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Reliable evidence to guide the management of melanoma in situ (MIS) and minimize the risk of recurrence is lacking.To identify clinicopathological predictors of local recurrence (LR) in patients with MIS and evaluate long-term outcomes according to pathological excision margins.A case-control study of patients with MIS treated at a large Australian melanoma treatment center from January 2008 to December 2012 was undertaken. Clinicopathological characteristics of patients who developed LR and those who did not were compared.LR developed in 34 of 1407 patients with MIS (2.5%). Median time to LR was 20 months. The primary lesion was removed with pathological margins4 mm (Retrospective, single-institution study.Pathological margins of ≥4 mm should be considered for patients with MIS who are treated with standard surgical excision and assessed by examining serial slices taken from the formalin-fixed, paraffin-embedded specimen.

This study sought to assess whether the interval between diagnostic excision-biopsy of a primary melanoma and definitive wide excision with sentinel node biopsy (SNB) influenced the size of SN metastatic deposits, which might have implications for management and prognosis.Data were collected for (i) a Dutch population-based cohort of patients treated between 2004 and 2014 who underwent SNB within 100 days of complete excision of their primary melanoma and who were SN-positive with known SN metastasis diameter (n = 1027) and (ii) a cohort from a large Australian melanoma treatment centre (n = 541) who presented in the same time period. The effects of SNB timing on the size of SN metastatic deposits were analysed.Dutch patients whose SNB was performed in the second or third months after diagnosis had significantly larger SN metastasis diameters than patients who had their SNB in the first month (median increases of 17% (95%CI -14, 60%, p = 0.211) and 71% (95%CI 15, 119%, p = 0.004), respectively). No significant difference in tumour diameter for early and late SNB was found in the Australian cohort.SN metastasis diameter became progressively greater with SN biopsy in the second and third months after primary melanoma diagnosis in the larger, population-based patient cohort. An increase in metastasis diameter was not observed in the smaller, institutional cohort, possibly due to detection of larger SN metastases by routine pre-operative ultrasound, with fine-needle biopsy confirmation. These patients did not proceed to SNB and were therefore not included in the study.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF

Wide local excision (WLE) to achieve adequate clearance margins is the standard initial definitive treatment for patients with biopsy-proven primary cutaneous melanoma. Residual melanoma in WLE specimens after prior complete excision-biopsy (CEB) is reported in 0-6.3% of cases. However, studies evaluating the prevalence, clinicopathological features and relevance of persistent disease in WLE specimens are limited. This study sought to determine the frequency of and clinicopathological characteristics associated with residual melanoma in WLE specimens performed after a CEB of primary cutaneous or acral melanoma (in situ or invasive) with clinically and histologically tumour-free margins, and assess its relevance. A review of the research database and pathology archives of a large Australian tertiary referral melanoma treatment centre was performed. Eligible patients were those for whom a definitive WLE was performed after CEB of a primary melanoma (in situ or invasive) with negative clinical and histological margins, between May 2013 and May 2015. All partial biopsies were excluded. Of 640 eligible patients, 510 (79.7%) had invasive melanoma and 130 (20.3%) had melanoma in situ. Residual disease was identified in 20 cases (20/640, 3.1%), of which three (15%) were melanoma in situ on CEB and 17 (85%) were invasive melanoma. On univariate analysis, the presence of residual disease in WLE specimens was associated with lentigo maligna (LM)/LM melanoma (LMM) subtype [odds ratio (OR) 10.33; 95% confidence interval (CI) 2.84-37.54; p=0.004], nodular melanoma (NM) subtype (OR 4.92; 95% CI 1.53-15.85; p=0.0076) and, for invasive tumours, higher tumour mitotic rate (mean 7.7, SD 7.51 vs 3.4, SD 4.83; OR 1.11; 95% CI 1.04-1.18; p=0.0014). Breslow thickness >4 mm was associated with a higher risk of residual disease (OR 7.30; 95% CI 1.88, 28.26; p=0.004). Cases with residual disease had primary tumours with a significantly larger diameter (median 14 mm, range 4-25) than those without residual disease (median 9 mm, range 2-60), (OR 1.07; 95% CI 1.03-1.11; p≤0.001) and were also more likely to be amelanotic (38% vs 14%), (OR 3.69; 95% CI 1.17, 11.60; p=0.026). Residual disease was associated with assessment of >3 slides of tissue (OR 6.98; 95% CI 1.54-31.62; p=0.0118) and complete blocking of the scar (OR 31.69; 95% CI 3.98-252.21; p=0.0011). Residual melanoma in WLE specimens is an infrequent occurrence. Risk factors for residual disease are LM/LMM and NM melanoma subtypes, higher mitotic rate, larger lesion diameter and amelanosis. Tumours with these features warrant more extensive pathological sampling. WLE after CEB for melanoma remains an important procedure to reduce local recurrence; however, limited pathological sampling of the WLE scar is probably appropriate for cases lacking high risk features.

