|
1
|
Laughlin BS, Bogan A, Allen-Rhoades WA, Rose PS, Polites SF, Ashman JB, Petersen I, Haddock MG, Mahajan A, Laack NN, Ahmed SK. Comprehensive Analysis of Treatment Approaches in Chest Wall Ewing Sarcoma: The Impact of Tumor Volume on Oncologic Outcomes. Adv Radiat Oncol 2025; 10:101729. [PMID: 40103664 PMCID: PMC11919283 DOI: 10.1016/j.adro.2025.101729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 01/03/2025] [Indexed: 03/20/2025] Open
Abstract
Purpose Local treatment with surgery (S) and radiation therapy (RT) for chest wall Ewing sarcoma (cwES) is often challenging given the extent of the tumor and the aggressiveness of local treatments needed for cure. We report tumor and treatment characteristics, oncologic outcomes, and toxicities of patients with cwES at 2 centers of a single institution. Methods and Materials Consecutive patients with cwES treated from 1997 to 2022 were retrospectively reviewed. All patients were treated with standard 5-drug chemotherapy (vincristine, doxorubicin, cyclophosphamide, alternating with ifosfamide and etoposide) before initiation of local therapy. Local treatment was S, RT, or both. The decision on modality and timing was determined by a multidisciplinary sarcoma group or by consensus between sarcoma experts regarding patient preferences. Results The cohort consisted of 39 patients. The median age at diagnosis was 19.2 years (range, 3.5-53.6 years). Median tumor volume (TV) was 235.5 mL (range, 5.3-6761.9 mL). The local control (LC) modality was S in 18 patients (46%), RT in 4 (10%), and S + RT in 17 (44%). Four (10%) patients treated with S + RT had R1 margins. The median follow-up was 3.2 years (range, 0.1-21.6 years). Grade 3 radiation-associated toxicity relative to the RT modality was 16.7% and 7.1% for photons (n = 6) and protons (n = 14), respectively. The 2-year LC by modality was 100% for RT (95% CI, 100%-100%), 88.2% (95% CI, 74.2%-100%) for S, and 73.3% (95% CI, 54.0%-99.5%) for S + RT. The 5-year LC, failure-free survival, and overall survival for all patients were 79.7% (95% CI, 67.3%-94.4%), 52.3% (95% CI, 38.1%-71.9%), and 64.2% (95% CI, 49.6%-83.1%), respectively. In univariate and multivariate analysis, TV ≥ 130 mL was associated with a significantly worse 5-year failure-free survival (31.8% TV ≥ 130 mL vs 80.8% TV < 130 mL; hazard ratio, 4.94, p = .013 and adjusted hazard ratio, 5.43; 95% CI, 1.28-22.98; p = .022). The multivariate model was adjusted for age, metastatic disease at diagnosis, and S. Conclusions Outcomes for cwES tumors are highly dependent on tumor size, even with the use of combined modality local therapy. With early follow-up, smaller tumors may be well controlled with either S or RT.
Collapse
Affiliation(s)
| | - Aaron Bogan
- Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, Arizona
| | | | - Peter S Rose
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
| | | | | | - Ivy Petersen
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | | | - Anita Mahajan
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Nadia N Laack
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - Safia K Ahmed
- Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona
| |
Collapse
|
|
2
|
Xie J, Mellado-Lagarde MM, Blankenship K, Ganguly D, Twarog NR, Bianski B, Kieffer M, Atkinson S, Sheppard H, Gartrell J, Cler S, Federico SM, Stewart EA, Tinkle CL, Shelat AA. The Combination of PARP and Topoisomerase 1 Inhibitors Improves Radiation Therapy for Ewing Sarcoma. Cancer Sci 2025. [PMID: 40069935 DOI: 10.1111/cas.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Although primary tumor control rates after surgery and/or radiation therapy (RT) are generally high in patients with Ewing sarcoma (EWS), those with unresectable tumors have failure rates approaching 30% and experience poorer outcomes. Additionally, although metastatic site irradiation is associated with improved survival, dose, and volume effects influence the long-term toxicity risk. Consequently, it is important to identify novel systemic agents to enhance the therapeutic ratio of RT. Given the reported DNA damage response deficits in EWS, we hypothesized that PARP inhibitors (PARPis) would preferentially potentiate radiation relative to standard-of-care (SOC) chemotherapeutics. We investigated primary and recurrent SOC drugs and PARPis with varied trapping potential in combination with radiation in EWS cell lines. At physiologically relevant concentrations, the strong PARP trapper talazoparib (TAL) potentiated radiation to a greater extent than did SOC or other PARPis, although the magnitude of the effect was modest. The radiosensitizing effect of TAL was mediated through the induction of DNA double-strand breaks, rather than through the catalytic inhibition of PARP1. Drug + RT combinations were further tested in vivo by using orthotopic xenograft models of EWS treated with image-guided fractionated radiation. The addition of RT to the combination of TAL plus irinotecan (IRN), a recently evaluated clinical regimen for relapsed pediatric solid tumors, significantly prolonged survival and reduced tumor burden in all EWS-treated mice. This triplet therapy (TAL + IRN + RT) was feasible and yielded responses in several patients with EWS and may represent a useful salvage strategy in recurrent or progressive disease.
Collapse
Affiliation(s)
- Jia Xie
- Department of Radiation Oncology, St. Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, USA
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
| | | | | | - Debolina Ganguly
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
| | - Nathaniel R Twarog
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
| | - Brandon Bianski
- Department of Radiation Oncology, St. Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, USA
| | | | - Stefan Atkinson
- Department of Developmental Neurobiology, SJCRH, Memphis, Tennessee, USA
| | | | | | - Samuel Cler
- Department of Oncology, SJCRH, Memphis, Tennessee, USA
- Department of Developmental Neurobiology, SJCRH, Memphis, Tennessee, USA
| | | | - Elizabeth A Stewart
- Department of Oncology, SJCRH, Memphis, Tennessee, USA
- Department of Developmental Neurobiology, SJCRH, Memphis, Tennessee, USA
| | - Christopher L Tinkle
- Department of Radiation Oncology, St. Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, USA
| | - Anang A Shelat
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
| |
Collapse
|
|
3
|
Chen B, Li HZ, He XF. Relationship between surgical compliance and survival outcome in patients with Ewing sarcoma. Indian J Cancer 2024; 61:749-758. [PMID: 39960704 DOI: 10.4103/ijc.ijc_138_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 08/17/2021] [Indexed: 05/09/2025]
Abstract
BACKGROUND The impact of surgical compliance on survival outcomes in patients with Ewing sarcoma (ES) is unclear, so this study was performed to explore the association between them. METHODS We used the SEER*Stat software (version 8.3.6.1) to extract information on ES patients from the SEER database. Patients were divided into two groups based on their adherence to surgical recommendations: the surgical compliance group and the surgical noncompliance group. Categorical variables were expressed as percentages. Multivariate logistic regression and Chi-square test were used to explore variables related to surgical compliance. Univariate Cox regression analysis was used to initially select potential prognostic factors, and then the factors selected in the univariate Cox regression analysis were further analyzed in a multivariate Cox proportional risk model to ultimately determine the risk prognostic factors significantly related to the survival of patients with ES. RESULTS Multiple logistic regression analysis suggested that adults (OR = 0.373, 95% confidence interval (CI): 0.164-0.849), Grade IV (OR = 0.373, 95% CI: 0.164-0.849), and unmarried patients (OR = 0.568, 95% CI: 0.339-0.954) were more inclined to accept surgery recommendations, while patients from 2001 to 2010 were less compliant with surgery. Multifactorial Cox regression analysis suggested that surgical compliance was an independent prognostic factor for patients with ES. Through the Kaplan-Meier survival curves, we could clearly observe that the overall survival was higher in the surgical compliance group than in the surgical noncompliance group. Furthermore, subgroup analysis also reached similar conclusions. CONCLUSION In this study, we found that surgical compliance was an independent predictor of patient prognosis. Furthermore, we found that age, tumor grade, year of diagnosis, and marital status may be related to surgical compliance.
Collapse
Affiliation(s)
- Bin Chen
- Department of Orthopaedics, The Second Affiliated Hospital of Suzhou University, Jiangsu Province, Suzhou, China
| | - Hong-Zhuo Li
- Department of Orthopaedics, Heping Hospital Affiliated to Changzhi Medical College, Shanxi, Changzhi, China
| | - Xiao-Feng He
- Department of Science and Education, Heping Hospital Affiliated to Changzhi Medical College, Shanxi, Changzhi, China
| |
Collapse
|
|
4
|
Wells ME, Eckhoff MD, Davis W, Singh V, Rajani R, Polfer EM. Ewing Sarcoma in the Pediatric Population: Predictors of Survival Within the United States. J Am Acad Orthop Surg Glob Res Rev 2024; 8:01979360-202410000-00017. [PMID: 39436736 PMCID: PMC11498927 DOI: 10.5435/jaaosglobal-d-24-00281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 08/25/2024] [Indexed: 10/25/2024]
Abstract
INTRODUCTION Bone and joint tumors are the third most common cause of pediatric cancer-related deaths in the United States. Although there have been improvements in survival rates among pediatric cancer patients over the past few decades, bone and joint cancers remain the exception. Considering current clinical trials involving novel targeted therapies, the establishment of updated mortality rates and predictors of survival for this cancer would be prudent. This investigation sought to determine updated 5-year survival rates and predictors of survival among pediatric Ewing sarcoma (ES) of bone treated within the United States. METHODS The National Cancer Database was retrospectively inquired for all pediatric ES cases within the most updated bone and joint public use file available in September 2022. The reported data were truncated to only include patients with reported 5-year vital (ie, survival) status. Cox proportional hazard regression was conducted on both the truncated data and the entire cohort to validate the findings. The patients were then separated into alive versus deceased cohorts, and univariate regression analysis was done followed by multivariable regression of notable variables of interest. RESULTS Overall, an aggregated 5-year survival rate of 74.5% was found in the included patient cohort. Patients with localized cancer had a comparatively improved 5-year survival rate of 84.70% as opposed to those with macrometastatic disease on presentation with a survival rate of 50.4%. Patient demographic-, tumor-, and treatment-specific variables all demonstrated an effect on survival. The multivariable predictors of worse mortality were found to include older age, larger tumor size (>8 cm), macrometastatic disease on presentation, and positive surgical margins. CONCLUSION This analysis serves to establish updated survival rates of pediatric ES treated within the United States to set standards for comparison among future studies. Continued multi-institutional and international collaboration is needed to optimize current treatment results and develop novel targeted therapies.
Collapse
Affiliation(s)
- Matthew E. Wells
- From the Department of Orthopedic Surgery, William Beaumont Army Medical Center (Dr. Wells, Dr. Eckhoff, and Dr. Polfer); the Department of Orthopedic Surgery, Texas Tech University Health Sciences Center El Paso (Dr. Wells, Dr. Eckhoff, Dr. Davis, Dr. Rajani, and Dr. Polfer); and Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX (Dr. Singh)
| | - Michael D. Eckhoff
- From the Department of Orthopedic Surgery, William Beaumont Army Medical Center (Dr. Wells, Dr. Eckhoff, and Dr. Polfer); the Department of Orthopedic Surgery, Texas Tech University Health Sciences Center El Paso (Dr. Wells, Dr. Eckhoff, Dr. Davis, Dr. Rajani, and Dr. Polfer); and Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX (Dr. Singh)
| | - William Davis
- From the Department of Orthopedic Surgery, William Beaumont Army Medical Center (Dr. Wells, Dr. Eckhoff, and Dr. Polfer); the Department of Orthopedic Surgery, Texas Tech University Health Sciences Center El Paso (Dr. Wells, Dr. Eckhoff, Dr. Davis, Dr. Rajani, and Dr. Polfer); and Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX (Dr. Singh)
| | - Vishwajeet Singh
- From the Department of Orthopedic Surgery, William Beaumont Army Medical Center (Dr. Wells, Dr. Eckhoff, and Dr. Polfer); the Department of Orthopedic Surgery, Texas Tech University Health Sciences Center El Paso (Dr. Wells, Dr. Eckhoff, Dr. Davis, Dr. Rajani, and Dr. Polfer); and Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX (Dr. Singh)
| | - Rajiv Rajani
- From the Department of Orthopedic Surgery, William Beaumont Army Medical Center (Dr. Wells, Dr. Eckhoff, and Dr. Polfer); the Department of Orthopedic Surgery, Texas Tech University Health Sciences Center El Paso (Dr. Wells, Dr. Eckhoff, Dr. Davis, Dr. Rajani, and Dr. Polfer); and Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX (Dr. Singh)
| | - Elizabeth M. Polfer
- From the Department of Orthopedic Surgery, William Beaumont Army Medical Center (Dr. Wells, Dr. Eckhoff, and Dr. Polfer); the Department of Orthopedic Surgery, Texas Tech University Health Sciences Center El Paso (Dr. Wells, Dr. Eckhoff, Dr. Davis, Dr. Rajani, and Dr. Polfer); and Biostatistics and Epidemiology Consulting Lab, Texas Tech University Health Sciences Center El Paso, El Paso, TX (Dr. Singh)
| |
Collapse
|
|
5
|
Rask GC, Taslim C, Bayanjargal A, Cannon MV, Selich-Anderson J, Crow JC, Duncan A, Theisen ER. Seclidemstat blocks the transcriptional function of multiple FET-fusion oncoproteins. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.19.594897. [PMID: 38826330 PMCID: PMC11142045 DOI: 10.1101/2024.05.19.594897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. New therapies are needed. These translocations fuse the 5' portion of the FET gene with a 3' partner gene encoding a transcription factor (TF). The resulting fusion proteins are oncogenic TFs with a FET protein low complexity domain (LCD) and a DNA binding domain. FET fusion proteins have proven stubbornly difficult to target directly and promising strategies target critical co-regulators. One candidate is lysine specific demethylase 1 (LSD1). LSD1 is recruited by multiple FET fusions, including EWSR1::FLI1. LSD1 promotes EWSR1::FLI1 activity and treatment with the noncompetitive inhibitor SP-2509 blocks EWSR1::FLI1 transcriptional function. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649). However, whether seclidemstat has pharmacological activity against FET fusions has not been demonstrated. Here, we evaluate the in vitro potency of seclidemstat against multiple FET-rearranged sarcoma cell lines, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also define the transcriptomic effects of seclidemstat treatment and evaluated the activity of seclidemstat against FET fusion transcriptional regulation. Seclidemstat showed potent activity in cell viability assays across FET-rearranged sarcomas and disrupted the transcriptional function of all tested fusions. Though epigenetic and targeted inhibitors are unlikely to be effective as a single agents in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged sarcomas.
