The impact of chromosomal translocation locus and fusion oncogene coding sequence in synovial sarcomagenesis.

Synovial sarcomas are aggressive soft-tissue malignancies that express chromosomal translocation-generated fusion genes, SS18-SSX1 or SS18-SSX2 in most cases. Here, we report a mouse sarcoma model expressing SS18-SSX1, complementing our prior model expressing SS18-SSX2. Exome sequencing identified no recurrent secondary mutations in tumors of either genotype. Most of the few mutations identified in single tumors were present in genes that were minimally or not expressed in any of the tumors. Chromosome 6, either entirely or around the fusion gene expression locus, demonstrated a copy number gain in a majority of tumors of both genotypes. Thus, by fusion oncogene coding sequence alone, SS18-SSX1 and SS18-SSX2 can each drive comparable synovial sarcomagenesis, independent from other genetic drivers. SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences overall. In direct tumorigenesis comparisons, SS18-SSX2 was slightly more sarcomagenic than SS18-SSX1, but equivalent in its generation of biphasic histologic features. Meta-analysis of human synovial sarcoma patient series identified two tumor-gentoype-phenotype correlations that were not modeled by the mice, namely a scarcity of male hosts and biphasic histologic features among SS18-SSX2 tumors. Re-analysis of human SS18-SSX1 and SS18-SSX2 tumor transcriptomes demonstrated very few consistent differences, but highlighted increased native SSX2 expression in SS18-SSX1 tumors. This suggests that the translocated locus may drive genotype-phenotype differences more than the coding sequence of the fusion gene created. Two possible roles for native SSX2 in synovial sarcomagenesis are explored. Thus, even specific partial failures of mouse genetic modeling can be instructive to human tumor biology

Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children\u27s Oncology Group.

BACKGROUND: The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite. OBJECTIVES: Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target) in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes. RESULTS: A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes. CONCLUSIONS: These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma

Salient features of mesenchymal stem cells-implications for Ewing sarcoma modeling.

Despite a heightened appreciation of the many defining molecular aberrations in Ewing sarcoma, the cooperative genetic environment and permissive cell of origin essential for EWS/ETS-mediated oncogenesis remain elusive. Consequently, inducible animal and in vitro models of Ewing sarcoma from a native cellular context are unable to fully recapitulate malignant transformation. Despite these shortcomings, human, and murine mesenchymal stem cells (MSCs) are the closest working in vitro systems available. MSCs are tolerant of ectopic EWS/FLI expression, which is accompanied by a molecular signature most similar to Ewing sarcoma. Whether MSCs are the elusive cell of origin or simply a tolerant platform of the EWS/FLI transcriptome, these cells have become an excellent molecular tool to investigate and manipulate oncogenesis in Ewing sarcoma. Our understanding of the biological complexity and heterogeneity of human MSCs (hMSCs) has increased substantially over time and as such, appreciation and utilization of these salient complexities may greatly enhance the efficient use of these cells as surrogate models for Ewing sarcoma tumorigenesis

Salient features of mesenchymal stem cells-implications for Ewing sarcoma modeling.

Despite a heightened appreciation of the many defining molecular aberrations in Ewing sarcoma, the cooperative genetic environment and permissive cell of origin essential for EWS/ETS-mediated oncogenesis remain elusive. Consequently, inducible animal and in vitro models of Ewing sarcoma from a native cellular context are unable to fully recapitulate malignant transformation. Despite these shortcomings, human, and murine mesenchymal stem cells (MSCs) are the closest working in vitro systems available. MSCs are tolerant of ectopic EWS/FLI expression, which is accompanied by a molecular signature most similar to Ewing sarcoma. Whether MSCs are the elusive cell of origin or simply a tolerant platform of the EWS/FLI transcriptome, these cells have become an excellent molecular tool to investigate and manipulate oncogenesis in Ewing sarcoma. Our understanding of the biological complexity and heterogeneity of human MSCs (hMSCs) has increased substantially over time and as such, appreciation and utilization of these salient complexities may greatly enhance the efficient use of these cells as surrogate models for Ewing sarcoma tumorigenesis

Rotationplasty: Beauty is in the Eye of the Beholder.

Rotationplasty is an alternative reconstructive strategy after sarcoma resection that often gets overlooked due to concerns about cosmesis. "Rotating" a distal segment 180 degrees and fixing it to a proximal segment leaves a highly-functional, durable reconstruction that functionally compares favorably to other limb-salvage techniques. Cosmetic outcomes have no discernible impact of the emotional and social functioning of cancer survivors following rotationplasty. This chapter discusses techniques of rotationplasty, as well as its oncologic, functional and emotional outcomes

What Are the 5-year Survivorship Outcomes of Compressive Endoprosthetic Osseointegration Fixation of the Femur?