Regression in melanoma is an immunological phenomenon that results in partial or complete replacement of the tumor with variably vascular fibrous tissue, often accompanied by pigment-laden macrophages and chronic inflammation. In some cases, tumor-infiltrating lymphocytes (TILs) may represent the earliest phase of this process. The prognostic significance of regression has long been a matter of debate, with inconsistent findings reported in the literature to date. This study sought to determine whether regression in primary cutaneous melanomas predicted sentinel lymph node (SLN) status and survival outcomes in a large cohort of patients managed at a single centre. Clinical and pathological parameters for 8,693 consecutive cases were retrieved. Associations between regression and SLN status, overall survival (OS), melanoma-specific survival (MSS) and recurrence-free survival (RFS) were investigated using logistic and Cox regression. Histological evidence of regression was present in 1958 cases (22.5%). Regression was significantly associated with lower Breslow thickness, lower mitotic rate, and absence of ulceration (p

Introduction It has been reported that the survival of patients having sentinel node (SN) biopsy for melanoma the day after lymphoscintigraphy using Tc99m-nanocolloid is worse than that of patients having lymphoscintigraphy and SN biopsy on the same day [1,2]. A possible explanation suggested is that overnight migration of the tracer from SNs to 2nd-tier nodes occurs, causing failure to remove true SNs. Materials and methods The possibility of overnight tracer migration leading to errors in SN-identification was investigated in 12 patients scheduled for lymphoscintigraphy the day before surgery by repeating SPECT-CT imaging the next morning, before their SN biopsy. The aim was to check whether onward migration of colloid from previously-identified SNs had occurred. Results No significant migration of Tc99m-nanocolloid occurred overnight in any patient. All nodes reported to be SNs on day 1 imaging were also present and regarded as SNs on day 2 images. No new foci were visualised on day 2, but some that had been identified on day 1 were not seen on day 2. Conclusions Since migration of nanocolloid overnight did not occur, this cannot explain the reported survival disadvantage for patients undergoing SN biopsy the day after lymphoscintigraphy. A likely alternative possibility is that inadequate doses of radioisotope were used for next-day procedures, causing the mistaken removal of 2nd-tier nodes instead of true SNs more frequently. Further research is required to explain the reported reduction in survival of patients having next-day SN biopsy procedures, since the possibility has important clinical implications.

Aortic diameter (AD), used traditionally for abdominal aortic aneurysm (AAA) screening may have a role in assessing cardiovascular risk. Unfortunately, AD estimates for those without AAA are underutilised, whilst cardiovascular risk is sub-optimally managed in those with AAA. Our objective was to examine the association between AD measurements and future cardiovascular risk.Retrospective analysis of three databases of male participants screened for aortic aneurysm disease. Imaging and clinical data were obtained from three independent sources: 1) the Multi-centre Aneurysm Screening Study (MASS) trial (n = 26 882 men); 2) the 2013/14 cohort of the English NHS AAA Screening Programme (NAAASP) (n = 237 441 men) linked with NHS hospital admission and death registry data; and 3) the Framingham Heart Study (FHS) offspring cohort (n = 649). Associations between maximal aortic diameter, as measured on ultrasound or computed tomography, and cardiovascular outcomes were examined.Cardiovascular mortality in the MASS trial, was higher in men with AAA at 13 years of follow up, compared to those without (Hazard Ratio [HR] 2.22, 95% CI 1.97-2.50, p.001). Contemporary risk of major adverse cardiovascular events in the NAAASP was highest in those with an AAA (HR 2.91, 95% CI 2.00-4.25), whilst, extremes of aortic diameter were associated with increased risk for cardiovascular events. Aortic diameter was an independent risk factor for cardiovascular events in the FHS dataset.Irrespective of the diagnosis of AAA, men attending for AAA screening who are found to have an abnormal aortic diameter are at high risk of future cardiovascular events. This currently unutilised data from AAA screening programmes has the potential to improve preventative management of cardiovascular risk.

