Publications by authors named "Jay S Wunder"

192 Publications

Radiological progression of extremity soft tissue sarcoma following preoperative radiotherapy predicts for poor survival.

Br J Radiol 2021 Nov 26:20210936. Epub 2021 Nov 26.

University of Toronto Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Canada.

Objectives: To determine if radiological response to preoperative radiotherapy is related to oncologic outcome in patients with extremity soft tissue sarcomas (STS).

Methods: 309 patients with extremity STS who underwent preoperative radiation and wide resection were identified from a prospective database. Pre-and post-radiation MRI scans were retrospectively reviewed. Radiological response was defined by the modified Response Evaluation Criteria in Solid Tumours (RECIST).Local recurrence-free (LRFS), metastasis-free (MFS) and overall survival (OS) were compared across response groups.

Results: Tumour volume decreased in 106 patients (34.3%; PR- Partial Responders), remained stable in 97 (31.4%; SD- Stable Disease), increased in 106 (34.3%; PD- Progressive Disease). The PD group were older ( = 0.007), had more upper extremity ( = 0.03) and high grade tumours ( < 0.001). 81% of myxoid liposarcomas showed substantial decrease in size. There was no difference in initial tumour diameter ( = 0.5), type of surgery ( = 0.5), margin status ( = 0.4), or complications ( = 0.8) between the three groups. There were ten (3.2%) local recurrences with no differences between the three response groups ( = 0.06). Five-year MFS was 52.1% for the PD group versus 73.8 and 78.5% for the PR and SD groups respectively ( < 0.001). OS was similar ( < 0.001). Following multivariable analysis, worse MFS and OS were associated with higher grade, larger tumour size at diagnosis and tumour growth following preoperative radiation. Older age was also associated with worse OS.

Conclusion: STS that enlarge according to RECIST criteria following preoperative radiotherapy identify a high risk group of patients with worse systemic outcomes but equivalent local control.

Advances In Knowledge: Post radiation therapy, STS enlargement may identify patients with potential for worse systemic outcomes but equivalent local control. Therefore, adjunct therapeutic approaches could be considered in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1259/bjr.20210936DOI Listing
November 2021

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Cell Rep 2021 Nov;37(8):110047

University of Toronto Musculoskeletal Oncology Unit, Sinai Health System; Department of Surgery, University of Toronto, Toronto, ON, Canada.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.110047DOI Listing
November 2021

The Utility of Chest Imaging for Surveillance of Atypical Lipomatous Tumors.

Sarcoma 2021 11;2021:4740924. Epub 2021 Oct 11.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, USA.

Background: Unlike 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.

Methods: This 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.

Results: 190 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.

Conclusions: This 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/4740924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8523289PMC
October 2021

Detection and utility of cell-free and circulating tumour DNA in bone and soft-tissue sarcomas.

Bone Joint Res 2021 Sep;10(9):602-610

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada.

Aims: Cell-free DNA (cfDNA) and circulating tumour DNA (ctDNA) are used for prognostication and monitoring in patients with carcinomas, but their utility is unclear in sarcomas. The objectives of this pilot study were to explore the prognostic significance of cfDNA and investigate whether tumour-specific alterations can be detected in the circulation of sarcoma patients.

Methods: Matched tumour and blood were collected from 64 sarcoma patients (n = 70 samples) prior to resection of the primary tumour (n = 57) or disease recurrence (n = 7). DNA was isolated from plasma, quantified, and analyzed for cfDNA. A subset of cases (n = 6) underwent whole exome sequencing to identify tumour-specific alterations used to detect ctDNA using digital droplet polymerase chain reaction (ddPCR).

Results: Cell-free was present in 69 of 70 samples above 0.5 ng/ml. Improved disease-free survival was found for patients with lower cfDNA levels (90% vs 48% at one-year for ≤ 6 ng/ml and > 6 ng/ml, respectively; p = 0.005). Digital droplet PCR was performed as a pilot study and mutant alleles were detectable at 0.5% to 2.5% of the wild type genome, and at a level of 0.25 ng tumour DNA. Tumour-specific alterations (ctDNA) were found in five of six cases.

Conclusion: This work demonstrates the feasibility and potential utility of cfDNA and ctDNA as biomarkers for bone and soft-tissue sarcomas, despite the lack of recurrent genomic alterations. A larger study is required to validate these findings. Cite this article:  2021;10(9):602-610.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1302/2046-3758.109.BJR-2021-0014.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479566PMC
September 2021

Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival.

Nat Commun 2021 07 23;12(1):4496. Epub 2021 Jul 23.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-24677-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302638PMC
July 2021

Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development.

Am J Cancer Res 2021 15;11(6):3271-3284. Epub 2021 Jun 15.

INSERM UMR1251 Marseille Medical Genetics Genetics Marseille, France.

