Are Pathological Fractures in Patients with Ewing Sarcoma Associated with Worse Survival Outcomes?

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Hisaki Aiba, Ayano Aso, Alberto Righi, Marco Gambarotti, Paolo Spinnato, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9216618/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives Pathological fractures occur in 5–10% of patients with Ewing sarcoma and may disseminate tumor cells from the fractured bone, potentially affecting the treatment strategy. This study analyzed the clinical course of patients with pathological fractures of Ewing sarcoma using propensity score matching to minimize selection bias. Methods This retrospective study assessed the outcomes from 2003 to 2020. Among the 437 patients with Ewing sarcoma, 12 had pathological fractures of the extremities. For comparison with patients without pathological fractures, a 1:3 propensity score-matched control group (n = 36, adjusted group) was used. Results Among the 12 patients, limb-sparing surgery was performed in 11 patients (91.7%), and limb salvage was achieved in 10 patients (83.3%). Three-year overall survivals were 75.0% in patients with pathological fractures and 66.4% in the adjusted group (p = 0.29). Local recurrence was observed in two patients (16.7%) in the pathological fracture group; both had a poor histologic response (25% and 40%). Conclusion Pathological fractures in Ewing sarcoma were not associated with worse oncological outcomes, even after propensity score matching. Limb-sparing surgery may be a reasonable treatment option when preoperative chemotherapy is effective in patients with pathological fractures. Ewing sarcoma bone tumor surgery pathological fracture Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Ewing sarcoma is the second most common primary bone tumor in children and adolescents [ 1 ]; the standard treatment consists of surgical resection combined with preoperative and postoperative chemotherapy [ 2 , 3 ]. Because of the fragility of the affected bone, pathological fractures occur in 5–10% of patients with Ewing sarcoma [ 4 , 5 ]. These fractures commonly affect long, weight-bearing bones, most frequently the proximal third of the femur (50%) [ 6 ]. Fractures result from cortical bone destruction driven by tumor cell invasion or treatment-induced bone weakening [ 6 ]. Because fractures can induce tumor cell dissemination around the destroyed cortical bone [ 6 ], it may necessitate altering surgical strategies [ 7 ]. In osteosarcoma, another common primary bone tumor in children and adolescents [ 8 , 9 ], a systematic review and meta-analysis comprising 21 studies involving 7,604 patients investigated the prognostic significance of pathologic fractures [ 10 ]. Patients with pathological fractures had significantly lower overall survival (OS) rates than those without fractures (relative risk = 1.27, p < 0.001), concomitant with an increased risk of metastases (relative risk = 1.33, p = 0.01) [ 10 ]. Moreover, a retrospective study of 46 patients with non-metastatic extremity osteosarcoma and pathologic fractures versus 689 contemporaneous patients without fractures found similar local recurrence rates (2% vs. 4%, respectively; p = 0.80) [ 11 ]. However, extrapolating these results to Ewing sarcoma is challenging, as this tumor exhibits different chemosensitivity and treatment protocols than osteosarcoma [ 12 ]. Moreover, the paucity of studies on pathological fractures in Ewing sarcoma limits the reliability and interpretability of the findings, a consequence of the rarity of the tumor and the inherent variabilities among studies [ 13 ]. This study analyzed the clinical course of patients with pathological fractures of Ewing sarcoma and the impact of these fractures on treatment outcomes, utilizing propensity score matching to minimize selection bias. Materials and methods Patient selection and preparation of matched-pair cohort We retrospectively reviewed the records of 437 patients diagnosed with Ewing sarcoma between 2003 and 2020 at a single institution. The diagnoses were based on histological and/or molecular cytogenetic findings [ 14 ]. We excluded 127 patients with axial tumors, 126 with incomplete resected specimen data, 19 who received radiotherapy only at the primary site, and 16 with extra skeletal Ewing sarcoma. A total of 149 patients were included: 12 in the pathological fracture group and 137 in the control group (unadjusted group). For matched‑pair analysis, we performed 1:3 propensity score matching and selected 36 patients from the control group for the adjusted group (Fig. 1 ). As a supplemental analysis, we performed another 1:3 propensity score matching in patients without metastases at diagnosis (pathological fracture group, 9; adjusted group, 27). This study was approved by the Ethics Committee of the Institutional Review Board (approval number: 0001336) and conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study. Definition of variables The histological response to preoperative chemotherapy and/or radiotherapy was determined retrospectively by two pathologists (A.R. and M.G.) who were blinded to the clinical outcomes. Histological responses were assessed based on tumor necrosis and reparative fibrous tissue [ 15 ]. Based on histological response, patients were categorized into two groups: good (necrosis ≥ 90%) or poor (necrosis < 90%) [ 16 ]. OS was defined as the period from diagnosis to the date of the last follow-up or death. Statistical analyses Continuous variables were summarized as medians with interquartile ranges (IQRs) and compared between groups using the Wilcoxon rank-sum test. Categorical variables are presented as counts with percentages and were compared using the χ² test. OS was visualized using the Kaplan–Meier method, and differences were assessed using the log-rank test. Propensity scores were calculated based on age, sex, tumor volume at diagnosis, presence of metastasis at diagnosis, radiotherapy administration, and histological response to preoperative therapy. Matching was performed with a 0.2 caliper width at a 1:3 ratio. Covariate balance before and after matching was evaluated using absolute standardized mean differences (ASMD) based on the pooled standard deviation; an ASMD < 0.2 indicated adequate balance. Univariate and multivariate analyses were performed to identify the risk factors for OS in the entire cohort (149 patients, pathological fracture group, and unadjusted group). Variables with a p value < 0.10 in the univariate analysis were entered as covariates into a stepwise Cox proportional hazards regression model to identify multivariate predictors of OS. All statistical analyses were conducted using R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria), with a significance threshold of p < 0.05. Results Characteristics of the patients with pathological fractures Among the 12 patients with pathological fractures, the primary tumor location was the humerus in six patients (50.0%; four diaphysis, two proximal), the femur in four (33.3%; three proximal, one distal), the forearm in one (8.3%; proximal ulna), and the scapula in one (8.3%). The median age at diagnosis was 16.0 years (IQR, 10.3–31.5). Metastasis at diagnosis was identified in three patients (25.0%). Pathological fractures were present at diagnosis in ten patients (83.3%); two patients (16.7%) progressed to fractures during preoperative chemotherapy (Table 1 ). Table 1 Clinical characteristics and treatment details of patients with pathological fracture Number Location Age Gender Fracture type Metastasis at diagnosis Treatment for primary site Radiotherapy Margin status Histological response (%) Local recurrence Distant metastasis Final status Follow-up period (days) 1 Humerus, Diaphysis 38 Women Complete No Megaprosthesis No R0 65 No No CDF 3168 2 Humerus, Diaphysis 12 Women Impending (complete, during chemotherapy) No Megaprosthesis Preoperative R0 85 No Yes DOD 879 3 Humerus, Diaphysis 14 Women Impending No Allograft + Megaprosthesis Preoperative R0 100 No No CDF 1412 4 Humerus, Diaphysis 62 Men Impending No Megaprosthesis No R0 40 Yes (amputation) Yes DOD 829 5 Humerus, Proximal 21 Men Complete No Megaprosthesis No R0 25 Yes (en bloc resection of soft tissue recurrence) Yes (lung metastasectomy) NED 2624 6 Humerus, Proximal 7 Men Complete No Megaprosthesis Postoperative R1 88 No No CDF 4973 7 Femur, Proximal 24 Men Complete Yes Megaprosthesis (Infection) No R0 86 No No NED*1 5275 8 Femur, Proximal 18 Men Complete Yes Megaprosthesis No R0 75 No N/A DOD 622 9 Femur, Proximal 10 Men Impending (complete, during chemotherapy) No Megaprosthesis No R0 95 No No CDF 3602 10 Femur, Distal 11 Men Complete No Rotationplasty No R0 30 No No CDF 6331 11 Ulna, Proximal 34 Men Complete No En bloc resection Preoperative R0 100 No No CDF 1825 12 Scapula 9 Men Complete Yes En bloc resection (total scapulectomy) No R0 60 No No NED 3777 CDF, complete disease-free; DOD, dead of disease; NED, no evidence of disease. *1, The metastatic lesion was controlled with whole lung irradiation and high-dose chemotherapy and autologous peripheral blood stem cell transfusion. Limb-sparing surgery was performed in 11 patients (91.7%), whereas rotation-plasty was conducted in one (8.3%). The median time from diagnosis to surgery was 107 days (IQR, 99.8–169.5 days). Resection margins were classified as wide or radical in 11 patients (91.7%) and marginal in one (8.3%). Three patients (25.0%) received preoperative radiotherapy, and one (8.3%) underwent marginal resection and postoperative radiotherapy. The median follow-up period was 7.9 years. Representative clinical courses are shown in Figs. 2 and 3 . Comparisons between unadjusted and matched-pair cohorts The covariate balance plot displays the absolute mean differences in covariates between the pathological fracture group and the adjusted and unadjusted groups following propensity score matching. Before matching, several covariates, such as tumor volume and histological response, exceeded the threshold (ASMD > 0.2) (Fig. 4 ). The χ² test indicated that these imbalances approached statistical significance (tumor volume, p = 0.119; histological response, p = 0.054). However, after matching, the ASMD predominantly fell below the threshold, indicating a satisfactory covariate balance. These trends were consistent in the χ² test, with no significant differences detected across matched cohorts (Table 2 ). Table 2 Comparison of patients’ characteristics between groups Gender (men, women) Pathological fracture group (n = 12) Unadjusted control group (n = 137) p-value Adjusted control group (n = 36) p-value 9 (75.0%)/ 3 (25.0%) 97 (70.8%)/ 40 (29.2%) 0.758 23 (63.9%)/ 13 (36.1%) 0.480 Age (< 18 years, ≥ 18 years) 7 (58.3%)/ 5 (41.7%) 94 (68.6%)/ 43 (31.4%) 0.465 20 (55.6%)/ 16 (44.4%) 0.867 Metastasis at diagnosis (no, yes) 9 (75.0%)/ 3 (25.0%) 107 (78.1%)/ 30 (21.9%) 0.804 23 (63.9%)/ 13 (36.1%) 0.480 Initial tumor volume (< 200 mL, ≥ 200 mL) 6 (50.0%)/ 6 (50.0%) 98 (71.5%)/ 39 (28.5%) 0.119 16 (44.4%)/ 20 (55.6%) 0.738 Response to preoperative chemotherapy (good, poor) 8 (75.0%)/ 4 (25.0%) 63 (46.0%)/ 74 (54.0%) 0.054 27 (75.8%) 9 (24.2%) 1.000 Resection margin (wide, marginal/ intralesional) 11 (91.7%)/ 1 (8.3%) 128(93.4%)/ 9 (6.6%) 0.815 32 (88.9%)/ 4 (11.1%) 0.785 Addition of radiotherapy (no, yes) 8 (66.7%)/ 4 (33.3% 108 (78.8%)/ 29 (21.2%) 0.330 21 (58.3%)/ 15 (41.7%) 0.609 Local recurrence (no, yes) 10 (83.3%) 2 (16.7%)/ 123 (89.8%)/ 14 (10.2%) 0.835 32 (88.9%)/ 4 (11.1%) 0.785 Regarding oncological outcomes, three-year OS was 75.0% in the pathological fracture group and 78.8% in the unadjusted group (p = 0.62, log-rank test). After matching, three-year OS was 66.4% in the adjusted group (p = 0.29, log-rank test) (Fig. 5 ). Local recurrence was observed in two patients (16.7%) in the pathological fracture group; both had a poor histologic response (25% and 40%). One patient underwent en bloc resection, whereas the other required amputation. Local recurrence did not differ significantly between the pathological fracture and the unadjusted (10.2%, p = 0.835) or adjusted (11.1%, p = 0.785) groups (Table 2 ). In a supplemental analysis that excluded patients with metastasis at diagnosis, three-year OS rates were 77.8% in the pathological fracture group (n = 9) and 86.9% in the unadjusted group (n = 107) (p = 0.98, log-rank test). After matching, the three-year OS rate was 92.6% (p = 0.91, log-rank test) in the adjusted group (n = 27) (Supplemental Fig. 1). Risk factors for OS Univariate analysis revealed that age > 18 years (p = 0.041), metastasis at diagnosis (p < 0.001), and histological response (p = 0.004) were associated with poor survival. Pathological fractures were not significant prognostic factors (p = 0.097). Multivariate analysis identified metastasis at diagnosis (p < 0.001) and histological response (p = 0.009) as independent predictors of OS (Table 3 ). Table 3 Risk factors for overall survival Variables HR (95% confidence interval), Univariate p-value HR (95% confidence interval), Multivariate p-value Gender (men, women) 1.68 (0.78–3.61) 0.182 Age (≥ 18 years, < 18 years,) 1.85 (1.03–3.33) 0.041 Metastasis at diagnosis (yes, no) 3.20 (1.76–5.81) < 0.001 3.89 (2.18–6.93) < 0.001 Initial tumor volume ( ≧ 200 mL, < 200 mL,) 1.33 (0.70–2.52) 0.388 Response to preoperative chemotherapy (good, poor) 0.38 (0.20–0.73) 0.004 0.44 (0.23–0.81) 0.009 Resection margin (wide, marginal/intralesional) 0.55 (0.14–2.08) 0.373 Addition of radiotherapy (yes, no) 0.83 (0.39–1.79) 0.631 Pathological fracture (yes, no) 1.33 (0.42–4.35) 0.607 HR, hazard ratio. Discussion This study analyzed the outcomes of patients with Ewing sarcoma presenting with pathological fractures. Although limb-sparing surgery was attempted in most patients, the risk of local recurrence was not higher than that in the control group. There was also no difference in the overall survival between the pathological fracture and control groups. Similarly, multivariate analysis identified metastasis at diagnosis and histological response, but not pathological fracture, as independent predictors of worse overall survival. This study had several limitations. First, its retrospective nature and chronological changes in clinical practice, such as chemotherapeutic protocols, may have affected the data consistency. Furthermore, heterogeneity between the pathological fracture and control groups may have persisted even after matched-pair adjustment. Additionally, because of the rarity of the disease, the study's statistical power to confirm the non-inferiority of the pathological fracture group was limited. Despite these limitations, this study represents the first attempt to perform a matched-pairs analysis in a relatively large cohort. Further multi-institutional studies are required to validate these findings. Pathological fractures in patients with malignant bone tumors present significant treatment challenges [ 17 ]. A retrospective study involving 447 patients with various malignant bone tumors (osteosarcoma, 190; chondrosarcoma, 130; Ewing sarcoma, 79; others, 48) investigated the impact of pathological fractures (1985–2005) [ 18 ]. Among them, 52 patients with pathological fractures had a significantly increased mortality risk (hazard ratio [HR] = 1.82, p = 0.015) [ 18 ]. Furthermore, patients with fractures presented distant metastases more frequently (17.3% vs. 8.0%, p = 0.001) than those without fractures [ 18 ]. Another retrospective study from the Royal Orthopedic Hospital (1975–1994) involving 40 patients with pathological fractures from localized osteosarcoma of the long bones reported that limb-sparing surgery was achieved in 27 of the 40 patients (67.5%) [ 17 ]. Local recurrence developed in 19% of those treated with limb-sparing surgery, whereas none occurred in patients who underwent amputation; the incidence of distant metastasis was similar between groups (44.4% vs. 75.0%, p = 0.23, those with limb-sparing surgery, amputation, respectively) [ 17 ]. In contrast, because of the high sensitivity of Ewing sarcoma to chemotherapy and radiotherapy, pathological fractures in these patients may carry a lower risk of recurrence or metastasis than those in patients with osteosarcoma [ 18 – 20 ]. Indeed, a retrospective study of 127 patients with osteosarcoma and 78 with Ewing sarcoma revealed a higher percentage of good responders to preoperative chemotherapy in the Ewing sarcoma group than in the osteosarcoma group (73.6% vs. 47.6%) [ 21 ]. A retrospective analysis of 52 patients with Ewing sarcoma who presented with pathological fractures and were treated according to the German Society of Pediatric Oncology and Hematology protocols (1980–1993) reported a relapse-free survival of 58% for patients with pathological fractures, which was comparable to the control group [ 22 ]. Similarly, another retrospective study of 78 patients with Ewing sarcoma (2000–2011), nine with pathological fractures, reported that pathological fracture was not associated with a significant difference in survival; the five-year survival rate was 81.8% in the non-fracture group and 77.8% in the fracture group (p = 0.436) [ 21 ]. Our study showed no difference in OS between patients with or without pathological fractures, which aligns with previous findings, even after statistical adjustment. A retrospective analysis of 52 patients with Ewing sarcoma (1980–1993) investigated the influence of surgical timing on pathological fractures [ 22 ]. The authors reported that patients who received conservative treatment with preoperative chemotherapy had better overall and relapse-free survival than those who underwent immediate surgery (OS, p = 0.06; relapse-free survival, p = 0.06) [ 22 ]. Thus, a