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BackgroundUnlike other soft tissue sarcomas, atypical lipomatous tumors (ALTs) are thought to have a low propensity for metastasis. Despite this, a standard of care for pulmonary metastasis (PM) surveillance has not been established. This study aimed to evaluate the utility of chest imaging for PM surveillance following ALT excision.MethodsThis was a multi-institution, retrospective review of all patients with primary ALTs of the extremities or superficial torso who underwent excision between 2006 and 2018. Minimum follow-up was two years. Long-term survival was evaluated using the Kaplan-Meier method.Results190 patients with ALT were included. Average age was 61.7 years and average follow-up was 58.6 months (24 to 180 months). MDM2 testing was positive in 88 patients (46.3%), and 102 (53.7%) did not receive MDM2 testing. 188 patients (98.9%) had marginal excision, and 127 (66.8%) had marginal or positive margins. Patients received an average of 0.9 CT scans and 1.3 chest radiographs over the surveillance period. 10-year metastasis-free survival was 100%, with no documented deaths from disease.ConclusionsThis study suggests that chest imaging does not have a significant role in PM surveillance following ALT excision, but advanced local imaging and chest surveillance may be considered in cases of local recurrence or concern for dedifferentiation.

Despite a considerable expenditure of time and resources and significant advances in experimental models of disease, cancer research continues to suffer from extremely low success rates in translating preclinical discoveries into clinical practice. The continued failure of cancer drug development, particularly late in the course of human testing, not only impacts patient outcomes, but also drives up the cost for those therapies that do succeed. It is clear that a paradigm shift is necessary if improvements in this process are to occur. One promising direction for increasing translational success is comparative oncology-the study of cancer across species, often involving veterinary patients that develop naturally-occurring cancers. Comparative oncology leverages the power of cross-species analyses to understand the fundamental drivers of cancer protective mechanisms, as well as factors contributing to cancer initiation and progression. Clinical trials in veterinary patients with cancer provide an opportunity to evaluate novel therapeutics in a setting that recapitulates many of the key features of human cancers, including genomic aberrations that underly tumor development, response and resistance to treatment, and the presence of comorbidities that can affect outcomes. With a concerted effort from basic scientists, human physicians and veterinarians, comparative oncology has the potential to enhance the cost-effectiveness and efficiency of pipelines for cancer drug discovery and other cancer treatments.

Osteosarcoma, a malignant primary bone tumor most commonly diagnosed in children and adolescents, has a poorly understood genetic etiology. Genome-wide association studies (GWAS) and candidate-gene analyses have identified putative risk variants in subjects of European ancestry. However, despite higher incidence among African-American and Hispanic children, little is known regarding common heritable variation that contributes to osteosarcoma incidence and clinical presentation across racial/ethnic groups. In a multi-ethnic sample of non-Hispanic white, Hispanic, African-American and Asian/Pacific Islander children (537 cases, 2165 controls), we performed association analyses assessing previously-reported loci for osteosarcoma risk and metastasis, including meta-analysis across racial/ethnic groups. We also assessed a previously described association between genetic predisposition to longer leukocyte telomere length (LTL) and osteosarcoma risk in this independent multi-ethnic dataset. In our sample, we were unable to replicate previously-reported loci for osteosarcoma risk or metastasis detected in GWAS of European-ancestry individuals in either ethnicity-stratified analyses or meta-analysis across ethnic groups. Our analyses did confirm that genetic predisposition to longer LTL is a risk factor for osteosarcoma (ORmeta: 1.22; 95% CI: 1.09-1.36; P = 3.8 × 10-4), and the strongest effect was seen in Hispanic subjects (OR: 1.32; 95% CI: 1.12-1.54, P = 6.2 × 10-4). Our findings shed light on the replicability of osteosarcoma risk loci across ethnicities and motivate further characterization of these genetic factors in diverse clinical cohorts.