Liposarcomas are a heterogeneous group of sarcomas, including well-differentiated and dedifferentiated liposarcoma, myxoid/round cell liposarcoma, and pleomorphic liposarcoma. Complete surgical resection is the key of treatment. Radiotherapy, based on the tumor grade and the vicinity of critical structures with the tumor, can be used to prevent local recurrence. The group of dedifferentiated liposarcomas (DDLS) is poorly sensitive to adjuvant chemotherapy. Improved understanding of the genetic aberrations that lead to liposarcoma initiation is necessary for the development of targeted therapies to improve tumor control and survival. DDLS share genetic abnormalities with other groups, exhibiting high-level amplifications of chromosome 12, including the and genes, and harbor additional amplifications of chromosomes 6 and 1. Novel therapies targeted at the gene products of chromosome 12 are currently considered in clinical trials. Our work consisted in a genomic characterization of DDLS to draw up a complete picture of alterations, including genomic signatures, tumor mutation burden, gene mutations, copy number variations, translocations, gene fusions and methylation modifications. Analysis of translocations helped to understand the mechanisms underlying the amplification processes. Combination of mutations and loss of heterozygosity or homozygous deletions were detected and led to inactivate tumor suppressor genes (TSG). In contrast, methylation anomalies seemed not linked to any particular genomic profile. All identified anomalies, whether amplifications and/or TSG inactivation, involve genes playing a role in p53 regulation, that appears to be the epicenter of the initiation process in DDLS tumorigenesis, as is also known to be responsible for Li-Fraumeni syndrome, a family cancer syndrome highly predisposing to sarcomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263664PMC
June 2021

Staging and Surveillance of Myxoid Liposarcoma: Follow-up Assessment and the Metastatic Pattern of 169 Patients Suggests Inadequacy of Current Practice Standards.

Ann Surg Oncol 2021 Nov 7;28(12):7903-7911. Epub 2021 May 7.

Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Background: Unlike 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.

Methods: The 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.

Results: An 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).

Conclusion: Due 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-021-10091-1DOI Listing
November 2021

Imaging features of gluteal in vitro fertilization injection granulomas, with delayed clinical presentation simulating soft tissue sarcoma.

Skeletal Radiol 2021 Nov 7;50(11):2267-2272. Epub 2021 May 7.

Department of Surgery, University of Toronto Musculoskeletal Oncology Unit, Mount Sinai Hospital, and Division of Orthopedic Surgery, University of Toronto, Toronto, Ontario, Canada.

Objectives: To review the clinical and imaging findings of patients with remote history of intramuscular (IM) in vitro fertilization (IVF) gluteal injections, presenting with signs and symptoms of a possible gluteal soft tissue sarcoma.

Methods And Methods: Retrospective review of consecutive patients with a history of prior IVF therapy referred for MRI evaluation of a gluteal soft tissue mass was performed. Six patients were reviewed, with 5 patients meeting study inclusion criteria. Imaging exams (ultrasound n = 3, MRI n = 5) were assessed for lesion location, morphology, and intrinsic imaging characteristics. One case proceeded to percutaneous biopsy with histopathologic correlation.

Results: Average patient age was 43 years (range 38-50). Mean time interval between IVF IM injections and MRI was 5.7 years (range 2.2-13 years). Clinical findings included palpable gluteal mass (5/5) and local pain (4/5). Ultrasound showed heterogeneous subcutaneous lesions with varying complex cystic/solid internal echogenicity. On MRI, each case illustrated an irregularly marginated lesion, mean maximal dimension 3.5 cm (range 1.5-5.9 cm), within the deep gluteal subcutaneous fat composed of solitary (1/5) or multifocal (4/5) lobules demonstrating internal areas of high T1 and homogeneous low T2 fat suppressed signal with surrounding peripheral reticular high T2 signal. Correlative histological assessment showed central areas with features of fat necrosis and a peripheral inflammatory rim.

Conclusions: In the setting of prior IVF therapy, imaging features of an irregularly marginated, deep subcutaneous gluteal lesion with inflammatory soft tissue changes surrounding solitary or multifocal areas of loculated fat signal may be seen as an inflammatory response to previous inadvertent subcutaneous injection(s).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00256-021-03791-yDOI Listing
November 2021

Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes.

Cancer Metab 2021 Mar 24;9(1):13. Epub 2021 Mar 24.

Department of Orthopaedic Surgery, Duke University, 311 Trent, Durham, NC, 27710, USA.

Background: Majority of chondrosarcomas are associated with a number of genetic alterations, including somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, but the downstream effects of these mutated enzymes on cellular metabolism and tumor energetics are unknown. As IDH mutations are likely to be involved in malignant transformation of chondrosarcomas, we aimed to exploit metabolomic changes in IDH mutant and non-mutant chondrosarcomas.

Methods: Here, we profiled over 69 metabolites in 17 patient-derived xenografts by targeted mass spectrometry to determine if metabolomic differences exist in mutant IDH1, mutant IDH2, and non-mutant chondrosarcomas. UMAP (Uniform Manifold Approximation and Projection) analysis was performed on our dataset to examine potential similarities that may exist between each chondrosarcoma based on genotype.

Results: UMAP revealed that mutant IDH chondrosarcomas possess a distinct metabolic profile compared with non-mutant chondrosarcomas. More specifically, our targeted metabolomics study revealed large-scale differences in organic acid intermediates of the tricarboxylic acid (TCA) cycle, amino acids, and specific acylcarnitines in chondrosarcomas. Lactate and late TCA cycle intermediates were elevated in mutant IDH chondrosarcomas, suggestive of increased glycolytic metabolism and possible anaplerotic influx to the TCA cycle. A broad elevation of amino acids was found in mutant IDH chondrosarcomas. A few acylcarnitines of varying carbon chain lengths were also elevated in mutant IDH chondrosarcomas, but with minimal clustering in accordance with tumor genotype. Analysis of previously published gene expression profiling revealed increased expression of several metabolism genes in mutant IDH chondrosarcomas, which also correlated to patient survival.

Conclusions: Overall, our findings suggest that IDH mutations induce global metabolic changes in chondrosarcomas and shed light on deranged metabolic pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40170-021-00247-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992867PMC
March 2021

Computer-assisted surgical planning of complex bone tumor resections improves negative margin outcomes in a sawbones model.

