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PURPOSE Monoclonal antibodies directed against insulin-like growth factor-1 receptor (IGF-1R) have shown activity in patients with relapsed Ewing sarcoma. The primary objective of Children's Oncology Group trial AEWS1221 was to determine if the addition of the IGF-1R monoclonal antibody ganitumab to interval-compressed chemotherapy improves event-free survival (EFS) in patients with newly diagnosed metastatic Ewing sarcoma. METHODS Patients were randomly assigned 1:1 at enrollment to standard arm (interval-compressed vincristine/doxorubicin/cyclophosphamide alternating once every 2 weeks with ifosfamide/etoposide = VDC/IE) or to experimental arm (VDC/IE with ganitumab at cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). A planned sample size of 300 patients was projected to provide 81% power to detect an EFS hazard ratio of 0.67 or smaller for the experimental arm compared with the standard arm with a one-sided α of .025. RESULTS Two hundred ninety-eight eligible patients enrolled (148 in standard arm; 150 in experimental arm). The 3-year EFS estimates were 37.4% (95% CI, 29.3 to 45.5) for the standard arm and 39.1% (95% CI, 31.3 to 46.7) for the experimental arm (stratified EFS-event hazard ratio for experimental arm 1.00; 95% CI, 0.76 to 1.33; 1-sided, P = .50). The 3-year overall survival estimates were 59.5% (95% CI, 50.8 to 67.3) for the standard arm and 56.7% (95% CI, 48.3 to 64.2) for the experimental arm. More cases of pneumonitis after radiation involving thoracic fields and nominally higher rates of febrile neutropenia and ALT elevation were reported on the experimental arm. CONCLUSION Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing sarcoma, with outcomes similar to prior trials without IGF-1R inhibition or interval compression. The addition of ganitumab may be associated with increased toxicity.

Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes.AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/mThirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules.The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.

The ideal local treatment modality for pelvic and sacral Ewing sarcoma (EWS) is controversial.We present the data from the American College of Surgeon's National Cancer Database (NCDB) and the National Cancer Institute's Surveillance, Epidemiology and End Result (SEER) database to investigate the impact of local treatment modalities on survival for nonmetastatic pelvic and sacral Ewing sarcoma. Local treatment includes "surgery," "radiation," and a combination of "surgery and radiation."A total of 235 cases from SEER and 285 cases from NCDB were analyzed. Patients with "localized" stage (intraosseous) in the SEER database did not show any statistically significant difference in the disease-specific survival (DSS) for any of the local treatment modalities. Similar findings were observed for overall survival among patients with American Joint Committee on Cancer (AJCC) stage II and III in the NCDB database. However, patients with nonmetastatic disease, particularly regional disease (extraosseous), showed improved DSS with surgery only, in the SEER.We found similar levels of efficacy for different treatment modalities for patients with intraosseous and AJCC II and III pelvic and sacral EWS. "Radiotherapy" is the most common local treatment modality employed in the United States. A prospective, randomized controlled trial with a direct head-to-head comparison is needed for a definitive conclusion.

Supplementary Figure 1 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Table 10 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

The highly aggressive muscle cancer alveolar rhabdomyosarcoma (ARMS) is one of the most common soft tissue sarcoma of childhood, yet the outcome for the unresectable and metastatic disease is dismal and unchanged for nearly three decades. To better understand the pathogenesis of this disease and to facilitate novel preclinical approaches, we previously developed a conditional mouse model of ARMS by faithfully recapitulating the genetic mutations observed in the human disease, i.e., activation of Pax3:Fkhr fusion gene with either p53 or Cdkn2a inactivation. In this report, we show that this model recapitulates the immunohistochemical profile and the rapid progression of the human disease. We show that Pax3:Fkhr expression increases during late preneoplasia but tumor cells undergoing metastasis are under apparent selection for Pax3:Fkhr expression. At a whole-genome level, a cross-species gene set enrichment analysis and metagene projection study showed that our mouse model is most similar to human ARMS when compared with other pediatric cancers. We have defined an expression profile conserved between mouse and human ARMS, as well as a Pax3:Fkhr signature, including the target gene, SKP2. We further identified 7 “druggable” kinases overexpressed across species. The data affirm the accuracy of this genetically engineered mouse model. [Cancer Res 2009;69(7):2902–11]