INTRODUCTION Lentigo maligna (LM), a subtype of melanoma in-situ commonly occurring in the head and neck region, often presents a treatment challenge due to anatomical constraints, particularly on the face of mostly elderly patients. This study sought to assess the clinical outcomes of wide local excision of head and neck LM, identify predictors of recurrence and define optimal excision margins. MATERIALS AND METHODS Patients with LM treated between January 1997 and December 2012 were identified from the large institutional database of a tertiary center and their data were analyzed. RESULTS In 379 patients, 382 lesions were eligible for analysis. Median maximal lesion diameter was 10.5 mm. The mean surgical excision and histopathological clearance margins were 6.2 mm and 4.0 mm, respectively. Median follow-up was 32 months. The LM recurrence rate was 9.9%, and subsequent invasive melanoma developed in 2.3% of cases (mean Breslow thickness 0.7 mm). The recurrence rate was 27.2% if the histological margin was

Primary dermal melanoma (PDM) is a subtype of cutaneous melanoma, confined to the dermis, which poses a challenging clinical dilemma. It may represent a true primary melanoma or a dermal cutaneous metastasis. This study aimed to delineate the histopathological characteristics and prognosis of PDM in a large patient cohort to guide appropriate treatment strategies.A search of the Melanoma Research Database at Melanoma Institute Australia was conducted to identify all possible PDM patients at our institution diagnosed from 1978 to 2013. Overall, melanoma-specific and disease-free survival outcomes of the PDM group were compared to those of similar cohorts of Stage I-II and Stage IV M1a melanoma patients based on propensity score matching.Sixty-two PDM patients were identified from the MRD with a median follow-up of 6.3 years. Five-year survival was 87.1% and overall survival was 74.2%. PDMs had a significantly improved overall survival (p = 0.0002) and melanoma-specific survival (p = 0.001) compared to Stage I-II controls, however there was no difference in disease-free survival (p = 0.08). PDMs also demonstrated improved overall survival (p 0.0001), melanoma-specific survival (p 0.0001) and disease-free survival (p 0.0001) compared to Stage IV M1a controls.These findings demonstrate that PDMs have a more favorable prognosis compared to stage I-II cutaneous melanomas and suggest that these are in fact true primary lesions. This study thus provides evidence to justify a treatment approach, by way of a wide local excision and possibly sentinel lymph node biopsy, as for early stage primary cutaneous melanomas.

Background\ud Scaphoid fractures account for 90% of carpal fractures and occur predominantly in young men. The use of immediate surgical fixation to manage this type of fracture has increased, despite insufficient evidence of improved outcomes over non-surgical management. The SWIFFT trial compared the clinical effectiveness of surgical fixation with cast immobilisation and early fixation of fractures that fail to unite in adults with scaphoid waist fractures displaced by 2 mm or less.\ud Methods\ud This pragmatic, parallel-group, multicentre, open-label, two-arm, randomised superiority trial included adults (aged 16 years or older) who presented to orthopaedic departments of 31 hospitals in England and Wales with a clear bicortical fracture of the scaphoid waist on radiographs. An independent remote randomisation service used a computer-generated allocation sequence with randomly varying block sizes to randomly assign participants (1:1) to receive either early surgical fixation (surgery group) or below-elbow cast immobilisation followed by immediate fixation if non-union of the fracture was confirmed (cast immobilisation group). Randomisation was stratified by whether or not there was displacement of either a step or a gap of 1–2 mm inclusive on any radiographic view. The primary outcome was the total patient-rated wrist evaluation (PRWE) score at 52 weeks after randomisation, and it was analysed on an available case intention-to-treat basis. This trial is registered with the ISRCTN registry, ISRCTN67901257, and is no longer recruiting, but long-term follow-up is ongoing.\ud Findings\ud Between July 23, 2013, and July 26, 2016, 439 (42%) of 1047 assessed patients (mean age 33 years; 363 [83%] men) were randomly assigned to the surgery group (n=219) or to the cast immobilisation group (n=220). Of these, 408 (93%) participants were included in the primary analysis (203 participants in the surgery group and 205 participants in the cast immobilisation group). 16 participants in the surgery group and 15 participants in the cast immobilisation group were excluded because of either withdrawal, no response, or no follow-up data at 6, 12, 26, or 52 weeks. There was no significant difference in mean PRWE scores at 52 weeks between the surgery group (adjusted mean 11·9 [95% CI 9·2–14·5]) and the cast immobilisation group (14·0 [11·3 to 16·6]; adjusted mean difference −2·1 [95% CI −5·8 to 1·6], p=0·27). More participants in the surgery group (31 [14%] of 219 participants) had a potentially serious complication from surgery than in the cast immobilisation group (three [1%] of 220 participants), but fewer participants in the surgery group (five [2%]) had cast-related complications than in the cast immobilisation group (40 [18%]). The number of participants who had a medical complication was similar between the two groups (four [2%] in the surgery group and five [2%] in the cast immobilisation group).\ud Interpretation\ud Adult patients with scaphoid waist fractures displaced by 2 mm or less should have initial cast immobilisation, and any suspected non-unions should be confirmed and immediately fixed with surgery. This treatment strategy will help to avoid the risks of surgery and mostly limit the use of surgery to fixing fractures that fail to unite.\ud Funding\ud National Institute for Health Research Health Technology Assessment Programme.