Int J Comput Assist Radiol Surg 2021 Apr 16;16(4):695-701. Epub 2021 Mar 16.

Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Purpose: Several technologies have been implemented in orthopedic surgery to improve surgical outcomes, usually focusing on more accurate execution of a surgical plan, but the development of the plan itself is also of great importance. The purpose of this study is to examine whether the use of preoperative computer planning platforms can improve the surgical plan?

Methods: Eight surgeons created a preoperative surgical plan to resect a distal femur parosteal osteosarcoma in two settings: (1) Using a 2-D and 3-D CT scan only (current standard); and (2) using a computer-assisted planning platform. The plans were thereafter virtually executed using a novel surgical navigation system and a Sawbones model. This simulated model was derived from, and identical to, an actual patient scenario. The outcomes of interest were the number of positive margin cuts, and the volume of the resected specimen.

Results: Using the surgical plan developed with computer assistance, there were 4 positive margin cuts made by 2 surgeons. In comparison, using standard planning, there were 14 positive margin cuts made by all 8 surgeons (p = 0.02). The resection volume was larger in the computer-assisted plans (96 ± 10 mm) than in the standard plans (88 ± 7 mm) (p = 0.055).

Conclusions: Computer-assisted planning significantly decreased the risk of a positive margin resection in this Sawbones tumor model used to simulate resection of a primary bone sarcoma. This proof of concept study highlights the importance of advanced surgical planning and sets the ground for developing beneficial surgical planning systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11548-021-02337-wDOI Listing
April 2021

Comparison of reconstructive techniques after acetabular resection for pelvic chondrosarcoma.

Bone Joint J 2021 Feb;103-B(2):391-397

Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA.

Aims: Hip reconstruction after resection of a periacetabular chondrosarcoma is complex and associated with a high rate of complications. Previous reports have compared no reconstruction with historical techniques that are no longer used. The aim of this study was to compare the results of tantalum acetabular reconstruction to both historical techniques and no reconstruction.

Methods: We reviewed 66 patients (45 males and 21 females) with a mean age of 53 years (24 to 81) who had undergone acetabular resection for chondrosarcoma. A total of 36 patients (54%) underwent acetabular reconstruction, most commonly with a saddle prosthesis (n = 13; 36%) or a tantalum total hip arthroplasty (THA) (n = 10; 28%). Mean follow-up was nine years (SD 4).

Results: There was no difference in the mean age (p = 0.63), sex (p = 0.110), tumour volume (p = 0.646), or type of resection carried out (p > 0.05) between patients with and without reconstruction. Of the original 66 patients, 61 (92%) were ambulant at final follow-up. There was no difference in the proportion of patients who could walk in the reconstruction and 'no reconstruction' groups (p = 0.649). There was no difference in the mean Musculoskeletal Tumor Society (MSTS) score between patients who were reconstructed and those who were not (61% vs 56%; p = 0.378). Patients with a tantalum THA had a significantly (p = 0.015) higher mean MSTS score (78%) than those who were reconstructed with a saddle prosthesis (47%) or who had not been reconstructed (56%). Patients who had undergone reconstruction were more likely to have complications (81% vs 53%; p = 0.033).

Conclusion: Reconstruction after resection of the acetabulum is technically demanding. In selected cases, reconstruction is of benefit, especially when reconstruction is by tantalum THA; however, the follow-up for these patients remains mid-term. When not feasible, patients with no reconstruction have an acceptable functional outcome. Level of Evidence: Level III Therapeutic. Cite this article: 2021;103-B(2):391-397.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1302/0301-620X.103B2.BJJ-2020-1012.R1DOI Listing
February 2021

Osteosarcoma and soft-tissue sarcomas with an immune infiltrate express PD-L1: relation to clinical outcome and Th1 pathway activation.

Oncoimmunology 2020 03 18;9(1):1737385. Epub 2020 Mar 18.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.

Immune checkpoint proteins, such as PD-L1 and PD-1, are important in several cancers; however, their role in osteosarcoma (OSA) and soft tissue sarcoma (STS) remains unclear. Our aims were to determine whether subsets of OSA/STS harbor tumor-infiltrating lymphocytes (TILs) and express PD-L1, and how PD-L1 expression is related to clinical outcome. Tissue sections of 25 cases each of untreated undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma (MFS), liposarcoma (LPS) and 24 of leiomyosarcoma (LMS) were subjected to immunohistochemistry (IHC) for immune cells, PD-L1 and PD-1. RT-qPCR was utilized to quantify levels of PD-L1 mRNA from 33 UPS, 57 MFS and 79 OSA primary-untreated specimens. PD-L1 mRNA levels were tested for their correlation with overall survival in patients presenting without metastases. Transcriptome analysis evaluated biological pathway differences between high and low PD-L1 expressers. A subset of UPS and MFS contained TILs and expressed PD-L1 and PD-1; LMS and LPS did not. PD-L1 levels by IHC and RT-qPCR were positively correlated. PD-L1 over-expression was associated with better survival for UPS and OSA, but not MFS. The Th1 pathway was significantly activated in UPS with high levels of PD-L1 and improved survival. Some sarcoma subtypes harbor TILs and express PD-L1. Patients with UPS and OSA with high levels of PD-L1 had better overall survival than those with low expression levels. Important biological pathways distinguish PD-L1 high and low groups. The stratification of patients with OSA/STS with respect to potential immune therapies may be improved through investigation of the expression of immune cells and checkpoint proteins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1737385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790526PMC
March 2020

The role of Denosumab in joint preservation for patients with giant cell tumour of bone.