Supplementary Figure 2 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Methods and Materials from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Figure 5 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Tables 1-7 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Figure 3 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Table 8 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Table 9 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

Supplementary Figure 4 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

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Supplementary Figure Legends 1-5 from Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma

BackgroundWe have analyzed sex, race/ethnicity or socioeconomic disparities in the incidence of metastatic bone disease (MBD).MethodsPatients with the diagnosis of MBD at presentation for five most common primary anatomical sites was extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset. Mean incidence of MBD for different sex, racial/ethnic and socioeconomic groups were compared.ResultsThe five most common anatomical sites with MBD at presentation include "lung: (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal" (n = 7718) and "colon" (n = 3068). There was an increase in incidence of MBD among cancers originating from prostate (annual percentage change [APC] 4.94), renal (APC 2.55), and colon (APC 3.21) (p

Background Endoprosthetic reconstruction after oncologic resection of bone tumors requires stable fixation between the prosthesis and residual host bone. Compressive osseointegration has been developed as an alternative to traditional stemmed implants to address the challenges and complications of achieving this fixation. Sufficient time has now passed from the advent of compressive implants to allow for an assessment of the intermediate-term and long-term results of this form of fixation. Questions/purposes At a minimum follow-up of 10 years after implantation of a compressive osseointegration device for oncologic reconstruction: (1) What is the risk of periprosthetic fracture, aseptic loosening, or implant breakage resulting in revision surgery for endoprosthesis removal? (2) What is the long-term cortical response at the host-endoprosthesis interface as visualized on plain radiographs? Methods A single-center, retrospective study was performed between 2002 and 2010, in which 110 patients with primary bone sarcoma of the proximal or distal femur were considered for oncologic resection and reconstruction. Patients were considered for a compressive osseointegration endoprosthesis if they were 50 years of age or younger, had not previously received femoral radiation, had no metabolic disease impairing bone healing, were not diagnosed with metastatic disease, and had life expectancy greater than six months. Of the 110 patients, 25 were treated with a compressive osseointegration implant of the proximal or distal femur, and 85 patients were treated with conventional stemmed implants or amputation because of older age, advanced disease, metabolic comorbidities, inability to tolerate a nonweightbearing postoperative period, or in the case of rotationplasty, patient preference. All patients who received this device during the period of study were considered eligible for inclusion in this review. The median (range) age was 18 years (7 to 50), and 13 of 25 patients were men. Five patients died of disease before the minimum follow-up duration of 10 years; two underwent amputation due to local recurrence and three died with the implant in situ, leaving 20 patients for complete analysis. Median follow-up was 144 months, and all 20 surviving patients had a minimum follow-up of 10 years (121 to 230 months). The primary endpoint was reoperation and implant removal for periprosthetic fracture, aseptic loosening, or mechanical breakage of any component of the compressive device in the endoprosthesis. In final analysis, death was considered a competing event to revision surgery, and cumulative incidence was reported after competing-event analysis. A secondary aim was radiographic evaluation of the host-implant interface to assess the long-term cortical response to compressive osseointegration. Results Spindle fracture or loosening was noted in three patients, and the remaining 17 patients maintained the compression device until the final follow-up. The risk of reoperation for aseptic loosening, periprosthetic fracture, or mechanical breakage of the implant using a competing risks estimator was 12% at 10 years (95% CI 0% to 26%). These complications occurred within 29 months of the index surgery; no patients had implant loosening or mechanical breakdown after this initial period. On radiographic assessment, 14 patients demonstrated cortical hypertrophy of the bone-implant interface, six patients had maintenance of the native cortical contour, and no patients had cortical atrophy or narrowing at the implant interface.Conclusion Long-term follow-up in patients with compressive osseointegrative endoprosthetic devices demonstrated no late revisions because of periprosthetic fracture, aseptic loosening, or implant breakage in this cohort with a minimum 10-year follow-up. There was no evidence of late-onset cortical atrophy or stress shielding at the host-implant interface. This study supports the long-term stability of the interface between host bone and the endoprosthesis in compressive osseointegration devices. Level of evidence Level IV, therapeutic study.

