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Genetic analysis of melanomas from 37 patients sampled in 150 different areas showed that BRAF mutations were present from the first stages of tumor development, and progressively more malignant lesions showed acquisition of abnormalities in a predictable sequence. Cancer arises through the accumulation of genetic alterations that lead to unrestrained cell proliferation. Large-scale sequencing projects that catalogue mutations in melanoma have been carried out mostly on advanced tumors, so it is difficult to infer the order of mutations. Melanomas often arise from distinctive precursor lesions such as melanocytic nevi, intermediate lesions, or melanoma in situ, which makes the analysis of their progression possible. The succession of genetic alterations that leads to melanoma is incompletely understood. Somatic mutations in dominant melanoma oncogenes such as BRAF , NRAS , GNAQ , or GNA11 and rearrangements resulting in fusion kinases are . . .

The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2 , Trp53 , and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression. The process by which actinic keratosis differentiates to malignant invasive cutaneous squamous cell carcinoma is unclear. Here, the authors use RNA-seq to illustrate a disease continuum between the two states, and use in vivo models to confirm the role of Tgfbr2, Trp53, and Notch1 in this process.

Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential and development of metastases carries a poor prognosis. To address the need for reliable risk stratification, we developed cSCCNet, a deep learning model using digital pathology of primary cSCC to predict metastatic risk. A retrospective cohort of 227 primary cSCC from four centres is used for model development. cSCCNet automatically selects the tumour area in standard histopathological slides and then stratifies primary cSCC into high- vs. low-risk categories, with heatmaps indicating most predictive tiles contributing to explainability. On a 20% hold-out testing cohort, cSCCNet achieves an area under the curve (AUC) of 0.95 and 95% accuracy in predicting risk of metastasis, outperforming gene expression-based tools and clinicopathologic classifications. Multivariate analysis including common clinicopathologic classifications confirms cSCCNet as an independent predictor for metastasis, implying it identifies predictive features beyond known clinicopathologic risk factors. Histopathological analysis including multiplex immunohistochemistry suggests that tumour differentiation, acantholysis, desmoplasia, and the spatial localisation of lymphocytes relative to tumour tissue may be important in predicting risk of developing metastasis. Although further validation including prospective evaluation is required, cSCCNet has potential as a reliable and accurate tool for metastatic risk prediction that could be easily integrated into existing histopathology workflows.

Cryptococcus neoformans is an encapsulated yeast which causes opportunistic infection in the context of immunosuppression, including advanced HIV infection. Cryptococcal infection is systemic and can result in a fatal meningoencephalitis. Cutaneous lesions occur in 15% of those with systemic cryptococcosis and may be the first indicator of infection. Identification of these lesions may therefore expedite diagnosis and access to treatment. Cutaneous lesions typically present as papulonodular molluscum-like lesions; however, may vary significantly in appearance. We describe a rare case of extraneuronal cryptococcal infection manifesting as large subcutaneous tumours in a patient with advanced HIV-related immune deficiency.

We present the rare case of a 61-year-old man with Crohn’s disease who developed a cutaneous Kaposi’s sarcoma in the setting of long-term treatment with 6-mercaptopurine. Deciding on the best course of management provided a clinical challenge in an ‘evidence-light’ area. Relevant case reports and guidelines were reviewed. In general, the withdrawal of immunosuppressive therapy is advised; however, a multidisciplinary, case-by-case approach is also emphasised. The patient’s lesion was removed and, following collaborative discussion, immunosuppression was continued post resection. This is thought to be the first reported case involving a Kaposi’s sarcoma in inflammatory bowel disease where immune therapy was not subsequently discontinued.

The mass of well-preserved calcite in planktonic foraminifera shells provides an indication of the calcification potential of the surface ocean. Here we report the shell weight of 8 different abundant planktonic foraminifera species from a set of core-top sediments along the Mid-Atlantic Ridge. The analyses showed that near the equator, foraminifera shells of equivalent size weigh on average 1/3 less than those from the middle latitudes. The carbonate preservation state of the samples was assessed by high resolution X-ray microcomputed tomographic analyses of Globigerinoides ruber and Globorotalia truncatulinoides specimens. The specimen preservation was deemed good and does not overall explain the observed shell mass variations. However, G. ruber shell weights might be to some extent compromised by residual fine debris internal contamination. Deep dwelling species possess heavier tests than their surface-dwelling counterparts, suggesting that the weight of the foraminifera shells changes as a function of the depth habitat. Ambient seawater carbonate chemistry of declining carbonate ion concentration with depth cannot account for this interspecies difference. The results suggest a depth regulating function for plankton calcification, which is not dictated by water column acidity.