Bone Joint J 2021 Jan;103-B(1):184-191

University Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

Aims: Local recurrence remains a challenging and common problem following curettage and joint-sparing surgery for giant cell tumour of bone (GCTB). We previously reported a 15% local recurrence rate at a median follow-up of 30 months in 20 patients with high-risk GCTB treated with neoadjuvant Denosumab. The aim of this study was to determine if this initial favourable outcome following the use of Denosumab was maintained with longer follow-up.

Methods: Patients with GCTB of the limb considered high-risk for unsuccessful joint salvage, due to minimal periarticular and subchondral bone, large soft tissue mass, or pathological fracture, were treated with Denosumab followed by extended intralesional curettage with the goal of preserving the joint surface. Patients were followed for local recurrence, metastasis, and secondary sarcoma.

Results: A total of 25 patients with a mean age of 33.8 years (18 to 67) with high-risk GCTB received median six cycles of Denosumab before surgery. Tumours occurred most commonly around the knee (17/25, 68%). The median follow-up was 57 months (interquartile range (IQR) 13 to 88). The joint was salvaged in 23 patients (92%). Two required knee arthroplasty due to intra-articular fracture and arthritis. Local recurrence developed in 11 patients (44%) at a mean of 32.5 months (3 to 75) following surgery, of whom four underwent repeat curettage and joint salvage. One patient developed secondary osteosarcoma and another benign GCT lung metastases.

Conclusion: The use of Denosumab for joint salvage was associated with a higher than expected rate of local recurrence at 44%. Neoadjuvant Denosumab for joint-sparing procedures should be considered with caution in light of these results. Cite this article: 2021;103-B(1):184-191.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1302/0301-620X.103B1.BJJ-2020-0274.R1DOI Listing
January 2021

Development and external validation of nomograms to predict sarcoma-specific death and disease progression after surgical resection of localized high-grade conventional primary central chondrosarcoma and dedifferentiated chondrosarcoma.

Bone Joint J 2020 Dec;102-B(12):1752-1759

Department of Oncology, Royal Orthopaedic Hospital, Birmingham, UK.

Aims: Our aim was to develop and validate nomograms that would predict the cumulative incidence of sarcoma-specific death (CISSD) and disease progression (CIDP) in patients with localized high-grade primary central and dedifferentiated chondrosarcoma.

Methods: The study population consisted of 391 patients from two international sarcoma centres (development cohort) who had undergone definitive surgery for a localized high-grade (histological grade II or III) conventional primary central chondrosarcoma or dedifferentiated chondrosarcoma. Disease progression captured the first event of either metastasis or local recurrence. An independent cohort of 221 patients from three additional hospitals was used for external validation. Two nomograms were internally and externally validated for discrimination (c-index) and calibration plot.

Results: In the development cohort, the CISSD at ten years was 32.9% (95% confidence interval (CI) 19.8% to 38.4%). Age at diagnosis, grade, and surgical margin were found to have significant effects on CISSD and CIDP in multivariate analyses. Maximum tumour diameter was also significantly associated with CISSD. In the development cohort, the c-indices for CISSD and CIDP at five years were 0.743 (95% CI 0.700 to 0.819) and 0.761 (95% CI 0.713 to 0.800), respectively. When applied to the validation cohort, the c-indices for CISSD and CIDP at five years were 0.839 (95% CI 0.763 to 0.916) and 0.749 (95% CI 0.672 to 0.825), respectively. The calibration plots for these two nomograms demonstrated good fit.

Conclusion: Our nomograms performed well on internal and external validation and can be used to predict CISSD and CIDP after resection of localized high-grade conventional primary central and dedifferentiated chondrosarcomas. They provide a new tool with which clinicians can assess and advise individual patients about their prognosis. Cite this article: 2020;102-B(12):1752-1759.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1302/0301-620X.102B12.BJJ-2020-0810.R1DOI Listing
December 2020

Clinical outcomes of non-osteogenic, non-Ewing soft-tissue sarcoma of bone--experience of the Toronto Sarcoma Program.

Cancer Med 2020 12 16;9(24):9282-9292. Epub 2020 Oct 16.

Toronto Sarcoma Program at Mount Sinai Hospital, Toronto, Canada.

