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The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system does not have sufficient details to encompass the variety of soft-tissue sarcomas, and available prognostic methods need refinement. We aimed to develop and externally validate two prediction nomograms for overall survival and distant metastases in patients with soft-tissue sarcoma in their extremities. Consecutive patients who had had an operation at the Istituto Nazionale Tumori (Milan, Italy), from Jan 1, 1994, to Dec 31, 2013, formed the development cohort. Three cohorts of patient data from the Institut Gustave Roussy (Villejuif, France; from Jan 1, 1996, to May 15, 2012), Mount Sinai Hospital (Toronto, ON, Canada; from Jan 1, 1994, to Dec 31, 2013), and the Royal Marsden Hospital (London, UK; from Jan 1, 2006, to Dec 31, 2013) formed the external validation cohorts. We developed the nomogram for overall survival using a Cox multivariable model, and a Fine and Gray multivariable model for the distant metastases nomogram. We applied a backward procedure for variables selection for both nomograms. We assessed nomogram model performance by examining overall accuracy (Brier score), calibration (calibration plots and Hosmer–Lemeshow calibration test), and discrimination (Harrell C index). We plotted decision curves to evaluate the clinical usefulness of the two nomograms. 1452 patients were included in the development cohort, with 420 patients included in the French validation cohort, 1436 patients in the Canadian validation cohort, and 444 patients in the UK validation cohort. In the development cohort, 10-year overall survival was 72·9% (95% CI 70·2–75·7) and 10-year crude cumulative incidence of distant metastases was 25·0% (95% CI 22·7–27·5). For the overall survival nomogram, the variables selected applying a backward procedure in the multivariable Cox model (patient's age, tumour size, Fédération Française des Centres de Lutte Contre le Cancer [FNCLCC] grade, and histological subtype) had a significant effect on overall survival. The same variables, except for patient age, were selected for the distant metastases nomogram. In the development cohort, the Harrell C index for overall survival was 0·767 (95% CI 0·743–0·789) and for distant metastases was 0·759 (0·736–0·781). In the validation cohorts, the Harrell C index for overall survival and distant metastases were 0·698 (0·638–0·754) and 0·652 (0·605–0·699; French), 0·775 (0·754–0·796) and 0·744 (0·720–0·768; Canadian), and 0·762 (0·720–0·806) and 0·749 (0·707–0·791; UK). The two nomograms both performed well in terms of discrimination (ability to distinguish between patients who have had an event from those who have not) and calibration (accuracy of nomogram prediction) when applied to the validation cohorts. Our nomograms are reliable prognostic methods that can be used to predict overall survival and distant metastases in patients after surgical resection of soft-tissue sarcoma of the extremities. These nomograms can be offered to clinicians to improve their abilities to assess patient prognosis, strengthen the prognosis-based decision making, enhance patient stratification, and inform patients in the clinic. None.

Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36–to–methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.

Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis. Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.

Background Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. Methods Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. Results Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery ( n  = 106; 48 %) or had a less morbid procedure ( n  = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4–28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % ( n  = 24/25) for patients with planned joint/prosthesis replacement and 86 % ( n  = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5–17.9] months), local recurrence occurred in 17 (15 %) patients. Conclusion For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure.

ObjectiveTo analyze radiomic features obtained from pre-treatment T2-weighted MRI acquisitions in patients with histologically proven intramedullary high-grade osteosarcomas and assess the accuracy of radiomic modelling as predictive biomarker of tumor necrosis following neoadjuvant chemotherapy (NAC), overall survival (OS), and disease-free survival (DFS).Materials and MethodsPre-treatment MRI exams in 105 consecutive patients who underwent NAC and resection of high-grade intramedullary osteosarcoma were evaluated. Histologic necrosis following NAC, and clinical outcome-survival data was collected for each case. Radiomic features were extracted from segmentations performed by two readers, with poorly reproducible features excluded from further analysis. Cox proportional hazard model and Spearman correlation with multivariable modelling were used for assessing relationships of radiomics features with OS, DFS, and histologic tumor necrosis.ResultsStudy included 74 males, 31 females (mean 32.5yrs, range 15–77 years). Histologic assessment of tumor necrosis following NAC was available in 104 cases, with good response (≥ 90% necrosis) in 41, and poor response in 63. Fifty-three of 105 patients were alive at follow-up (median 40 months, range: 2–213 months). Median OS was 89 months. Excluding 14 patients with metastases at presentation, median DFS was 19 months. Eleven radiomics features were employed in final radiomics model predicting histologic tumor necrosis (mean AUC 0.708 ± 0.046). Thirteen radiomic features were used in model predicting OS (mean concordance index 0.741 ± 0.011), and 12 features retained in predicting DFS (mean concordance index 0.745 ± 0.010).ConclusionsT2-weighted MRI radiomic models demonstrate promising results as potential prognostic biomarkers of prospective tumor response to neoadjuvant chemotherapy and prediction of clinical outcomes in conventional osteosarcoma.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury ( T ) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma. Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury ( T ), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.