In order to determine the impact of COVID-19 on the treatment and outcomes in patients with proximal femoral fracture’s (PFF), we analyzed a national US sample. This is a retrospective review of American College of Surgery’s (ACS) National Surgical Quality Improvement Program (NSQIP) for patients with proximal femoral fractures. A total of 26,830 and 26,300 patients sustaining PFF and undergoing surgical treatment were sampled during 2019 and 2020, respectively. On multivariable logistic regression, patients were less likely to have ‘presence of non-healing wound’ (p < 0.001), functional status ‘independent’ (p = 0.012), undergo surgical procedures of ‘hemiarthroplasty’(p = 0.002) and ‘ORIF IT, Peritroch, Subtroch with plates and screws’ (p < 0.001) and to be ‘alive at 30-days post-op’ (p = 0.001) in 2020 as compared to 2019. Patients were more likely to have a case status ‘emergent’, ‘loss of ≥10% body weight’, discharge destination of ‘home’ (p < 0.001 for each) or ‘leaving against medical advice’ (p = 0.026), postoperative ‘acute renal failure (ARF)’ (p = 0.011), ‘myocardial infarction (MI)’ (p = 0.006), ‘pulmonary embolism (PE)’ (p = 0.047), and ‘deep venous thrombosis (DVT)’ (p = 0.049) in 2020 as compared to 2019. Patients sustaining PFF and undergoing surgical treatment during pandemic year 2020 differed significantly in preoperative characteristics and 30-day postoperative complications when compared to patients from the previous year.

PURPOSE Neoplasms originating from the "small bones of the lower limb and the overlapping joints" are rare but portend a serious prognosis. Current study utilizes a population-based registry in the United States to characterize the malignancies of the foot. METHODS National Cancer Institute's Surveillance, Epidemiology and End Result database from 1975 to 2017 was queried to report incidence and survival data in 514 patients in the Uited States. Kaplan-Meier and Cox Regression were used to determine the prognostic factors affecting survival. Chi square test was used to assess the correlation. RESULTS Hematological malignancies constituted 14.8% of the entire cohort. Incidence of the foot neoplasms was 0.024 per 100 000 persons in 2017 and has not significantly changed since 1975 (p > 0.05). Disease-specific-5-year survival for the entire cohort was 73%. On multivariate analysis younger age groups, "localized" stage and extent of surgical resection were predictors of improved outcomes. A significant correlation was found between amputation with male sex and Hispanic ethnicity. CONCLUSIONS The current study analyzes data from population-based registry reporting incidence and survival data for patients with neoplasms of the foot. Independent prognostic factors include age, stage and extent of surgical resection. Amputation was found to be associated with male sex and Hispanic ethnicity.

Approximately 5% of cancer patients in the United States presented with metastatic bone disease (MBD) at diagnosis. Current study explores the disparities in survival for patients with MBD.Patients with the diagnosis of MBD at presentation for the five most common primary anatomical sites were extracted from Surveillance, Epidemiology, and End Results Census tract-level dataset (2010-2016). Kaplan-Meier and Cox Proportional Hazard models were used to evaluate survival, and prognostic factors for each cohort. Prognostic significance of socioeconomic status (SES) and insurance status were ascertained.The five most common anatomical-sites with MBD at presentation included "lung" (n = 59 739), "prostate" (n = 19 732), "breast" (n = 16 244), "renal and urothelium" (n = 7718) and "colon" (n= 3068). Lower SES was an independent risk factor for worse disease-specific survival (DSS) for patients with MBD originating from lung, prostate, breast and colon. Lack of insurance was an independent risk factor for worse DSS for MBD patients with primary tumors in lung and breast.MBD patients from the five most common primary sites demonstrated SES and insurance-related disparities in disease-specific survival. This is the first and largest study to explore SES and insurance-related disparities among patients specifically afflicted with MBD. Our findings highlight vulnerability of patients with MBD across multiple primary sites to financial toxicity.