Collapse
Affiliation(s)
- Galen C. Rask
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43215, USA
| | - Cenny Taslim
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43215, USA
| | - Ariunaa Bayanjargal
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43215, USA
- Medical Scientist Training Program, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| | - Matthew V. Cannon
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43215, USA
| | - Julia Selich-Anderson
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43215, USA
| | - Jesse C. Crow
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43215, USA
| | | | - Emily R. Theisen
- Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43215, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA
| |
Collapse
|
|
6
|
Jamshidi K, Toloue Ghamari B, Ammar W, Mirzaei A. Outcomes of ilium and iliosacral Ewing's sarcoma resection reconstructed with tibial strut allograft. Bone Jt Open 2024; 5:385-393. [PMID: 38736406 PMCID: PMC11089335 DOI: 10.1302/2633-1462.55.bjo-2024-0049.r1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/14/2024] Open
Abstract
Aims Ilium is the most common site of pelvic Ewing's sarcoma (ES). Resection of the ilium and iliosacral joint causes pelvic disruption. However, the outcomes of resection and reconstruction are not well described. In this study, we report patients' outcomes after resection of the ilium and iliosacral ES and reconstruction with a tibial strut allograft. Methods Medical files of 43 patients with ilium and iliosacral ES who underwent surgical resection and reconstruction with a tibial strut allograft between January 2010 and October 2021 were reviewed. The lesions were classified into four resection zones: I1, I2, I3, and I4, based on the extent of resection. Functional outcomes, oncological outcomes, and surgical complications for each resection zone were of interest. Functional outcomes were assessed using a Musculoskeletal Tumor Society (MSTS) score and Toronto Extremity Salvage Score (TESS). Results The mean age of the patients was 17 years (SD 9.1). At a mean follow-up of 70.8 months (SD 50), the mean functional outcomes were 24.2 points (SD 6.3) for MSTS and 81 points (SD 11) for TESS. The mean MSTS and TESS scores were associated with the iliac resection zone (< 0.001). Nine patients (20.9%) had local recurrence. The recurrence was not associated with the zone of iliac resection (p = 0.324). The two-year disease-free survival of the patients was 69.4%. The mean time to graft union was longer in patients with the I4 resection zone (p < 0.001). The complication rate was 34.9%, and nerve palsy (11.6%) was the most common. The rate of surgical complications was not associated with the resection zone. Conclusion Reconstruction using tibial strut allograft is an efficient procedure after the resection of the ilium and iliosacral ES. Functional outcomes and complications of iliac ES depend on the resection zone, and inferior outcomes could be generally expected when more segments of the pelvic ring are resected, even if it is reconstructed.
Collapse
Affiliation(s)
- Khodamorad Jamshidi
- Department of Orthopaedics, Bone and Joint Reconstruction Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Babak Toloue Ghamari
- Department of Orthopaedics, Bone and Joint Reconstruction Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Wael Ammar
- Department of Orthopaedics, Bone and Joint Reconstruction Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Mirzaei
- Department of Orthopaedics, Bone and Joint Reconstruction Research Center, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| |
Collapse
|
|
7
|
Chen Y, Liu Z, Wang Y, Zhan H, Liu J, Niu Y, Yang A, Teng F, Li J, Geng B, Xia Y. The development and external validation of a web-based nomogram for predicting overall survival with Ewing sarcoma in children. J Child Orthop 2024; 18:236-245. [PMID: 38567041 PMCID: PMC10984150 DOI: 10.1177/18632521241229963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 01/12/2024] [Indexed: 04/04/2024] Open
Abstract
Background Ewing sarcoma remains the second most prevalent primary aggressive bone tumor in teens and young adults. The aim of our study was to develop and validate a web-based nomogram to predict the overall survival for Ewing sarcoma in children. Methods A total of 698 patients, with 640 cases from the Surveillance, Epidemiology, and End Results (the training set) and 58 cases (the external validation set), were included in this study. Cox analyses were carried out to determine the independent prognostic indicators, which were further included to establish a web-based nomogram. The predictive abilities were tested through the concordance index, calibration curve, decision curve analysis, and area under the receiver operating characteristic curve. Results As suggested by univariate and multivariate Cox analyses, age, primary site, tumor size, metastasis stage (M stage), and chemotherapy were included as the independent predictive variables. The area under the receiver operating characteristic curve values, calibration curves, concordance index, and decision curve analysis from training and validation groups suggested the model has great clinical applications. Conclusion We developed a convenient and precise web-based nomogram to evaluate overall survival for Ewing sarcoma in children. The application of this nomogram would assist physicians and patients in making decisions.
Collapse
Affiliation(s)
- Yi Chen
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Zirui Liu
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Yaobin Wang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Hongwei Zhan
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Jinmin Liu
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Yongkang Niu
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Ao Yang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Fei Teng
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Jinfeng Li
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bin Geng
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| | - Yayi Xia
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou, China
| |
Collapse
|
|
8
|
Duffaud F, Blay JY, Le Cesne A, Chevreau C, Boudou-Rouquette P, Kalbacher E, Penel N, Perrin C, Laurence V, Bompas E, Saada-Bouzid E, Delcambre C, Bertucci F, Cancel M, Schiffler C, Monard L, Bouvier C, Vidal V, Gaspar N, Chabaud S. Regorafenib in patients with advanced Ewing sarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre Phase II study. Br J Cancer 2023; 129:1940-1948. [PMID: 37914801 PMCID: PMC10703915 DOI: 10.1038/s41416-023-02413-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 07/23/2023] [Accepted: 08/21/2023] [Indexed: 11/03/2023] Open
Abstract
BACKGROUND The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort. METHODS Patients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success. RESULTS From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%-[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%-[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%). CONCLUSION Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.
Collapse
Affiliation(s)
- Florence Duffaud
- APHM Hopital La Timone, Medical Oncology Unit, and Aix-Marseille University (AMU), Marseille, France.
| | - Jean-Yves Blay
- Medical Oncology Department, Centre Léon Bérard, Lyon, France
| | - Axel Le Cesne
- Medical Oncology Department, Gustave Roussy, Villejuif, France
| | - Christine Chevreau
- Medical Oncology Department, Institut Universitaire de Cancérologie de Toulouse, Oncopole, Toulouse, France
| | | | - Elsa Kalbacher
- Medical Oncology Department, CHU J Minjoz, Besançon, France
| | - Nicolas Penel
- Medical Oncology Department, Centre Oscar Lambret and Lille University Hospital, Lille, France
| | | | | | - Emmanuelle Bompas
- Medical Oncology Department, Centre René Gauduchau, Saint Herblain, France
| | - Esma Saada-Bouzid
- Medical Oncology Department, Centre Antoine Lacassagne, Nice, France
| | | | - François Bertucci
- Medical Oncology Department, Institut Paoli-Calmettes, Marseille, France
| | - Mathilde Cancel
- Medical Oncology Department, Centre Hospitalier Régional Universitaire Bretonneau, Tours, France
| | | | | | - Corinne Bouvier
- APHM Hopital La Timone, Pathology Department, and Aix-Marseille University, Marseille, France
| | - Vincent Vidal
- APHM Hopital La Timone, Radiology Department, and Aix-Marseille University Marseille, Marseille, France
| | - Nathalie Gaspar
- Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Villejuif, France
| | - Sylvie Chabaud
- Department of Statistics, Centre Léon Bérard, Lyon, France
| |
Collapse
|
|
9
|
Zandaki D, Ismael T, Halalsheh H, Ibrahimi AKH, Sarhan N, Ghandour K, Shehadeh A, Sultan I. Outcomes of Pediatric Patients With Metastatic Ewing Sarcoma Treated With Interval Compression. J Pediatr Hematol Oncol 2023; 45:111-115. [PMID: 35537074 DOI: 10.1097/mph.0000000000002478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/31/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Interval compression (IC), a regimen of alternating vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide every 2 weeks, improves survival for localized Ewing sarcoma (ES), with uncertain effect on metastatic disease. MATERIALS AND METHODS We reviewed the charts of pediatric patients with metastatic ES treated with IC at our center between January 2013 and March 2020. We calculated event-free survival and overall survival (OS) and used log-rank tests for univariate comparisons. RESULTS We identified 34 patients 2.7 to 17.1 years of age (median: 11.6 y). Twenty-six patients (76%) had pulmonary metastases, and 14 (41%) had extrapulmonary metastases. All patients received local control therapy: surgery only (n=7, 21%), radiotherapy only (n=18, 53%), or both (n=9, 26%). The estimated 3-year OS and event-free survival were 62%±9% and 39%±9%, respectively. Patients with pulmonary-only and extrapulmonary metastasis had a 3-year OS of 88%±8% and 27%±13%, respectively ( P =0.0074). Age group (above vs. below 12 y), or primary tumor site did not affect survival, but local control therapy did (surgery only, 83%±15%; combined surgery and radiation, 30%±18%; radiation only, 15%±10%; P =0.048). CONCLUSION IC yielded similar outcomes for patients with metastatic ES to other reported regimens. We suggest including this approach to other blocks of therapy.
Collapse
Affiliation(s)
- Dua'a Zandaki
- Department of Pediatrics, King Hussein Cancer Center
| | - Taleb Ismael
- Department of Pediatrics, King Hussein Cancer Center
- Department of Pediatrics, the University of Jordan, Amman, Jordan
| | - Hadeel Halalsheh
- Department of Pediatrics, King Hussein Cancer Center
- Department of Pediatrics, the University of Jordan, Amman, Jordan
| | | | - Nasim Sarhan
- Department of Pediatrics, King Hussein Cancer Center
| | | | | | - Iyad Sultan
- Department of Pediatrics, King Hussein Cancer Center
- Department of Pediatrics, the University of Jordan, Amman, Jordan
| |
Collapse
|
|
10
|
Padwal J, Baratto L, Chakraborty A, Hawk K, Spunt S, Avedian R, Daldrup-Link HE. PET/MR of pediatric bone tumors: what the radiologist needs to know. Skeletal Radiol 2023; 52:315-328. [PMID: 35804163 PMCID: PMC9826799 DOI: 10.1007/s00256-022-04113-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 06/11/2022] [Accepted: 06/29/2022] [Indexed: 02/02/2023]
Abstract
Integrated 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/magnetic resonance (MR) imaging can provide "one stop" local tumor and whole-body staging in one session, thereby streamlining imaging evaluations and avoiding duplicate anesthesia in young children. 18F-FDG PET/MR scans have the benefit of lower radiation, superior soft tissue contrast, and increased patient convenience compared to 18F-FDG PET/computerized tomography scans. This article reviews the 18F-FDG PET/MR imaging technique, reporting requirements, and imaging characteristics of the most common pediatric bone tumors, including osteosarcoma, Ewing sarcoma, primary bone lymphoma, bone and bone marrow metastases, and Langerhans cell histiocytosis.
Collapse
Affiliation(s)
- Jennifer Padwal
- Department of Radiology, Stanford University, Stanford, CA, 94305, USA
| | - Lucia Baratto
- Department of Radiology, Stanford University, Stanford, CA, 94305, USA
| | - Amit Chakraborty
- Department of Radiology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Kristina Hawk
- Department of Radiology, Stanford University, Stanford, CA, 94305, USA
| | - Sheri Spunt
- Department of Pediatrics, Stanford University, 725 Welch Rd., Rm. 1665, Stanford, CA, 94305-5614, USA
| | - Raffi Avedian
- Department of Surgery, Division of Pediatric Orthopedic Surgery, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, 94305, USA
| | - Heike E Daldrup-Link
- Department of Radiology, Stanford University, Stanford, CA, 94305, USA.
- Cancer Imaging Program, Stanford Cancer Institute, Stanford, USA.
- Department of Pediatrics, Stanford University, 725 Welch Rd., Rm. 1665, Stanford, CA, 94305-5614, USA.
| |
Collapse
|
|
11
|
Ahmed SK, Witten BG, Harmsen WS, Rose PS, Krailo M, Marcus KJ, Randall RL, DuBois SG, Janeway KA, Womer RB, Grier HE, Gorlick RG, Laack NNI. Analysis of Local Control Outcomes and Clinical Prognostic Factors in Localized Pelvic Ewing Sarcoma Patients Treated With Radiation Therapy: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 2023; 115:337-346. [PMID: 36302496 PMCID: PMC9839580 DOI: 10.1016/j.ijrobp.2022.07.1840] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/13/2022] [Accepted: 07/24/2022] [Indexed: 12/14/2022]
Abstract
PURPOSE To identify potential clinical prognostic factors associated with a higher risk of local recurrence in patients with localized pelvic Ewing sarcoma treated with radiation therapy. METHODS AND MATERIALS Data for 101 patients treated with definitive radiation therapy (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; therefore, patients with surgery alone were not included. Cumulative incidence rates for local failure at 5 years from time of local control were calculated accounting for competing risks. RESULTS The most common pelvic subsite was sacrum (44.6%). RT was used 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 = .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 = .02, vs sacrum and iliac/buttock tumors), particularly those treated with RT (50.0%, P = .06). A higher incidence of local failure was seen with each additional 100 mL of tumor at diagnosis (P = .04). Multivariable analysis demonstrated RT alone (hazard ratio [HR], 5.1; P = .04), tumor subsite (particularly ischiopubic-acetabulum tumors; HR 4.6; P = .02), and increasing volume per 100 mL (HR, 1.2; P = .01) were associated with a higher incidence of local recurrence. CONCLUSIONS Combination surgery and RT is associated with improved local control in patients with pelvic Ewing sarcoma compared with 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.
Collapse
Affiliation(s)
- Safia K Ahmed
- Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona.
| | - Brent G Witten
- Orthopedic Surgery, Aurora Orthopedics, Milwaukee, Minnesota
| | - William S Harmsen
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Peter S Rose
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
| | - Mark Krailo
- Department of Preventative Medicine, University of Southern California, Los Angeles, California
| | - Karen J Marcus
- Department of Radiation Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - R Lor Randall
- Department of Orthopedic Surgery, UC Davis, Davis, California
| | - Steven G DuBois
- Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - Katherine A Janeway
- Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - Richard B Womer
- Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine & Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Holcombe E Grier
- Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - Richard G Gorlick
- Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nadia N I Laack
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
12
|
Li W, Dong S, Lin Y, Wu H, Chen M, Qin C, Li K, Zhang J, Tang ZR, Wang H, Huo K, Xie X, Hu Z, Kuang S, Yin C. A tool for predicting overall survival in patients with Ewing sarcoma: a multicenter retrospective study. BMC Cancer 2022; 22:914. [PMID: 35999524 PMCID: PMC9400324 DOI: 10.1186/s12885-022-09796-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 06/10/2022] [Indexed: 11/06/2023] Open
Abstract
OBJECTIVE The aim of this study was to establish and validate a clinical prediction model for assessing the risk of metastasis and patient survival in Ewing's sarcoma (ES). METHODS Patients diagnosed with ES from the Surveillance, Epidemiology and End Results (SEER) database for the period 2010-2016 were extracted, and the data after exclusion of vacant terms was used as the training set (n=767). Prediction models predicting patients' overall survival (OS) at 1 and 3 years were created by cox regression analysis and visualized using Nomogram and web calculator. Multicenter data from four medical institutions were used as the validation set (n=51), and the model consistency was verified using calibration plots, and receiver operating characteristic (ROC) verified the predictive ability of the model. Finally, a clinical decision curve was used to demonstrate the clinical utility of the model. RESULTS The results of multivariate cox regression showed that age, , bone metastasis, tumor size, and chemotherapy were independent prognostic factors of ES patients. Internal and external validation results: calibration plots showed that the model had a good agreement for patient survival at 1 and 3 years; ROC showed that it possessed a good predictive ability and clinical decision curve proved that it possessed good clinical utility. CONCLUSIONS The tool built in this paper to predict 1- and 3-year survival in ES patients ( https://drwenleli0910.shinyapps.io/EwingApp/ ) has a good identification and predictive power.