Microscopic satellite metastases are an adverse prognostic feature in primary cutaneous melanoma patients. The prognostic significance of microsatellites, including their number, size and distance from the primary melanoma, using the 8th edition American Joint Committee on Cancer definition, has not previously been evaluated. This study sought to determine the prognostic significance of microsatellites in histopathologically reviewed cases. Eighty-seven cases of primary cutaneous melanoma with the presence of microsatellites documented in the original pathology report and all histopathology slides available were reviewed and the findings were correlated with clinical outcome. Matched control cases were selected for all confirmed microsatellites cases. The presence of microsatellites was confirmed in 69 cases. The microsatellite group had significantly worse prognosis, with 21% 5-year disease-free survival compared with 56% in the control group (p

The prognosis for patients with metastatic melanoma (MM) involving distant organs is grim, and treatment resistance is potentiated by tumor-initiating cells (TICs) that thrive under hypoxia. MM cells, including TICs, express a unique glycome featuring i-linear poly-N-acetyllactosamines through the loss of I-branching enzyme, β1,6 N-acetylglucosaminyltransferase 2. Whether hypoxia instructs MM TIC development by modulating the glycome signature remains unknown. In this study, we explored hypoxia-dependent alterations in MM glycome–associated genes and found that β1,6 N-acetylglucosaminyltransferase 2 was downregulated and a galectin (Gal)-8eligand axis, involving both extracellular and cell-intrinsic Gal-8, was induced. Low β1,6 N-acetylglucosaminyltransferase 2 levels correlated with poor patient outcomes, and patient serum samples were elevated for Gal-8. Depressed β1,6 N-acetylglucosaminyltransferase 2 in MM cells upregulated TIC marker, NGFR/CD271, whereas loss of MM cell–intrinsic Gal-8 markedly lowered NGFR and reduced TIC activity in vivo. Extracellular Gal-8 bound preferentially to i-linear poly-N-acetyllactosamines on N-glycans of the TIC marker and prometastatic molecule CD44, among other receptors, and activated prosurvival factor protein kinase B. This study reveals the importance of hypoxia governing the MM glycome by enforcing i-linear poly-N-acetyllactosamine and Gal-8 expression. This mechanistic investigation also uncovers glycome-dependent regulation of pro-MM factor, NGFR, implicating i-linear poly-N-acetyllactosamine and Gal-8 as biomarkers and therapeutic targets of MM.

The benign melanocytic nevus is the most common tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi consisting of both congenital and acquired types. All nevi had driver mutations in the MAPK signaling pathway, either BRAF V600E or NRAS Q61R/L. No additional definite driver mutations were identified. Somatic mutations in nevi with higher mutation loads showed a predominance of mutational signatures 7a and 7b, consistent with UVR exposure, whereas nevi with lower mutation loads (including all three congenital nevi) had a predominance of the ubiquitous signatures 1 and 5. Two nevi had mutations in promoter regions predicted to bind E26 transformation-specific family transcription factors, as well as subclonal mutations in the TERT promoter. This paper presents whole genome data from melanocytic nevi. We confirm that UVR is involved in the etiology of a subset of nevi. This study also establishes that TERT promoter mutations are present in morphologically benign skin nevi in subclonal populations, which has implications regarding the interpretation of this emerging biomarker in sensitive assays.

Summary Background Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma. Methods NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB–C (American Joint Committee on Cancer [AJCC] 7th edition), BRAFV600-mutant melanoma, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Patients received 150 mg dabrafenib orally, twice daily, plus 2 mg trametinib orally, once daily, for 52 weeks (12 weeks of neoadjuvant therapy before complete resection of the pre-therapy tumour bed, and 40 weeks of adjuvant therapy thereafter). CT and PET scans were done at baseline and before resection. The primary outcomes were the proportion of patients achieving a complete pathological response and the proportion of patients achieving a response according to RECIST at week 12, analysed as per protocol. This trial is registered with ClinicalTrials.gov , NCT01972347 , and follow-up of patients is ongoing. Findings Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21–36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29–63) had a complete response and 14 (40%; 24–58) had a partial response. Five patients (14%; 95% CI 5–30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31–66) patients had a complete pathological response and 18 (51%; 95% CI 34–69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3–4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported. Interpretation Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy. Funding GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.

Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.