Background Primary sarcomas originating from the mobile spine portends a particularly sinister outcome. Rarity of the disease process has resulted in inconsistent data due to small sample size and heterogeneity in patient selection and analytics. Methods Surveillance, Epidemiology and End Result (SEER) database from 1975 to 2017 was queried to report incidence and survival data in 712 patients in the United States. Kaplan-Meier and Cox Regression were used to determine the prognostic factors affecting survival. Results Incidence of spinal sarcoma was 0.019 per 100,000 persons in 2017 and has not significantly changed since 2000 (p > 0.05). Disease-specific 5-year survival for the entire cohort was 57%. Osteosarcoma has the worst 5-year survival (39%) and chondrosarcoma has the best 5-year survival (69%). Independent predictors of survival for the entire cohort included age, grade, and stage. Stage was an independent predictor of survival for every histologic subtype. Additional predictors of survival for spinal osteosarcoma, Ewing sarcoma, and chondrosarcoma included age, size, and grade, respectively. Conclusions The current study is an analysis of a population-based registry reporting incidence survival data for patients with sarcoma of mobile vertebral column. Survival and prognostic factors vary by histologic subtypes. There is lack of improvement in survival over the last three decades.

A 15-year-old boy presented with left-sided hip pain and imaging consistent with the diagnosis of femoroacetabular impingement. Following hip arthroscopy, which included an osteochondroplasty, labral repair, and capsular repair, the patient's anterior hip pain improved. However, his deep aching hip pain persisted until an ischial osteoid osteoma was identified and treated with radiofrequency ablation. At 3 years follow-up, the patient reports high satisfaction and minimal pain. We present this case to illustrate the importance of considering all potential causes of persistent hip pain following hip arthroscopy, including benign bone tumors which may be difficult to visualize on plain radiographs.

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15-39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.

To identify potential clinical prognostic factors associated with a higher risk of local recurrence in localized pelvic Ewing sarcoma (ES) patients treated with radiation therapy.Data for 101 patients treated with definitive radiotherapy (RT) or both surgery and radiation (S+RT) to primary pelvic tumors on INT-0091, INT-0154, and AEWS0031 were analyzed. Imaging data for patients who did not receive radiation were not available for central review, so surgery alone patients were not included. Cumulative incidence rates for local failure at 5-years from time of local control were calculated accounting for competing risks.The most common pelvic subsite was sacrum (44.6%). RT was utilized in 68% of patients and S+RT in 32%. The local failure rate was 25.0% for RT and 6.3% for S+RT (p=0.046). There was no statistically significant difference in local control modality by tumor characteristics. Tumors originating in the ischiopubic-acetabulum region were associated with the highest local failure incidence, 37.5% (p=0.02, vs. sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, p=0.06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (p=0.04). Multivariable analysis demonstrated RT alone (HR 5.1, p=0.04), tumor subsite (particularly ischiopubic-acetabulum tumors, HR 4.6, p=0.02), and increasing volume per 100 mL (HR 1.2, p=0.01) were associated with a higher incidence of local recurrence.Combination surgery and RT is associated with improved local control in patients with pelvic ES compared to definitive RT. Tumors involving the ischiopubic-acetabulum region and increasing tumor volume at diagnosis are associated with inferior local control. Tumor characteristics did not correlate with choice of local therapy modality suggesting an opportunity to develop best local therapy practices guidelines for future studies based on tumor features.