BackgroundAseptic complications such as stress shielding leading to bone loss are major problems associated with revision of cemented and uncemented long-stem tumor endoprostheses. Endoprosthetic reconstruction using compressive osseointegration fixation is a relatively new limb salvage technology designed to enhance osseointegration, prevent stress shielding, and provide fixation for short end-segments.Questions/purposes(1) What is the survivorship of this technique at minimum 5-year followup? (2) Were patient factors (age, sex, body mass index), oncological factors, or anatomic locations associated with implant failure? (3) Were there any prosthesis-related variables associated with failure?MethodsA single-center, retrospective review of patients with a minimum 5-year followup (mean, 8 years; range, 5-12 years) treated with an osseointegration compressive device for endoprosthetic fixation of proximal and distal femoral limb salvage reconstructions was performed. We have previously published the implant survivorship of this patient cohort with a minimum 2-year followup and are now reporting on the 5-year survivorship data. From 2002 to 2008, we performed 22 such procedures in 22 patients. Four patients died of their disease within 5 years of surgery and all surviving patients (n = 18) had complete followup data at a minimum of 5 years. General indications for this device during that time were pediatric and adult patients requiring primary endoprosthetic reconstructions of the proximal or distal femur for benign and malignant bone lesions. The primary outcome was reoperations for mechanical (aseptic) failures. Secondary outcomes included implant removal for nonmechanical failures and any patient-, oncological-, or implant-related variables associated with implant removal.ResultsAt a minimum of 5 years followup, overall mechanical (aseptic) implant survivorship was 16 of 18. Survivorship for all modes of failure (oncological failure, infection, arthrofibrosis, and mechanical failure) was 12 of 18. All mechanical failures occurred early, within the first 30 months. We identified no patient-, oncological-, or implant-related features predictive of failure.ConclusionsOur intermediate-term experience with compressive osseointegration fixation for endoprosthetic limb reconstructions demonstrates with longer clinical followup, no additional mechanical failures were observed as compared with our early analysis. Our experience with this fixation at a minimum of 5-years followup adds to a very limited but increasing body of literature demonstrating that after a transient period of increased risk for implant failures, survivorship stabilizes. Assessment of this fixation strategy beyond 10 years of clinical followup is needed.Level of evidenceLevel IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence

What are the 5-year survivorship outcomes of compressive endoprosthetic osseointegration fixation of the femur?

BackgroundAseptic complications such as stress shielding leading to bone loss are major problems associated with revision of cemented and uncemented long-stem tumor endoprostheses. Endoprosthetic reconstruction using compressive osseointegration fixation is a relatively new limb salvage technology designed to enhance osseointegration, prevent stress shielding, and provide fixation for short end-segments.Questions/purposes(1) What is the survivorship of this technique at minimum 5-year followup? (2) Were patient factors (age, sex, body mass index), oncological factors, or anatomic locations associated with implant failure? (3) Were there any prosthesis-related variables associated with failure?MethodsA single-center, retrospective review of patients with a minimum 5-year followup (mean, 8 years; range, 5-12 years) treated with an osseointegration compressive device for endoprosthetic fixation of proximal and distal femoral limb salvage reconstructions was performed. We have previously published the implant survivorship of this patient cohort with a minimum 2-year followup and are now reporting on the 5-year survivorship data. From 2002 to 2008, we performed 22 such procedures in 22 patients. Four patients died of their disease within 5 years of surgery and all surviving patients (n = 18) had complete followup data at a minimum of 5 years. General indications for this device during that time were pediatric and adult patients requiring primary endoprosthetic reconstructions of the proximal or distal femur for benign and malignant bone lesions. The primary outcome was reoperations for mechanical (aseptic) failures. Secondary outcomes included implant removal for nonmechanical failures and any patient-, oncological-, or implant-related variables associated with implant removal.ResultsAt a minimum of 5 years followup, overall mechanical (aseptic) implant survivorship was 16 of 18. Survivorship for all modes of failure (oncological failure, infection, arthrofibrosis, and mechanical failure) was 12 of 18. All mechanical failures occurred early, within the first 30 months. We identified no patient-, oncological-, or implant-related features predictive of failure.ConclusionsOur intermediate-term experience with compressive osseointegration fixation for endoprosthetic limb reconstructions demonstrates with longer clinical followup, no additional mechanical failures were observed as compared with our early analysis. Our experience with this fixation at a minimum of 5-years followup adds to a very limited but increasing body of literature demonstrating that after a transient period of increased risk for implant failures, survivorship stabilizes. Assessment of this fixation strategy beyond 10 years of clinical followup is needed.Level of evidenceLevel IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence

Erratum to: Outcomes of Modified Harrington Reconstructions for Nonprimary Periacetabular Tumors: An Effective and Inexpensive Technique.

Background: Metastatic disease to the acetabulum presents a difficult technical and philosophical challenge: complicated surgeries in patients with often short life expectancies force us to examine both the outcome and cost of these operations. Therefore, we studied the durability of a cement-screw rebar reconstruction technique and risk factors for failure, and we compare the results to other reconstruction options. Methods: This is a retrospective review of 52 acetabular reconstructions in 50 patients for nonprimary disease using a retrograde screw-rebar-cement all-polyethylene technique. Mean age was 57 years (range 25–81 years). Twenty-four lesions were classified as Harrington class II; 28 were Harrington class III. Mean follow-up was 17.7 months (range 1–92 months). Outcomes included patient survival, prosthesis survival, and complications. Results: Forty-eight of 50 (96 %) patients ambulated after surgery. Five of 52 (9.6 %) of prostheses failed, three from loosening due to tumor progression, one from aseptic loosening, and one from soft tissue instability (dislocation). The three cases of tumor progression failure occurred in patients with massive preoperative ischial tumor burden. Mean surgical time was 198 min, and hospital stay was 5.2 days. Discussion: The screw-cement-rebar all-polyethylene cup reconstruction technique is a comparatively successful and inexpensive reconstruction option for treating nonprimary oncologic disease in the acetabulum. All cases of loosening occurred beyond the median patient survival. Surgeons should be wary of massive ischial tumor burden in patients with projected longevity, as it may be associated with implant failure. Surgical time and hospital stay are consistent with historical data for alternative implants, and implant cost is lower