Background Isolated limb infusion (ILI) is a minimally invasive treatment for patients with locally advanced extremity melanoma. Most studies combine results of upper-limb ILI (UL-ILI) and lower-limb ILI (LL-ILI), leaving UL-ILIs relatively underreported as LL-ILIs comprise the vast majority in these reports. However, differences between the two procedures may be clinically important. The aim of this study was to evaluate the efficacy and toxicity of UL-ILI in an Australian multi-center setting. Patients and methods 316 ILI procedures for melanoma performed between 1992 and 2008 in five Australian institutions were analyzed. In all institutions melphalan (±actinomycin D) was circulated in the isolated limb for 20–30 min. Results Baseline patient characteristics for UL-ILI (n = 27) and LL-ILI (n = 289) were similar, except that more men underwent UL-ILI (66% vs. 38%; p = 0.007) and disease in LL-ILI was mostly located on the distal limb (p = 0.02). Median tourniquet times were shorter for UL-ILI (38 vs. 48 min; p = 0.04) and UL-ILI patients experienced less limb toxicity (Grade III/IV in 24% vs. 31%; p = 0.01). Complete response (CR) rates were similar: 33% after LL-ILI (p = 0.70), 30% after UL-ILI, while overall response (OR) rates were higher after LL-ILI: (76%) than UL-ILI (59%; p = 0.05). No difference in survival was seen. Conclusions UL-ILI is safe to perform and effective, resulting in low limb toxicity. CR rates were similar to those for LL-ILI, but OR rates were lower for UL-ILI. It may be possible to improve OR rates achieved by UL-ILI by optimizing perioperative factors, while maintaining low toxicity.

The Candelaria-Punta del Cobre district is the largest Iron-Oxide Cu and Au (IOCG) district in the Chilean IOCG belt with more than 13 Mt of contained copper. Candelaria is the most important deposit in the district, which includes seven other smaller producers (Carola, Punta del Cobre, Mantos de Cobre, Candelaria Norte, Granate, Alcaparrosa, Atacama Kozan, Las Pintadas). The district, which is characterized by an Early-Cretaceous volcanic-sedimentary arc sequence (∼135–132 Ma; Punta del Cobre Formation) overlain by the marine-sedimentary Chanarcillo Group, formed in an extensional back-arc basin (∼132–130 Ma). The Copiapo batholith, which occupies the western side of the district, was emplaced between ∼118 and 110 Ma during the change from extensional to transpressional tectonics. Mineralization is hosted predominately in the upper part of the Lower Andesite member and the overlying Volcano-sedimentary and Dacite members all within the Punta del Cobre Formation. Mineralization is hosted by fault zones, breccias, and specific lithologies. North-northwest faults are the dominant host for vertically extensive orebodies. Stratigraphically-controlled mineralization forms extensive stratabound ore bodies (“mantos”). Textural evidence suggest that the hydrothermal system evolved and advanced upwards over time. The earliest event was dominated by magnetite-actinolite in stratigraphically-controlled mantos and extensive zones of disseminated magnetite-actinolite below Candelaria, which were subsequently overprinted by chalcopyrite-dominant mineralization with magnetite-actinolite-biotite-K-feldspar alteration. In addition to magnetite, iron oxides include widespread mushketovite and hematite in the upper part of some deposits. Geochronological data suggest that the main phase of mineralization occurred between ∼122 Ma and ∼115 Ma (U-Pb in zircon), overlapping in age with the two major early phases of the Copiapo batholith. There is no field evidence to indicate that exposed phases of the batholith were the source of mineralizing fluids. Alteration and mineralization in the earliest phase of the batholith (La Brea) occurs in structures and is minor compared to mineralization in the Punta del Cobre Formation. Later phases of the batholith cut the main stage of mineralization. The extent of IOCG mineralization in the Candelaria-Punta del Cobre district reflects a combination of factors including changing regional kinematics and related fault architecture, multiple intrusive events, fluid access to permeable and reactive lithologies, vertical changes in redox conditions, and the potential role of multiple fluids.

Background Coronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes. Objectives This study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention. Methods Using a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank. Results The hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age. Conclusions The genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.

International audience; BACKGROUND: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting. METHODS: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0\textperiodcentered5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445. FINDINGS: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28\textperiodcentered0 months [IQR 23\textperiodcentered3-35\textperiodcentered5] in the MAGE-A3 group and 28\textperiodcentered1 months [23\textperiodcentered7-36\textperiodcentered9] in the placebo group. Median disease-free survival was 11\textperiodcentered0 months (95% CI 10\textperiodcentered0-11\textperiodcentered9) in the MAGE-A3 group and 11\textperiodcentered2 months (8\textperiodcentered6-14\textperiodcentered1) in the placebo group (hazard ratio [HR] 1\textperiodcentered01, 0\textperiodcentered88-1\textperiodcentered17, p=0\textperiodcentered86). In the GS-positive population, median disease-free survival was 9\textperiodcentered9 months (95% CI 5\textperiodcentered7-17\textperiodcentered6) in the MAGE-A3 group and 11\textperiodcentered6 months (5\textperiodcentered6-22\textperiodcentered3) in the placebo group (HR 1\textperiodcentered11, 0\textperiodcentered83-1\textperiodcentered49, p=0\textperiodcentered48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [\textless1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment. INTERPRETATION: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped. FUNDING: GlaxoSmithKline Biologicals SA.

