BRAF wild-type melanoma in situ arising in a BRAF V600E mutant dysplastic nevus

IMPORTANCE The BRAF V600E mutation accounts for the majority of BRAF mutations found in cutaneous melanoma and is also commonly found in nevi. We used dermoscopy-targeted sampling and a microbiopsy device coupled with DNA sequence analysis to highlight BRAF V600E heterogeneity within a multicomponent melanocytic proliferation. This sampling technique demonstrates the prospect of in vivo application in a clinical setting

Pregnancy as driver for melanoma

Whether or not pregnancy favours the occurrence and growth of melanoma is a source of controversy in the literature. Several case reports have shown dramatic courses of diseases in pregnancy. We present a case of a 36-year-old woman with multiple naevi with one melanoma detected in 2009 in the first trimester and a second primary melanoma in 2010 in the third trimester of her pregnancy. Both lesions have been present for at least 5 years and have been interpreted as dysplastic naevi. Because of their growth during pregnancy they were removed. No metastatic disease has been found between 2010 and early 2016. This case shows the difficulty of detecting melanomas in pregnancy, particularly when they mimic dysplastic naevi in women with multiple naevi, who are at higher risk. Therefore, we suggest that pregnant women with numerous naevi should be precautious of any changes of their naevi in size, shape and colour. Every suspicious lesion should be either excised or documented/monitored carefully, e.g. with sequential digital dermoscopy imaging

Multiparameter analysis of naevi and primary melanomas identifies a subset of naevi with elevated markers of transformation

Here we have carried out a multiparameter analysis using a panel of 28 immunohistochemical markers to identify markers of transformation from benign and dysplastic naevus to primary melanoma in three separate cohorts totalling 279 lesions. We have identified a set of eight markers that distinguish naevi from melanoma. None of markers or parameters assessed differentiated benign from dysplastic naevi. Indeed, the naevi clustered tightly in terms of their immunostaining patterns whereas primary melanomas showed more diverse staining patterns. A small subset of histopathologically benign lesions had elevated levels of multiple markers associated with melanoma, suggesting that these represent naevi with an increased potential for transformation to melanoma

Genomics: Think Global, Act Local

Long a slogan for environmentalists, “think global, act local” could be a new rallying cry for biologists. As genome-wide techniques advance and their costs drop, scientists are expanding into larger and larger territories—metagenomics, global proteomic approaches, and analyses of thousands of genomes. These massive data sets are opening up new possibilities for understanding some of the smallest details of the genome. Here, we look at four such cases—investigating the evolutionary role of insertions and deletions in the genome, connecting an orphan enzyme with its gene, mapping the fine details of chromatin structure, and characterizing global interactions between proteins and RNA—all of which depend on a combination of global thinking and local action

Whole-exome sequencing of acquired nevi identifies mechanisms for development and maintenance of benign neoplasms

The melanoma transformation rate of each nevus is rare despite the detection of oncogenic BRAF or NRAS mutations in 100% of nevi. Acquired melanocytic nevi (AMN) do however mimic melanoma and ∼30% of all melanomas arise within pre-existing nevi. Using whole-exome sequencing of 30 matched nevi, adjacent normal skin, and saliva we sought to identify the underlying genetic mechanisms for nevus development. All nevi were clinically, dermoscopically, and histopathologically documented. In addition to identifying somatic mutations, we found mutational signatures relating to ultra-violet radiation (UVR) mirroring those found in cutaneous melanoma. In nevi we frequently observed the presence of the UVR mutation signature compared to adjacent normal skin (97% vs 10% respectively). In copy number aberration (CNA) analysis, in nevi with copy number loss of tumor suppressor genes (TSG), these were balanced by loss of potent oncogenes. Moreover, reticular and non-specific patterned nevi revealed an increased (

Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model

We aimed to create a prognostic model in metastatic melanoma based on independent prognostic factors in 321 patients receiving interleukin-2 (IL-2)-based immunotherapy with a median follow-up time for patients currently alive of 52 months (range 15–189 months). The patients were treated as part of several phase II protocols and the majority received treatment with intermediate dose subcutaneous IL-2 and interferon-α. Neutrophil and monocyte counts, lactate dehydrogenase (LDH), number of metastatic sites, location of metastases and performance status were all statistically significant prognostic factors in univariate analyses. Subsequently, a multivariate Cox's regression analysis identified elevated LDH (P<0.001, hazard ratio 2.8), elevated neutrophil counts (P=0.02, hazard ratio 1.4) and a performance status of 2 (P=0.008, hazard ratio 1.6) as independent prognostic factors for poor survival. An elevated monocyte count could replace an elevated neutrophil count. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the three independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 12.6 months (95% confidence interval (CI), 11.4–13.8), 6.0 months (95% CI, 4.8–7.2) and 3.4 months (95% CI, 1.2–5.6), respectively. The low-risk group encompassed the majority of long-term survivors, whereas the patients in the high-risk group with a very poor prognosis should probably not be offered IL-2-based immunotherapy

THz QCL self-mixing interferometry for biomedical applications

In this paper, we introduce the self-mixing phenomenon in terahertz quantum cascade lasers (THz QCLs) and present recent advancements in the development of coherent THz imaging and sensing systems that exploit the self-mixing effect. We describe an imaging method which utilises the interferometric nature of optical feedback in a THz QCL to employ it as a homodyning transceiver. This results in a highly sensitive and compact scheme. Due to the inherently low penetration depth of THz radiation in hydrated biological tissue, imaging of superficial skin is an ideal application for this technique. We present results for imaging of excised skin tissue, showing high-contrast between different tissue types and pathologies

Human melanoma brain metastases cell line MUG-Mel1, isolated clones and their detailed characterization

Melanoma is a leading cause of high mortality that frequently spreads to the brain and is associated with deterioration in quality and quantity of life. Treatment opportunities have been restricted until now and new therapy options are urgently required. Our focus was to reveal the potential heterogeneity of melanoma brain metastasis. We succeeded to establish a brain melanoma metastasis cell line, namely MUG-Mel1 and two resulting clones D5 and C8 by morphological variety, differences in lipidome, growth behavior, surface, and stem cell markers. Mutation analysis by next-generation sequencing, copy number profiling, and cytogenetics demonstrated the different genetic profile of MUG-Mel1 and clones. Tumorigenicity was unsuccessfully tested in various mouse systems and finally established in a zebra fish model. As innovative treatment option, with high potential to pass the blood-brain barrier a peptide isolated from lactoferricin was studied in potential toxicity. Brain metastases are a major clinical challenge, therefore the development of relevant in vitro and in vivo models derived from brain melanoma metastases provides valuable information about tumor biology and offers great potential to screen for new innovative therapies.Animal science

An ex vivo human tumour assay reveals distinct patterns of EGFR trafficking in squamous cell carcinoma correlating to therapeutic outcomes

EGFR overexpression is associated with squamous cell carcinoma development. Altered endocytosis and polarization of receptor tyrosine kinases, including EGFR, affect migration and invasion in 3D culture. These studies have been completed via genetic sequencing, cell line or 3D in vitro and in vivo murine models. Here we describe an imaging method that allows ex-vivo examination of ligand-induced endocytosis of EGFR in non-dissociated human tumours. We analyzed sets of tumour samples from advanced cutaneous squamous cell carcinoma and Head and Neck squamous cell carcinoma, actinic keratosis, intra-epidermal carcinoma and cutaneous squamous cell carcinoma. We demonstrate that EGFR endocytosis is dysregulated in advanced SCC and correlates with anti-EGFR monoclonal antibody therapy outcomes. In actinic keratosis, intra-epidermal carcinoma and well-differentiated cutaneous squamous cell carcinoma different patterns of epidermal growth factor ligand uptake and binding were observed at the leading edge of different dysplastic lesions, suggesting that these differences in EGFR endocytosis might influence the metastatic potential of dysplastic squamous epithelium. These studies in live ex-vivo human tumours confirm that endocytosis dysregulation is a physiological event in human tumours and has therapeutic implications