Collapse
Affiliation(s)
- Wenle Li
- Department of Orthopedic Surgery II, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, 710004, China
- College of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
- Molecular Imaging and Translational Medicine Research Center, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen University, Xiamen, 361005, China
- Clinical Medical Research Center, Xianyang Central Hospital, Xianyang, 712099, China
| | - Shengtao Dong
- Department of Spine Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116000, China
| | - Yuewei Lin
- The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China
| | - Huitao Wu
- Intelligent Healthcare Team, Baidu Inc, Beijing, 100089, China
| | - Mengfei Chen
- Emergency Department, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750000, China
| | - Chuan Qin
- Department of Spine Surgery, Liuzhou People's Hospital, Liuzhou, 545000, China
| | - Kelin Li
- Department of Spine Surgery, Liuzhou People's Hospital, Liuzhou, 545000, China
| | - JunYan Zhang
- Medical Big Data Research Center, PLA General Hospital, Beijing, 100853, China
- National Engineering Laboratory for Medical Big Data Application Technology, Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhi-Ri Tang
- School of Physics and Technology, Wuhan University, Wuhan, 430072, China
| | - Haosheng Wang
- Orthopaedic Medical Center, The Second Hospital of Jilin University, Changchun, 130000, China
| | - Kang Huo
- Neurology department, Xi'an jiaotong university 1st affiliated hospital, Xian, 71000, China
| | - Xiangtao Xie
- Department of Spine Surgery, Liuzhou People's Hospital, Liuzhou, 545000, China
| | - Zhaohui Hu
- Department of Spine Surgery, Liuzhou People's Hospital, Liuzhou, 545000, China.
| | - Sirui Kuang
- Faculty of Medicine, Macau University of Science and Technology, Macau, 999078, China.
| | - Chengliang Yin
- Faculty of Medicine, Macau University of Science and Technology, Macau, 999078, China.
| |
Collapse
|
|
13
|
Jacobson JC, Clark RA, Cairo SB, Murphy JT, Chung DH. Multimodality treatment of pediatric Ewing sarcoma: A single-center 10-year analysis of outcomes. Surgery 2022; 172:1251-1256. [PMID: 35933175 DOI: 10.1016/j.surg.2022.05.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/10/2022] [Accepted: 05/30/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND Ewing sarcoma, a malignancy originating from the bone or soft tissues most commonly diagnosed in adolescents, requires multimodality therapy. Although both surgical resection and radiation therapy are effective local control modalities, there are limited data comparing outcomes in patients treated with surgery versus radiation. We sought to determine whether there were differences in 5-year local failure-free survival, event-free survival, and overall survival based on the modality used for local control. METHODS Patients treated for Ewing sarcoma at a single tertiary pediatric hospital between 2010 and 2020 were included for retrospective analysis. Patient and tumor demographics, treatment information, and patient response to therapies were collected from the medical record. Outcome measures were local failure-free survival, event-free survival, and overall survival at 5 years from diagnosis. RESULTS Sixty-one patients met inclusion criteria. All patients received chemotherapy, and 68.9% of patients presented with localized disease. Of these, 23.8% were treated with radiation alone; the remaining 76.2% underwent resection ± radiation. A total of 52.4% of patients with localized disease achieved R0 resection. Only 3 patients experienced local progression; there was no difference between treatment groups. There was no significant association between local control modality and event-free survival or overall survival in patients with localized disease, regardless of margin status. CONCLUSION There was no significant difference in 5-year local failure-free survival, event-free survival, or overall survival in Ewing sarcoma patients treated with radiation versus surgery ± radiation, regardless of whether or not R0 resection was achieved. Future directions include a multi-institutional study to allow for further subgroup analysis and increased sample size.
Collapse
Affiliation(s)
- Jillian C Jacobson
- Department of Pediatric Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX
| | - Rachael A Clark
- Department of Pediatric Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX
| | - Sarah B Cairo
- Department of Pediatric Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX
| | - Joseph T Murphy
- Department of Pediatric Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX
| | - Dai H Chung
- Department of Pediatric Surgery, University of Texas Southwestern Medical Center and Children's Health, Dallas, TX.
| |
Collapse
|
|
14
|
Wright A, Desai M, Bolan CW, Badawy M, Guccione J, Rao Korivi B, Pickhardt PJ, Mellnick VM, Lubner MG, Chen L, Elsayes KM. Extraskeletal Ewing Sarcoma from Head to Toe: Multimodality Imaging Review. Radiographics 2022; 42:1145-1160. [PMID: 35622491 DOI: 10.1148/rg.210226] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Extraskeletal Ewing sarcoma (EES) is a rare subtype in the Ewing sarcoma family of tumors (ESFT), which also includes Ewing sarcoma of bone (ESB) and, more recently, primitive neuroectodermal tumors. Although these tumors often have different manifestations, they are grouped on the basis of common genetic translocation and diagnosis from specific molecular and immunohistochemical features. While the large majority of ESFT cases occur in children and in bones, approximately 25% originate outside the skeleton as EES. Importantly, in the adult population these extraskeletal tumors are more common than ESB. Imaging findings of EES tumors are generally nonspecific, with some variation based on location and the tissues involved. A large tumor with central necrosis that does not cross the midline is typical. Despite often nonspecific findings, imaging plays an important role in the evaluation and management of ESFT, with MRI frequently the preferred imaging modality for primary tumor assessment and local staging. Chest CT and fluorine 18 fluorodeoxyglucose PET/CT are most sensitive for detecting lung and other distant or nodal metastases. Management often involves chemotherapy with local surgical excision, when possible. A multidisciplinary treatment approach should be used given the propensity for large tumor size and local invasion, which can make resection difficult. Despite limited data, outcomes are similar to those of other ESFT cases, with 5-year survival exceeding 80%. However, with metastatic disease, the long-term prognosis is poor. ©RSNA, 2022.
Collapse
Affiliation(s)
- Alexandra Wright
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Madhura Desai
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Candice W Bolan
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Mohamed Badawy
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Jeffrey Guccione
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Brinda Rao Korivi
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Perry J Pickhardt
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Vincent M Mellnick
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Meghan G Lubner
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Longwen Chen
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| | - Khaled M Elsayes
- From the Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030 (A.W., M.B., B.R.K., K.M.E.); Department of Radiology, Mayo Clinic, Jacksonville, Fla (M.D., C.W.B.); Department of Radiology, The University of Texas Health Science Center at Houston, Tex (J.G.); Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wis (P.J.P., M.G.L.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (V.M.M.); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Ariz (L.C.)
| |
Collapse
|
|
15
|
Jiang R, Hu J, Zhou H, Wei H, He S, Xiao J. A Novel Defined Hypoxia-Related Gene Signature for Prognostic Prediction of Patients With Ewing Sarcoma. Front Genet 2022; 13:908113. [PMID: 35719404 PMCID: PMC9201760 DOI: 10.3389/fgene.2022.908113] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/18/2022] [Indexed: 11/25/2022] Open
Abstract
The therapeutic strategy of Ewing sarcoma (EWS) remains largely unchanged over the past few decades. Hypoxia is reported to have an impact on tumor cell progression and is regarded as a novel potential therapeutic target in tumor treatment. This study aimed at developing a prognostic gene signature based on hypoxia-related genes (HRGs). EWS patients from GSE17674 in the GEO database were analyzed as a training cohort, and differently expressed HRGs between tumor and normal samples were identified. The univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate Cox regression analyses were used in this study. A total of 57 EWS patients from the International Cancer Genome Consortium (ICGC) database were set as the validation cohort. A total of 506 differently expressed HRGs between tumor and normal tissues were identified, among which 52 were associated with the prognoses of EWS patients. Based on 52 HRGs, EWS patients were divided into two molecular subgroups with different survival statuses. In addition, a prognostic signature based on 4 HRGs (WSB1, RXYLT1, GLCE and RORA) was constructed, dividing EWS patients into low- and high-risk groups. The 2-, 3- and 5-years area under the receiver operator characteristic curve of this signature was 0.913, 0.97 and 0.985, respectively. It was found that the survival rates of patients in the high-risk group were significantly lower than those in the low-risk group (p < 0.001). The risk level based on the risk score could serve as an independent clinical factor for predicting the survival probabilities of EWS patients. Additionally, antigen-presenting cell (APC) related pathways and T cell co-inhibition were differently activated in two risk groups, which may result in different prognoses. CTLA4 may be an effective immune checkpoint inhibitor to treat EWS patients. All results were verified in the validation cohort. This study constructed 4-HRGs as a novel prognostic marker for predicting survival in EWS patients.
Collapse
Affiliation(s)
- Runyi Jiang
- Spinal Tumor Center, Department of Orthopaedic Oncology, No.905 Hospital of PLA Navy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Jinbo Hu
- Spinal Tumor Center, Department of Orthopaedic Oncology, No.905 Hospital of PLA Navy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Hongfei Zhou
- Spinal Tumor Center, Department of Orthopaedic Oncology, No.905 Hospital of PLA Navy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- The Third Convalescent Department, Hangzhou Sanatorium, Hangzhou, China
| | - Haifeng Wei
- Spinal Tumor Center, Department of Orthopaedic Oncology, No.905 Hospital of PLA Navy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- *Correspondence: Jianru Xiao, ; Shaohui He, ; Haifeng Wei,
| | - Shaohui He
- Spinal Tumor Center, Department of Orthopaedic Oncology, No.905 Hospital of PLA Navy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- *Correspondence: Jianru Xiao, ; Shaohui He, ; Haifeng Wei,
| | - Jianru Xiao
- Spinal Tumor Center, Department of Orthopaedic Oncology, No.905 Hospital of PLA Navy, Changzheng Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
- *Correspondence: Jianru Xiao, ; Shaohui He, ; Haifeng Wei,
| |
Collapse
|
|
16
|
Zheng Y, Lu J, Shuai Z, Wu Z, Qian Y. A novel nomogram and risk classification system predicting the Ewing sarcoma: a population-based study. Sci Rep 2022; 12:8154. [PMID: 35581219 PMCID: PMC9113999 DOI: 10.1038/s41598-022-11827-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 04/29/2022] [Indexed: 01/07/2023] Open
Abstract
Ewing sarcoma (ES) is a rare disease that lacks a prognostic prediction model. This study aims to develop a nomogram and risk classification system for estimating the probability of overall survival (OS) of patients with ES. The clinicopathological data of ES were collected from the Surveillance, Epidemiology and Final Results (SEER) database from 2010 to 2018. The primary cohort was randomly assigned to the training set and the validation set. Univariate and multiple Cox proportional hazard analyses based on the training set were performed to identify independent prognostic factors. A nomogram was established to generate individualized predictions of 3- and 5-year OS and evaluated by the concordance index (C-index), the receiver operating characteristic curve (ROC), the calibration curve, the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI). Based on the scores calculated with the nomogram, ES patients were divided into three risk groups to predict their survival. A total of 935 patients were identified, and a nomogram consisting of 6 variables was established. The model provided better C-indices of OS (0.788). The validity of the Cox model assumptions was evaluated through the Schönfeld test and deviance residual. The ROC, calibration curve, IDI and NRI indicated that the nomogram exhibited good performance. A risk classification system was built to classify the risk group of ES patients. The nomogram compares favourably and accurately to the traditional SEER tumour staging systems, and risk stratification provides a more convenient and effective tool for clinicians to optimize treatment options.
Collapse
Affiliation(s)
- Yongshun Zheng
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Jinsen Lu
- Department of Orthopedics, The First Affiliated Hospital of University of Science and Technology of China, 17 Lujiang Road, Hefei, 230001, Anhui, China
| | - Ziqiang Shuai
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Zuomeng Wu
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China
| | - Yeben Qian
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China.
| |
Collapse
|
|
17
|
Development and Validation of a Novel Clinical Prediction Model to Predict the Risk of Lung Metastasis from Ewing Sarcoma for Medical Human-Computer Interface. COMPUTATIONAL INTELLIGENCE AND NEUROSCIENCE 2022; 2022:1888586. [PMID: 35392046 PMCID: PMC8983195 DOI: 10.1155/2022/1888586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/07/2022] [Accepted: 03/09/2022] [Indexed: 01/11/2023]
Abstract
Background. This study aimed at establishing and validating a quantitative and visual prognosis model of Ewing Sarcoma (E.S.) via a nomogram. This model was developed to predict the risk of lung metastasis (L.M.) in patients with E.S. to provide a practical tool and help in clinical diagnosis and treatment. Methods. Data of all patients diagnosed with Ewing sarcoma between 2010 and 2016 were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. A training dataset from the enrolled cohorts was built (n = 929). Predictive factors for L.M. were identified based on the results of multivariable logistic regression analyses. A nomogram model and a web calculator were constructed based on those key predictors. A multicenter dataset from four medical institutions was established for model validation (n = 51). The predictive ability of the nomogram model was evaluated by the receiver operating characteristic (ROC) curve and calibration plot. Decision curve analysis (DCA) was applied to explain the accuracy of the nomogram model in clinical practice. Results. Five independent factors, including survival time, surgery, tumor (T) stage, node (N) stage, and bone metastasis, were identified to develop a nomogram model. Internal and external validation indicated significant predictive discrimination: the area under the ROC curve (AUC) value was 0.769 (95% CI: 0.740 to 0.795) in the training cohort and 0.841 (95% CI: 0.712 to 0.929) in the validation cohort, respectively. Calibration plots and DCA presented excellent performance of the nomogram model with great clinical utility. Conclusions. In this study, a nomogram model was constructed and validated to predict L.M. in patients with E.S. for medical human-computer interface—a web calculator (https://drliwenle.shinyapps.io/LMESapp/). This practical tool could help clinicians make better decisions to provide precision prognosis and treatment for patients with E.S.
Collapse
|
|
18
|
Primary Ewing sarcoma/peripheral primitive neuroectodermal tumors in the cranial bone and mobile spine: what is the difference? BMC Surg 2022; 22:4. [PMID: 34996420 PMCID: PMC8742462 DOI: 10.1186/s12893-021-01452-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/23/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Primary Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumors (pPNETs) are aggressive bone tumors that rarely occur in the axial skeleton, including the cranial bone and mobile spine. The purpose of this study was to investigate whether there were any differences in patient characteristics, treatment strategies, and outcomes between patients with ES/pPNETs of the cranial bone and those with ES/pPNETs of the mobile spine. METHODS A retrospective study was performed on 33 patients with ES/pPNETs who had been surgically treated and pathologically confirmed at our institution between 2010 and 2020. Patient characteristics were compared using Fisher exact tests or independent t tests. Survival rates were estimated via Kaplan-Meier survival analysis and compared using log-rank tests. RESULTS Thirteen patients had ES/pPNETs of the cranial bone (39.4%), while 20 patients had ES/pPNETs of the mobile spine (60.6%). Patients with ES/pPNETs of the cranial bone had a younger mean age (14.8 vs 22.6 years; p = 0.047) and longer mean disease duration (2.5 vs 1.9 months; p = 0.008) compared with those of patients with ES/pPNETs of the mobile spine. Kaplan-Meier analysis showed that gross total resection (GTR) and radiotherapy resulted in a longer median survival time. The overall survival rates and progression-free survival rates of patients with ES/pPNETs of the cranial bone versus those of the mobile spine were not significantly different (p = 0.386 and p = 0.368, respectively). CONCLUSIONS Patients with ES/pPNETs of the cranial bone were younger compared to patients with ES/pPNETs of the mobile spine. There was no significant difference in the prognosis of patients with ES/pPNETs of the cranial bone versus those of the mobile spine. Taken together, our findings suggest that GTR and radiotherapy offer the best prognosis for improved long-term survival.