Non-osteogenic, non-Ewing soft-tissue sarcoma (NONE-STS) of bone is a rare presentation of primary bone cancers. Optimal treatments and outcomes for this heterogenous group are poorly described. We evaluated the factors associated with long-term outcomes in patients with this disease. Patients with localized NONE-STS of bone treated at the Toronto Sarcoma Program from 1987 to 2017 were identified. Clinical characteristics, treatment, and survival information were collected. Kaplan-Meier (log-rank) survival estimates from the time of definitive surgery, with uni-/multivariate analyses (Cox) of sarcoma-specific survival were performed. A total of 106 patients (60.4% male; median age 46 years) with NONE-STS of bone were identified. Common histologies included undifferentiated pleomorphic sarcoma [UPS]/malignant fibrous histiocytoma [MFH] (UPS/MFH, 41.5%), leiomyosarcoma (LMS, 20.8%), and fibrosarcoma (FS, 11.3%). Tumors were often high grade (59.4%) and involved the extremities (88.7%), with most receiving chemotherapy (67.9%) with cisplatin/doxorubicin-based regimens (73.6%). In the full cohort, 10-year DFS (45.7%, [95%CI: 35.7-55.8%]), OS (53.4%, [95%CI: 41.7-62.2%]), and SSS (63.9%, [95%CI: 53.9-72.5%]) were moderate. Histology specific, 10-year SSS was 70.7% [95%CI: 56.1-85.5%] for UPS/MFH, 51.8% [95%CI: 29.8-73.8%] for LMS, and 72.2% [95%CI: 45.1-99.2%] for FS. Only UPS/MFH (n = 4) showed sarcoma-related death >10 years. Multivariate analysis identified axial location (HR = 35.5, [95%CI: 3.4-369.6]), high grade (HR = 16.9, [95%CI: 1.6-185.1]), and disease relapse (HR = 485.1, [95%CI: 36.3-6482.6]) as risk factors for death (p < 0.05). Treatment with chemotherapy (HR = 0.1, [95%CI: 0.01-0.86]) and necrosis ≥85% (HR = 0.2, [95%CI: 0.04-0.99]) showed improved survival (p < 0.05). NONE-STS of bone has favorable long-term survival similar to osteosarcoma. Patients receiving chemotherapy derive benefit in retrospective analyses. UPS/MFH histologies show sarcoma-related death beyond 10 years. Further data on histologic subgroups are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774718PMC
December 2020

RNA expression profiling reveals PRAME, a potential immunotherapy target, is frequently expressed in solitary fibrous tumors.

Mod Pathol 2021 05 2;34(5):951-960. Epub 2020 Oct 2.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-00687-5DOI Listing
May 2021

The Toronto Sarcoma Flap Score: A Validated Wound Complication Classification System for Extremity Soft Tissue Sarcoma Flap Reconstruction.

Ann Surg Oncol 2021 Jun 1;28(6):3345-3353. Epub 2020 Oct 1.

Division of Plastic and Reconstructive Surgery, Department of Surgical Oncology, University Health Network, Toronto, ON, Canada.

Background: Flap reconstruction plays an important role in limb preservation after wide resection of extremity soft tissue sarcoma (ESTS), but can be associated with high rates of postoperative wound complications. Currently, no standardized system exists for the classification of these complications. This study aimed to develop a standardized classification system for wound complications after ESTS flap reconstruction.

Methods: Outcomes of ESTS flap reconstructions were analyzed in a retrospective cohort of 300 patients. All wound- and flap-related complications were identified and categorized. Based on these data, a scoring system was developed and validated with a prospective cohort of 100 patients who underwent ESTS flap reconstruction.

Results: A 10-point scoring system was developed based on the level of intervention required to treat each complication observed in the retrospective cohort. Raters applied the scoring system to the prospective patient cohort. Validation studies demonstrated excellent inter-rater and intra-rater reliability (weighted Cohen's kappa range, 0.82 [95% CI, 0.5-1.0] to 0.99 [95% CI, 0.98-1.0] and 0.95 [95% CI, 0.84-1.0] to 0.97 [95% CI, 0.92-1.0], respectively). The majority of the raters reported the score to be simple, objective, and reproducible (respective mean scores, 4.76 ± 0.43, 4.53 ± 0.62, and 4.56 ± 0.56 on 5-point Likert scales).

Conclusion: The Toronto Sarcoma Flap Score (TSFS) is a simple and objective classification system with excellent inter- and intra-rater reliability. Universal adoption of the TSFS could standardize outcome reporting in future studies and aid in the establishment of clinical benchmarks to improve the quality of care in sarcoma reconstruction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-09166-2DOI Listing
June 2021

H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone.

Cancer Discov 2020 12 23;10(12):1968-1987. Epub 2020 Sep 23.

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR-Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a osteoblast-like progenitor population toward an myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. SIGNIFICANCE: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-20-0461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710565PMC
December 2020

Curability of patients with lymph node metastases from extremity soft-tissue sarcoma.

Cancer 2020 12 10;126(23):5098-5108. Epub 2020 Sep 10.

Musculoskeletal Oncology Unit, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: Lymph node metastases (LNM) rarely occur in adult extremity soft-tissue sarcoma (STS), affecting approximately 5% of patients. To the authors' knowledge, few studies to date have evaluated the prognosis and survival of patients with LNM.

Methods: A retrospective review was performed of a single-center, prospectively collected STS database. Demographic, treatment, and oncologic data for patients with STS of the extremity with LNM were obtained from clinical and radiographic records.

Results: Of 2689 patients with extremity STS, a total of 120 patients (4.5%) were diagnosed with LNM. LNM occurred most frequently among patients diagnosed with clear cell sarcoma (27.6%), epithelioid sarcoma (21.9%), rhabdomyosarcoma (17.3%), angiosarcoma (14.0%), and extraskeletal myxoid chondrosarcoma (9.3%). A total of 98 patients (81.7%) underwent LNM surgical resection. Patients with isolated LNM had a greater 5-year overall survival (57.3%) compared with patients with American Joint Committee on Cancer (AJCC) eighth edition stage IV STS with only systemic metastases (14.6%) or both LNM and systemic disease (0%; P < .0001). Patients with isolated LNM had an overall survival rate (52.9%) similar to that of patients with localized AJCC stage III tumors (ie, large, high-grade tumors) (49.3%) (P = .8). Patients with late, isolated, metachronous LNM had a 5-year overall survival rate (61.2%) that was similar to that of patients with isolated synchronous LNM at the time of presentation (53.6%) (P = .4).

