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Insight into the Etiology of Undifferentiated Soft Tissue Sarcomas from a Novel Mouse Model.
Fleming JT, Brignola E, Chen L, Guo Y, Zhao S, Wang Q, Li B, Correa H, Ermilov AN, Dlugosz AA, Chiang C
(2019) Mol Cancer Res 17: 1024-1035
MeSH Terms: Animals, Gene Expression Regulation, Neoplastic, Hedgehog Proteins, Homeodomain Proteins, Humans, Mice, Neoplasm Transplantation, Nerve Tissue Proteins, Sarcoma, Ewing, Signal Transduction, Zebrafish Proteins, Zinc Finger Protein Gli3
Show Abstract · Added April 10, 2019
Aberrant activation of the Hedgehog signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report , a novel mouse model in which human GLI2A, a constitutive activator of Hedgehog signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in mice featured some characteristics that were reminiscent of Ewing sarcoma. Even though it is widely understood that Ewing sarcoma formation is driven by gene fusions, a genetically defined mouse model is not well-established. While gene fusions were not present in sarcomas, precluding their designation as Ewing sarcoma, we did find that GLI2A induced expression of known gene targets essential to Ewing pathogenesis, most notably, . Moreover, we found that naïve mesenchymal progenitors originate tumors in mice. Altogether, our work provides a novel genetic mouse model, which directly connects oncogenic Hedgehog activity to the etiology of undifferentiated soft tissue sarcomas for the first time. IMPLICATIONS: The finding that activation of Gli2 transcription factor is sufficient to induce Ewing-like sarcomas provides a direct transformative role of the Hedgehog signaling pathway in undifferentiated soft tissue sarcoma.
©2019 American Association for Cancer Research.
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12 MeSH Terms
Linear Accelerator-Based Stereotactic Radiosurgery for Cranial Intraparenchymal Metastasis of a Malignant Peripheral Nerve Sheath Tumor: Case Report and Review of the Literature.
Fenlon JB, Khattab MH, Ferguson DC, Luo G, Keedy VL, Chambless LB, Kirschner AN
(2019) World Neurosurg 123: 123-127
MeSH Terms: Adult, Brain Neoplasms, Humans, Magnetic Resonance Imaging, Male, Nerve Sheath Neoplasms, Neurofibrosarcoma, Particle Accelerators, Positron-Emission Tomography, Radiosurgery
Show Abstract · Added April 2, 2019
BACKGROUND - Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive soft tissue sarcomas. MPNST intracranial metastasis is exceedingly rare with only 22 documented cases in the literature and, to our knowledge, only 1 case with intraparenchymal brain metastasis. Most have been managed surgically; however, 2 documented cases were treated with Gamma Knife radiosurgery. Excluding this case report, there are no other documented cases of linear accelerator-based stereotactic radiosurgery (SRS) to treat MPNST brain metastasis.
CASE DESCRIPTION - A 41-year-old man with MPNST of the lung initially underwent tumor resection. He developed multiple systemic metastases that were managed with directed radiation therapy. A parietal brain metastasis was treated with linear accelerator-based SRS. Following SRS therapy, the patient was treated with a tropomyosin receptor kinase inhibitor. Complete resolution of brain metastasis was seen on brain magnetic resonance imaging 5 months after treatment with SRS. At 11 months after SRS, there was no evidence of recurrence or progression of the intraparenchymal disease. The patient continued to have stable extracranial disease on his ninth cycle of systemic treatment.
CONCLUSIONS - This report provides important insights into efficacy of linear accelerator-based SRS to treat MPNST brain metastases.
Copyright © 2018 Elsevier Inc. All rights reserved.
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AJCC eighth edition for soft tissue sarcoma of the extremities and trunk.