We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironment are associated with response to immunotherapy. No specific mutation correlates with therapy response. A multivariable model combining the TMB and IFNγ-related gene expression robustly predicts response (89% sensitivity, 53% specificity, area under the curve [AUC], 0.84); tumors with high TMB and a high IFNγ signature show the best response to immunotherapy. This model validates in an independent cohort (80% sensitivity, 59% specificity, AUC, 0.79). Except for a JAK3 loss-of-function mutation, for patients who did not respond as predicted there is no obvious biological mechanism that clearly explained their outlier status, consistent with intratumor and intertumor heterogeneity in response to immunotherapy.

Understanding the mechanisms of acquired resistance to anti-PD-1 will allow development of better treatment strategies for cancer patients. This study evaluated potential mechanisms of acquired resistance to anti-PD-1 in longitudinally collected metastatic melanoma patient biopsies. Thirty-four metastatic melanoma biopsies were collected from 16 patients who had initially responded to either anti-PD-1 (n=13) alone or combination of anti-PD-1 and ipilimumab (n=3) and then progressed. Biopsies were taken prior to treatment (PRE, n=12) and following progression of disease (PROG, n=22). Immunohistochemistry was performed on all biopsies to detect CD8, FOXP3, PD-1 and VISTA expression on T-cells and PTEN, β-catenin, PD-L1, HLA-A, and HLA-DPB1 expression in the tumor. The majority of patients showed significantly increased density of VISTA+ lymphocytes from PRE to PROG (12/18) (P=0.009) and increased expression of tumor PD-L1 from PRE to PROG (11/18). Intratumoral expression of FOXP3+ lymphocytes significantly increased (P=0.018) from PRE to PROG (10/18). Loss of tumor PTEN and downregulation of tumor HLA-A from PRE to PROG were each identified in 5/18 and 4/18 PROG biopsies, respectively. Downregulation of HLA-DPB1 from PRE to PROG was present in 3/18 PROG biopsies, whereas nuclear β-catenin activation was only identified in 2/18 PROG biopsies. Negative immune checkpoint regulation by VISTA represents an important potential mechanism of acquired resistance in melanoma patients treated with anti-PD-1. Downregulation of HLA-associated antigen presentation also occurs with acquired resistance. Augmentation of the VISTA immune checkpoint pathway may hold promise as a therapeutic strategy in metastatic melanoma patients, particularly those failing anti-PD-1 therapy, and warrants assessment in clinical trials.

Background Increased use of PET/CT scans in oncology patients has raised detection of Colorectal incidentalomas (CIs). The frequency and diagnostic outcomes of identifying these lesions in melanoma patients have not previously been studied. This studies primary objective was to determine the prevalence of CIs found on PET/CT scans in melanoma patients. The secondary objectives were to correlate the PET/CT findings with the pathology found at colonoscopy, and identify which patients were referred for colonoscopy. Methods A retrospective analysis of patients identified from the prospectively collected research database of Melanoma Institute Australia. 2509 patients with melanoma underwent PET/CT scans between 2001 and 2013. The prevalence of CIs, the correlation of lesions, and the survival of patients who underwent colonoscopy versus patients who did not were analyzed. Results The prevalence of CIs in melanoma patients who had PET/CT scans was 3.2%. Forty-five of the 81 (56%) patients with CIs underwent colonoscopy. Of these, premalignant or malignant disease was found in 58%. Patients with previous metastatic melanoma were significantly less likely to be referred for colonoscopy. Patients undergoing colonoscopy had significantly better survival, as did those without previous distant metastases before the CIs were found, and those without any metastases at the time the CIs were found. These factors were not significant on multivariate analysis. Conclusion The prevalence of incidental colorectal lesions identified on PET/CT scans in melanoma patients was found to be equivalent to that in the general cancer population. Patients undergoing colonoscopy had better survival than those who did not.

