling a seamless work flow to achieve brain control of cursor movement. The Craniux software framework is made available to the scientific research community to provide a LabVIEW-based BMI software platform for future BMI research and development. © 2011 Alan D. Degenhart et al.

In the presented work, standard and high-density electrocorticographic (ECoG) electrodes were used to record cortical field potentials in three human subjects during a hand posture task requiring the application of specific levels of force during grasping. We show two-class classification accuracies of up to 80% are obtained when classifying between two-finger pinch and whole-hand grasp hand postures despite differences in applied force levels across trials. Furthermore, we show that a four-class classification accuracy of 50% is achieved when predicting both hand posture and force level during a two-force, two-hand-posture grasping task, with hand posture most reliably predicted during high-force trials. These results suggest that the application of force plays a significant role in ECoG signal modulation observed during motor tasks, emphasizing the potential for electrocorticography to serve as a source of control signals for dexterous neuroprosthetic devices. © 2011 IEEE.

A kinetic and thermodynamic survey of 35 WW domain sequences is used in combination with a model to discern the energetic requirements for the transition from two-state folding to downhill folding. The sequences used exhibit a 600-fold range of folding rates at the temperature of maximum folding rate. Very stable proteins can achieve complete downhill folding when the temperature is lowered sufficiently below the melting temperature, and then at even lower temperatures they become two-state folders again because of cold denaturation. Less stable proteins never achieve a sufficient bias to fold downhill because of the onset of cold denaturation. The model, considering both heat and cold denaturation, reveals that to achieve incipient downhill folding (barrier <3 RT) or downhill folding (no barrier), the WW domain average melting temperatures have to be >50°C for incipient downhill folding and >90°C for downhill folding. © 2008 by The National Academy of Sciences of the USA.