Cates JMM
(2018) Ann Oncol 29: 2023
MeSH Terms: Extremities, Humans, Neoplasm Staging, Sarcoma, Soft Tissue Neoplasms, United States
Added November 1, 2018
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6 MeSH Terms
The proto-oncogene function of Mdm2 in bone.
Olivos DJ, Perrien DS, Hooker A, Cheng YH, Fuchs RK, Hong JM, Bruzzaniti A, Chun K, Eischen CM, Kacena MA, Mayo LD
(2018) J Cell Biochem 119: 8830-8840
MeSH Terms: Analysis of Variance, Animals, Bone Density, Bone Remodeling, Calcification, Physiologic, Cancellous Bone, Cell Line, Tumor, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Osteoblasts, Osteoclasts, Osteogenesis, Osteosarcoma, Proto-Oncogene Proteins c-mdm2, Proto-Oncogenes
Show Abstract · Added April 1, 2019
Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2 ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2 ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals.
© 2018 Wiley Periodicals, Inc.
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19 MeSH Terms
Simple staging system for osteosarcoma performs equivalently to the AJCC and MSTS systems.
Cates JMM
(2018) J Orthop Res 36: 2802-2808
MeSH Terms: Adolescent, Adult, Bone Neoplasms, Bone and Bones, Female, Humans, Male, Neoplasm Metastasis, Neoplasm Staging, Osteosarcoma, Prognosis, Retrospective Studies, SEER Program, United States, Young Adult
Show Abstract · Added November 1, 2018
Both the American Joint Committee on Cancer (AJCC) and Musculoskeletal Tumor Society (MSTS) staging systems for skeletal sarcomas have major weaknesses. A revised staging system for osteosarcoma (the Vanderbilt system) was developed based on exploratory analyses of the relative prognostic impacts of histologic grade, tumor size, local tumor extension, and specific anatomic sites of metastasis using case records from the National Cancer Database (N = 4,285). AJCC, MSTS, and Vanderbilt staging schemes were then compared using a separate, population-based cancer registry (the Surveillance, Epidemiology, and End Results database; N = 2,246) as a validation dataset. Predictive accuracy for 5-year sarcoma-specific survival was evaluated by comparing areas under receiver-operating characteristic curves generated from logistic regression. Three different concordance indices and Bayesian information criteria were also calculated for model comparisons. The Vanderbilt staging system showed comparable predictive accuracy for 5-year disease-specific survival (65%) compared to the AJCC (67%) and MSTS (67%) staging systems. Most cross-comparisons of model concordance were not significantly different either. Bayesian information criterion was lowest for the MSTS staging system. Substaging osteosarcoma by current anatomical criteria is ineffectual. A simplified staging system based only on histologic grade and the presence of distant metastasis to any anatomic site performs similarly to the current AJCC and MSTS staging systems by multiple statistical criteria and is proposed for clinical and pathological staging of osteosarcomas of the non-pelvic appendicular and non-spinal axial skeleton. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2802-2808, 2018.
© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.
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15 MeSH Terms
The AJCC 8th Edition Staging System for Soft Tissue Sarcoma of the Extremities or Trunk: A Cohort Study of the SEER Database.
