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Summary: Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

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: Bone Joint Res 2021;10(9):602–610.

Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.

Background:. Computer-assisted surgery (CAS) can improve surgical precision in orthopaedic oncology. Accurate alignment of the patient’s imaging coordinates with the anatomy, known as registration, is one of the most challenging aspects of CAS and can be associated with substantial error. Using intraoperative, on-the-table, cone-beam computed tomography (CBCT), we performed a pilot clinical study to validate a method for automatic intraoperative registration. Methods:. Patients who were ≥18 years of age, had benign bone tumors, and underwent resection were prospectively enrolled. In addition to inserting a navigation tracking tool into the exposed bone adjacent to the surgical field, 2 custom plastic ULTEM tracking tools (UTTs) were attached to each patient’s skin adjacent to the tumor using an adhesive. These were automatically localized within the 3-dimensional CBCT volume to be used as image landmarks for registration, and the corresponding tracker landmarks were captured using an infrared camera. The main outcomes were the fiducial registration error (FRE) and the target registration error (TRE). The navigation time was recorded. Results:. Thirteen patients with benign tumors in the femur (n = 10), tibia (n = 2), and humerus (n = 1) underwent navigation-assisted resections. The mean values were 0.67 ± 0.15 mm (range, 0.47 to 0.97 mm) for FRE and 0.83 ± 0.51 mm (range, 0.42 to 2.28 mm) for TRE. Registration was successful in all cases. The mean time for CBCT imaging and tracker registration was 7.5 minutes. Conclusions:. We present a novel automatic registration method for CAS exploiting intraoperative CBCT capabilities, which provided improved accuracy and reduced operative times compared with more traditional methods. Clinical Relevance:. This proof-of-principle study validated a novel process for automatic registration to improve the accuracy of resecting bone tumors using a surgical navigation system.

Abstract 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.

Synopsis. For ALTs, the utility of chest surveillance has not been well defined. This study suggests that chest imaging does not have a significant role in the surveillance of ALTs. Advanced local imaging and more intensive chest surveillance may be considered in cases of local recurrence. 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.

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.

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. Keywords: Dynamic prediction, Landmark analysis, Prognostic nomogram, Sarcoma, Soft tissue sarcoma: Survivors

The cell of origin for most mesenchymal tumors is unclear. One cell type that contributes to this lineages is the pericyte, a cell expressing Ng2/Cspg4. Using lineage tracing, we demonstrated that bone and soft tissue sarcomas driven by the deletion of the Trp53 tumor suppressor, or desmoid tumors driven by a mutation in Apc, can derive from cells expressing Ng2/Cspg4. Deletion of the Trp53 tumor suppressor gene in these cells resulted in the bone and soft tissue sarcomas that closely resemble human sarcomas, while stabilizing β-catenin in this same cell type caused desmoid tumors. Comparing expression between Ng2/Cspg4-expressing pericytes lacking Trp53 and sarcomas that arose from deletion of Trp53 showed inhibition of β-catenin signaling in the sarcomas. Activation of β-catenin inhibited the formation and growth of sarcomas. Thus, pericytes can be a cell of origin for mesenchymal tumors, and β-catenin dysregulation plays an important role in the neoplastic phenotype.

It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk

Abstract Objective This study was aimed to describe perinatal outcome of a cohort of pregnant patients with bone and soft tissue tumors and to compare the current series with our group's previously reported experience. Methods Pregnant women diagnosed before and during pregnancy were identified, retrospectively, for the years 2004 to 2014. Relevant maternal and neonatal data were collected. Results Forty-eight patients were identified. Ten cases were diagnosed during pregnancy. Pelvis, abdomen, and extremities were the most common tumor locations. Osteosarcoma, liposarcoma, and Ewing's sarcoma were the most common histological types and comprise more than 50% of the cases. Metastases occurred in nine cases. Most of the cases (60%) were treated surgically during pregnancy and delivery occurred at term. Chemotherapy was delayed until after delivery. There were no perinatal or infant deaths. Patients presented with advanced maternal disease in 18% in previous report (1983–2003) versus 40% in present report (2004–2014). Metastases were present in 40% and maternal death rate was approximately 20% in both cohorts. Conclusion Pregnant women with bone and soft tissue tumors are candidates for standard surgical management during pregnancy. Other treatments, such as chemotherapy and radiotherapy must be evaluated for each woman on a case-by-case basis. Iatrogenic prematurity was common in our findings.

Developing multiple soft tissue sarcomas (STSs) is a rare process, sparsely reported in the literature to date. Little is known about the pattern of disease development or outcomes in these patients. Patients were identified from three tertiary orthopaedic oncology centres in Canada and the UK. Patients who developed multiple extremity STSs were collated retrospectively from prospective oncology databases. A literature review using MEDLINE was also performed. Six patients were identified in the case series from these three institutions, and five studies were identified from the literature review. Overall, 17 patients were identified with a median age of 51 years (range: 19 to 77). The prevalence of this manifestation in STS patients is 1 in 1225. The median disease-free interval between diagnoses was 2.3 years (range: 0 to 19 years). Most patients developed the secondary STS in a metachronous pattern, the remaining, synchronously. The median survival after the first sarcoma was 6 years, and it was 1.6 years after the second sarcoma. The 5-year overall survival rate was 83.3% and 50% following the first and second STS diagnoses, respectively. A diagnosis of two STSs does not confer a worse prognosis than the diagnosis of a single STS. Developing a second STS is a rare event with no identifiable histological pattern of occurrence. Presentation in a metachronous pattern is more common. A high degree of vigilance is required in patients with a previous STS both to detect both local recurrence and to identify new masses remote from the previous STS site. Acquiring an early histological diagnosis should be attempted.