chemotherapy-first approach is an important treatment strategy that capitalizes on the chemosensitivity of Ewing sarcoma. Pathological fractures may be iatrogenic; for instance, a biopsy can weaken the affected bone, thereby increasing the fracture risk [ 23 – 25 ]. Chemotherapy and radiotherapy may also contribute to bone weakening because of their suppressive effects on osteoblastic activity, as well as tumor destruction and necrosis [ 26 – 29 ]. A retrospective study of 16 patients with Ewing sarcoma of the proximal femur treated at the Mayo Clinic (1976–1993) reported two pathological fractures through the biopsy site and six approximately 1.5 years after definitive radiotherapy (mean dose, 57.6 Gy) [ 4 ]. We suggest that reconstruction with prophylactic internal fixation should be considered after definitive radiotherapy [ 4 ]. Conclusion This analysis of pathological fractures in patients with Ewing sarcoma demonstrated no inferiority in oncologic outcomes compared with the control group, regardless of propensity matching. Limb-sparing surgery may be a reasonable treatment option when preoperative chemotherapy is effective in patients with pathological fractures. Declarations Funding information No funding support Author Contribution Conceptualization, H.A., C.E.; methodology, H.A., A.A.; software, H.A.; validation, E.N., G.F.; formal analysis, H.A., A.A., A.R., M.G.; investigation, H.A., A.A., P.S., E.N., M.F.; resources, D.M.D, C.E.; data curation, E.N.; writing—original draft preparation, H.A.; writing—review and editing, all authors; visualization, H.A.; supervision, D.M.D, C.E; project administration, H.A. References Esiashvili N, Goodman M, Marcus RB Jr (2008) Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30(6):425430. 10.1097/MPH.0b013e31816e22f3 Granowetter L, Womer R, Devidas M et al (2009) Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27(15):2536–2541. 10.1200/JCO.2008.19.1478 Womer RB, West DC, Krailo MD, Dickman PS et al (2012) Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30(33):4148–4154. 10.1200/JCO.2011.41.5703 Damron TA, Sim FH, O'Connor MI, Pritchard DJ, Smithson WA (1996) Ewing's sarcoma of the proximal femur. Clin Orthop Relat Res. (322):232–244 Vlasak R, Sim FH (1996) Ewing's sarcoma. Orthop Clin North Am 27:591–603 Wagner LM, Neel MD, Pappo AS, Merchant TE et al (2001) Fractures in pediatric Ewing sarcoma. J Pediatr Hematol Oncol 23(9):568–571. 10.1097/00043426-200112000-00003 Fuchs B, Valenzuela RG, Sim FH (2003) Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop Relat Res 41525–30. 10.1097/01.blo.0000093893.12372.9d Grimer RJ, Taminiau AM, Cannon SR (2002) Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 84(3):395–400. 10.1302/0301-620x.84b3.12019 Aiba H, Kamei M, Ito Y, Takeda R et al (2023) Outcomes of Window Therapy with Carboplatin and Ifosfamide for Pediatric Osteosarcoma: A Case Series. Child (Basel) 10(4). 10.3390/children10040736 Gonzalez MR, Bedi A, Karczewski D, Lozano-Calderon SA (2023) Are Pathologic Fractures in Patients With Osteosarcoma Associated With Worse Survival Outcomes? A Systematic Review and Meta-analysis. Clin Orthop Relat Res 481(12):2433–2443. 10.1097/CORR.0000000000002687 Bacci G, Ferrari S, Longhi A, Donati D et al (2003) Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74(4):449–454. 10.1080/00016470310017776 Kgagudi MP, Ramokgopa MT, Jingo M (2025) Epidemiology and Chemosensitivity of Primary Malignant Bone Tumors at a Teaching Hospital in South Africa: A 5-Year Retrospective Analysis. Med Sci Monit 31:e948274. 10.12659/MSM.948274 Choi GJ, Kang H (2025) Heterogeneity in meta-analyses: an unavoidable challenge worth exploring. Korean J Anesthesiol 78(4):301–314. 10.4097/kja.25001 Hoang NT, Acevedo LA, Mann MJ, Tolani B (2018) A review of soft-tissue sarcomas: translation of biological advances into treatment measures. Cancer Manag Res 10:1089–1114. 10.2147/CMAR.S159641 Righi A, Pacheco M, Palmerini E, Carretta E et al (2021) Histological response to neoadjuvant chemotherapy in localized Ewing sarcoma of the bone: A retrospective analysis of available scoring tools. Eur J Surg Oncol 47(7):1778–1783. 10.1016/j.ejso.2021.02.009 Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH (1998) The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 80(7):1020–1033. 10.2106/00004623-199807000-00011 Abudu A, Sferopoulos NK, Tillman RM, Carter SR, Grimer RJ (1996) The surgical treatment and outcome of pathological fractures in localised osteosarcoma. J Bone Joint Surg Br 78(5):694–698 Moradi B, Zahlten-Hinguranage A, Lehner B, Zeifang F (2010) The impact of pathological fractures on therapy outcome in patients with primary malignant bone tumours. Int Orthop 34(7):1017–1023. 10.1007/s00264-009-0921-z Weber KL, Sim FH (2001) Ewing's sarcoma: presentation and management. J Orthop Sci 6(4):366–371. 10.1007/s007760100034 Zeifang F, Sabo D, Ewerbeck V (2000) [Pathological fracture in primary malignant bone tumors]. Chirurg 71(9):1121–1125 Schlegel M, Zeumer M, Prodinger PM, Woertler K et al (2018) Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients. Oncology 94(6):354–362. 10.1159/000487142 Hoffmann C, Jabar S, Ahrens S, Rödl R, Rübe C, Winkelmann W, Dunst J, Jürgens H (1995) [Prognosis in Ewing sarcoma patients with initial pathological fractures of the primary tumor site]. Klin Padiatr 207(4):151–157. 10.1055/s-2008-1046532 Traina F, Errani C, Toscano A, Pungetti C et al (2015) Current concepts in the biopsy of musculoskeletal tumors: AAOS exhibit selection. J Bone Joint Surg Am 97(2):e7 Iwai T, Hoshi M, Oebisu N, Orita K et al (2021) Prediction of Risk Factors for Pathological Fracture After Bone Tumor Biopsy Using Finite Element Analysis. Cancer Manag Res 13:3849–3856. 10.2147/CMAR.S307586 Springfield DS, Pagliarulo C (1985) Fractures of long bones previously treated for Ewing's sarcoma. J Bone Joint Surg Am 67(3):477–481 Aiba H, Aso A, Righi A, Gambarotti M et al (2025) Comparison of histological response across patients with Ewing sarcoma treated with preoperative chemotherapy with or without preoperative radiotherapy. Eur J Orthop Surg Traumatol 35(1):251. 10.1007/s00590-025-04378-2 Rosenstock JG, Jones PM, Pearson D, Palmer MK (1978) Ewing's sarcoma, adjuvant chemotherapy and pathologic fracture. Eur J Cancer (1965) 14(7):799–803. 10.1016/0014-2964(78)90012-9 Friedlaender GE, Tross RB, Doganis AC, Kirkwood JM, Baron R (1984) Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg Am 66(4):602–607 Willey JS, Lloyd SA, Nelson GA, Bateman TA (2011) Space Radiation and Bone Loss. Gravit Space Biol Bull 25(1):14–21 Additional Declarations No competing interests reported. Supplementary Files supple.tiff Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Rizzoli","correspondingAuthor":false,"prefix":"","firstName":"Paolo","middleName":"","lastName":"Spinnato","suffix":""},{"id":614816657,"identity":"638a8d84-694b-4dbd-b355-c39c555a6e8d","order_by":5,"name":"Eiji Nakata","email":"","orcid":"","institution":"Clinica Ortopedica e Traumatologica III a Prevalente Indirizzo Oncologico, IRCCS Istituto Ortopedico Rizzoli","correspondingAuthor":false,"prefix":"","firstName":"Eiji","middleName":"","lastName":"Nakata","suffix":""},{"id":614816658,"identity":"6b9e99be-f0cb-499e-bb95-14832a845542","order_by":6,"name":"Marco Focaccia","email":"","orcid":"","institution":"Clinica Ortopedica e Traumatologica III a Prevalente Indirizzo Oncologico, IRCCS Istituto Ortopedico Rizzoli","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Focaccia","suffix":""},{"id":614816659,"identity":"b6f927c5-09ca-4183-a4fd-c13ab026b07e","order_by":7,"name":"Giorgio Frega","email":"","orcid":"","institution":"Istituto Ortopedico Rizzoli","correspondingAuthor":false,"prefix":"","firstName":"Giorgio","middleName":"","lastName":"Frega","suffix":""},{"id":614816660,"identity":"4723e06b-e3b4-45c8-9dc0-1ad4da840c5c","order_by":8,"name":"Davide Maria Donati","email":"","orcid":"","institution":"Clinica Ortopedica e Traumatologica III a Prevalente Indirizzo Oncologico, IRCCS Istituto Ortopedico Rizzoli","correspondingAuthor":false,"prefix":"","firstName":"Davide","middleName":"Maria","lastName":"Donati","suffix":""},{"id":614816661,"identity":"fc61aa08-becf-4780-982a-ac90516ca3bd","order_by":9,"name":"Costantino Errani","email":"","orcid":"","institution":"Clinica Ortopedica e Traumatologica III a Prevalente Indirizzo Oncologico, IRCCS Istituto Ortopedico Rizzoli","correspondingAuthor":false,"prefix":"","firstName":"Costantino","middleName":"","lastName":"Errani","suffix":""}],"badges":[],"createdAt":"2026-03-25 00:23:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9216618/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9216618/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105907585,"identity":"3b75c142-7c33-4188-b85b-ce6b5c1b81bf","added_by":"auto","created_at":"2026-04-01 10:32:51","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1535833,"visible":true,"origin":"","legend":"\u003cp\u003ePatients’ selection\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-9216618/v1/70bc041a48e118efdb678012.png"},{"id":105907593,"identity":"7fb07e15-9384-4ba1-8e6e-903f8d2a41db","added_by":"auto","created_at":"2026-04-01 10:32:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":8497494,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative patient (No. 10)\u003c/p\u003e\n\u003cp\u003eAn 11-year-old boy was referred to our hospital for a fracture of the right distal femur (a, anteroposterior radiograph; b, lateral radiograph). Magnetic resonance imaging (MRI) revealed a massive extraskeletal lesion invading neurovascular bundles (c, lateral view of T1-weighted image with contrast). After diagnosis, he received high-dose chemotherapy using a brace with ischial support. The effect of chemotherapy was not sufficient to perform limb-sparing surgery (d, lateral view of T1-weighted image with contrast), so the patient underwent rotation-plasty (e, anteroposterior postoperative radiograph). The pathological response of the resected specimen was 30%.