BackgroundUnlike other sarcoma subtypes, myxoid liposarcoma (MLS) has a propensity for extra-pulmonary metastases. Computed tomography (CT) scan of the chest, abdomen, and pelvis has become an accepted practice for surveillance. However, recent literature suggests that this may be inadequate. This study aimed to assess the ability of current imaging methods to detect metastases adequately in this population.MethodsThe study identified 169 patients with MLS diagnosed between 2000 and 2016. The timing and location of metastases, the reasons leading to the MLS diagnosis, and the imaging methods were recorded. The locations of metastases were classified into the following categories: pulmonary, soft tissue, bone, retroperitoneal, intraperitoneal, solid organ, and lymph node.ResultsAn initial diagnosis of metastasis was made at presentation with staging CT scan for 3 (10 %) of 31 patients, with a follow-up surveillance CT scan for 15 (48 %) of the patients or with subsequent imaging obtained in response to patient-reported symptoms for 13 (42 %) of the patients. The proportions of patients who had metastases in each location were as follows: soft tissue (84 %), pulmonary (68 %), intraabdominal (48 %), solid organ (48 %), bone (45 %), lymph node (32 %), and retroperitoneal (29 %). Although 14 patients had bone metastases, only 1 patient had a sclerotic/blastic presentation visualized on CT scan, and the diagnosis for the remaining 13 patients was determined by magnetic resonance imaging (MRI).ConclusionDue to metastatic disease identified outside surveillance imaging for 58 % of the patients, the diversity of locations, and the significant failure of CT and bone scan to identify bone metastases, this study questioned the adequacy of CT scan for surveillance of MLS. Consideration should be given to the use of whole-body MRI for detection of metastasis in MLS.

Background The potential for local recurrence and pulmonary metastasis after treatment of primary bone sarcomas necessitates careful patient followup; however, minimal data exist regarding the incidence and timing of these events, and therefore an evidence-based surveillance protocol has not been developed. Questions/purposes The purposes of this study were to (1) describe the frequency and timing of local recurrence by histologic grade over time; (2) describe the frequency and timing of metastasis by histologic grade and diagnosis over time; and (3) use these data to either justify current surveillance schedules and/or propose modifications that may improve the rate of new pulmonary metastatic events detected per examination. Methods A retrospective review was performed of all patients who underwent resection of a primary, nonmetastatic bone sarcoma (excluding chordoma) at a single tertiary oncology center from 1989 to 2010. Of the 680 patients identified, 15 were excluded for loss of followup in the first 2 years, leaving 665 eligible for study. Of these, 437 patients were alive with no evidence of disease at the conclusion of the study (mean followup, 136 months; range, 25–321 months). Cox regression analysis was performed to evaluate and control for patient age, tumor size, tumor location, and surgical margins. With patients stratified by sarcoma grade, Kaplan-Meier survival curves were constructed for the endpoints of local recurrence and metastasis, and log-rank tests were used to compare the rates of these events between grades and diagnoses. The number of new pulmonary metastatic events per patient-year was calculated for each sarcoma grade over the time intervals used in current surveillance protocols (0–2, 2–5, 5–10, and > 10 years) to facilitate development of a surveillance schedule that would maximize events detected per imaging study performed. In addition, to determine the effect of disease type, subset analysis was performed for osteosarcoma (OSA) and chondrosarcoma because these were the only diagnoses with sufficient numbers to support individual statistical analysis. Results With the numbers available for study, the overall local recurrence-free survival did not differ between sarcoma grades at any time points (p = 0.864). Metastasis-free survival curves differed between sarcoma grades (p < 0.001), and the pattern of Grade 2 OSA metastasis was more consistent with other Grade 3 sarcomas, so it was subsequently classified as high grade. No metastases of Grade 1 sarcomas occurred after 3 years, whereas Grade 2 and 3 sarcomas continued to metastasize until 10 years and rarely thereafter. According to the number of new pulmonary metastatic events per patient-year in each group, we propose that chest surveillance be performed according to the following schedule: annually only until 5 years for low-grade sarcomas; every 3 months for 2 years and annually from 2 to 10 years for intermediate-grade sarcomas; and every 3 months for 2 years, every 6 months from 2 to 5 years, and annually from 5 to 10 years for high-grade sarcomas. Conclusions Pulmonary screening beyond 5 years may not be necessary for Grade 1 tumors but should be continued until 10 years for Grade 2 and 3 bone sarcomas. The surveillance frequency listed here, which is based on the number of new pulmonary metastatic events per patient-year in each grade, would increase the number of such events detected per examination performed. Level of Evidence Level III, therapeutic study.

Solitary fibrous tumors are a type of translocation-associated sarcoma with up to 30% rates of metastasis and poor response to conventional chemotherapy. Other translocation-associated sarcomas have been shown to display elevated expression of various cancer-testis antigens which may render them susceptible to immunotherapy strategies such as cancer vaccines and adoptive T-cell therapy. After an RNA sequencing assay brought the cancer-testis antigen Preferentially Expressed Antigen In Melanoma (PRAME) to our attention as possibly being upregulated in aggressive TERT promoter-mutated solitary fibrous tumors, we used tissue microarrays to asses PRAME expression in a large series of previously characterized solitary fibrous tumors, with correlation to various clinicopathologic features, as well as with tumor-infiltrating macrophages and the associated signal regulatory protein α (SIRPα)-CD47 regulatory checkpoint. We found that PRAME was expressed in 165/180 solitary fibrous tumors, with high expression seen in 58%, irrespective of TERT promoter status. Elevated PRAME expression was more frequent in primary intrathoracic solitary fibrous tumors and correlated with older age at primary diagnosis. Elevated PRAME was also associated with features suggestive of immune evasion, including lower numbers of antigen-presenting CD163+ and CD68+ macrophages, and expression of the “don't eat me” receptor CD47 on tumor cells. Taken together, these features suggest that strategies targeting PRAME with or without concomitant SIRPα-CD47 axis inhibition may represent a potential future therapeutic option in aggressive solitary fibrous tumor.