Conclusions: Many different types of STS develop LNM. Patients with extremity STS with isolated LNM should not be considered as having stage IV disease as they are according to the current AJCC eighth edition classification because they have significantly better survival than those with systemic metastases. Patients with isolated, late, metachronous LNM have a survival similar to that of patients with isolated synchronous LNM at the time of presentation.

Lay Summary: The results of the current study demonstrated that patients diagnosed with isolated lymph node metastases have a prognosis similar to that of patients diagnosed with localized American Joint Committee on Cancer stage III soft-tissue sarcomas, which also equates to a significantly better overall survival compared with patients with systemic metastases. Therefore, the authors recommend modifications to the most recent eighth edition of the American Joint Committee on Cancer staging system to clearly distinguish patients with isolated lymph node metastases to acknowledge their better prognosis compared with those with systemic metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33189DOI Listing
December 2020

Comparison of Porous Tantalum Acetabular Implants and Harrington Reconstruction for Metastatic Disease of the Acetabulum.

J Bone Joint Surg Am 2020 Jul;102(14):1239-1247

Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota.

Background: The periacetabular region is a common location for metastatic disease. Although large lytic acetabular defects are commonly treated with a hip arthroplasty with a cemented component according to a Harrington-style reconstruction, the use of highly porous uncemented tantalum acetabular components has been described. Currently, there are no direct comparisons of these reconstructive techniques. The purpose of this study was to compare the outcomes of the Harrington technique and tantalum acetabular component reconstruction for periacetabular metastases.

Methods: From 2 tertiary sarcoma centers, we retrospectively reviewed 115 patients (70 female and 45 male) with an acetabular metastatic defect who had been treated between 2002 and 2015 with a total hip arthroplasty using either the cemented Harrington technique (78 patients) or a tantalum acetabular reconstruction (37 patients). The mean patient age was 61 years, and the most common Eastern Cooperative Oncology Group status was 3 (39 patients). The mean follow-up for surviving patients was 4 years.

Results: An additional surgical procedure was performed in 24 patients (21%). Harrington-style reconstructions were more likely to require a reoperation compared with tantalum reconstructions (hazard ratio [HR], 4.59; p = 0.003). The acetabular component was revised in 13 patients (11%); 5 patients (4%) underwent revisions that were due to loosening of the acetabular component. The 10-year cumulative incidence of revision of the acetabular component for loosening was 9.6% in the Harrington group and 0% in the tantalum group (p = 0.09). The mean Harris hip score significantly improved following reconstruction (31 to 67 points; p < 0.001), with no significant difference (p = 0.29) between groups.

Conclusions: In patients with periacetabular metastatic disease treated with total hip arthroplasty, an acetabular reconstruction strategy utilizing highly porous tantalum acetabular components and augments successfully provided patients with a more durable construct with fewer complications compared with the cemented Harrington-style technique.

Levels Of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2106/JBJS.19.01189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431144PMC
July 2020

The Long Noncoding RNA Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways.

Mol Cancer Res 2020 10 19;18(10):1534-1544. Epub 2020 Jun 19.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Soft-tissue sarcomas (STS) are rare malignancies showing lineage differentiation toward diverse mesenchymal tissues. Half of all high-grade STSs develop lung metastasis with a median survival of 15 months. Here, we used a genetically engineered mouse model that mimics undifferentiated pleomorphic sarcoma (UPS) to study the molecular mechanisms driving metastasis. High-grade sarcomas were generated with Cre recombinase technology using mice with conditional mutations in and (KP) genes. After amputation of the limb bearing the primary tumor, mice were followed for the development of lung metastasis. Using RNA-sequencing of matched primary KP tumors and lung metastases, we found that the long noncoding RNA (lncRNA) Nuclear Enriched Abundant Transcript 1 () is significantly upregulated in lung metastases. Furthermore, RNA ISH of human UPS showed that is upregulated within a subset of lung metastases compared with paired primary UPS. Remarkably, CRISPR/Cas9-mediated knockout of suppressed the ability of KP tumor cells to colonize the lungs. To gain insight into the underlying mechanisms by which the lncRNA promotes sarcoma metastasis, we pulled down RNA and used mass spectrometry to identify interacting proteins. Interestingly, most interacting proteins are involved in RNA splicing regulation. In particular, KH-Type Splicing Regulatory Protein (KHSRP) interacts with and is associated with poor prognosis of human STS. Moreover, depletion of KHSRP suppressed the ability of KP tumor cells to colonize the lungs. Collectively, these results suggest that and its interacting proteins, which regulate RNA splicing, are involved in mediating sarcoma metastasis. IMPLICATIONS: Understanding that lncRNA promotes sarcoma metastasis, at least in part, through interacting with the RNA splicing regulator KHSRP may translate into new therapeutic approaches for sarcoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1541-7786.MCR-19-1170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541426PMC
October 2020

Designing a Rational Follow-Up Schedule for Patients with Extremity Soft Tissue Sarcoma.

Ann Surg Oncol 2020 Jun 9;27(6):2033-2041. Epub 2020 Mar 9.

University Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Purpose: The risk of tumor recurrence after resection of soft tissue sarcoma (STS) necessitates surveillance in follow-up. The objective of this study was to determine the frequency/timing of metastasis and local recurrence following treatment for soft tissue sarcoma, and to use these data to justify an evidence-based follow-up schedule.

Methods: Utilizing a prospective database, a retrospective single center review was performed of all patients with minimum 2-year follow-up after resection of a localized extremity STS. Kaplan-Meier estimates were used to calculate the incidence of local recurrence and metastases on an annual basis for 10 years.