Collapse
|
|
19
|
Identifying the Risk Factors and Estimating the Prognosis in Patients with Pelvis and Spine Ewing Sarcoma: A Population-Based Study. Spine (Phila Pa 1976) 2021; 46:1315-1325. [PMID: 34517400 DOI: 10.1097/brs.0000000000004022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Retrospective analysis. OBJECTIVE The study was designed to: (1) figure out risk factors of metastasis; (2) explore prognostic factors and develop a nomogram for pelvis and spine Ewing sarcoma (PSES). SUMMARY OF BACKGROUND DATA Tools to predict survival of PSES are still insufficient. Nomogram has been widely developed in clinical oncology. Moreover, risk factors of PSES metastasis are still unclear. METHODS The data were collected and analyzed from the Surveillance, Epidemiology, and End Results (SEER) database. The optimal cutoff values of continuous variables were identified by X-tile software. The prognostic factors of survival were performed by Kaplan-Meier method and multivariate Cox proportional hazards modeling. Nomograms were further constructed for estimating 3- and 5-year cancer-specific survival (CSS) and overall survival (OS) by using R with rms package. Meanwhile, Pearson χ2 test or Fisher exact test, and logistic regression analysis were used to analyze the risk factors for the metastasis of PSES. RESULTS A total of 371 patients were included in this study. The 3- and 5-year CSS and OS rate were 65.8 ± 2.6%, 55.2 ± 2.9% and 64.3 ± 2.6%, 54.1 ± 2.8%, respectively. The year of diagnosis, tumor size, and lymph node invasion were associated with metastasis of patients with PSES. A nomogram was developed based on identified factors including: age, tumor extent, tumor size, and primary site surgery. The concordance index (C-index) of CSS and OS were 0.680 and 0.679, respectively. The calibration plot showed the similar trend of 3-year, 5-year CSS, and OS of PSES patients between nomogram-based prediction and actual observation, respectively. CONCLUSION PSES patients with earlier diagnostic year (before 2010), larger tumor size (>59 mm), and lymph node invasion, are more likely to have metastasis. We developed a nomogram based on age, tumor extent, tumor size, and surgical treatments for determining the prognosis for patients with PSES, while more external patient cohorts are warranted for validation.Level of Evidence: 3.
Collapse
|
|
20
|
Haveman LM, van Ewijk R, van Dalen EC, Breunis WB, Kremer LC, van den Berg H, Dirksen U, Merks JH. High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with first recurrence of Ewing sarcoma. Cochrane Database Syst Rev 2021; 9:CD011406. [PMID: 34472084 PMCID: PMC8411193 DOI: 10.1002/14651858.cd011406.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Ewing sarcoma is a solid tumour, which is the second most common primary bone malignancy in children, often occurring in the long bones and pelvis. An incidence rate of 4.5 per million a year is reported, with a peak incidence of 11 per million at the age of 12 years. Despite more intensive chemotherapy, 30% to 40% of young people with Ewing sarcoma will have recurrence of the disease. Less than 30% of young people with a recurrence of Ewing sarcoma are alive at 24 months, and less than 10% are alive at 48 months. High-dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT), is used in a variety of paediatric groups with diverse solid tumours. The hypothesis is that HDC regimens may overcome resistance to standard polychemotherapy, and this way may eradicate minimal residual disease, leading to improved survival after a first recurrence of disease. OBJECTIVES To assess the efficacy of HDC with AHCT versus conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with first recurrence of Ewing sarcoma, and to determine the toxicity of the treatment. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, conference proceedings from the SIOP, ASPHO, CTOS, ASBMT, EBMT, and EMSOS, and two trial registries in January 2020. We also searched reference lists of relevant articles and review articles. SELECTION CRITERIA We planned to include randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC plus AHCT with conventional chemotherapy for children, adolescents, and young adults (up to 30 years old at the date of diagnostic biopsy) with a first recurrence of Ewing sarcoma. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We did not identify any eligible studies. AUTHORS' CONCLUSIONS Since we did not identify any eligible studies, we are unable to draw any conclusions about the efficacy and toxicity of HDC with AHCT versus conventional chemotherapy in children, adolescents, and young adults with a first recurrence of Ewing sarcoma. Further high-quality research is urgently needed.
Collapse
Affiliation(s)
- Lianne M Haveman
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
| | - Roelof van Ewijk
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
| | | | - Willemijn B Breunis
- Department of Paediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Leontien Cm Kremer
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Department of Paediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Henk van den Berg
- Department of Paediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Uta Dirksen
- Pediatrics III, Sarcoma Centre, West German Cancer Centre, University Hospital Essen, Essen, Germany
| | - Johannes Hm Merks
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Department of Paediatric Oncology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| |
Collapse
|
|
21
|
Bajpai J, Panda GS, Chandrasekharan A, Bhargava P, Srinivas S, Laskar S, Dandekar S, Mokal S, Rekhi B, Khanna N, Menon N, Patil V, Noronha V, Joshi A, Prabhash K, Banavali SD, Gupta S. Adolescent-adult nonmetastatic Ewing sarcoma-Experience from a large developing country. Pediatr Blood Cancer 2021; 68:e29081. [PMID: 33991401 DOI: 10.1002/pbc.29081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/01/2021] [Accepted: 04/09/2021] [Indexed: 11/07/2022]
Abstract
BACKGROUND Outcome and toxicity data in adolescent-adult Ewing sarcoma (AA-ES) patients are sparse and merits exploration. METHODS Histopathologically confirmed, nonmetastatic AA-ES patients, who received standard institutional combination chemotherapy regimen (Ewing's family of tumors-2001 [EFT-2001]) comprising of ifosfamide plus etoposide and vincristine, doxorubicin plus cyclophosphamide, lasting a total of 12 months between 2013 and 2018, were analyzed for treatment-related toxicities, event-free survival (EFS), and overall survival (OS). RESULTS There were 235 patients (primary safety cohort [PSC]) with median age of 23 (15-61) years; 159 (67.7%) were males, 155 (65.9%) had skeletal primary and 114 (48.5%) had extremity tumors. One hundred ninety-six (83.4%) were treatment naïve (primary efficacy cohort [PEC]) and of these 119 (60.7%) had surgery. In PEC, at a median follow-up of 36.4 (interquartile range [IQR] 20-55) months, estimated 3-year EFS and OS were 67.3% (95% CI 60.3-75.1%) and 91.1% (95% CI 86.7-95.7%), respectively. Of these, 158 (80.6%) complying with intended treatment, at a median follow-up of 39 (IQR 26-57) months had an estimated 3-year EFS of 68.2% (95% CI 60.3-76.1%). In multivariable analysis, good prognostic factors included longer symptom(s) duration (HR 0.93, 95% CI 0.86-0.994), ≥99% necrosis (HR 0.30, 95% CI 0.11-0.77), and treatment completion (HR 0.32, 95% CI 0.14-0.74). Among PSC, grade 3-4 toxicities were febrile neutropenia (119, 50.6%), anemia (130, 55.3%), peripheral neuropathy (37, 15.7%), with three (1.3%) chemo-toxic deaths. CONCLUSIONS The outcomes of AA nonmetastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity. This regimen can be considered a standard of care in AA-ES.
Collapse
Affiliation(s)
- Jyoti Bajpai
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Goutam Santosh Panda
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Arun Chandrasekharan
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Prabhat Bhargava
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Sujay Srinivas
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Siddhartha Laskar
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Sonal Dandekar
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Smruti Mokal
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Bharat Rekhi
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Nehal Khanna
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Nandini Menon
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Vijay Patil
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Vanita Noronha
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Amit Joshi
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Kumar Prabhash
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Shripad D Banavali
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| | - Sudeep Gupta
- Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India
| |
Collapse
|
|
22
|
Zhang L, Xiong L, Wu LM, Shen WH, Zhou P, Lian CL, Zhang WT, Wu SG. The patterns of distant metastasis and prognostic factors in patients with primary metastatic Ewing sarcoma of the bone. J Bone Oncol 2021; 30:100385. [PMID: 34401227 PMCID: PMC8355910 DOI: 10.1016/j.jbo.2021.100385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/21/2021] [Accepted: 07/21/2021] [Indexed: 10/25/2022] Open
Abstract
Background Ewing sarcoma (ES) of bone is accounting for the second most common type of primary bone cancer in children and adolescents. However, the patterns of distant metastasis (DM) and the effect of the sites of DM on survival outcomes were not investigated. Aims This study aimed to investigate the patterns of DM and the prognostic factors related to outcomes in primary metastatic ES of the bone. Methods Patients who were diagnosed with primary metastatic ES between 2010 and 2018 were identified from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier analysis, log-rank tests, and Cox proportional-hazards regression models were used for statistical analyses. Results We identified 277 patients in this study and 95.3% of them (n = 264) receiving chemotherapy. A total of 371 sites of DM were observed. Lung was the most common distant metastatic site (n = 182, 49.1%), followed by bone (n = 139, 37.5%), distant lymph node (n = 26, 7.0%), liver (n = 14, 3.8%), and brain (n = 10, 2.7%). Three-year cause-specific survival (CSS) was 56.1% in the entire cohort. Older age (hazard ratio [HR] 2.210, P < 0.001) and bone metastasis (HR 1.903, P = 0.002) were the independent prognostic factors associated with inferior CSS. Similar results were found in those with bone-only metastasis (n = 80) or lung-only metastasis (n = 117), which showed that patients with bone-only metastasis had an inferior CSS compared to those with metastases only to the lung (HR 1.926, P = 0.005). Conclusions Lung and bone are the most frequently distant metastatic sites in patients with primary metastatic ES of bone. Bone metastasis is an independent risk factor for inferior survival.
Collapse
Affiliation(s)
- Lei Zhang
- Department of Orthopaedic Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen 361000, People's Republic of China
| | - Lu Xiong
- Medical Center, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, People's Republic of China
| | - Li-Mei Wu
- Department of Anesthesiology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People's Republic of China
| | - Wen-Hui Shen
- Department of Orthopaedic Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen 361000, People's Republic of China
| | - Ping Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People's Republic of China
| | - Chen-Lu Lian
- Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People's Republic of China
| | - Wen-Tong Zhang
- Department of Orthopaedic Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen 361000, People's Republic of China
| | - San-Gang Wu
- Department of Radiation Oncology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People's Republic of China
| |
Collapse
|
|
23
|
Double Endoprosthesis in the Management of Refractory Metastatic Primary Bone Tumors in Children and Young Adults. Adv Orthop 2021; 2021:9944702. [PMID: 34336294 PMCID: PMC8324344 DOI: 10.1155/2021/9944702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/07/2021] [Accepted: 07/17/2021] [Indexed: 11/23/2022] Open
Abstract
Background Although not all children can be cured yet, much more emphasis is placed on the quality of life during and after cancer treatment. In the case of recurrence, mutilating treatment is still the prevalent option. In our study, we explored the role of limb salvage surgery for young patients with metastatic malignant bone tumors after endoprosthesis reconstruction during the first line of treatment and evaluated the impact of the local control modality in disease control and functional outcomes. Materials and Methods Eleven patients with bone tumor treated between 2007 and 2018 were included in this study. Both during primary treatment and during recurrence, limb salvage surgery was performed using a modular or expandable custom-made replacement system. Peri- and postoperative care for both surgeries were similar. All patients were given chemotherapy before and after both surgeries, according to the oncological guidelines. Results Seven patients (63.6%) are alive with a median follow-up of 6.5 years from diagnosis. None had local recurrence. Five-year estimates of event-free survival and overall survival were 36.27% and 79.55%, respectively. Median time between the first and second surgery was 2.7 years. Three patients presented with postoperative complications following both surgeries and required resurgical intervention. Three months following the second surgery, the Musculoskeletal Tumor Society Scale (MSTS) scores were 15–27 points (21 points on average—60%). Conclusions Limb salvage surgery is feasible and offers good chance of cure with a reasonable rate of complications and good function in patients with recurrent bone sarcoma after endoprosthesis reconstruction during the first line of treatment.
Collapse
|
|
24
|
Bouhani M, Sassi I, Zemni I, Sahraoui G, Bouida A, Slimene M, Rahal K. Intraabdominal lesser sac metastasis from Ewing's sarcoma: An exceptional localization. SAGE Open Med Case Rep 2021; 9:2050313X211022426. [PMID: 34158949 PMCID: PMC8182168 DOI: 10.1177/2050313x211022426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 05/11/2021] [Indexed: 11/23/2022] Open
Abstract
Ewing's sarcoma/primitive neuroectodermal tumor is rare and aggressive with a poor prognosis. Intraabdominal metastases are an uncommon condition. Metastasis in the lesser sac is an exceptional occurrence. To the best of our knowledge, this location has not been described previously. We report a case of a 15-year-old patient treated for Ewing's sarcoma of the left arm 6 years back. She had developed a suspicious mass in the lesser sac 6 years following her primary tumor. The histopathologic exam revealed a tumor with "small round cells" that were positive for CD99, confirming the relapse of Ewing's sarcoma. The relapse was successfully managed with chemotherapy and surgery. Intraabdominal, extraintestinal masses in patients treated previously for Ewing's sarcoma should be considered as Ewing's sarcoma relapse in the differential diagnosis. We fully describe the management of this atypical relapse, with different components of clinical, radiological, and histological findings.