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus. In the absence of Atrx, irradiated sarcomas had increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. Our work also showed that Atrx deletion resulted in downregulation of the CGAS/STING signaling pathway at multiple points in the pathway and was not driven by mutations or transcriptional downregulation of the CGAS/STING pathway components. We found that both human and mouse models of Atrx-deleted sarcoma had a reduced adaptive immune response, markedly impaired CGAS/STING signaling, and increased sensitivity to TVEC, an oncolytic herpesvirus that is currently FDA approved for the treatment of aggressive melanomas. Translation of these results to patients with ATRX-mutant cancers could enable genomically guided cancer therapy approaches to improve patient outcomes., Introduction ATRX, or [alpha]-thalassemia/mental retardation, X-linked, is a chromatin remodeling protein and tumor suppressor, with mutations or copy number alterations occurring in approximately 6% of the more than 65,163 tumors [...]

Malignant phyllodes tumours (PTs) are aggressive neoplasms with high rates of local recurrence and distant metastasis. With no known effective chemotherapy and no approved targeted therapy in the setting of metastatic disease, prognosis is limited with an often-relapsing course of disease. We report a case of a woman in her late 30s with a diagnosis of recurrent metastatic malignant PT who was found to have acrometastases of the malignant PT to the right distal index and small digits. We emphasise the potential for atypical patterns of metastases in patients with malignant PT and the need to recognise acrometastasis as an unusual but morbid manifestation of disease. Given the high growth rate of malignant PTs, the lack of systemic treatment options, and the ensuing distress for patients, prompt diagnosis and early intervention is crucial. [ABSTRACT FROM AUTHOR]

BackgroundAlthough increased height has been associated with osteosarcoma risk in previous epidemiologic studies, to the authors' knowledge the relative contribution of stature during different developmental timepoints remains unclear. Furthermore, the question of how genetic determinants of height impact osteosarcoma etiology remains unexplored. Genetic variants associated with stature in previous genome-wide association studies may be biomarkers of osteosarcoma risk.MethodsThe authors tested the associations between osteosarcoma risk and polygenic scores for adult height (416 variants), childhood height (6 variants), and birth length (5 variants) in 864 osteosarcoma cases and 1879 controls of European ancestry.ResultsEach standard deviation increase in the polygenic score for adult height, corresponding to a 1.7-cm increase in stature, was found to be associated with a 1.10-fold increase in the risk of osteosarcoma (95% confidence interval [95% CI], 1.01-1.19; P =.027). Each standard deviation increase in the polygenic score for childhood height, corresponding to a 0.5-cm increase in stature, was associated with a 1.10-fold increase in the risk of osteosarcoma (95% CI, 1.01-1.20; P =.023). The polygenic score for birth length was not found to be associated with osteosarcoma risk (P =.11). When adult and childhood height scores were modeled together, they were found to be independently associated with osteosarcoma risk (P =.037 and P = .043, respectively). An expression quantitative trait locus for cartilage intermediate layer protein 2 (CILP2), rs8103992, was significantly associated with osteosarcoma risk after adjustment for multiple comparisons (odds ratio, 1.35; 95% CI, 1.16-1.56 [P = 7.93×10-5 and Padjusted =.034]).ConclusionsA genetic propensity for taller adult and childhood height attainments contributed independently to osteosarcoma risk in the current study data. These results suggest that the biological pathways affecting normal bone growth may be involved in osteosarcoma etiology.

Purpose. Recently, the association between ATRX and a more aggressive sarcoma phenotype has been shown. We performed a retrospective study of sarcomas from an individual institution to evaluate ATRX as a prognosticator in soft tissue sarcoma. Experimental Design. 128 sarcomas were collected from a single institution and stained for ATRX. The prognostic significance of these markers was evaluated in a smaller cohort of primary soft tissue sarcomas (n = 68). Kaplan–Meier curves were created for univariate analysis, and Cox regression was utilized for multivariate analysis. Results. High expression of ATRX was found to be a positive prognostic indicator for overall survival and metastasis-free survival in our group of soft tissue sarcomas both in univariate analysis and multivariate analysis (HR: 0.38 (0.17–0.85), P = 0.02 and HR: 0.49 (0.24–0.99), P = 0.05 , respectively). Conclusions. High expression of ATRX is a positive prognostic indicator of overall survival and metastasis-free survival in patients with STS. This is consistent with studies in osteosarcoma, which indicate possible mechanisms through which loss of ATRX leads to more aggressive phenotypes. Future prospective clinical studies are required to validate the prognostic significance of these findings. [ABSTRACT FROM AUTHOR]

Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-Kras(G12D); Trp53(Flox/Flox) mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-Kras(G12D); p53(Flox/Flox) mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.