Results: We identified a total of 230 low-grade, 626 intermediate-grade and 940 high-grade extremity STS and a total of 721 events, 150 local recurrences and 571 metastases. Based on tumor size and grade, follow-up cohorts were developed that had similar metastatic risk. Using pre-determined thresholds for metastatic event, a follow-up schedule was established for each cohort.

Conclusion: Based on our results we recommend that patients with small low-grade tumors undergo annual follow-up for 5 years following definitive local treatment. Patients with large low-grade tumors, small intermediate-grade and small high-grade tumors should have follow-up every 6 months for the first 2 years, then yearly to 10 years. Only patients with large intermediate- or high-grade tumors require follow-up every 3 months for the first 2 years, then every 6 months for years 3-5, followed by annually until 10 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1245/s10434-020-08240-zDOI Listing
June 2020

Author Correction: Human somatic cell mutagenesis creates genetically tractable sarcomas.

Nat Genet 2020 Apr;52(4):464

Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-0589-2DOI Listing
April 2020

Midterm Success of a Custom, Non-Fluted, Diaphyseal, Press-Fit Stem Used With a Tumor Megaprosthesis System.

J Arthroplasty 2020 05 31;35(5):1333-1338. Epub 2019 Dec 31.

Department of Orthopaedic Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Background: High rates of aseptic loosening with cemented prostheses have led to increased utilization of uncemented stems in the setting of megaprosthetic reconstruction. Theoretic concerns of rotational instability resulted in early stem designs with de-rotational mechanisms such as flutes or side plates. However, these designs have their own associated complications, and mechanical data suggest they are unnecessary. The purpose of this study is to evaluate outcomes and survivorship of an unfluted diaphyseal press-fit stem in the setting of megaprosthetic reconstruction.

Methods: Forty-five patients (46 stems), with a minimum 3-year follow-up, underwent reconstruction using 1 of 2 fully porous coated, unfluted, press-fit stems between 2005 and 2013: revision stem with adapter to the megaprosthesis (revision stem), or custom megaprosthesis stem (custom stem). Complications were described using the Henderson classification system, and subanalyses evaluated stem-related failures and survival. Radiographic evaluation of stem fixation was determined via evidence of bone bridging, spot welding, resorption, subsidence, and pedestal formation. Four patients had early stem removal for local recurrence or infection and were thus excluded from the radiographic analyses.

Results: Twenty-eight femoral (15 revision stem, 13 custom stem) and 14 tibial (6 revision stem, 8 custom stem) stems were reviewed. Average follow-up was 81 months (range, 42-140 months). Revision for implant-related complications occurred in 7 of 41 (17%), all in revision stems (3 adapter failures, 4 polyethylene wear). At final follow-up, all stems were retained without evidence of aseptic loosening, although 7 of 41 (17%) exhibited mild stress shielding.

Conclusion: A non-fluted, press-fit stem used with a tumor prosthesis provided a stable bone-prosthesis interface at midterm follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.arth.2019.12.032DOI Listing
May 2020

Can the ACS-NSQIP surgical risk calculator predict postoperative complications in patients undergoing sacral tumor resection for chordoma?

J Surg Oncol 2020 May 7;121(6):1036-1041. Epub 2020 Feb 7.

University Musculoskeletal Oncology Unit Mount Sinai Hospital, Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Toronto, Canada.

Background And Objectives: The ACS-NSQIP surgical risk calculator is an online tool that estimates the risk of postoperative complications. Sacrectomies for chordoma are associated with a high rate of complications. This study was to determine if the ACS-NSQIP calculator can predict postoperative complications following sacrectomy.

Methods: Sixty-five (42 male, 23 female) patients who underwent sacrectomy were analyzed using the Current Procedural Terminology (CPT) codes: 49215 (excision of presacral/sacral tumor), 63001 (laminectomy of sacral vertebrae), 63728 (laminectomy for biopsy/excision of sacral neoplasm) and 63307 (sacral vertebral corpectomy for intraspinal lesion). The predicted rates of complications were compared to the observed rates.

Results: Complications were noted in 44 (68%) patients. Of the risk factors available to input to the ACS-NSQIP calculator, tobacco use (OR, 20.4; P < .001) was predictive of complications. The predicted risk of complications based off the CPT codes were: 49215 (16%); 63011 (6%); 63278 (11%) and 63307 (15%). Based on ROC curves, the use of the ACS-NSQIP score were poor predictors of complications (49215, AUC 0.65); (63011, AUC 0.66); (63307, AUC 0.67); (63278, AUC 0.64).

Conclusion: The ACS-NSQIP calculator was a poor predictor of complications and was marginally better than a coin flip in its ability to predict complications following sacrectomy for chordoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25865DOI Listing
May 2020

Advancing patient age is associated with worse outcomes in low- and intermediate-grade primary chondrosarcoma of the pelvis.

J Surg Oncol 2020 Mar 27;121(4):638-644. Epub 2020 Jan 27.

Division of Orthopaedic Surgery, Department of Surgery, University Musculoskeletal Oncology Unit, Mount Sinai Hospital, University of Toronto, Toronto, Canada.

Background: Conventional primary pelvic chondrosarcoma often presents as a low- or intermediate-grade tumor in older patients. Although this is the most common variant of pelvic chondrosarcoma, studies examining treatment outcomes are lacking. The purpose of this study was to evaluate patients with these tumors to determine their outcomes of treatment.

Methods: Seventy-three patients (grade I [n = 19, 26%] and grade II [n = 54, 74%]) were reviewed including 55 (75%) males and 18 (25%) females, with a mean age of 51 (range, 17-81) years and follow-up of 9 ± 5 years.

