Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.

The Prediction of Survival after Surgical Management of Bone Metastases of the Extremities-A Comparison of Prognostic Models.

Individualized survival prognostic models for symptomatic patients with appendicular metastatic bone disease are key to guiding clinical decision-making for the orthopedic surgeon. Several prognostic models have been developed in recent years; however, most orthopedic surgeons have not incorporated these models into routine practice. This is possibly due to uncertainty concerning their accuracy and the lack of comparison publications and recommendations. Our aim was to conduct a review and quality assessment of these models. A computerized literature search in MEDLINE, EMBASE and PubMed up to February 2022 was done, using keywords: "Bone metastasis", "survival", "extremity" and "prognosis". We evaluated each model's performance, assessing the estimated discriminative power and calibration accuracy for the analyzed patients. We included 11 studies out of the 1779 citations initially retrieved. The 11 studies included seven different models for estimating survival. Among externally validated survival prediction scores, PATHFx 3.0, 2013-SPRING and potentially Optimodel were found to be the best models in terms of performance. Currently, it is still a challenge to recommend any of the models as the standard for predicting survival for these patients. However, some models show better performance status and other quality characteristics. We recommend future, large, multicenter, prospective studies to compare between PATHfx 3.0, SPRING 2013 and OptiModel using the same external validation dataset.