Objective:. Soft-tissue sarcomas are most frequently located deep within myofascial compartments. Superficial soft-tissue sarcomas (S-STS) are relatively less common and may be managed differently than deep sarcomas because generous resection margins are often possible without sacrificing critical structures. We sought to investigate the frequency and types of soft-tissue reconstructive procedures that are required following excision of S-STS. Methods:. We reviewed 457 consecutively treated patients with S-STS with a minimum 2-year follow-up from our prospectively maintained database between 1989 and 2009. Results:. Mean follow-up was 10.5 years (range, 2–23). Four hundred twenty-one tumors (91%) were excised with negative margins, 38 (8.3%) had microscopically positive margins, and three (0.7%) had grossly positive margins. One patient required an amputation. In 271 (58%) patients, the wounds were closed primarily. In comparison, 93 patients (20%) required a rotation flap, 70 (15%) required a split-thickness skin graft, and 23 (5%) underwent a free tissue transfer (ie, advanced reconstructive procedure). The overall complication rate was 12%, although 43% of patients undergoing free tissue transfer developed complications (P = 0.04). An unplanned excision before referral to our center was a risk factor for local recurrence (P = 0.03) when residual tumor was recovered in the reexcision specimen pathologically. Conclusions:. Although concern about the morbidity associated with a free tissue transfer (ie, advanced reconstructive procedure) may potentially limit the adequacy of resection in some patients with S-STS, the results of this study showed that the majority of patients had complete excisions with negative margins and primary closure. Obtaining a negative margin when excising a known or suspected S-STS rarely requires an advanced reconstructive procedure and almost never results in loss of limb.

Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high-grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration.

Purpose. Although pre-operative chemotherapy has improved the prognosis for individuals with osteosarcoma, approximately 40% of patients will die of their disease.The aim of this study was to quantitate proliferative activity in high grade osteosarcomas and to determine whether proliferation is a prognostic factor.

Purpose. The aims of this study were to describe the symptoms experienced by patients in the first year following treatment for lower extremity sarcoma by limb conservation and to describe the relationship between symptoms and physical disability.

Discussion. Thirty of 36 patients (83%) presenting with foot and ankle STS or fibromatosis were candidates for limb preservation. With excellent local control and good functional outcome demonstrated in this study, limb salvage should be a primary goal in the management of selected patients with STS and fibromatosis of the foot and ankle.

Background and Purpose. Lymphoedema is a serious complication following limb salvage for extremity soft tissue sarcomas (STSs) for which little is known. We aimed to evaluate its incidence, its, severity and its associated risk factors. Material and Method. Patient and tumor characteristics, treatment modalities and complications and functional outcomes (MSTS 1987, TESS), and lymphoedema severity (Stern) were all collected from prospective databases. Charts were retrospectively abstracted for BMI and comorbidities. Results. There were 289 patients (158 males). Mean age was 53 (16–88). Followup ranged between 12 and 60 months with an average of 35 and a median of 36 months. Mean BMI was 27.4 (15.8–52.1). 72% had lower extremity tumors and 38% upper extremity. Mean tumor size was 8.1 cm (1.0–35.6 cm). 27% had no adjuvant radiation, 62% had 50 Gy, and 11% received 66 Gy. The incidence of lymphoedema was 28.8% (206 none, 58 mild, 22 moderate, 3 severe, and 0 very severe). Mean MSTS score was 32 (11–35) and TESS was 89.4 (32.4–100). Radiation dose was significantly correlated with tumor size>5 cm (P=0.0001) and TESS score (P=0.001), but not MSTS score (P=0.090). Only tumor size>5 cm and depth were found to be independent predictors of significant lymphoedema. Conclusion. Nine percent of STS patients in our cohort developed significant (grade≥2) lymphoedema. Tumor size>5 cm and deep tumors were associated with an increased occurrence of lymphoedema but not radiation dosage.

Introduction. Ewing's sarcomas (EWSs) of bone and soft tissue are neuroectodermal tumors that affect both axial and appendicular locations. We hypothesized that axial location predicted poor outcome in EWS patients. Materials and Methods. Sixty-seven patients (57 with bone EWS and 10 with soft tissue EWS) were identified from our database. Thirty-four (51%) had axial EWS and 33 (49%) had appendicular EWS. Statistical analyses identified predictors of poor outcome. Results and Discussion. Axial location, large size, metastases at presentation, lack of definitive treatment, and positive surgical margins all correlated with poor outcome in univariate analysis. In multivariate analysis, axial location still predicted poor outcome when adjusted for pretreatment variables. Axial location was not statistically predictive of poor outcome when adjusted for treatment variables. Conclusions. Anatomic location has a negative effect on outcome in EWS that cannot be completely explained by pretreatment or treatment factors. Additional studies are required to determine if there is a biologic difference between axial and appendicular EWS.