Collapse
Affiliation(s)
- Malek Bouhani
- Department of Oncologic Surgery,
Salah Azaiz Institute, Tunis, Tunisia
- DUniversité de Tunis El Manar,
Faculté de Médecine de Tunis, Tunis, Tunisie
| | - Imen Sassi
- Department of Oncologic Surgery,
Salah Azaiz Institute, Tunis, Tunisia
- DUniversité de Tunis El Manar,
Faculté de Médecine de Tunis, Tunis, Tunisie
| | - Ines Zemni
- Department of Oncologic Surgery,
Salah Azaiz Institute, Tunis, Tunisia
- DUniversité de Tunis El Manar,
Faculté de Médecine de Tunis, Tunis, Tunisie
| | - Ghada Sahraoui
- DUniversité de Tunis El Manar,
Faculté de Médecine de Tunis, Tunis, Tunisie
- DDepartment of anatomopathology,
Salah Azaiz Institute, Tunis, Tunisia
| | - Amine Bouida
- Department of Oncologic Surgery,
Salah Azaiz Institute, Tunis, Tunisia
- DUniversité de Tunis El Manar,
Faculté de Médecine de Tunis, Tunis, Tunisie
| | - Maher Slimene
- Department of Oncologic Surgery,
Salah Azaiz Institute, Tunis, Tunisia
- DUniversité de Tunis El Manar,
Faculté de Médecine de Tunis, Tunis, Tunisie
| | - Khaled Rahal
- Department of Oncologic Surgery,
Salah Azaiz Institute, Tunis, Tunisia
- DUniversité de Tunis El Manar,
Faculté de Médecine de Tunis, Tunis, Tunisie
| |
Collapse
|
|
25
|
Abstract
STUDY DESIGN Single-center retrospective study. OBJECTIVE We discuss the widespread misdiagnosis of primary extraosseous spinal Ewing Sarcomas (PESES) to begnin tumors leading to poor treatment. SUMMARY OF BACKGROUND DATA PESES is a particular entity of spinal Ewing sarcoma (SES) appearing in a similar shape and features to benign tumors such as schwannomas. This imaging mimicry and subsequent possible misdiagnosis lead to primary surgery, without neoadjuvant chemotherapy, which remains deleterious for survival and progression. METHODS We identified a total of 13 patients: seven women (53.8%) and six men operated between 2001 and 2018 for PESES and initially misdiagnosed as schwannomas or ependymomas. RESULTS The mean age of our series was 35.8 years (range, 18.1-47.2 years). The first clinical symptom was neuralgia (61.5%) followed or associated with nerves deficits (38.5%). Median progression-free survival (PFS) was 31.7 months (SD 5.8). Tumor recurrence rates at 1 and 3 years were respectively 21.2% (SD 3.1) and 60.1% (SD 15.8). Median overall survival (OS) was 61.5 months (SD 16.27). The 1-year, 2-year, and 5-year survival estimates were 100.0%, 88.9% (SD 10.5), and 44.4% (SD 16.6). Six patients (46.13%) died following their SES. In univariate analyses, patients with metastastic PESES had a significantly lower OS than others (41.2 months, P = 0.03). CONCLUSION PESES must be ruled out at diagnosis of a spinal tumor when facing a fast-growing lesion with neurological deficits in a young adult. Thoracoabdominopelvic extension should be carried out. Presurgical biopsy must be performed. In case of PESES, neoadjuvant chemotherapy must be established before considering surgical intervention.Level of Evidence: 4.
Collapse
|
|
26
|
Meazza C, Luksch R, Luzzati A. Managing axial bone sarcomas in childhood. Expert Rev Anticancer Ther 2021; 21:747-764. [PMID: 33593222 DOI: 10.1080/14737140.2021.1891886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Introduction: Axial osteosarcoma and Ewing sarcoma are rare, aggressive neoplasms with a worse prognosis than with tumors involving the extremities because they are more likely to be associated with larger tumor volumes, older age, primary metastases, and a poor histological response to chemotherapy. The 5-year OS rates are reportedly in the range of 18-41% for axial osteosarcoma, and 46-64% for Ewing sarcoma.Area covered: The treatment of axial bone tumors is the same as for extremity bone tumors, and includes chemotherapy, surgery and/or radiotherapy.Expert opinion: Local treatment of axial tumors is particularly difficult due to their proximity to neurological and vascular structures, which often makes extensive and en bloc resections impossible without causing significant morbidity. The incidence of local relapse is consequently high, and this is the main issue in the treatment of these tumors. Radiotherapy is an option in the case of surgical resections with close or positive margins, as well as for inoperable tumors. Delivering high doses of RT to the spinal cord can be dangerous. Given the complexity and rarity of these tumors, it is essential for this subset of patients to be treated at selected reference institutions with specific expertise and multidisciplinary skills.
Collapse
Affiliation(s)
- Cristina Meazza
- Pediatric Oncology Unit, Medical Oncology and Emathology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy
| | - Roberto Luksch
- Pediatric Oncology Unit, Medical Oncology and Emathology Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milano, Italy
| | - Alessandro Luzzati
- Orthopedic Oncology and Spinal Reconstruction Surgery, Orthopedic Oncology Department, IRCCS Istituto Ortopedico Galeazzi, Milano, Italy
| |
Collapse
|
|
27
|
MacKay BJ, McCormack RA, Blank AT, Bettiol P, Cox C, Brindley G, Rapp TB. Diagnosis and management of primary malignant tumors in the upper extremity. Orthop Rev (Pavia) 2021; 12:8345. [PMID: 33569156 PMCID: PMC7868949 DOI: 10.4081/or.2020.8345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Bone and soft tissue sarcomas of the upper extremity are relatively uncommon. In many cases, they are discovered incidentally during evaluation of traumatic injuries or common ailments such as rotator cuff tendonitis or tennis elbow. Thus, it is important for all orthopedic surgeons to understand the differential diagnosis, workup, and treatment for upper extremity lesions. An appreciation of the clinical and radiographic features of primary malignant lesions aids in identifying patients that need referral to an orthopedic oncologist and a multidisciplinary team.
Collapse
Affiliation(s)
- Brendan J MacKay
- Department of Orthopaedic Surgery, Texas Tech University Health Sciences Center, Lubbock, TX.,University Medical Center, Lubbock, TX
| | | | - Alan T Blank
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL
| | - Patrick Bettiol
- Department of Orthopaedic Surgery, Texas Tech University Health Sciences Center, Lubbock, TX
| | - Cameron Cox
- Department of Orthopaedic Surgery, Texas Tech University Health Sciences Center, Lubbock, TX
| | - George Brindley
- Department of Orthopaedic Surgery, Texas Tech University Health Sciences Center, Lubbock, TX.,University Medical Center, Lubbock, TX
| | | |
Collapse
|
|
28
|
Guder WK, Hardes J, Nottrott M, Steffen AJ, Dirksen U, Streitbürger A. Pelvic Ewing sarcoma: a retrospective outcome analysis of 104 patients who underwent pelvic tumor resection at a single supra-regional center. J Orthop Surg Res 2020; 15:534. [PMID: 33198775 PMCID: PMC7667797 DOI: 10.1186/s13018-020-02028-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 10/20/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Local treatment in pelvic Ewing sarcoma (ES) consists of operation, radiation therapy, or a combination of both. Reported outcomes vary depending on the treatment modality performed. It is the objective of this study to analyze surgical outcome and complications as well as oncological outcome and complications of chemo- and radiation therapy in this patient cohort and evaluate prognostic factors. METHODS Retrospective review of 104 patients who underwent tumor resection for pelvic ES from 1988 to 2014. RESULTS All patients underwent pelvic resection and radiation therapy was administered in 77.9%. Margins were clear in 94.2%. The response to chemotherapy was good in 78.8%. Local recurrence occurred in 7.7%. The presence of distant metastases at the time of operation was the most important negative predictor for overall survival (p = 0.003). The cumulative 5- and 10-year survival rates were 82.7% and 80.1% for non-metastasized and 61.4% and 41.6% for metastasized pelvic ES at operation. In the presence of a single-distant metastatic site at operation compared to multiple metastatic sites, the cumulative survival rates were 64.3% versus 50% at five and 50.7% versus 16.7% at 10 years. CONCLUSIONS A combined treatment approach of tumor resection and radiation therapy leads to a local control and overall survival rates comparable with those of extremity locations in this study's patient cohort with localized pelvic ES. Therefore, surgical tumor resection (combined with (neo-)adjuvant radiation therapy) in non-metastatic pelvic ES seems feasible. In metastatic patients, however, the significance of tumor resection as a part of local treatment remains less certain and improved outcomes of combined local treatment approaches need to be weighed against these patients' prognosis and quality of life.
Collapse
Affiliation(s)
- Wiebke K Guder
- Department of Orthopedics and Tumor Orthopedics, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany. .,Department of Orthopedic Oncology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany.
| | - Jendrik Hardes
- Department of Orthopedics and Tumor Orthopedics, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.,Department of Orthopedic Oncology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
| | - Markus Nottrott
- Department of Orthopedics and Tumor Orthopedics, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.,Department of Orthopedic Oncology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
| | - Anne Juliane Steffen
- Department of Orthopedics and Tumor Orthopedics, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany
| | - Uta Dirksen
- Department of Pediatric Hematology and Oncology (III), University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
| | - Arne Streitbürger
- Department of Orthopedics and Tumor Orthopedics, University Hospital Muenster, Albert-Schweitzer-Campus 1, Building A1, 48149, Muenster, Germany.,Department of Orthopedic Oncology, University Hospital Essen, Hufelandstrasse 55, 45147, Essen, Germany
| |
Collapse
|
|
29
|
Salfelder MEA, Kessel KA, Thiel U, Burdach S, Kampfer S, Combs SE. Prospective evaluation of multitarget treatment of pediatric patients with helical intensity-modulated radiotherapy. Strahlenther Onkol 2020; 196:1103-1115. [PMID: 32748147 PMCID: PMC7686189 DOI: 10.1007/s00066-020-01670-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 07/07/2020] [Indexed: 02/06/2023]
Abstract
Background and purpose Radiotherapy (RT) is persistently gaining significance in the treatment of pediatric tumors. However, individual features of a growing body and multifocal stages complicate this approach. Tomotherapy offers advantages in the treatment of anatomically complex tumors with low risks of side effects. Here we report on toxicity incidence and outcome of tomotherapy with a focus on multitarget RT (mtRT). Materials and methods From 2008 to 2017, 38 children diagnosed with sarcoma were treated with tomotherapy. The median age was 15 years (6–19 years). Toxicity was graded according to the Common Terminology Criteria for Adverse Events v.4.03 and classified into symptoms during RT, acutely (0–6 months) and late (>6 months) after RT, and long-term sideeffects (>24 months). Results The main histologies were Ewing sarcoma (n = 23 [61%]) and alveolar rhabdomyosarcoma (n = 5 [13%]). RT was performed with a median total dose of 54 Gy (40.5–66.0 Gy) and a single dose of 2 Gy (1.80–2.27 Gy). Twenty patients (53%) received mtRT. Median follow-up was 29.7 months (95% confidence interval 15.3–48.2 months) with a 5-year survival of 55.2% (±9.5%). The 5‑year survival rate of patients with mtRT (n = 20) was 37.1 ± 13.2%, while patients who received single-target RT (n = 18) had a 5-year survival rate of 75 ± 10.8%. Severe toxicities (grade 3 and 4) emerged in 14 patients (70%) with mtRT and 7 patients (39%) with single-target RT. Two non-hematological grade 4 toxicities occurred during RT: one mucositis and one radiodermatitis. After mtRT 5 patients had grade 3 toxicities acute and after single-target RT 4 patients. One patient had acute non-hematological grade 4 toxicities (gastritis, pericarditis, and pericardial effusion) after mtRT. Severe late effects of RT occurred in 2 patients after mtRT and in none of the single-target RT patients. No severe long-term side effects appeared. Conclusion Our results showed acceptable levels of acute and late toxicities, considering the highly advanced diseases and multimodal treatment. Hence, tomotherapy is a feasible treatment method for young patients with anatomically complex tumors or multiple targets. Especially mtRT is a promising and innovative treatment approach for pediatric sarcomas, delivering unexpectedly high survival rates for patients with multifocal Ewing sarcomas in this study, whereby the limited number of patients should invariably be considered in the interpretation. Electronic supplementary material The online version of this article (10.1007/s00066-020-01670-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Maria-Elena A. Salfelder
- Department of Radiation Oncology, Technical University Munich (TUM), Ismaninger Straße 22, 81675 Munich, Germany
| | - Kerstin A. Kessel
- Department of Radiation Oncology, Technical University Munich (TUM), Ismaninger Straße 22, 81675 Munich, Germany
- DKTK Partner Site Munich, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Munich, Germany
- Institute of Radiation Medicine (IRM), Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, Germany
| | - Uwe Thiel
- Department of Pediatrics and Children’s Cancer Research Center, Kinderklinik München Schwabing, Technical University of Munich School for Medicine, Munich, Germany
| | - Stefan Burdach
- Department of Pediatrics and Children’s Cancer Research Center, Kinderklinik München Schwabing, Technical University of Munich School for Medicine, Munich, Germany
| | - Severin Kampfer
- Department of Radiation Oncology, Technical University Munich (TUM), Ismaninger Straße 22, 81675 Munich, Germany
| | - Stephanie E. Combs
- Department of Radiation Oncology, Technical University Munich (TUM), Ismaninger Straße 22, 81675 Munich, Germany
- DKTK Partner Site Munich, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Munich, Germany
- Institute of Radiation Medicine (IRM), Helmholtz Zentrum München, Ingolstädter Landstraße 1, Neuherberg, Germany
| |
Collapse
|
|
30
|
Precision medicine in Ewing sarcoma: a translational point of view. Clin Transl Oncol 2020; 22:1440-1454. [PMID: 32026343 DOI: 10.1007/s12094-020-02298-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/09/2020] [Indexed: 12/19/2022]
Abstract
Ewing sarcoma is a rare tumor that arises in bones of children and teenagers but, in 15% of the patients it is presented as a primary soft tissue tumor. Balanced reciprocal chimeric translocation t(11;22)(q24;q12), which encodes an oncogenic protein fusion (EWSR1/FLI1), is the most generalized and characteristic molecular event. Using conventional treatments, (chemotherapy, surgery and radiotherapy) long-term overall survival rate is 30% for patients with disseminated disease and 65-75% for patients with localized tumors. Urgent new effective drug development is a challenge. This review summarizes the preclinical and clinical investigational knowledge about prognostic and targetable biomarkers in Ewing sarcoma, finally suggesting a workflow for precision medicine committees.
Collapse
|
|
31
|
Danieau G, Morice S, Rédini F, Verrecchia F, Royer BBL. New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies? Int J Mol Sci 2019; 20:ijms20153751. [PMID: 31370265 PMCID: PMC6696068 DOI: 10.3390/ijms20153751] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 07/30/2019] [Accepted: 07/31/2019] [Indexed: 12/21/2022] Open
Abstract
Osteosarcoma and Ewing sarcoma are the most common malignant primary bone tumors mainly occurring in children, adolescents and young adults. Current standard therapy includes multidrug chemotherapy and/or radiation specifically for Ewing sarcoma, associated with tumor resection. However, patient survival has not evolved for the past decade and remains closely related to the response of tumor cells to chemotherapy, reaching around 75% at 5 years for patients with localized forms of osteosarcoma or Ewing sarcoma but less than 30% in metastatic diseases and patients resistant to initial chemotherapy. Despite Ewing sarcoma being characterized by specific EWSR1-ETS gene fusions resulting in oncogenic transcription factors, currently, no targeted therapy could be implemented. It seems even more difficult to develop a targeted therapeutic strategy in osteosarcoma which is characterized by high complexity and heterogeneity in genomic alterations. Nevertheless, the common point between these different bone tumors is their ability to deregulate bone homeostasis and remodeling and divert them to their benefit. Therefore, targeting different actors of the bone tumor microenvironment has been hypothesized to develop new therapeutic strategies. In this context, it is well known that the Wnt/β-catenin signaling pathway plays a key role in cancer development, including osteosarcoma and Ewing sarcoma as well as in bone remodeling. Moreover, recent studies highlight the implication of the Wnt/β-catenin pathway in angiogenesis and immuno-surveillance, two key mechanisms involved in metastatic dissemination. This review focuses on the role played by this signaling pathway in the development of primary bone tumors and the modulation of their specific microenvironment.