The cross section for coherent J/psi photoproduction accompanied by at least one neutron on one side of the interaction point and no neutron activity on the other side, X[n]0[n], is measured with the CMS experiment in ultra-peripheral PbPb collisions at sqrt(s[NN]) = 2.76 TeV. The analysis is based on a data sample corresponding to an integrated luminosity of 159 inverse microbarns, collected during the 2011 PbPb run. The J/psi mesons are reconstructed in the dimuon decay channel, while neutrons are detected using zero degree calorimeters. The measured cross section is dsigma[coh, X[n]0[n]] / dy(J/psi) = 0.36 +/- 0.04 (stat) +/- 0.04 (syst) mb in the rapidity interval 1.8 < abs(y) < 2.3. Using a model for the relative rate of coherent photoproduction processes, this X[z, n, z] measurement gives a total coherent photoproduction cross section of dsigma[coh] / dy(J/psi) = 1.82 +/- 0.22 (stat) +/- 0.20 (syst) +/- 0.19 (theo) mb. The data strongly disfavour the impulse approximation model prediction, indicating that nuclear effects are needed to describe coherent J/psi photoproduction in gamma + Pb interactions. The data are found to be consistent with the leading twist approximation, which includes nuclear gluon shadowing.

Imaging plays a critical role in the current multi-disciplinary management of patients with melanoma. It is used for primary disease staging, surgical planning, and surveillance in high-risk patients, and for monitoring the effects of systemic or loco-regional therapies. Several different imaging modalities have been utilised in the past. Contemporary imaging practises vary geographically depending on clinical guidelines, physician preferences, availability and cost. Targeted therapies and immunotherapies have revolutionised the treatment of patients with metastatic melanoma over the last few years. With this have come new patterns of disease that were not observed after conventional therapies, and new criteria to assess therapeutic responses. In this article we review the role of imaging for patients with melanoma in the era of effective systemic therapies and discuss likely future developments.

Rare earth elements are a critical component in many clean energy technologies. Extraction of individual rare earth elements from natural ores or recycled material is challenging due to the very similar chemical properties across the lanthanide series. Supercritical carbon dioxide has emerged in recent years as a possible extraction medium for rare earth elements, due to its tunability and selectivity as a solvent. In this study, rare earth elements were recovered from bastnasite concentrate using supercritical carbon dioxide extraction with nitric acid/tributyl phosphate adducts. Two bastnasite pretreatment methods were used to render the rare earth elements amenable to recovery: 1) dry roasting of the source material at 730 °C for 3 h, and 2) decomposition with 50% sodium hydroxide solution at 150 °C for 4 h. These pretreated powder samples were extracted in supercritical carbon dioxide at 34 MPa and 65 °C, with kinetic samples obtained at 15–30 min intervals. A range of tributyl phosphate/nitric acid adduct compositions (from 2 mol/L H+ to 6 mol/L H+) were used in order to determine the effect of adduct composition on recovery rate. The results showed the fastest extraction with an adduct containing approximately 4 mol/L H+. Adducts with higher acidity showed reduced extraction of cerium, praseodymium, and neodymium. This could be due to the formation of aqueous droplets which dissolve rare earth elements and create an equilibrium limitation, or due to competition between the rare earth nitrates and nitric acid for coordination with tributyl phosphate. Extraction with various adduct concentrations in supercritical CO2 showed the expected increase in reaction rate with increased adduct concentration. For the 4 mol/L H+ adduct at 5.0 mol% adduct concentration, roasted bastnasite recoveries were 72% for La, 96% for Ce, 88% for Pr, and 90% for Nd after 120 min. For 4 mol/L H+ adduct at 5.1 mol% adduct concentration, NaOH digested bastnasite recoveries were 93% for La, 100% for Ce, 99% for Pr, and 101% for Nd after 90 min. Though further research is needed, these results are a key step in demonstrating applicability of supercritical extraction to rare earth element ores.

Purpose Provide data to support expansion of FDA indications for the Bone anchored hearing system (BAHS). Materials and methods This retrospective study in a tertiary otologic referral center included106 consecutive subjects who were implanted with a Bone Anchored Hearing System (BAHS) between January 2009 and January 2015 for single sided deafness. Subjects were divided into three groups by bone conduction pure tone average (PTA) of the better hearing ear: 0–20 dB (group 1), 21–40 dB (group 2) and 41–55 dB (group 3). All patients underwent BAHS implantation. Speech perception data (Hearing In Noise Test and Consonant-Nucleus-Consonant testing) was collected before and after surgical intervention. Patient-reported quality of life measures were obtained at least 6 months after activation. These included the Abbreviated Profile of Hearing Aid Benefit and Glasgow Benefit Inventory. Results All three groups of subjects demonstrated statistically significant improvement in outcome measures following BAHS. Subject reported quality of life outcome measures demonstrated significant improvement in disability from hearing loss and in quality of life. Conclusions Patients with single sided deafness who have bone conduction thresholds worse than 20 dB in their contralateral ear are still able to benefit significantly from BAHS.

Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.