Cates JMM
(2018) J Natl Compr Canc Netw 16: 144-152
MeSH Terms: Aged, Cohort Studies, Extremities, Female, Humans, Incidence, Kaplan-Meier Estimate, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Practice Guidelines as Topic, Prognosis, ROC Curve, SEER Program, Sarcoma, Tumor Burden
Show Abstract · Added November 1, 2018
The AJCC recently published the 8th edition of its cancer staging system. Significant changes were made to the staging algorithm for soft tissue sarcoma (STS) of the extremities or trunk, including the addition of 2 additional T (size) classifications in lieu of tumor depth and grouping lymph node metastasis (LNM) with distant metastasis as stage IV disease. Whether these changes improve staging system performance is questionable. This retrospective cohort analysis of 21,396 adult patients with STS of the extremity or trunk in the SEER database compares the AJCC 8th edition staging system with the 7th edition and a newly proposed staging algorithm using a variety of statistical techniques. The effect of tumor size on disease-specific survival was assessed by flexible, nonlinear Cox proportional hazard regression using restricted cubic splines and fractional polynomials. The slope of covariate-adjusted log hazards for sarcoma-specific survival decreases for tumors >8 cm in greatest dimension, limiting prognostic information contributed by the new T4 classification in the AJCC 8th edition. Anatomic depth independently provides significant prognostic information. LNM is not equivalent to distant, non-nodal metastasis. Based on these findings, an alternative staging system is proposed and demonstrated to outperform both AJCC staging schemes. The analyses presented also disclose no evidence of improved clinical performance of the 8th edition compared with the previous edition. The AJCC 8th edition staging system for STS is no better than the previous 7th edition. Instead, a proposed staging system based on histologic grade, tumor size, and anatomic depth shows significantly higher predictive accuracy, with higher model concordance than either AJCC staging system. Changes to existing staging systems should improve the performance of prognostic models. Until such improvements are documented, AJCC committees should refrain from modifying established staging schemes.
Copyright © 2018 by the National Comprehensive Cancer Network.
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17 MeSH Terms
Modeling Continuous Prognostic Factors in Survival Analysis: Implications for Tumor Staging and Assessing Chemotherapy Effect in Osteosarcoma.
Cates JMM
(2018) Am J Surg Pathol 42: 485-491
MeSH Terms: Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Bone Neoplasms, Chemotherapy, Adjuvant, Child, Databases, Factual, Decision Support Techniques, Female, Humans, Male, Middle Aged, Models, Statistical, Necrosis, Neoadjuvant Therapy, Neoplasm Staging, Orthopedic Procedures, Osteosarcoma, Predictive Value of Tests, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Tumor Burden, United States, Young Adult
Show Abstract · Added November 1, 2018
Extent of response to neoadjuvant chemotherapy, tumor size, and patient age are important prognostic variables for patients with osteosarcoma, but applying information from these continuous variables in survival models is difficult. Dichotomization is usually inappropriate and alternative statistical techniques should be considered instead. Nonlinear multivariable regression methods (restricted cubic splines and fractional polynomials) were applied to data from the National Cancer Database to model continuous prognostic factors for overall survival from localized, high-grade osteosarcoma of the appendicular and nonspinal skeleton following neoadjuvant chemotherapy and surgical resection (N=2493). The assumption that log hazard ratios were linear in relation to these continuous prognostic factors was tested using likelihood ratio tests of model deviance and Wald tests of spline coefficients. Log hazard ratios for increasing patient age were linear over the range of 4 to 80 years, but showed evidence for variation in the coefficient over elapsed follow-up time. Tumor size also showed a linear relationship with log hazard over the range of 1 to 30 cm. Hazard ratios for chemotherapy effect profoundly deviated from log-linear (P<0.004), with significantly decreased hazard for death from baseline for patients with ≥90% tumor necrosis (hazard ratio, 0.32; 95% confidence interval, 0.20-0.52; P<0.0001). Important implications of these results include: (1) ≥90% tumor necrosis defines good chemotherapy response in a clinically useful manner; (2) staging osteosarcoma by dichotomizing tumor size is inappropriate; and (3) patient age can be modeled as a linear effect on the log hazard ratio in prognostic models with the caveat that risk may change over duration of the analysis.
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28 MeSH Terms
Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas.
Cancer Genome Atlas Research Network. Electronic address: elizabeth.demicco@sinaihealthsystem.ca, Cancer Genome Atlas Research Network
(2017) Cell 171: 950-965.e28
MeSH Terms: Adult, Aged, Aged, 80 and over, Cluster Analysis, DNA Copy Number Variations, Epigenomics, Genome, Human, Genome-Wide Association Study, Humans, Middle Aged, Mutation, Sarcoma, Young Adult
Show Abstract · Added October 30, 2019
Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
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Performance Analysis of the American Joint Committee on Cancer 8th Edition Staging System for Retroperitoneal Sarcoma and Development of a New Staging Algorithm for Sarcoma-Specific Survival.