Collapse
MESH Headings
- Adolescent
- Antineoplastic Agents/therapeutic use
- Bone Neoplasms/drug therapy
- Bone Neoplasms/genetics
- Bone Neoplasms/immunology
- Bone Neoplasms/mortality
- Bone and Bones
- Child
- Gene Expression Regulation, Neoplastic
- Humans
- Lymphatic Metastasis
- Molecular Targeted Therapy/methods
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/immunology
- Neovascularization, Pathologic/mortality
- Neovascularization, Pathologic/prevention & control
- Oncogene Proteins, Fusion/antagonists & inhibitors
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/immunology
- Osteosarcoma/drug therapy
- Osteosarcoma/genetics
- Osteosarcoma/immunology
- Osteosarcoma/mortality
- Proto-Oncogene Proteins c-ets/antagonists & inhibitors
- Proto-Oncogene Proteins c-ets/genetics
- Proto-Oncogene Proteins c-ets/immunology
- RNA-Binding Protein EWS/antagonists & inhibitors
- RNA-Binding Protein EWS/genetics
- RNA-Binding Protein EWS/immunology
- Sarcoma, Ewing/drug therapy
- Sarcoma, Ewing/genetics
- Sarcoma, Ewing/immunology
- Sarcoma, Ewing/mortality
- Survival Analysis
- Tumor Microenvironment/drug effects
- Tumor Microenvironment/genetics
- Tumor Microenvironment/immunology
- Wnt Signaling Pathway/drug effects
- Young Adult
- beta Catenin/antagonists & inhibitors
- beta Catenin/genetics
- beta Catenin/immunology
Collapse
Affiliation(s)
- Geoffroy Danieau
- Université de Nantes, INSERM, UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, 44035 Nantes, France
| | - Sarah Morice
- Université de Nantes, INSERM, UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, 44035 Nantes, France
| | - Françoise Rédini
- Université de Nantes, INSERM, UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, 44035 Nantes, France
| | - Franck Verrecchia
- Université de Nantes, INSERM, UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, 44035 Nantes, France
| | - Bénédicte Brounais-Le Royer
- Université de Nantes, INSERM, UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, 44035 Nantes, France.
| |
Collapse
|
|
32
|
Zhang J, Pan Z, Yang J, Yan X, Li Y, Lyu J. A nomogram for determining the disease-specific survival in Ewing sarcoma: a population study. BMC Cancer 2019; 19:667. [PMID: 31277591 PMCID: PMC6612178 DOI: 10.1186/s12885-019-5893-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 06/30/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND We aimed to develop and validate a nomogram for predicting the disease-specific survival of Ewing sarcoma (ES) patients. METHODS The Surveillance, Epidemiology, and End Results (SEER) program database was used to identify ES from 1990 to 2015, in which the data was extracted from 18 registries in the US. Multivariate analysis performed using Cox proportional hazards regression models was performed on the training set to identify independent prognostic factors and construct a nomogram for the prediction of the 3-, 5-, and 10-year survival rates of patients with ES. The predictive values were compared by using concordance indexes (C-indexes), calibration plots, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision curve analysis (DCA). RESULTS A total of 2,643 patients were identified. After multivariate Cox regression, a nomogram was established based on a new model containing the predictive variables of age, race, extent of disease, tumor size, and therapy of surgery. The new model provided better C-indexes (0.684 and 0.704 in the training and validation cohorts, respectively) than the model without therapy of surgery (0.661 and 0.668 in the training and validation cohorts, respectively). The good discrimination and calibration of the nomogram were demonstrated for both the training and validation cohorts. NRI and IDI were also improved. Finally, DCA demonstrated that the nomogram was clinically useful. CONCLUSION We developed a reliable nomogram for determining the prognosis and treatment outcomes of patients with ES in the US. However, the proposed nomogram still requires external data verification in future applications, especially for regions outside the US.
Collapse
Affiliation(s)
- Jun Zhang
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
- Department of Orthopaedics, Baoji Municipal Central Hospital, Baoji, Shaanxi, China
| | - Zhenyu Pan
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
- Department of Pharmacy, The Affiliated Children Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jin Yang
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
- School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
| | - Xiaoni Yan
- Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yuanjie Li
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotosng University Health Science Center, Xi'an, Shaanxi, China
| | - Jun Lyu
- Clinical Research Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
- School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
| |
Collapse
|
|
33
|
Malignant maxillofacial bone tumors. Curr Opin Otolaryngol Head Neck Surg 2019; 27:294-301. [PMID: 31219832 DOI: 10.1097/moo.0000000000000555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Malignant bone tumors of the head and neck region are rare. Due to the paucity of studies on these tumors, patients with these maxillofacial malignancies can suffer from high morbidity and mortality. RECENT FINDINGS Currently, mainstay management of these tumors includes wide surgical resection with margins followed by radiotherapy and/or adjuvant chemotherapy. Although much progress has been made over the last few decades regarding the prognosis of many of these tumors, large multicenter trials are needed to better determine their optimal management. SUMMARY The current review will provide a broad review of the most current epidemiology, pathogenesis, prognosis, and management of the most common bone malignancies of the maxillofacial skeleton.
Collapse
|
|
34
|
PET-CT imaging features that differentiate between positive and negative EWSR1 translocation in Ewing sarcoma. Nucl Med Commun 2019; 40:827-834. [PMID: 31107830 DOI: 10.1097/mnm.0000000000001031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVES Ewing sarcoma breakpoint region 1 (EWSR1) translocation-negative tumors represent a minor portion of small round cell tumors consistent with Ewing sarcoma morphology. The purpose of this study was to differentiate EWSR1 translocation-positive tumors from EWSR1 translocation-negative tumors using PET-computed tomography features. MATERIALS AND METHODS In this retrospective study 27, Ewing sarcoma patients (December 2011 to November 2016) were divided into two groups, EWSR1 translocation-positive and EWSR1 translocation-negative based on cytogenetic analysis. Pretreatment standardized uptake value maximum (SUVmax) and Hounsfield Units (HU) were measured in the primary tumor in the axial slice with the largest tumor diameter.The associations between SUVmax, HU and the presence of EWSR1 translocation were evaluated. Receiver operating characteristic curve analysis was used to determine cut-off levels of SUVmax and HU suggestive of EWSR1-negative tumors. RESULTS Twenty-one patients were classified as EWSR1-positive and six as EWSR1-negative. Eighteen had SUVmax and 21 had HU measurements. EWSR1-negative tumors had significantly higher SUVmax values (P = 0.003) and significantly lower HU values (P = 0.008). Receiver operating characteristic curve analysis showed that SUVmax had diagnostic ability to discriminate between EWSR1-negative and EWSR1-positive tumors (area under the curve = 0.964, P = 0.006). A SUVmax of at least 10 had a sensitivity of 100% and specificity of 85.7% for EWSR1-negative tumors. HU had lower diagnostic ability than SUVmax (area under the curve = 0.881, P = 0.012). A HU up to 57 had a sensitivity of 81.3% and specificity of 80.0% for EWSR1-negative tumors. CONCLUSION Higher SUVmax and lower HU may differentiate between EWSR1-positive and EWSR1-negative tumors. This may reflect EWSR1-negative tumor aggressiveness.
Collapse
|
|
35
|
Abstract
PURPOSE OF REVIEW Osteosarcoma and Ewing sarcoma, the most common primary bone tumours in young people, are curable in most patients. However, these tumours remain a significant challenge due to the complexity and intensity of treatment and its long-term morbidity and the significant proportion of patients in whom treatment is unsuccessful. This review addresses questions about current management and emerging therapeutic targets for patients with osteosarcoma, Ewing sarcoma and chondrosarcoma, the commonest bone sarcoma but more common in older patients. RECENT FINDINGS The largest collaborative international study in osteosarcoma, EURAMOS-1 determined that treatment of patients with resectable disease should not be altered on basis of pathological response to neoadjuvant chemotherapy. In view of little improvement in outcome being evident in recent years, novel therapeutic approaches are required. Putative targets and clinical trials of novel agents are discussed, including emerging targets such as poly (ADP-ribose) polymerase inhibition and isocitrate dehydrogenase inhibition in Ewing sarcoma and chondrosarcoma, respectively. Newer radiotherapy techniques including proton beam and particle ion therapy may be important for local tumour control in selected patients. SUMMARY Collaborative studies are essential to answer current questions and investigate novel therapies in these malignancies to improve outcome and quality of life for patients.
Collapse
|
|
36
|
Chaber R, Arthur CJ, Łach K, Raciborska A, Michalak E, Bilska K, Drabko K, Depciuch J, Kaznowska E, Cebulski J. Predicting Ewing Sarcoma Treatment Outcome Using Infrared Spectroscopy and Machine Learning. Molecules 2019; 24:molecules24061075. [PMID: 30893786 PMCID: PMC6470837 DOI: 10.3390/molecules24061075] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/03/2019] [Accepted: 03/14/2019] [Indexed: 12/03/2022] Open
Abstract
Background: Improved outcome prediction is vital for the delivery of risk-adjusted, appropriate and effective care to paediatric patients with Ewing sarcoma—the second most common paediatric malignant bone tumour. Fourier transform infrared (FTIR) spectroscopy of tissues allows the bulk biochemical content of a biological sample to be probed and makes possible the study and diagnosis of disease. Methods: In this retrospective study, FTIR spectra of sections of biopsy-obtained bone tissue were recorded. Twenty-seven patients (between 5 and 20 years of age) with newly diagnosed Ewing sarcoma of bone were included in this study. The prognostic value of FTIR spectra obtained from Ewing sarcoma (ES) tumours before and after neoadjuvant chemotherapy were analysed in combination with various data-reduction and machine learning approaches. Results: Random forest and linear discriminant analysis supervised learning models were able to correctly predict patient mortality in 92% of cases using leave-one-out cross-validation. The best performing model for predicting patient relapse was a linear Support Vector Machine trained on the observed spectral changes as a result of chemotherapy treatment, which achieved 92% accuracy. Conclusion: FTIR spectra of tumour biopsy samples may predict treatment outcome in paediatric Ewing sarcoma patients with greater than 92% accuracy.
Collapse
Affiliation(s)
- Radosław Chaber
- Clinic of Paediatric Oncology and Haematology, Faculty of Medicine, University of Rzeszow, ul. Kopisto 2a, 35-310 Rzeszow, Poland.
| | | | - Kornelia Łach
- Clinic of Paediatric Oncology and Haematology, Faculty of Medicine, University of Rzeszow, ul. Kopisto 2a, 35-310 Rzeszow, Poland.
| | - Anna Raciborska
- Department of Surgical Oncology for Children and Youth, Institute of Mother and Child, 01-211 Warsaw, Poland.
| | - Elżbieta Michalak
- Department of Pathology, Institute of Mother and Child, 01-211 Warsaw, Poland.
| | - Katarzyna Bilska
- Department of Surgical Oncology for Children and Youth, Institute of Mother and Child, 01-211 Warsaw, Poland.
| | - Katarzyna Drabko
- Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, Medical University of Lublin, 20-081 Lublin, Poland.
| | - Joanna Depciuch
- Institute of Nuclear Physics, Polish Academy of Sciences, 31-342 Krakow, Poland.
| | - Ewa Kaznowska
- Laboratory of Molecular Biology, Centre for Innovative Research in Medical and Natural Sciences, Faculty of Medicine, University of Rzeszow, 35-959 Rzeszow, Poland.
- Department of Human Histology, Chair of Morphological Sciences, Faculty of Medicine, University of Rzeszow, 35-959 Rzeszow, Poland.
| | - Józef Cebulski
- Center for Innovation and Transfer of Natural Sciences and Engineering Knowledge, University of Rzeszow, 35-959 Rzeszow, Poland.
| |
Collapse
|
|
37
|
Martin E, Senders JT, ter Wengel PV, Smith TR, Broekman MLD. Treatment and survival of osteosarcoma and Ewing sarcoma of the skull: a SEER database analysis. Acta Neurochir (Wien) 2019; 161:317-325. [PMID: 30578430 PMCID: PMC6373276 DOI: 10.1007/s00701-018-3754-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 11/26/2018] [Indexed: 11/27/2022]
Abstract
Background Common primary bone tumors include osteosarcomas (OSC) and Ewing sarcomas (EWS). The skull is a rare site, and literature about their treatment and survival is scarce. Using the Surveillance, Epidemiology, and End Results (SEER) database, this study aims to assess the treatment and survival of skull OSC and skull EWS, as well as predictors for survival. Methods Skull OSC and EWS cases were obtained from the SEER database. Patient and tumor characteristics, treatment modalities, and survival were extracted. Overall survival (OS) was assessed using multivariable Cox proportional hazard regression stratified by tumor histology. Kaplan-Meier curves were constructed for OS comparing OSC and EWS, as well as histological subtypes in OSC. Results A total of 321 skull OSC and 80 skull EWS patients were registered from 1973 to 2013. EWS was more common in younger patients (p < 0.001). Resection was the predominant treatment strategy (80.1%), frequently in combination with adjuvant radiotherapy (30.4%). The 5-year survival rate varied significantly between OSC and EWS (51.0% versus 68.5%, p = 0.02). Kaplan-Meier curves show that EWS had a significantly better survival compared to OSC. Comparing histological subtypes of skull OSC, chondroblastic OSC had the best OS, Paget OSC the worst. Older age, tumor advancement, no surgical treatment, and the use of radiotherapy were identified as independent predictors of decreased OS in skull OSC. Conclusion Overall prognosis is better for EWS compared to OSC. Chondroblastic OSC have the best overall survival, while OSC associated with Paget’s disease of the bone has the poorest overall survival.
Collapse
|
|
38
|
Chaber R, Łach K, Arthur CJ, Raciborska A, Michalak E, Ciebiera K, Bilska K, Drabko K, Cebulski J. Prediction of Ewing Sarcoma treatment outcome using attenuated tissue reflection FTIR tissue spectroscopy. Sci Rep 2018; 8:12299. [PMID: 30120284 PMCID: PMC6098133 DOI: 10.1038/s41598-018-29795-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Accepted: 07/18/2018] [Indexed: 01/10/2023] Open
Abstract
Ewing sarcoma is the second most common type of primary bone cancer and predominantly affects children and young people. Improved outcome prediction is key to delivering risk-adjusted, appropriate and effective care to cancer patients. Advances in the Fourier Transform Infrared (FTIR) spectroscopy of tissues enable it to be a non-invasive method to obtain information about the biochemical content of any biological sample. In this retrospective study, attenuated tissue reflection FTIR spectroscopy of biopsy samples from paediatric patients reveals spectral features that are diagnostic for Ewing Sarcoma. Furthermore, our results suggest that spectral features such as these may be of value for the prediction of treatment outcome independent to well-known, routinely used risk factors.