Thoracic outlet syndrome (TOS) is no longer considered to be a single entity. The syndromes are venous (V-TOS), arterial (A-TOS) and neurological (N-TOS), but may co-exist. The end stage of VTOS (Paget Schroetter syndrome or effort thrombosis of the subclavian vein) should be recognized early so that younger sportsmen and musicians in particular can be offered the opportunity of thrombolysis, decompression surgery and balloon venoplasty. Most uncomplicated cases of A-TOS and N-TOS can be treated conservatively with posture, diet, physiotherapy advice and reassurance. Complicated arterial TOS, with aneurysm or embolization, should be treated expeditiously by cervical rib excision and arterial reconstruction. Double crush syndromes are relatively common in patients with TOS. It is easier to treat carpal tunnel syndrome than N-TOS. Muscle wasting and pain are an indication for surgery in N-TOS.

Summary Whole genome sequencing (WGS) of cancer patients’ tumours offers the most comprehensive method of identifying both novel and known clinically-actionable genomic targets. However, the practicalities of performing WGS on clinical samples are poorly defined. This study was designed to test sample preparation, sequencing specifications and bioinformatic algorithms for their effect on accuracy and cost-efficiency in a large WGS analysis of human melanoma samples. WGS was performed on melanoma cell lines (n = 15) and melanoma fresh frozen tumours (n = 222). The appropriate level of coverage and the optimal mutation detection algorithm for the project pipeline were determined. An incremental increase in sequencing coverage from 36X to 132X in melanoma tissue samples and 30X to 103X for cell lines only resulted in a small increase (1–2%) in the number of mutations detected, and the quality scores of the additional mutations indicated a low probability that the mutations were real. The results suggest that 60X coverage for melanoma tissue and 40X for melanoma cell lines empower the detection of 98–99% of informative single nucleotide variants (SNVs), a sensitivity level at which clinical decision making or landscape research projects can be carried out with a high degree of confidence in the results. Likewise the bioinformatic mutation analysis methodology strongly influenced the number and quality of SNVs detected. Detecting mutations in the blood genomes separate to the tumour genomes generated 41% more SNVs than if the blood and melanoma tissue genomes were analysed simultaneously. Therefore, simultaneous analysis should be employed on matched melanoma tissue and blood genomes to reduce errors in mutation detection. This study provided valuable insights into the accuracy of SNV with WGS at various coverage levels in human clinical cancer specimens. Additionally, we investigated the accuracy of the publicly available mutation detection algorithms to detect cancer specific SNVs which will aid researchers and clinicians in study design and implementation of WGS for the identification of somatic mutations in other cancers.

In situ leaching offers a potentially attractive way to extract copper from the subsurface without costly fragmentation and processing. Applicability of in situ leaching is limited to deposits where sufficient permeability exists and where the copper and gangue mineralogy is amenable to leaching. A key challenge from past projects is establishing uniform contact between the fluid and the formation in fractured environments, particularly if fractures become blocked by gypsum and jarosite precipitation during leaching. Previous projects have demonstrated that in situ leaching of copper sulfides is feasible by regenerating ferric iron using atmospheric bacteria cultures, pressurized oxygen gas, or chemical oxidants. Oilfield technologies, including polymer injection for permeability modification and nanoparticle tracers, may have future applications for diagnosing and mitigating short circuiting between wells. Geophysical techniques such as electrical resistance tomography have the potential to provide real-time data on lixiviant movement in the subsurface, thus aiding in both recovery optimization and environmental control. In this review, data from past copper in situ leaching projects are assembled, with a focus on recovery without prior permeability enhancement. The resulting database includes key operating variables from copper in situ leaching projects ranging from field scale pilots to commercial operations.

The overall 5-year survival for melanoma is 91%. However, if distant metastasis occurs (stage IV), cure rates are, Highlights • A seven-miRNA panel (MELmiR-7) detected the presence of melanoma with high sensitivity (93%) and specificity (≥ 82%). • In serially collected stage IV specimens, members of the ‘MELmiR-7’ panel confirmed tumour progression in 100% of cases. • The ‘MELmiR-7’ panel is superior to currently used serological markers for melanoma progression, recurrence, and survival.

Prior studies have shown that combinations of histone deacetylase (HDAC) and BRAF inhibitors (BRAFi) have synergistic effects on BRAFi-resistant melanoma through enhanced apoptosis and inhibition of the cAMP-dependent drug resistance pathway. However, little is known about the expression of various HDACs and their associations with BRAF/NRAS mutation status, clinicopathologic characteristics, and patient outcome. The present study extensively profiled HDAC class 1 and their targets/regulators utilizing immunohistochemistry in human melanoma samples from patients with stage IV melanoma, known BRAF/NRAS mutational status, and detailed clinicopatholgical data. HDAC8 was increased in BRAF-mutated melanoma (P=0.016), however, no association between expression of other HDACs and NRAS/BRAF status was identified. There was also a correlation between HDAC1, HDAC8 expression, and phosphorylated NFκb p65 immunoreactivity (P