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-9216618/v1/65b5672e01b15bc2b95ca957.png"},{"id":105907562,"identity":"21ec57a0-d3ea-467d-8887-245c68bfeb7b","added_by":"auto","created_at":"2026-04-01 10:32:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":22730928,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative patient (No. 9)\u003c/p\u003e\n\u003cp\u003eAn 11-year-old boy was referred to our hospital for coxalgia lasting one month. A radiograph (a, anteroposterior view) and MRI (b, coronal view of T1-weighted image and short tau inversion recovery image) revealed an osteolytic lesion in the proximal femur, and he underwent an open biopsy with an initial diagnosis of a benign bone lesion (c, anteroposterior intraoperative radiograph). After one month, he sustained a fracture following mild trauma despite hip-spica orthosis (d, anteroposterior radiograph). Subsequently, he underwent en bloc resection of the proximal femur with reconstruction using a megaprosthesis (e, anteroposterior postoperative radiograph).\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-9216618/v1/b68051a2cf5a5bf7784cd77b.png"},{"id":105907711,"identity":"4026b46c-7c87-43dd-bc5c-e58792de3cd1","added_by":"auto","created_at":"2026-04-01 10:33:15","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":534660,"visible":true,"origin":"","legend":"\u003cp\u003eCovariate balance of characteristics\u003c/p\u003e\n\u003cp\u003eThe plots illustrate the balance of baseline covariates between comparison groups before and after propensity score matching. The X-axis represents the absolute mean differences (standardized) for each covariate, with values closer to zero indicating better balance. The Y-axis lists the individual covariates assessed. Grey dots show the covariate balance before matching (unadjusted group), whereas black dots represent the balance after propensity score matching (adjusted group). The vertical dashed line at 0.2 serves as a common threshold for acceptable covariate balance.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-9216618/v1/0cd3de769519e90229bbac8d.png"},{"id":105908905,"identity":"80904a7e-e6da-4217-962b-1110905a9358","added_by":"auto","created_at":"2026-04-01 10:40:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1339101,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for overall survival\u003c/p\u003e\n\u003cp\u003eThe plots display the probability of overall survival for patients with and without pathological fractures of Ewing sarcoma. (a) Kaplan-Meier curves with the unadjusted group; (b) Kaplan-Meier curves with the adjusted group.\u003c/p\u003e","description":"","filename":"FIg5.png","url":"https://assets-eu.researchsquare.com/files/rs-9216618/v1/409915e2fb3c24b9b4ca0ca3.png"},{"id":107706956,"identity":"975ee824-eaba-4ded-ba9d-6af2a97c88ea","added_by":"auto","created_at":"2026-04-24 09:19:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":33969467,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9216618/v1/aca47a8d-6d29-4393-9279-b21998ac0b42.pdf"},{"id":105907641,"identity":"da641a7f-0ad4-4cbd-8e3a-4d001f809522","added_by":"auto","created_at":"2026-04-01 10:33:12","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":27539882,"visible":true,"origin":"","legend":"","description":"","filename":"supple.tiff","url":"https://assets-eu.researchsquare.com/files/rs-9216618/v1/d9b2bf5b17cc05760da8b473.tiff"}],"financialInterests":"No competing interests reported.","formattedTitle":"Are Pathological Fractures in Patients with Ewing Sarcoma Associated with Worse Survival Outcomes?","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEwing sarcoma is the second most common primary bone tumor in children and adolescents [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]; the standard treatment consists of surgical resection combined with preoperative and postoperative chemotherapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Because of the fragility of the affected bone, pathological fractures occur in 5\u0026ndash;10% of patients with Ewing sarcoma [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These fractures commonly affect long, weight-bearing bones, most frequently the proximal third of the femur (50%) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Fractures result from cortical bone destruction driven by tumor cell invasion or treatment-induced bone weakening [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Because fractures can induce tumor cell dissemination around the destroyed cortical bone [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], it may necessitate altering surgical strategies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn osteosarcoma, another common primary bone tumor in children and adolescents [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], a systematic review and meta-analysis comprising 21 studies involving 7,604 patients investigated the prognostic significance of pathologic fractures [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Patients with pathological fractures had significantly lower overall survival (OS) rates than those without fractures (relative risk\u0026thinsp;=\u0026thinsp;1.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), concomitant with an increased risk of metastases (relative risk\u0026thinsp;=\u0026thinsp;1.33, p\u0026thinsp;=\u0026thinsp;0.01) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Moreover, a retrospective study of 46 patients with non-metastatic extremity osteosarcoma and pathologic fractures versus 689 contemporaneous patients without fractures found similar local recurrence rates (2% vs. 4%, respectively; p\u0026thinsp;=\u0026thinsp;0.80) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, extrapolating these results to Ewing sarcoma is challenging, as this tumor exhibits different chemosensitivity and treatment protocols than osteosarcoma [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Moreover, the paucity of studies on pathological fractures in Ewing sarcoma limits the reliability and interpretability of the findings, a consequence of the rarity of the tumor and the inherent variabilities among studies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study analyzed the clinical course of patients with pathological fractures of Ewing sarcoma and the impact of these fractures on treatment outcomes, utilizing propensity score matching to minimize selection bias.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection and preparation of matched-pair cohort\u003c/h2\u003e \u003cp\u003eWe retrospectively reviewed the records of 437 patients diagnosed with Ewing sarcoma between 2003 and 2020 at a single institution. The diagnoses were based on histological and/or molecular cytogenetic findings [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. We excluded 127 patients with axial tumors, 126 with incomplete resected specimen data, 19 who received radiotherapy only at the primary site, and 16 with extra skeletal Ewing sarcoma. A total of 149 patients were included: 12 in the pathological fracture group and 137 in the control group (unadjusted group). For matched‑pair analysis, we performed 1:3 propensity score matching and selected 36 patients from the control group for the adjusted group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). As a supplemental analysis, we performed another 1:3 propensity score matching in patients without metastases at diagnosis (pathological fracture group, 9; adjusted group, 27).