Collapse
Affiliation(s)
- Radosław Chaber
- Clinic of Paediatric Oncology and Haematology, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland.
| | - Kornelia Łach
- Clinic of Paediatric Oncology and Haematology, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland
| | | | - Anna Raciborska
- Department of Oncology and Surgical Oncology for Children and Youth, Institute of Mother and Child, Warsaw, Poland
| | - Elżbieta Michalak
- Department of Pathology, Institute of Mother and Child, Warsaw, Poland
| | | | - Katarzyna Bilska
- Department of Oncology and Surgical Oncology for Children and Youth, Institute of Mother and Child, Warsaw, Poland
| | - Katarzyna Drabko
- Department of Pediatric Hematology, Oncology and Bone Marrow Transplant, Medical University of Lublin, Lublin, Poland
| | - Józef Cebulski
- Center for Innovation and Transfer of Natural Sciences and Engineering Knowledge, University of Rzeszow, Rzeszow, Poland
| |
Collapse
|
|
39
|
Zhang WT, Zhang WW, He ZY, Sun JY, Zhang L, Xia Q, Wu SG. Comparison of the effects of local treatment strategies in non-metastatic Ewing sarcoma of bone. Expert Rev Anticancer Ther 2018. [PMID: 29537323 DOI: 10.1080/14737140.2018.1453360] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND To investigate the optimal local treatment strategies for patients with non-metastatic Ewing sarcoma (ES) of bone. METHODS Patients with ES of bone were identified using the Surveillance Epidemiology and End Results database. Kaplan-Meier log-rank test and Cox regression models were performed to assess the effect of the types of local treatment strategies on cause-specific survival and overall survival. RESULTS 560 patients were included with a median age of 16 years. A total of 284, 162 and 114 patients received surgery alone, surgery and radiotherapy, and radiotherapy alone, respectively. The types of local treatment strategies had no effect on survival outcomes in multivariate analysis. In the subgroup analysis of patients with tumor diameter <8 cm, surgery ± radiotherapy had a significantly improved cause-specific survival (P = 0.039), and had potential to improve overall survival (P = 0.070) in multivariate analysis. The local treatment strategies had no effect on survival in patients with different tumor location. CONCLUSION There is no local treatment of choice for non-metastatic ES of bone in terms of survival. More well-designed studies are needed to confirm our findings and investigate the role of various local treatment strategies in relation to primary tumor diameter.
Collapse
Affiliation(s)
- Wen-Tong Zhang
- a Department of Orthopaedic Surgery, Xiamen branch , Zhongshan Hospital, Fudan University , Xiamen , China
| | - Wen-Wen Zhang
- b Department of Radiation Oncology , Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine , Guangzhou , China
| | - Zhen-Yu He
- b Department of Radiation Oncology , Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine , Guangzhou , China
| | - Jia-Yuan Sun
- b Department of Radiation Oncology , Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine , Guangzhou , China
| | - Lei Zhang
- a Department of Orthopaedic Surgery, Xiamen branch , Zhongshan Hospital, Fudan University , Xiamen , China
| | - Qing Xia
- a Department of Orthopaedic Surgery, Xiamen branch , Zhongshan Hospital, Fudan University , Xiamen , China.,c Department of Orthopaedic Surgery , Zhongshan Hospital, Fudan University , Shanghai , China
| | - San-Gang Wu
- d Department of Radiation Oncology , Xiamen Cancer Hospital, the First Affiliated Hospital of Xiamen University , Xiamen , China
| |
Collapse
|
|
40
|
In silico and in vitro drug screening identifies new therapeutic approaches for Ewing sarcoma. Oncotarget 2018; 8:4079-4095. [PMID: 27863422 PMCID: PMC5354814 DOI: 10.18632/oncotarget.13385] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 10/14/2016] [Indexed: 12/29/2022] Open
Abstract
The long-term overall survival of Ewing sarcoma (EWS) patients remains poor; less than 30% of patients with metastatic or recurrent disease survive despite aggressive combinations of chemotherapy, radiation and surgery. To identify new therapeutic options, we employed a multi-pronged approach using in silico predictions of drug activity via an integrated bioinformatics approach in parallel with an in vitro screen of FDA-approved drugs. Twenty-seven drugs and forty-six drugs were identified, respectively, to have anti-proliferative effects for EWS, including several classes of drugs in both screening approaches. Among these drugs, 30 were extensively validated as mono-therapeutic agents and 9 in 14 various combinations in vitro. Two drugs, auranofin, a thioredoxin reductase inhibitor, and ganetespib, an HSP90 inhibitor, were predicted to have anti-cancer activities in silico and were confirmed active across a panel of genetically diverse EWS cells. When given in combination, the survival rate in vivo was superior compared to auranofin or ganetespib alone. Importantly, extensive formulations, dose tolerance, and pharmacokinetics studies demonstrated that auranofin requires alternative delivery routes to achieve therapeutically effective levels of the gold compound. These combined screening approaches provide a rapid means to identify new treatment options for patients with a rare and often-fatal disease.
Collapse
|
|
41
|
Ferrari S, Palmerini E, Alberghini M, Staals E, Mercuri M, Barbieri E, Longhi A, Cantero L, Cesari M, Abate M, Balladelli A, Picci P, Bacci G. Vincristine, Doxorubicin, Cyclophosfamide, Actinomycin D, Ifosfamide, and Etoposide in Adult and Pediatric Patients with Nonmetastatic Ewing Sarcoma. Final Results of a Monoinstitutional Study. TUMORI JOURNAL 2018; 96:213-8. [DOI: 10.1177/030089161009600205] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and background To investigate a six-drug combination in patients with non-metastatic Ewing sarcoma, focusing on chemotherapy-induced necrosis and chemotherapy toxicity in adult and pediatric patients. Methods and study design Alternating cycles of vincristine (1.5 mg/m2), doxorubicin (80 mg/m2) and cyclophosfamide (1200 mg/m2) (weeks 0, 6, 13, 22a nd 31), ifosfamide (9 g/m2), vincristine (1.5 mg/m2), and actinomycin D (1.5 mg/m2) (weeks 3, 16, 25 and 34), and ifosfamide (9 g/m2) and etoposide (450 mg/m2) (weeks 9, 19, 28 and 37) were administered. Primary chemotherapy-induced necrosis was graded: G3 (complete necrosis), G2 (microfoci of tumor cells) and G1 (macrofoci of tumor cells). Results From 1996 to 1999, 50 patients with Ewing sarcoma were enrolled. The median age was 23.5 years (range, 4–56). Chemotherapy-induced necrosis (in 28 patients) was G3 in 36%, G2 in 21% and G1 in 43%. At a median follow-up of 110 months (range, 36–129), 5-year overall survival and event-free survival were 72% and 66%, respectively. According to histologic response, 5-year event-free survival was 90% in G3, 83% in G2, and 42% in G1 (P = 0.02). In adult and pediatric (<18 years) patients, the incidence of G4 leukopenia was 62% and 74%, respectively, with febrile neutropenia in 13% and 21%, respectively. G4 thrombocytopenia occurred in 3% of cycles in adults and in 7% in pediatric patients. Platelet and red blood cell transfusions were required respectively in 1% and 11% of cycles in adults and in 6% and 24% of cycles in pediatric patients. Conclusions The six-drug combination can be administered safely in adult and pediatric populations. About 40% of patients have a poor chemotherapy-induced tumor necrosis, leading to poor probability of survival. New strategies are recommended to improve survival of poor responders to the six-drug combination.
Collapse
Affiliation(s)
| | | | | | - Eric Staals
- 5th Division of Orthopedic Surgery, Istituto Ortopedico Rizzoli, Bologna
| | - Mario Mercuri
- 5th Division of Orthopedic Surgery, Istituto Ortopedico Rizzoli, Bologna
| | - Enza Barbieri
- Unit of Radiotherapy, S Orsola Hospital, Bologna, Italy
| | | | | | | | | | - Alba Balladelli
- Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna
| | - Piero Picci
- Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna
| | | |
Collapse
|
|
42
|
Puri A, Gulia A, Crasto S, Vora T, Khanna N, Laskar S. Does Radiotherapy after Surgery Affect Outcomes in Ewing's Sarcoma of the Pelvis? Indian J Orthop 2018; 52:73-76. [PMID: 29416173 PMCID: PMC5791235 DOI: 10.4103/ortho.ijortho_388_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND The impact of postoperative radiotherapy (PORT) on outcomes has been a matter of debate after adequate resection in Ewing's sarcoma of the pelvis. We evaluated our cases after surgical excision in pelvic Ewing's sarcoma and assessed local control and overall survival (OS) with respect to PORT and chemotherapy-induced percentage necrosis. MATERIALS AND METHODS Forty four surgically operated patients (June 2002-November 2014) of localized Ewing's sarcoma were retrospectively reviewed. There were 31 males and 13 females. Age ranged from 2 to 53 years. All patients received institutional chemotherapy protocol. No patient received preoperative radiotherapy. Specimen was analyzed for margins and chemotherapy-induced percentage necrosis. PORT was offered to patients on case-by-case basis. Presence of a large preoperative soft-tissue component, margin evaluation, and percentage necrosis were factors considered. At time of the last followup, 29 patients were alive, 11 died, and 4 were lost to followup. Survivors had a minimum followup of 2 years (range: 31-118 months, mean = 69 months). RESULTS One of twenty (5%) patients with PORT had a local recurrence as against 2 of 24 (8%) without PORT. OS of all patients was 76% at 5 years. Twelve patients with <90% necrosis had OS of 56% and 32 with >90% necrosis had OS of 83% (P = 0.040). OS of patients with PORT was 74%, without PORT was 78% (P = 0.629). CONCLUSIONS The decision to offer PORT after surgical excision in pelvic Ewing's sarcoma is multifactorial; the absence of PORT in selected cases is not detrimental to local control. Poor responders to chemotherapy had poorer survival while PORT did not impact on outcomes.
Collapse
Affiliation(s)
- Ajay Puri
- Department of Surgical Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India,Address for correspondence: Prof. Ajay Puri, Room No: 45, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India. E-mail:
| | - Ashish Gulia
- Department of Surgical Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
| | - Saniya Crasto
- Department of Surgical Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
| | - Tushar Vora
- Department of Medical Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
| | - Nehal Khanna
- Department of Radiation Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
| | - Siddharth Laskar
- Department of Radiation Oncology, Tata Memorial Hospital, HBNI, Mumbai, Maharashtra, India
| |
Collapse
|
|
43
|
Weber DC, Murray FR, Correia D, Bolsi A, Frei-Welte M, Pica A, Lomax AJ, Schneider R, Bachtiary B. Pencil beam scanned protons for the treatment of patients with Ewing sarcoma. Pediatr Blood Cancer 2017. [PMID: 28627000 DOI: 10.1002/pbc.26688] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Few data exist regarding the clinical outcome of patients with Ewing sarcoma (EWS) treated with pencil beam scanning proton therapy (PT). We report the outcome of children, adolescents and young adults (AYA) treated with PT at the Paul Scherrer Institute. MATERIALS Thirty-eight patients (median age, 9.9 years) received a median dose of 54.9 Gy(RBE) (where RBE is relative biologic effectiveness). Size of the tumor ranged from 1.7 to 24 cm. Most common primary site was axial/pelvic (n = 27; 71%). Four patients (11%) presented with metastases at diagnosis. Twenty (53%) patients had chemo-PT only. Median follow-up was 49.6 months (range, 9.2-131.7). RESULTS The 5-year actuarial rate of local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) were 81.5%, 76.4%, and 83.0%, respectively. All local recurrences occurred in field and in patients with nonextremity primaries. Six patients died, all of tumor progression. Age < 10 years was a favorable factor of borderline significance for LC (P = 0.05) and OS (P = 0.05), but was significant for DMFS (P = 0.003). Tumor volume <200 ml was a significant prognostic factors for DMFS (P = 0.03), but not for OS (P = 0.07). Metastasis at diagnosis was a strong predictor of local failure (P = 0.003). Only two grade 3 late toxicities were observed. The 5-year actuarial rate of grade 3 toxicity-free survival was 90.9%. CONCLUSIONS These preliminary data suggest that the outcomes of children and AYA with EWS are good and PT was well tolerated with few late adverse events. The local and distant tumor control for older patients with large pre-PT tumor volumes remains problematic.
Collapse
Affiliation(s)
- Damien C Weber
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland.,Radiation Oncology Department, University Hospital of Bern, Bern, Switzerland.,Radiation Oncology Department, University Hospital of Zürich, Zürich, Switzerland
| | - Fritz R Murray
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland
| | - Dora Correia
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland.,Radiation Oncology Department, University Hospital of Bern, Bern, Switzerland
| | - Alessandra Bolsi
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland
| | - Martina Frei-Welte
- Department of Anesthesia, University Children's Hospital Zürich, Zürich, Switzerland
| | - Alessia Pica
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland
| | - Antony J Lomax
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland.,Department of Physics, ETH, Zürich, Switzerland
| | - Ralf Schneider
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland
| | - Barbara Bachtiary
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Switzerland
| |
Collapse
|
|
44
|
Jamet B, Carlier T, Campion L, Bompas E, Girault S, Borrely F, Ferrer L, Rousseau M, Venel Y, Kraeber-Bodéré F, Rousseau C. Initial FDG-PET/CT predicts survival in adults Ewing sarcoma family of tumors. Oncotarget 2017; 8:77050-77060. [PMID: 29100369 PMCID: PMC5652763 DOI: 10.18632/oncotarget.20335] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 06/27/2017] [Indexed: 01/22/2023] Open
Abstract
Purpose The aim of this retrospective study was to determine, at baseline, the prognostic value of different FDG-PET/CT quantitative parameters in a homogenous Ewing Sarcoma Family of Tumors (ESFT) adult population, compared with clinically relevant prognostic factors. Methods Adult patients from 3 oncological centers, all with proved ESFT, were retrospectively included. Quantitative FDG-PET/CT parameters (SUV (maximum, peak and mean), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of the primary lesion of each patient were recorded before treatment, as well as usual clinical prognostic factors (stage of disease, location, tumor size, gender and age). Then, their relation with progression free survival (PFS) and overall survival (OS) was evaluated. Results 32 patients were included. Median age was 21 years (range, 15 to 61). Nineteen patients (59%) were initially metastatic. On multivariate analysis, high SUVmax remained independent predictor of worst OS (p=0.02) and PFS (p=0.019), metastatic disease of worst PFS (p=0.01) and high SUVpeak of worst OS (p=0.01). Optimal prognostic cut-off of SUVpeak was found at 12.5 in multivariate analyses for PFS and OS (p=0.0001). Conclusions FDG-PET/CT, recommended at ESFT diagnosis for initial staging, can be a useful tool for predicting long-term adult patients outcome through semi-quantitative parameters.