Results: The 10-year disease-specific survival was 71%. Grade II disease (hazard ratio [HR], 6.74; P = .04) and age ≥50 years (HR, 3.97; P = .02) was associated with death due to disease. The 10-year local recurrence- and metastatic-free survival were 79% and 72%. Of the patients with a local recurrence (n = 11), 7 (64%) recurred at a higher histological grade. Patient age ≥50 years was associated with local recurrence (HR, 10.03; P = .02) and metastatic disease (HR, 4.20; P = .02).

Conclusion: Advancing patient age was an independent risk factor for worse survival and disease recurrence. Tumors often recurred locally at a higher grade and as such wide local excision remains the treatment of choice for these tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25854DOI Listing
March 2020

Development and external validation of a dynamic prognostic nomogram for primary extremity soft tissue sarcoma survivors.

EClinicalMedicine 2019 Dec 22;17:100215. Epub 2019 Nov 22.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133 , Italy.

Background: Prognostic nomograms for patients with extremity soft tissue sarcoma (eSTS) typically predict survival or the occurrence of local recurrence or distant metastasis at time of surgery. Our aim was to develop and externally validate a dynamic prognostic nomogram for overall survival in eSTS survivors for use during follow-up.

Methods: All primary eSTS patients operated with curative intent between 1994 and 2013 at three European and one Canadian sarcoma centers formed the development cohort. Patients with Fédération Française des Centres de Lutte Contre le Cancer (FNCLCC) grade II and grade III eSTS operated between 2000 and 2016 at seven other European reference centers formed the external validation cohort. We used a landmark analysis approach and a multivariable Cox model to create a dynamic nomogram; the prediction window was fixed at five years. A backward procedure based on the Akaike Information Criterion was adopted for variable selection. We tested the nomogram performance in terms of calibration and discrimination.

Findings: The development and validation cohorts included 3740 and 893 patients, respectively. The variables selected applying the backward procedure were patient's age, tumor size and its interaction with landmark time, tumor FNCLCC grade and its interaction with landmark time, histology, and both local recurrence and distant metastasis (as first event) indicator variables. The nomogram showed good calibration and discrimination. Harrell C indexes at different landmark times were between 0.776 (0.761-0.790) and 0.845 (0.823-0.862) in the development series and between 0.675 (0.643-0.704) and 0.810 (0.775-0.844) in the validation series.

Interpretation: A new dynamic nomogram is available to predict 5-year overall survival at different times during the first three years of follow-up in patients operated for primary eSTS. This nomogram allows physicians to update the individual survival prediction during follow-up on the basis of baseline variables, time elapsed from surgery and first-event history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933187PMC
December 2019

The role of chemotherapy and radiotherapy in localized extraskeletal osteosarcoma.

Eur J Cancer 2020 01 2;125:130-141. Epub 2019 Dec 2.

Japanese Musculoskeletal Oncology Group, Tokyo, Japan.

Purpose: The role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the association between CT/RT with recurrence and survival.

Patients And Methods: Retrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan-Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed.

Results: 370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n = 294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%-62%). Almost half of patients (n = 173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p = 0.50, systemic p = 0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 [95% CI 0.26-0.80], p = 0.01).

Conclusion: Although the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.07.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261507PMC
January 2020

Association between patient age and the risk of mortality following local recurrence of a sacral chordoma.

J Surg Oncol 2019 Nov 22. Epub 2019 Nov 22.

University Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

Background: Local recurrence (LR) of sacral chordoma is a difficult problem and the mortality risk associated with LR remains poorly described. The purpose of this study was to evaluate the risk of mortality in patients with LR and determine if patient age is associated with mortality.

Methods: A total of 218 patients (144 male, 69 female; mean age 59 ± 15 years) with sacrococcygeal chordomas were reviewed. Cumulative incidence functions and competing risks for death due to disease and nondisease mortality were employed to analyze mortality trends following LR.

Results: The 10-year overall survival (OS) was 55%. Patients with LR had 44% 10-year OS, similar to patients without (59%; P = .38). The 10-year OS between those less than 55 compared with ≥55 years were similar (69% vs 48%; P = .52). The 10-year death due to disease was worse in patients with LR compared with those without (44% vs 84%; P < .001). In patients without LR, patients ≥55 years were 1.6-fold more likely to experience death due to other causes.

Conclusions: Patients with an LR are more likely to die due to disease. Advanced patient age was associated with higher all-cause mortality following resection of sacral chordoma. LR of chordoma was associated with increased disease-specific mortality, regardless of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jso.25774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242148PMC
November 2019

Radial Neck-to-Humerus Transposition for Elbow Reconstruction Following Oncologic Resection of the Proximal Ulna: A Report of Two Cases.

JBJS Case Connect 2019 Dec;9(4):e0451

University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Department of Surgery, University of Toronto, Toronto, ON, Canada.

Case: Two young adult (aged 25 and 21 years) patients presented with sarcomas of the proximal ulna. To achieve an oncological margin, the proximal ulna required resection. Owing to the complex biomechanics of the elbow joint, reconstructive options are limited and have a high complication rate. The elbow was reconstructed with a transposition of the radial neck to the trochlea of the humerus in both patients. At over 2 years of follow-up, both patients have a stable and functional elbow.

Conclusions: Transposition of the radial neck to the trochlea of the humerus provides a biological reconstruction in this complex problem.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2106/JBJS.CC.18.00451DOI Listing
December 2019
-->