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e This study was approved by the Ethics Committee of the Institutional Review Board (approval number: 0001336) and conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDefinition of variables\u003c/h3\u003e\n\u003cp\u003eThe histological response to preoperative chemotherapy and/or radiotherapy was determined retrospectively by two pathologists (A.R. and M.G.) who were blinded to the clinical outcomes. Histological responses were assessed based on tumor necrosis and reparative fibrous tissue [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Based on histological response, patients were categorized into two groups: good (necrosis\u0026thinsp;\u0026ge;\u0026thinsp;90%) or poor (necrosis\u0026thinsp;\u0026lt;\u0026thinsp;90%) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. OS was defined as the period from diagnosis to the date of the last follow-up or death.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eContinuous variables were summarized as medians with interquartile ranges (IQRs) and compared between groups using the Wilcoxon rank-sum test. Categorical variables are presented as counts with percentages and were compared using the χ\u0026sup2; test. OS was visualized using the Kaplan\u0026ndash;Meier method, and differences were assessed using the log-rank test. Propensity scores were calculated based on age, sex, tumor volume at diagnosis, presence of metastasis at diagnosis, radiotherapy administration, and histological response to preoperative therapy. Matching was performed with a 0.2 caliper width at a 1:3 ratio. Covariate balance before and after matching was evaluated using absolute standardized mean differences (ASMD) based on the pooled standard deviation; an ASMD\u0026thinsp;\u0026lt;\u0026thinsp;0.2 indicated adequate balance. Univariate and multivariate analyses were performed to identify the risk factors for OS in the entire cohort (149 patients, pathological fracture group, and unadjusted group). Variables with a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in the univariate analysis were entered as covariates into a stepwise Cox proportional hazards regression model to identify multivariate predictors of OS. All statistical analyses were conducted using R version 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria), with a significance threshold of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of the patients with pathological fractures\u003c/h2\u003e \u003cp\u003eAmong the 12 patients with pathological fractures, the primary tumor location was the humerus in six patients (50.0%; four diaphysis, two proximal), the femur in four (33.3%; three proximal, one distal), the forearm in one (8.3%; proximal ulna), and the scapula in one (8.3%). The median age at diagnosis was 16.0 years (IQR, 10.3\u0026ndash;31.5). Metastasis at diagnosis was identified in three patients (25.0%). Pathological fractures were present at diagnosis in ten patients (83.3%); two patients (16.7%) progressed to fractures during preoperative chemotherapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics and treatment details of patients with pathological fracture\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLocation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFracture type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMetastasis\u003c/p\u003e \u003cp\u003eat diagnosis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003cp\u003efor primary site\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMargin\u003c/p\u003e \u003cp\u003estatus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eHistological\u003c/p\u003e \u003cp\u003eresponse (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eLocal\u003c/p\u003e \u003cp\u003erecurrence\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eDistant\u003c/p\u003e \u003cp\u003emetastasis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eFinal\u003c/p\u003e \u003cp\u003estatus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eFollow-up period (days)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHumerus, Diaphysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e3168\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHumerus, Diaphysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eImpending\u003c/p\u003e \u003cp\u003e(complete, during chemotherapy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eDOD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e879\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHumerus, Diaphysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eImpending\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAllograft\u0026thinsp;+\u0026thinsp;Megaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e1412\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHumerus, Diaphysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eImpending\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eYes (amputation)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eDOD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e829\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHumerus, Proximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e(en bloc resection of soft tissue recurrence)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e(lung metastasectomy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eNED\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e2624\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHumerus, Proximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePostoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e4973\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemur, Proximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003cp\u003e(Infection)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eNED*1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e5275\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemur, Proximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eDOD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e622\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemur, Proximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eImpending\u003c/p\u003e \u003cp\u003e(complete, during chemotherapy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMegaprosthesis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e3602\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemur, Distal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eRotationplasty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e6331\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUlna, Proximal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEn bloc resection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePreoperative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCDF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e1825\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eScapula\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eComplete\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEn bloc resection\u003c/p\u003e \u003cp\u003e(total scapulectomy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eNED\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c14\"\u003e \u003cp\u003e3777\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003eCDF, complete disease-free; DOD, dead of disease; NED, no evidence of disease.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e*1, The metastatic lesion was controlled with whole lung irradiation and high-dose chemotherapy and autologous peripheral blood stem cell transfusion.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eLimb-sparing surgery was performed in 11 patients (91.7%), whereas rotation-plasty was conducted in one (8.3%). The median time from diagnosis to surgery was 107 days (IQR, 99.8\u0026ndash;169.5 days). Resection margins were classified as wide or radical in 11 patients (91.7%) and marginal in one (8.3%). Three patients (25.0%) received preoperative radiotherapy, and one (8.3%) underwent marginal resection and postoperative radiotherapy. The median follow-up period was 7.9 years. Representative clinical courses are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComparisons between unadjusted and matched-pair cohorts\u003c/h2\u003e \u003cp\u003eThe covariate balance plot displays the absolute mean differences in covariates between the pathological fracture group and the adjusted and unadjusted groups following propensity score matching. Before matching, several covariates, such as tumor volume and histological response, exceeded the threshold (ASMD\u0026thinsp;\u0026gt;\u0026thinsp;0.2) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The χ\u0026sup2; test indicated that these imbalances approached statistical significance (tumor volume, p\u0026thinsp;=\u0026thinsp;0.119; histological response, p\u0026thinsp;=\u0026thinsp;0.054). However, after matching, the ASMD predominantly fell below the threshold, indicating a satisfactory covariate balance. These trends were consistent in the χ\u0026sup2; test, with no significant differences detected across