Non-melanoma skin cancer (NMSC) is the most common malignancy in fair-skinned populations. In Australia, NMSC is four times as common as all other cancers combined with an incidence of ~1000 per 100 000 person-years. The vast majority of NMSC are basal cell carcinomas (BCCs), which rarely metastasize, or squamous cell carcinomas (SCCs), which do have metastatic potential, especially in immune-suppressed individuals. Because of their high frequency in the general population, and particularly in older people, NMSCs are likely to occur in many general oncology patients. Skin cancer risk can be additionally increased in oncology patients as a result of disease-induced immune suppression (e.g., non-Hodgkin’s lymphoma) or by a range of cancer treatments including iatrogenic immune suppression, radiation therapy, arsenic, and BRAF inhibitors. Interestingly, chronic stress suppresses skin immune responses and increases susceptibility to UV-induced SCC in murine models.

Although rare, primary cutaneous ES/PNET should be considered in the differential diagnosis of cutaneous "small blue cell tumours". Immunostaining for FLI-1 and molecular testing for evidence of an EWS rearrangement are useful ancillary investigations to confirm the diagnosis. The prognosis of primary cutaneous ES/PNET appears to be more favourable than extracutaneous ES/PNET.

In Brief Objective: To improve selection for sentinel node (SN) biopsy (SNB) in patients with cutaneous melanoma using statistical models predicting SN status. Summary Background Data: About 80% of patients currently undergoing SNB are node negative. In the absence of conclusive evidence of a SNB-associated survival benefit, these patients may be over-treated. Here, we tested the efficiency of 4 different models in predicting SN status. Methods: The clinicopathologic data (age, gender, tumor thickness, Clark level, regression, ulceration, histologic subtype, and mitotic index) of 1132 melanoma patients who had undergone SNB at institutions in Italy and Australia were analyzed. Logistic regression, classification tree, random forest, and support vector machine models were fitted to the data. The predictive models were built with the aim of maximizing the negative predictive value (NPV) and reducing the rate of SNB procedures though minimizing the error rate. Results: After cross-validation logistic regression, classification tree, random forest, and support vector machine predictive models obtained clinically relevant NPV (93.6%, 94.0%, 97.1%, and 93.0%, respectively), SNB reduction (27.5%, 29.8%, 18.2%, and 30.1%, respectively), and error rates (1.8%, 1.8%, 0.5%, and 2.1%, respectively). Discussion: Using commonly available clinicopathologic variables, predictive models can preoperatively identify a proportion of patients (∼25%) who might be spared SNB, with an acceptable (1%–2%) error. If validated in large prospective series, these models might be implemented in the clinical setting for improved patient selection, which ultimately would lead to better quality of life for patients and optimization of resource allocation for the health care system. Most of melanoma patients who undergo sentinel node biopsy are node negative. Four different statistical models, constructed and validated on 2 large retrospective patients series, identified patients who may safely be treated without sentinel node biopsy.

Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNFα cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T-cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as a target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pretreatment expression as a biomarker to stratify melanoma patients. <i>Cancer Res; 77(17); 4697-709. ©2017 AACR</i>.

The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We then employed a machine learning approach to stratify tumours according to telomere repeat content with an accuracy of 91.6%. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. Overall, our approach demonstrates that telomere sequence content can be used to stratify ALT activity in cancers, and begin to define the molecular pathways involved in ALT activation.

The introduction of immunotherapy based on the blockade of the PD1/PD-L1 checkpoints has been associated with high response rates and durable remissions of disease in patients with metastatic melanoma, to the extent that it is now considered the standard of care for a wide range of patients, irrespective of their <i>BRAF</i> or <i>NRAS</i> mutation status. In addition, more frequent follow-up of patients who are at high risk of recurrence after surgical treatment appears to be justified, as does neoadjuvant treatments in order to render patients treatable by surgery. The limitations of this treatment include failure of some patients to respond, a low rate of complete responses and relapses of the disease during treatment. New initiatives in order to overcome these limitations include the identification of biomarkers for the selection responders and evaluations of treatment combinations that will increase responses and their durability. The latter includes combinations with antibodies against other checkpoints on T cells and cotreatments with inhibitors of resistance pathways in melanoma.