Author(s): Blank, Alan T; Larson, Brandon Michael; Shaw, Sara; Wakefield, Connor J; King, Tricia; Jones, Kevin B; Randall, R Lor | Abstract: BackgroundClinical workup and treatment guidelines have been published by the National Comprehensive Cancer Network (NCCN) to ensure patients are treated uniformly and appropriately. This study sought to retrospectively review patients with a new diagnosis of sarcoma who were treated in a National Cancer Institute (NCI) designated center and determine compliance rates with guidelines for sarcoma.AimTo evaluate our compliance of NCCN sarcoma guidelines at a major NCI designated center and to report instances of deviation that could be used for future studies to improve patient care.MethodsData was collected retrospectively as an internal review and quality assessment of 35 newly diagnosed and treated patients. Demographic data were recorded and information concerning whether patients had appropriate imaging, biopsy and management. Variables of interest were expressed as raw numbers and percentages.ResultsPrimary site imaging was obtained in 100% of cases. Chest and full-body imaging were obtained in 97% and 100% of indicated cases, respectively. Tissue was obtained preoperatively in 97% of cases. Imaging was reviewed at multidisciplinary Treatment Planning Conference (TPC) in 97% of cases. Pathology was reviewed in 94% of cases in TPC. Both tumor, node, metastasis staging and plan of care were reviewed in 100% of cases in TPC. Treatment guidelines were followed in 94% of cases reviewed.ConclusionThis study evaluated the workup and treatment provided by a single NCI designated sarcoma service to a series of patients with pathologies defined with the NCCN sarcoma treatment guidelines. Although adherence to NCCN was reported to be very high future prospective studies are required to investigate whether NCCN guidelines impact patient outcomes.

Osteoid osteomas are common, benign osteoblastic tumors that can occur in any bone in the body. They are almost always solitary, with only rare reports of multiple tumors in the same patient. When multiple, they typically are found within the same bone. We present a unique case of a young female athlete who presented initially at 16 years old with a right tibial osteoid osteoma and later at 18 years old with a right acetabular osteoid osteoma. Our case demonstrates the rare entity of polyostotic osteoid osteoma, the potential limitations of MRI in the diagnosis of osteoid osteoma, and the utility of radiofrequency ablation in the treatment of osteoid osteoma. Keywords: Benign bone tumor, Osteoid osteoma, Multifocal, Multicentric, Metachronous, Radiofrequency ablation

All orthopaedic surgeons during the course of their career will likely encounter both benign and malignant musculoskeletal neoplasms. Given the rarity of these entities and the stress conferred by diagnosing a tumor or tumorlike condition, many orthopaedic surgeons may benefit from a review of the contemporary treatment of such patients. Whether in the outpatient clinic or following a high-energy trauma, special attention should be given to concerning signs and symptoms that will aid in the workup of children and adults with a possible tumor. A thorough and logical workup in this manner will often lead to a definitive diagnosis such as metastatic bone disease or perhaps a benign lesion. In these instances, the informed general orthopaedic surgeon or subspecialist may choose to treat the patient independently. However, if the workup is inconclusive or if the diagnosis is even questionably malignant, referral to an orthopaedic oncologist should be sought as to avoid pitfalls in diagnosis and treatment.

A 7-week-old girl presented with a recurrent primitive myxoid mesenchymal tumor of infancy requiring extensive resection of lower back musculature, L3-S2 vertebral bodies, and left L5 nerve root. Reconstruction consisted of transverse rectus abdominis muscle (TRAM) flow-through to free fibular flap to reconstruct the bony defect and fill the soft-tissue void. One-year postoperative imaging revealed a well-incorporated fibula graft. At the 30-month follow-up, the patient can bear weight on the autograft while sitting upright, allowing for efficient ambulation with a wheelchair.TRAM flow-through to free fibular flap is an efficacious reconstructive method for a multilevel vertebral spinal defect in a pediatric patient.