matched cohorts (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of patients\u0026rsquo; characteristics between groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGender (men, women)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePathological fracture group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUnadjusted control group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;137)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdjusted control group (n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75.0%)/\u003c/p\u003e \u003cp\u003e3 (25.0%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97 (70.8%)/\u003c/p\u003e \u003cp\u003e40 (29.2%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (63.9%)/\u003c/p\u003e \u003cp\u003e13 (36.1%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.480\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026lt;\u0026thinsp;18 years, \u0026ge; 18 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (58.3%)/\u003c/p\u003e \u003cp\u003e5 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (68.6%)/\u003c/p\u003e \u003cp\u003e43 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.465\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (55.6%)/\u003c/p\u003e \u003cp\u003e16 (44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.867\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis at diagnosis (no, yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75.0%)/\u003c/p\u003e \u003cp\u003e3 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e107 (78.1%)/\u003c/p\u003e \u003cp\u003e30 (21.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.804\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (63.9%)/\u003c/p\u003e \u003cp\u003e13 (36.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.480\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial tumor volume (\u0026lt;\u0026thinsp;200 mL, \u0026ge;\u0026thinsp;200 mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (50.0%)/\u003c/p\u003e \u003cp\u003e6 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e98 (71.5%)/\u003c/p\u003e \u003cp\u003e39 (28.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (44.4%)/\u003c/p\u003e \u003cp\u003e20 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse to preoperative chemotherapy (good, poor)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (75.0%)/\u003c/p\u003e \u003cp\u003e4 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (46.0%)/\u003c/p\u003e \u003cp\u003e74 (54.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27 (75.8%)\u003c/p\u003e \u003cp\u003e9 (24.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection margin\u003c/p\u003e \u003cp\u003e(wide, marginal/ intralesional)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (91.7%)/\u003c/p\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e128(93.4%)/\u003c/p\u003e \u003cp\u003e9 (6.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.815\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32 (88.9%)/\u003c/p\u003e \u003cp\u003e4 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.785\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAddition of radiotherapy (no, yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (66.7%)/\u003c/p\u003e \u003cp\u003e4 (33.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e108 (78.8%)/\u003c/p\u003e \u003cp\u003e29 (21.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.330\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (58.3%)/\u003c/p\u003e \u003cp\u003e15 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.609\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal recurrence (no, yes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (83.3%)\u003c/p\u003e \u003cp\u003e2 (16.7%)/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e123 (89.8%)/\u003c/p\u003e \u003cp\u003e14 (10.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.835\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32 (88.9%)/\u003c/p\u003e \u003cp\u003e4 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.785\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding oncological outcomes, three-year OS was 75.0% in the pathological fracture group and 78.8% in the unadjusted group (p\u0026thinsp;=\u0026thinsp;0.62, log-rank test). After matching, three-year OS was 66.4% in the adjusted group (p\u0026thinsp;=\u0026thinsp;0.29, log-rank test) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Local recurrence was observed in two patients (16.7%) in the pathological fracture group; both had a poor histologic response (25% and 40%). One patient underwent en bloc resection, whereas the other required amputation. Local recurrence did not differ significantly between the pathological fracture and the unadjusted (10.2%, p\u0026thinsp;=\u0026thinsp;0.835) or adjusted (11.1%, p\u0026thinsp;=\u0026thinsp;0.785) groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn a supplemental analysis that excluded patients with metastasis at diagnosis, three-year OS rates were 77.8% in the pathological fracture group (n\u0026thinsp;=\u0026thinsp;9) and 86.9% in the unadjusted group (n\u0026thinsp;=\u0026thinsp;107) (p\u0026thinsp;=\u0026thinsp;0.98, log-rank test). After matching, the three-year OS rate was 92.6% (p\u0026thinsp;=\u0026thinsp;0.91, log-rank test) in the adjusted group (n\u0026thinsp;=\u0026thinsp;27) (Supplemental Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRisk factors for OS\u003c/h3\u003e\n\u003cp\u003eUnivariate analysis revealed that age\u0026thinsp;\u0026gt;\u0026thinsp;18 years (p\u0026thinsp;=\u0026thinsp;0.041), metastasis at diagnosis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and histological response (p\u0026thinsp;=\u0026thinsp;0.004) were associated with poor survival. Pathological fractures were not significant prognostic factors (p\u0026thinsp;=\u0026thinsp;0.097). Multivariate analysis identified metastasis at diagnosis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and histological response (p\u0026thinsp;=\u0026thinsp;0.009) as independent predictors of OS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factors for overall survival\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% confidence interval), Univariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% confidence interval),\u003c/p\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (men, women)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.68 (0.78\u0026ndash;3.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026ge;\u0026thinsp;18 years, \u0026lt; 18 years,)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.85 (1.03\u0026ndash;3.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastasis at diagnosis (yes, no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.20 (1.76\u0026ndash;5.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.89 (2.18\u0026ndash;6.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial tumor volume (\u0026thinsp;≧\u0026thinsp;200 mL, \u0026lt;\u0026thinsp;200 mL,)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.33 (0.70\u0026ndash;2.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse to preoperative chemotherapy (good, poor)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.38 (0.20\u0026ndash;0.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.44 (0.23\u0026ndash;0.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection margin\u003c/p\u003e \u003cp\u003e(wide, marginal/intralesional)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.55 (0.14\u0026ndash;2.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.373\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAddition of radiotherapy (yes, no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.83 (0.39\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological fracture (yes, no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.33 (0.42\u0026ndash;4.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.607\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eHR, hazard ratio.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study analyzed the outcomes of patients with Ewing sarcoma presenting with pathological fractures. Although limb-sparing surgery was attempted in most patients, the risk of local recurrence was not higher than that in the control group. There was also no difference in the overall survival between the pathological fracture and control groups. Similarly, multivariate analysis identified metastasis at diagnosis and histological response, but not pathological fracture, as independent predictors of worse overall survival.