Melanin in pigmented lesions can be bleached effectively with an H202 procedure without significantly affecting AgNOR staining properties in contrast to bleaching with KMnO4.

<b>Purpose:</b> In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria may be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis.<b>Experimental Design:</b> Targeted next-generation sequencing, array-based genome-wide methylation analysis, and BAP1 IHC were performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, including 47 primary tumors of the central nervous system, 16 uveal melanomas, 13 cutaneous melanoma metastases, and 2 blue nevus-like melanomas. Gene mutation, DNA-methylation, and copy-number profiles were correlated with clinicopathologic features.<b>Results:</b> Combining mutation, copy-number, and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas, and blue nevus-like melanoma showed common DNA-methylation, copy-number alteration, and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group.<b>Conclusions:</b> Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma, and blue nevus-like melanoma share molecular similarity with chromosome 3 and <i>BAP1</i> alterations, markers of poor prognosis. <i>Clin Cancer Res; 24(18); 4494-504. ©2018 AACR</i>.

MTH1 helps prevent misincorporation of ROS-damaged dNTPs into genomic DNA; however, there is little understanding of how MTH1 itself is regulated. Here, we report that MTH1 is regulated by polyubiquitination mediated by the E3 ligase Skp2. In melanoma cells, MTH1 was upregulated commonly mainly due to its improved stability caused by K63-linked polyubiquitination. Although Skp2 along with other components of the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex was physically associated with MTH1, blocking the SCF function ablated MTH1 ubiquitination and expression. Conversely, overexpressing Skp2-elevated levels of MTH1 associated with an increase in its K63-linked ubiquitination. In melanoma cell lines and patient specimens, we observed a positive correlation of Skp2 and MTH1 expression. Mechanistic investigations showed that Skp2 limited DNA damage and apoptosis triggered by oxidative stress and that MAPK upregulated Skp2 and MTH1 to render cells more resistant to such stress. Collectively, our findings identify Skp2-mediated K63-linked polyubiquitination as a critical regulatory mechanism responsible for MTH1 upregulation in melanoma, with potential implications to target the MAPK/Skp2/MTH1 pathway to improve its treatment. <i>Cancer Res; 77(22); 6226-39. ©2017 AACR</i>.

Purpose Standard cancer staging and prognostic estimates are determined at the time of the patient's initial disease presentation. Conditional survival is an alternative, dynamic assessment from follow-up time points after the initial disease diagnosis and is based on the condition of survivorship. Estimates of conditional survival can provide critical prognostic information for patients and clinicians, guide subsequent cancer follow-up schedules, and influence decisions regarding treatments. The current study presents conditional survival estimates developed from a cohort of 4,540 patients diagnosed with stage III melanoma treated at a single institution. Methods Patients with stage III disease at first melanoma diagnosis (initial; n = 2,042), or who developed locoregional metastasis as a first recurrence some time after primary diagnosis (recurrent; n = 2,498), were assessed. Conditional melanoma-specific survival (MSS) estimates up to 5 years after diagnosis were adjusted for age, sex, and 8th edition American Joint Committee on Cancer (AJCC) stage. Results Older age at diagnosis of stage III disease conveyed a worse prognosis at each conditional survival time point. Males had significantly worse MSS outcomes for up to 2 years of conditional survival, after which males and females had similar MSS. For patients with AJCC stage IIIB and stage IIIC disease, MSS outcomes were similar to those of patients with stage IIIA disease after 3 and 5 years of survivorship, respectively. Conclusion Adjuvant systemic treatments may have the greatest benefit when administered within the first 2 years of stage III melanoma diagnosis, during which period prognosis is significantly worse for male patients of increasing age and AJCC substage. Conditional survival estimates illustrate improved survival prospects for patients with cancer returning for follow-up and may define a finite period of increased risk after diagnosis.