Cates JMM
(2017) Ann Surg Oncol 24: 3880-3887
MeSH Terms: Algorithms, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Staging, Retroperitoneal Neoplasms, Retrospective Studies, SEER Program, Sarcoma, Survival Rate, United States
Show Abstract · Added November 1, 2018
BACKGROUND - The American Joint Committee on Cancer (AJCC) recently published the 8th edition of the AJCC Cancer Staging Manual. Major changes were made to the staging algorithm for retroperitoneal sarcoma; however, whether these changes improve staging system performance is questionable.
METHODS - This retrospective cohort analysis of 3703 adult patients with retroperitoneal sarcoma in the Surveillance, Epidemiology, and End Results (SEER) database compares a novel staging system incorporating histologic subtype of sarcoma with current and prior AJCC soft tissue sarcoma staging systems using multiple statistical techniques. The effect of tumor size on sarcoma-specific survival was also assessed by flexible, non-linear Cox proportional hazard regression using restricted cubic splines and fractional polynomials.
RESULTS - The relationship between the covariate-adjusted log hazard for disease-specific survival and tumor size is non-linear. Although the new AJCC T classification approximates this hazard fairly well, the overall prognostic impact of tumor size is limited after accounting for other predictive factors. Predictive accuracy and concordance indices of the AJCC 8th edition staging system for retroperitoneal sarcoma are significantly lower than the prior 7th edition. A proposed staging system incorporating histologic grade, tumor size, and histologic subtype is superior to both the AJCC 7th and 8th editions in predicting sarcoma-specific survival.
CONCLUSION - AJCC committees should not revise tumor staging algorithms unless the changes actually improve the staging system. A proposed staging scheme incorporating data regarding histologic subtype of sarcoma performs significantly better than both the 7th and 8th AJCC staging systems.
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The fine needle aspiration of translocation sarcomas.
VandenBussche CJ, Adams CL, McDonald OG, Whitworth SA, Ali SZ
(2017) Cytopathology 28: 356-363
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Biopsy, Fine-Needle, Child, Child, Preschool, Cytodiagnosis, Female, Humans, Infant, Male, Middle Aged, Retrospective Studies, Sarcoma
Show Abstract · Added July 20, 2018
INTRODUCTION - Soft tissue sarcomas comprise a heterogeneous group of clinically aggressive cancers that are often hard to classify on limited cytological samples. "Translocation sarcomas" (TS) are a diverse subset of such cancers, different from pleomorphic sarcomas, and characterised by unique single chromosomal translocations in each sarcoma subtype. Interestingly, despite their high-grade biological behaviour, TS have deceptively monotonous and bland cytomorphology, therefore creating diagnostic issues on limited samples.
MATERIALS AND METHODS - A retrospective search was conducted of the cytopathology archives of The Johns Hopkins Hospital revealing 147 translocation sarcoma cases over a 25-year period.
RESULTS - The common morphological denominators for most translocation sarcomas were: hypercellularity, cellular monotony, mostly discohesive and single cells, round-to-oval or short spindled cells and a lack of necrosis. The exceptions were an inflammatory myofibroblastic tumour, in which cellular monotony was not present owing to the prominence of lymphocytes and plasma cells, and low-grade fibromyxoid sarcoma, in which the specimens were generally hypocellular. Ancillary testing, especially immunoperoxidase staining, was often required for primary lesions.
CONCLUSION - Distinct morphological clues and subsequent ancillary testing (particularly immunoperoxidase staining) provide an accurate diagnosis on cytological interpretation of both, primary and recurrent/metastatic lesions.
© 2017 John Wiley & Sons Ltd.
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