\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, its retrospective nature and chronological changes in clinical practice, such as chemotherapeutic protocols, may have affected the data consistency. Furthermore, heterogeneity between the pathological fracture and control groups may have persisted even after matched-pair adjustment. Additionally, because of the rarity of the disease, the study's statistical power to confirm the non-inferiority of the pathological fracture group was limited. Despite these limitations, this study represents the first attempt to perform a matched-pairs analysis in a relatively large cohort. Further multi-institutional studies are required to validate these findings.\u003c/p\u003e \u003cp\u003ePathological fractures in patients with malignant bone tumors present significant treatment challenges [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A retrospective study involving 447 patients with various malignant bone tumors (osteosarcoma, 190; chondrosarcoma, 130; Ewing sarcoma, 79; others, 48) investigated the impact of pathological fractures (1985\u0026ndash;2005) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Among them, 52 patients with pathological fractures had a significantly increased mortality risk (hazard ratio [HR]\u0026thinsp;=\u0026thinsp;1.82, p\u0026thinsp;=\u0026thinsp;0.015) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Furthermore, patients with fractures presented distant metastases more frequently (17.3% vs. 8.0%, p\u0026thinsp;=\u0026thinsp;0.001) than those without fractures [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Another retrospective study from the Royal Orthopedic Hospital (1975\u0026ndash;1994) involving 40 patients with pathological fractures from localized osteosarcoma of the long bones reported that limb-sparing surgery was achieved in 27 of the 40 patients (67.5%) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Local recurrence developed in 19% of those treated with limb-sparing surgery, whereas none occurred in patients who underwent amputation; the incidence of distant metastasis was similar between groups (44.4% vs. 75.0%, p\u0026thinsp;=\u0026thinsp;0.23, those with limb-sparing surgery, amputation, respectively) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast, because of the high sensitivity of Ewing sarcoma to chemotherapy and radiotherapy, pathological fractures in these patients may carry a lower risk of recurrence or metastasis than those in patients with osteosarcoma [\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Indeed, a retrospective study of 127 patients with osteosarcoma and 78 with Ewing sarcoma revealed a higher percentage of good responders to preoperative chemotherapy in the Ewing sarcoma group than in the osteosarcoma group (73.6% vs. 47.6%) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A retrospective analysis of 52 patients with Ewing sarcoma who presented with pathological fractures and were treated according to the German Society of Pediatric Oncology and Hematology protocols (1980\u0026ndash;1993) reported a relapse-free survival of 58% for patients with pathological fractures, which was comparable to the control group [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Similarly, another retrospective study of 78 patients with Ewing sarcoma (2000\u0026ndash;2011), nine with pathological fractures, reported that pathological fracture was not associated with a significant difference in survival; the five-year survival rate was 81.8% in the non-fracture group and 77.8% in the fracture group (p\u0026thinsp;=\u0026thinsp;0.436) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our study showed no difference in OS between patients with or without pathological fractures, which aligns with previous findings, even after statistical adjustment.\u003c/p\u003e \u003cp\u003eA retrospective analysis of 52 patients with Ewing sarcoma (1980\u0026ndash;1993) investigated the influence of surgical timing on pathological fractures [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The authors reported that patients who received conservative treatment with preoperative chemotherapy had better overall and relapse-free survival than those who underwent immediate surgery (OS, p\u0026thinsp;=\u0026thinsp;0.06; relapse-free survival, p\u0026thinsp;=\u0026thinsp;0.06) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Thus, a chemotherapy-first approach is an important treatment strategy that capitalizes on the chemosensitivity of Ewing sarcoma.\u003c/p\u003e \u003cp\u003ePathological fractures may be iatrogenic; for instance, a biopsy can weaken the affected bone, thereby increasing the fracture risk [\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Chemotherapy and radiotherapy may also contribute to bone weakening because of their suppressive effects on osteoblastic activity, as well as tumor destruction and necrosis [\u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. A retrospective study of 16 patients with Ewing sarcoma of the proximal femur treated at the Mayo Clinic (1976\u0026ndash;1993) reported two pathological fractures through the biopsy site and six approximately 1.5 years after definitive radiotherapy (mean dose, 57.6 Gy) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. We suggest that reconstruction with prophylactic internal fixation should be considered after definitive radiotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis analysis of pathological fractures in patients with Ewing sarcoma demonstrated no inferiority in oncologic outcomes compared with the control group, regardless of propensity matching. Limb-sparing surgery may be a reasonable treatment option when preoperative chemotherapy is effective in patients with pathological fractures.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding information\u003c/h2\u003e \u003cp\u003eNo funding support\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization, H.A., C.E.; methodology, H.A., A.A.; software, H.A.; validation, E.N., G.F.; formal analysis, H.A., A.A., A.R., M.G.; investigation, H.A., A.A., P.S., E.N., M.F.; resources, D.M.D, C.E.; data curation, E.N.; writing\u0026mdash;original draft preparation, H.A.; writing\u0026mdash;review and editing, all authors; visualization, H.A.; supervision, D.M.D, C.E; project administration, H.A.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEsiashvili N, Goodman M, Marcus RB Jr (2008) Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30(6):425430. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MPH.0b013e31816e22f3\u003c/span\u003e\u003cspan address=\"10.1097/MPH.0b013e31816e22f3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGranowetter L, Womer R, Devidas M et al (2009) Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children's Oncology Group Study. J Clin Oncol 27(15):2536\u0026ndash;2541. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2008.19.1478\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2008.19.1478\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWomer RB, West DC, Krailo MD, Dickman PS et al (2012) Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30(33):4148\u0026ndash;4154. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2011.41.5703\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2011.41.5703\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDamron TA, Sim FH, O'Connor MI, Pritchard DJ, Smithson WA (1996) Ewing's sarcoma of the proximal femur. Clin Orthop Relat Res. (322):232\u0026ndash;244\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVlasak R, Sim FH (1996) Ewing's sarcoma. Orthop Clin North Am 27:591\u0026ndash;603\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWagner LM, Neel MD, Pappo AS, Merchant TE et al (2001) Fractures in pediatric Ewing sarcoma. J Pediatr Hematol Oncol 23(9):568\u0026ndash;571. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/00043426-200112000-00003\u003c/span\u003e\u003cspan address=\"10.1097/00043426-200112000-00003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuchs B, Valenzuela RG, Sim FH (2003) Pathologic fracture as a complication in the treatment of Ewing's sarcoma. Clin Orthop Relat Res 41525\u0026ndash;30. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/01.blo.0000093893.12372.9d\u003c/span\u003e\u003cspan address=\"10.1097/01.blo.0000093893.12372.9d\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrimer RJ, Taminiau AM, Cannon SR (2002) Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 84(3):395\u0026ndash;400. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1302/0301-620x.84b3.12019\u003c/span\u003e\u003cspan address=\"10.1302/0301-620x.84b3.12019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAiba H, Kamei M, Ito Y, Takeda R et al (2023) Outcomes of Window Therapy with Carboplatin and Ifosfamide for Pediatric Osteosarcoma: A Case Series. Child (Basel) 10(4). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/children10040736\u003c/span\u003e\u003cspan address=\"10.3390/children10040736\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGonzalez MR, Bedi A, Karczewski D, Lozano-Calderon SA (2023) Are Pathologic Fractures in Patients With Osteosarcoma Associated With Worse Survival Outcomes? A Systematic Review and Meta-analysis. Clin Orthop Relat Res 481(12):2433\u0026ndash;2443. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/CORR.0000000000002687\u003c/span\u003e\u003cspan address=\"10.1097/CORR.0000000000002687\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBacci G, Ferrari S, Longhi A, Donati D et al (2003) Nonmetastatic osteosarcoma of the extremity with pathologic fracture at presentation: local and systemic control by amputation or limb salvage after preoperative chemotherapy. Acta Orthop Scand 74(4):449\u0026ndash;454. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/00016470310017776\u003c/span\u003e\u003cspan address=\"10.1080/00016470310017776\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKgagudi MP, Ramokgopa MT, Jingo M (2025) Epidemiology and Chemosensitivity of Primary Malignant Bone Tumors at a Teaching Hospital in South Africa: A 5-Year Retrospective Analysis. Med Sci Monit 31:e948274. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.12659/MSM.948274\u003c/span\u003e\u003cspan address=\"10.12659/MSM.948274\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChoi GJ, Kang H (2025) Heterogeneity in meta-analyses: an unavoidable challenge worth exploring. Korean J Anesthesiol 78(4):301\u0026ndash;314. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4097/kja.25001\u003c/span\u003e\u003cspan address=\"10.4097/kja.25001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoang NT, Acevedo LA, Mann MJ, Tolani B (2018) A review of soft-tissue sarcomas: translation of biological advances into treatment measures. Cancer Manag Res 10:1089\u0026ndash;1114. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/CMAR.S159641\u003c/span\u003e\u003cspan address=\"10.2147/CMAR.S159641\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRighi A, Pacheco M, Palmerini E, Carretta E et al (2021) Histological response to neoadjuvant chemotherapy in localized Ewing sarcoma of the bone: A retrospective analysis of available scoring tools. Eur J Surg Oncol 47(7):1778\u0026ndash;1783. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejso.2021.02.009\u003c/span\u003e\u003cspan address=\"10.1016/j.ejso.2021.02.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH (1998) The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 80(7):1020\u0026ndash;1033. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2106/00004623-199807000-00011\u003c/span\u003e\u003cspan address=\"10.2106/00004623-199807000-00011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbudu A, Sferopoulos NK, Tillman RM, Carter SR, Grimer RJ (1996) The surgical treatment and outcome of pathological fractures in localised osteosarcoma. J Bone Joint Surg Br 78(5):694\u0026ndash;698\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoradi B, Zahlten-Hinguranage A, Lehner B, Zeifang F (2010) The impact of pathological fractures on therapy outcome in patients with primary malignant bone tumours. Int Orthop 34(7):1017\u0026ndash;1023. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00264-009-0921-z\u003c/span\u003e\u003cspan address=\"10.1007/s00264-009-0921-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeber KL, Sim FH (2001) Ewing's sarcoma: presentation and management. J Orthop Sci 6(4):366\u0026ndash;371. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s007760100034\u003c/span\u003e\u003cspan address=\"10.1007/s007760100034\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeifang F, Sabo D, Ewerbeck V (2000) [Pathological fracture in primary malignant bone tumors]. Chirurg 71(9):1121\u0026ndash;1125\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchlegel M, Zeumer M, Prodinger PM, Woertler K et al (2018) Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients. Oncology 94(6):354\u0026ndash;362. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000487142\u003c/span\u003e\u003cspan address=\"10.1159/000487142\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoffmann C, Jabar S, Ahrens S, R\u0026ouml;dl R, R\u0026uuml;be C, Winkelmann W, Dunst J, J\u0026uuml;rgens H (1995) [Prognosis in Ewing sarcoma patients with initial pathological fractures of the primary tumor site]. Klin Padiatr 207(4):151\u0026ndash;157. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1055/s-2008-1046532\u003c/span\u003e\u003cspan address=\"10.1055/s-2008-1046532\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTraina F, Errani C, Toscano A, Pungetti C et al (2015) Current concepts in the biopsy of musculoskeletal tumors: AAOS exhibit selection. J Bone Joint Surg Am 97(2):e7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIwai T, Hoshi M, Oebisu N, Orita K et al (2021) Prediction of Risk Factors for Pathological Fracture After Bone Tumor Biopsy Using Finite Element Analysis. Cancer Manag Res 13:3849\u0026ndash;3856. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/CMAR.S307586\u003c/span\u003e\u003cspan address=\"10.2147/CMAR.S307586\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpringfield DS, Pagliarulo C (1985) Fractures of long bones previously treated for Ewing's sarcoma. J Bone Joint Surg Am 67(3):477\u0026ndash;481\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAiba H, Aso A, Righi A, Gambarotti M et al (2025) Comparison of histological response across patients with Ewing sarcoma treated with preoperative chemotherapy with or without preoperative radiotherapy. Eur J Orthop Surg Traumatol 35(1):251. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00590-025-04378-2\u003c/span\u003e\u003cspan address=\"10.1007/s00590-025-04378-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenstock JG, Jones PM, Pearson D, Palmer MK (1978) Ewing's sarcoma, adjuvant chemotherapy and pathologic fracture. Eur J Cancer (1965) 14(7):799\u0026ndash;803. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0014-2964(78)90012-9\u003c/span\u003e\u003cspan address=\"10.1016/0014-2964(78)90012-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedlaender GE, Tross RB, Doganis AC, Kirkwood JM, Baron R (1984) Effects of chemotherapeutic agents on bone. I. Short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg Am 66(4):602\u0026ndash;607\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilley JS, Lloyd SA, Nelson GA, Bateman TA (2011) Space Radiation and Bone Loss. Gravit Space Biol Bull 25(1):14\u0026ndash;21\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ewing sarcoma, bone tumor, surgery, pathological fracture","lastPublishedDoi":"10.21203/rs.3.rs-9216618/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9216618/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjectives\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePathological fractures occur in 5\u0026ndash;10% of patients with Ewing sarcoma and may disseminate tumor cells from the fractured bone, potentially affecting the treatment strategy. This study analyzed the clinical course of patients with pathological fractures of Ewing sarcoma using propensity score matching to minimize selection bias.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis retrospective study assessed the outcomes from 2003 to 2020. Among the 437 patients with Ewing sarcoma, 12 had pathological fractures of the extremities. For comparison with patients without pathological fractures, a 1:3 propensity score-matched control group (n\u0026thinsp;=\u0026thinsp;36, adjusted group) was used.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAmong the 12 patients, limb-sparing surgery was performed in 11 patients (91.7%), and limb salvage was achieved in 10 patients (83.3%). Three-year overall survivals were 75.0% in patients with pathological fractures and 66.4% in the adjusted group (p\u0026thinsp;=\u0026thinsp;0.29). Local recurrence was observed in two patients (16.7%) in the pathological fracture group; both had a poor histologic response (25% and 40%).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePathological fractures in Ewing sarcoma were not associated with worse oncological outcomes, even after propensity score matching. Limb-sparing surgery may be a reasonable treatment option when preoperative chemotherapy is effective in patients with pathological fractures.\u003c/p\u003e","manuscriptTitle":"Are Pathological Fractures in Patients with Ewing Sarcoma Associated with Worse Survival Outcomes?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-01 10:13:22","doi":"10.21203/rs.3.rs-9216618/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7b26869a-d3f2-404a-9177-f6c243bff73a","owner":[],"postedDate":"April 1st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-22T15:10:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-01 10:13:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9216618","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9216618","identity":"rs-9216618","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}