Collapse
Affiliation(s)
- Bastien Jamet
- Nuclear Medicine Unit, ICO Cancer Center Gauducheau, Saint Herblain, France
| | - Thomas Carlier
- Nantes-Angers Cancer Research Center, INSERM U892, CNRS UMR 6299, University of Nantes, Nantes, France.,Nuclear Medicine Unit, University Hospital, Nantes, France
| | - Loic Campion
- Nantes-Angers Cancer Research Center, INSERM U892, CNRS UMR 6299, University of Nantes, Nantes, France.,Oncology Unit, ICO Cancer Center Gauducheau, Saint Herblain, France
| | | | - Sylvie Girault
- Nuclear Medicine Unit, ICO Cancer Center Papin, Angers, France
| | - Fanny Borrely
- Nuclear Medicine Unit, University Hospital Bretonneau, Tours, France
| | - Ludovic Ferrer
- Physics Unit, ICO Cancer Center Gauducheau, Saint Herblain, France
| | - Maxime Rousseau
- Nuclear Medicine Unit, ICO Cancer Center Gauducheau, Saint Herblain, France
| | - Yann Venel
- Nuclear Medicine Unit, University Hospital Bretonneau, Tours, France
| | - Françoise Kraeber-Bodéré
- Nuclear Medicine Unit, ICO Cancer Center Gauducheau, Saint Herblain, France.,Nantes-Angers Cancer Research Center, INSERM U892, CNRS UMR 6299, University of Nantes, Nantes, France.,Nuclear Medicine Unit, University Hospital, Nantes, France
| | - Caroline Rousseau
- Nuclear Medicine Unit, ICO Cancer Center Gauducheau, Saint Herblain, France.,Nantes-Angers Cancer Research Center, INSERM U892, CNRS UMR 6299, University of Nantes, Nantes, France
| |
Collapse
|
|
45
|
Ahmed SK, Randall RL, DuBois SG, Harmsen WS, Krailo M, Marcus KJ, Janeway KA, Geller DS, Sorger JI, Womer RB, Granowetter L, Grier HE, Gorlick RG, Laack NNI. Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 2017; 99:1286-1294. [PMID: 28964585 DOI: 10.1016/j.ijrobp.2017.08.020] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 08/01/2017] [Accepted: 08/16/2017] [Indexed: 12/15/2022]
Abstract
PURPOSE To identify clinical and treatment variables associated with a higher risk of local failure in Ewing sarcoma patients treated on recent Children's Oncology Group protocols. METHODS AND MATERIALS Data for 956 patients treated with ifosfamide and etoposide-based chemotherapy on INT-0091, INT-0154, and AEWS0031 were analyzed. Local treatment modalities were defined as surgery, definitive radiation therapy (RT), or surgery plus radiation (S+RT). Five-year cumulative incidence of local failure was determined. RESULTS The local failure rate for the entire cohort was 7.3%, with a 3.9% rate for surgery, 15.3% for RT (P<.01), and 6.6% for S+RT (P=.12). The local failure incidence was 5.4% for extremity tumors, 13.2% for pelvis tumors (P<.01), 5.3% for axial non-spine tumors (P=.90), 9.1% for extraskeletal tumors (P=.08), and 3.6% for spine tumors (P=.49). The incidence of local failure was 14.8% for extremity tumors and 22.4% for pelvis tumors treated with RT, compared with 3.7% for extremity tumors and 3.9% for pelvis tumors treated with surgery (P≤.01). There was no difference in local failure incidence by local treatment modality for axial non-spine, spine, and extraskeletal tumors. The local failure incidence was 11.9% in patients aged ≥18 years versus 6.7% in patients aged <18 years (P=.02). Age ≥18 years (hazard ratio 1.9, P=.04) and treatment with RT (hazard ratio 2.40, P<.01) remained independent prognostic factors for higher local failure incidence on multivariate analysis. Tumor size (</≥ 8 cm) was available in 40% of patients and did not correlate with local failure incidence. CONCLUSIONS Local tumor control is excellent and similar between surgery and RT for axial non-spine, spine, and extraskeletal tumors. Age ≥18 years and use of RT, primarily for pelvis and extremity tumors, are associated with the highest risk of local failure. Further efforts should focus on improving outcomes for these patients.
Collapse
Affiliation(s)
- Safia K Ahmed
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
| | - R Lor Randall
- Department of Orthopedics, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah
| | - Steven G DuBois
- Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - William S Harmsen
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Mark Krailo
- Department of Preventative Medicine, University of Southern California, Los Angeles, California
| | - Karen J Marcus
- Department of Radiation Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - Katherine A Janeway
- Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - David S Geller
- Department of Pediatrics and Orthopedic Surgery, Montefiore Medical Center & Albert Einstein College of Medicine, Bronx, New York
| | - Joel I Sorger
- Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio
| | - Richard B Womer
- Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine & Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Linda Granowetter
- Department of Pediatrics, New York University (NYU) Medical School and NYU Langone Medical Center, New York, New York
| | - Holcombe E Grier
- Department of Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center & Harvard Medical School, Boston, Massachusetts
| | - Richard G Gorlick
- Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nadia N I Laack
- Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.
| |
Collapse
|
|
46
|
Sechler M, Parrish JK, Birks DK, Jedlicka P. The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis. Oncogene 2017; 36:4150-4160. [PMID: 28319067 PMCID: PMC5519422 DOI: 10.1038/onc.2017.44] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 01/27/2017] [Accepted: 02/02/2017] [Indexed: 12/15/2022]
Abstract
Ewing Sarcoma is the second most common solid pediatric malignant neoplasm of bone and soft tissue. Driven by EWS/Ets, or rarely variant, oncogenic fusions, Ewing Sarcoma is a biologically and clinically aggressive disease with a high propensity for metastasis. However, the mechanisms underpinning Ewing Sarcoma metastasis are currently not well understood. In the present study, we identify and characterize a novel metastasis-promotional pathway in Ewing Sarcoma, involving the histone demethylase KDM3A, previously identified by our laboratory as a new cancer-promoting gene in this disease. Using global gene expression profiling, we show that KDM3A positively regulates genes and pathways implicated in cell migration and metastasis, and demonstrate, using functional assays, that KDM3A promotes migration in vitro and experimental, post-intravasation, metastasis in vivo. We further identify the melanoma cell adhesion molecule (MCAM) as a novel KDM3A target gene in Ewing Sarcoma, and an important effector of KDM3A pro-metastatic action. Specifically, we demonstrate that MCAM depletion, like KDM3A depletion, inhibits cell migration in vitro and experimental metastasis in vivo, and that MCAM partially rescues impaired migration due to KDM3A knock-down. Mechanistically, we show that KDM3A regulates MCAM expression both through a direct mechanism, involving modulation of H3K9 methylation at the MCAM promoter, and an indirect mechanism, via the Ets1 transcription factor. Finally, we identify an association between high MCAM levels in patient tumors and poor survival, in two different Ewing Sarcoma clinical cohorts. Taken together, our studies uncover a new metastasis-promoting pathway in Ewing Sarcoma, with therapeutically targetable components.
Collapse
Affiliation(s)
- Marybeth Sechler
- Cancer Biology Graduate Training Program
- University of Colorado Denver, Anschutz Medical Campus, Aurora CO
| | - Janet K. Parrish
- Department of Pathology
- University of Colorado Denver, Anschutz Medical Campus, Aurora CO
| | - Diane K. Birks
- Department of Neurosurgery
- University of Colorado Denver, Anschutz Medical Campus, Aurora CO
| | - Paul Jedlicka
- Cancer Biology Graduate Training Program
- Department of Pathology
- University of Colorado Denver, Anschutz Medical Campus, Aurora CO
| |
Collapse
|
|
47
|
Kuo C, Kent PM, Logan AD, Tamulonis KB, Dalton KL, Batus M, Fernandez K, Mcfall RE. Docetaxel, bevacizumab, and gemcitabine for very high risk sarcomas in adolescents and young adults: A single-center experience. Pediatr Blood Cancer 2017; 64. [PMID: 28221727 DOI: 10.1002/pbc.26265] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 08/21/2016] [Accepted: 08/22/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Adolescent and young adult (AYA) patients with very high risk sarcomas have poor outcomes and are in need of novel therapies. PROCEDURE From January 2005 to February 2016, we retrospectively identified all AYA patients with relapsed or metastatic high-grade sarcomas, who were treated with at least one cycle of docetaxel (T), bevacizumab (A), and gemcitabine (G) (TAG ; T = 100 mg/m2 Day 8, A = 15 mg/kg Day 1, G = 1,000 mg/m2 Days 1 and 8). RESULTS Fourteen patients, median age of 20 (15-30), received a total of 80 cycles of TAG, and were followed for a median of 83 months. Diagnosis included osteosarcoma (OST; 8), Ewing sarcoma (3), and soft tissue sarcoma (3). Five of 14 patients achieved clinical remission (CR), 3 had partial responses (PR), 3 had stable disease (SD), and 3 had progressive disease (PD). The median progression-free survival and overall survival were 7 and 19 months, respectively. The objective response rate (CR + PR) and tumor control rate (CR + PR + SD) were 57% and 79%, respectively, with two patients alive after 5 years; toxicities included thrombocytopenia, neutropenia, and capillary leak syndrome. CONCLUSIONS Our study builds on previous studies utilizing TAG in adult leiomyosarcoma (LMS) by focusing on AYA, non-LMS sarcomas, especially OST. Our experience suggests that TAG is well tolerated and has activity in very high risk sarcomas in AYA.
Collapse
Affiliation(s)
- Christopher Kuo
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois
| | - Paul M Kent
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois
| | - Antonio D Logan
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois
| | - Karen B Tamulonis
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Rush University Medical Center, Chicago, Illinois
| | - Kristen L Dalton
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Marta Batus
- Division of Medical Oncology, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| | - Karen Fernandez
- Division of Hematology/Oncology, Department of Pediatrics, University of Illinois College of Medicine, Peoria, Illinois
| | - Rebecca E Mcfall
- Division of Hematology/Oncology, Department of Pediatrics, Advocate Christ Medical Center, Oak Lawn, Illinois
| |
Collapse
|
|
48
|
Tong AA, Hashem H, Eid S, Allen F, Kingsley D, Huang AY. Adoptive natural killer cell therapy is effective in reducing pulmonary metastasis of Ewing sarcoma. Oncoimmunology 2017; 6:e1303586. [PMID: 28507811 PMCID: PMC5414867 DOI: 10.1080/2162402x.2017.1303586] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/27/2017] [Accepted: 03/01/2017] [Indexed: 12/30/2022] Open
Abstract
The survival of patients with metastatic or relapsed Ewing sarcoma (ES) remains dismal despite intensification of combination chemotherapy and radiotherapy, precipitating the need for novel alternative therapies with minimal side effects. Natural killer (NK) cells are promising additions to the field of cellular immunotherapy. Adoptive NK cell therapy has shown encouraging results in hematological malignancies. Despite these initial promising successes, however, NK cell therapy for solid tumors remains to be investigated using in vivo tumor models. The purpose of this study is to evaluate the efficacy of ex vivo expanded human NK cells in controlling primary and metastatic ES tumor growth in vitro and in vivo. Using membrane-bound IL-21 containing K562 (K562-mbIL-21) expansion platform, we were able to obtain sufficient numbers of expanded NK (eNK) cells that display favorable activation phenotypes and inflammatory cytokine secretion, along with a strong in vitro cytotoxic effect against ES. Furthermore, eNK therapy significantly decreased lung metastasis without any significant therapeutic effect in limiting primary tumor growth in an in vivo xenograft model. Our data demonstrate that eNK may be effective against pulmonary metastatic ES, but challenges remain to direct proper trafficking and augmenting the cytotoxic function of eNK to target primary tumor sites.
Collapse
Affiliation(s)
- Alexander A Tong
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Hasan Hashem
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Saada Eid
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Frederick Allen
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Daniel Kingsley
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Alex Y Huang
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,Angie Fowler AYA Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA
| |
Collapse
|
|
49
|
Theisen ER, Pishas KI, Saund RS, Lessnick SL. Therapeutic opportunities in Ewing sarcoma: EWS-FLI inhibition via LSD1 targeting. Oncotarget 2017; 7:17616-30. [PMID: 26848860 PMCID: PMC4951237 DOI: 10.18632/oncotarget.7124] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 01/23/2016] [Indexed: 11/25/2022] Open
Abstract
Ewing sarcoma is an aggressive primary pediatric bone tumor, often diagnosed in adolescents and young adults. A pathognomonic reciprocal chromosomal translocation results in a fusion gene coding for a protein which derives its N-terminus from a FUS/EWS/TAF15 (FET) protein family member, commonly EWS, and C-terminus containing the DNA-binding domain of an ETS transcription factor, commonly FLI1. Nearly 85% of cases express the EWS-FLI protein which functions as a transcription factor and drives oncogenesis. As the primary genomic lesion and a protein which is not expressed in normal cells, disrupting EWS-FLI function is an attractive therapeutic strategy for Ewing sarcoma. However, transcription factors are notoriously difficult targets for the development of small molecules. Improved understanding of the oncogenic mechanisms employed by EWS-FLI to hijack normal cellular programming has uncovered potential novel approaches to pharmacologically block EWS-FLI function. In this review we examine targeting the chromatin regulatory enzymes recruited to conspire in oncogenesis with a focus on the histone lysine specific demethylase 1 (LSD1). LSD1 inhibitors are being aggressively investigated in acute myeloid leukemia and the results of early clinical trials will help inform the future use of LSD1 inhibitors in sarcoma. High LSD1 expression is observed in Ewing sarcoma patient samples and mechanistic and preclinical data suggest LSD1 inhibition globally disrupts the function of EWS-ETS proteins.
Collapse
Affiliation(s)
- Emily R Theisen
- Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kathleen I Pishas
- Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.,Cancer Therapeutics Laboratory, Centre for Personalized Cancer Medicine, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia
| | - Ranajeet S Saund
- Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Stephen L Lessnick
- Center for Childhood Cancer and Blood Disorders, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.,Division of Pediatric Hematology/Oncology/Bone Marrow Transplant at The Ohio State University, Columbus, Ohio, USA
| |
Collapse
|
|
50
|
Margaix-Muñoz M, Bagán J, Poveda-Roda R. Ewing sarcoma of the oral cavity. A review. J Clin Exp Dent 2017; 9:e294-e301. [PMID: 28210452 PMCID: PMC5303334 DOI: 10.4317/jced.53575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 12/16/2016] [Indexed: 11/09/2022] Open
Abstract
Objectives A review is made of the clinical, diagnostic, therapeutic and survival characteristics of Ewing sarcoma (ES) of the oral cavity. Material and Methods A systematic literature search was carried out, with restrictions referred to time (1960-2014), language (English and Spanish) and type of study (case reports, letters, datasets, reviews). The following MeSH terms and boolean operators were used: Ewing AND Sarcoma AND [tongue, jaw, maxilla, cheek, condyle OR temporomandibular, floor AND mouth, gum OR gingiva, palate OR palatal, lip, uvula, head AND neck]. Results Seventy-one cases of ES of the oral cavity were documented from 53 articles. The main differences versus ES of other locations were a younger age at manifestation, a shorter time from symptoms onset to diagnosis, and swelling as the most frequent clinical manifestation versus swelling and pain in the rest of disease locations. The way in which ES manifests in the oral cavity is varied and comprises dental displacement (19.7%), dental mobility (7%), root reabsorption (5.6%), destruction of the dental follicle (4.2%), premature exfoliation (4.2%) and paresthesia of the chin (2.8%). Metastatic neck adenopathies appear in 11.3% of the cases. Significant differences in survival are observed between patients with a complete diagnosis of ES (hematoxylin-eosin staining, PAS positivity, CD99 positivity) and those with an incomplete diagnosis. Conclusions Ewing sarcoma of the oral cavity presents a series of specific features that distinguish it from ES of other locations. Key words:Primitive neuroectodermal tumor, PNET, Ewing sarcoma, Ewing tumor, sarcoma, oral cavity.
Collapse
Affiliation(s)
- Maria Margaix-Muñoz
- DDS, PhD. Associate Professor of Oral Medicine. Department of Stomatology, University of Valencia. Valencia (Spain)
| | - José Bagán
- MD, DDS, PhD. Charmain of Oral Medicine. Department of Stomatology, University of Valencia. Head of Stomatology and Maxillofacial Surgery Service. General Universitary Hospital of Valencia. Valencia (Spain)
| | - Rafael Poveda-Roda
- MD, DDS, PhD. Staff physician. Stomatology and Maxillofacial Surgery Service. General Universitary Hospital of Valencia. Valencia (Spain)
| |
Collapse
|