Pediatric Ewing Sarcoma Research Articles

Ewing Sarcoma in the Pediatric Population: Predictors of Survival Within the United States.

Bone and joint tumors are the third most common cause of pediatric cancer-related deaths in the United States. Although there have been improvements in survival rates among pediatric cancer patients over the past few decades, bone and joint cancers remain the exception. Considering current clinical trials involving novel targeted therapies, the establishment of updated mortality rates and predictors of survival for this cancer would be prudent. This investigation sought to determine updated 5-year survival rates and predictors of survival among pediatric Ewing sarcoma (ES) of bone treated within the United States. The National Cancer Database was retrospectively inquired for all pediatric ES cases within the most updated bone and joint public use file available in September 2022. The reported data were truncated to only include patients with reported 5-year vital (ie, survival) status. Cox proportional hazard regression was conducted on both the truncated data and the entire cohort to validate the findings. The patients were then separated into alive versus deceased cohorts, and univariate regression analysis was done followed by multivariable regression of notable variables of interest. Overall, an aggregated 5-year survival rate of 74.5% was found in the included patient cohort. Patients with localized cancer had a comparatively improved 5-year survival rate of 84.70% as opposed to those with macrometastatic disease on presentation with a survival rate of 50.4%. Patient demographic-, tumor-, and treatment-specific variables all demonstrated an effect on survival. The multivariable predictors of worse mortality were found to include older age, larger tumor size (>8 cm), macrometastatic disease on presentation, and positive surgical margins. This analysis serves to establish updated survival rates of pediatric ES treated within the United States to set standards for comparison among future studies. Continued multi-institutional and international collaboration is needed to optimize current treatment results and develop novel targeted therapies.

Prognostic factors and outcome of relapsed/progressive pediatric Ewing sarcoma: single-center 10-year experience

BackgroundEwing sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Despite more intensive chemotherapy regimens and improved local control therapy, there is still a considerable rate of recurrent/progressive disease.MethodsA retrospective study of 50 relapsed/progressive ES patients who were treated at the National Cancer Institute (NCI), Cairo University, during the period from 1st of January 2008 to the end of December 2018, to assess different prognostic variables and disease outcomes.ResultsOut of fifty eligible cases, 32 patients (64%) had disease recurrence, and 18 (36%) developed disease progression on treatment. The median follow-up period was 7.4 months. The median overall survival (OS) was 7.5 months, and the cumulative OS was 64% at 6 months and 32.6% at 1 year. The cumulative event-free survival (EFS) was 41.3% at 6 months and 22.3% at 1 year. Patients with disease recurrence had better OS and EFS than patients with disease progression (p = 0.019). Patients who underwent local control at relapse/progression had a significantly better outcome than patients who received chemotherapy only (p < 0.001). Recurrence > 2 years from initial diagnosis was the only independent predictor of better survival outcome.ConclusionsPatients with relapsing/progressive ES portended a poor outcome, with disease progression on treatment faring worse than relapse. Better outcome was observed in patients who experienced recurrence > 2 years after diagnosis, patients with disease recurrence rather than disease progression on treatment, and patients who underwent local control along with intensive chemotherapy.

Is bone marrow biopsy and aspiration still mandatory when 18F-FDG PET/CT is available for the initial assessment of bone marrow metastasis in pediatric Ewing sarcoma?

To compare the diagnostic value of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) and bone marrow biopsy and aspiration (BMBA) for evaluating bone marrow metastases (BMM) in newly diagnosed pediatric Ewing sarcoma (ES). To assess the diagnostic accuracy of 18F-FDG PET/CT against BMBA for marrow infiltration in ES patients, a retrospective analysis encompassed 103 ES patients from the Children's Hospital of Chongqing Medical University, spanning nine years, who underwent both 18F-FDG PET/CT and BMBA at the point of diagnosis. The median age of this study was 9.3(15 days to 17.1 years), 52(50.5%) patients were male. Among the cohort, 8 subjects received a BMM diagnosis via marrow cytology or histopathology, concomitant with positive 18F-FDG PET/CT findings. An additional 4 patients were identified with BMM solely through 18F-FDG PET/CT. No cytologically or histologically positive BMM were found in PET/CT-negative patients. Therefore, within this selected sample group, the 18F-FDG PET/CT imaging technique exhibited sensitivity of 100% and specificity of 95.8%. The five-year overall survival rate decreased from 57.5% among the entire cohort of patients to a mere 30% for individuals suffering from BMM. Given these findings, the prevailing reliance on BMBA warrants reevaluation when 18F-FDG PET/CT is available, potentially heralding a shift towards less invasive diagnostic modalities in the management of ES.

Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study

Background and purposePatients with Ewing Sarcoma (EWS) are treated with multimodality therapy which includes radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) to the primary site for localized and metastatic EWS. Materials and methodsForty-two children with EWS (33 localized, 9 metastatic) treated between 2007 and 2020 were enrolled on 2 prospective registry protocols for pediatric patients undergoing PRT. PRT was delivered by passive scatter (74 %), pencil-beam scanning (12 %) or mixed technique (14 %). Treated sites included the spine (45 %), pelvis/sacrum (26 %), skull/cranium (14 %), extraosseous (10 %), and chest wall (5 %). Median radiation dose was 54 Gy-RBE (range 39.6–55.8 Gy-RBE). Patients with metastatic disease received consolidative RT to metastatic sites (4 at the time of PRT to the primary site, 5 after completion of chemotherapy). Median follow-up time was 47 months after PRT. ResultsThe 4-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 83 %, 71 %, and 86 %, respectively. All local failures (n = 6) were in-field failures. Tumor size ≥ 8 cm predicted for inferior 4-year LC (69 % vs 95 %, p = 0.04). 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72 % vs 67 %, p = 0.70; 89 % vs 78 %, p = 0.38, respectively). ConclusionIn conclusion, LC for pediatric patients with EWS treated with PRT was comparable to that of historical patients who received photon-RT. Tumor size ≥ 8 cm predicted increased risk of local failure. Patients with metastatic disease, including non-pulmonary only metastases, received radiation therapy to all metastatic sites and had favorable survival outcomes.

Detection of early prognostic biomarkers for metastasis of Ewing's sarcoma in pediatric patients

AimsEwing's Sarcoma is an extremely aggressive tumor in children. The disease is associated with highly metastatic rate, especially at the time of diagnosis, contributing to a lower survival rate and poor prognosis. The study aimed to identify predictive biomarkers for metastatic Ewing's sarcoma through in-depth analysis of the plasma proteome profile of pediatric Ewing's sarcoma patients. Main methodsPlasma samples from Ewing's sarcoma patients and control individuals were profiled using both shotgun and dimethyl-labeled proteomics analysis. Subsequently, Ewing's sarcoma patients were further stratified according to their metastatic state and chemotherapy response. Western blot was used for validation. Univariate and multivariate analyses were performed to determine proteome metastasis predictors. Receiver operating characteristic (ROC) analysis was done to assess the diagnostic significance of the potential plasma Ewing's sarcoma biomarkers. Key findingsOur results revealed a set of proteins significantly associated with the metastatic Ewing's sarcoma disease profile. These proteins include ceruloplasmin and several immunoglobulins. Additionally, our study disclosed significant differentially expressed proteins in pediatric Ewing's sarcoma, including CD5 antigen-like, clusterin, and dermcidin. Stable isotope dimethyl labeling and western blot further confirmed our results, strengthening the impact of such proteins in disease development. Furthermore, an unbiased ROC curve evaluated and confirmed the predictive power of these biomarker candidates. SignificanceThis study presented potential empirical predictive circulating biomarkers for determining the disease status of pediatric Ewing's sarcoma, which is vital for early prediction.

Evaluation of Potential Targets for Fluorescence-Guided Surgery in Pediatric Ewing Sarcoma: A Preclinical Proof-of-Concept Study.

Fluorescence-guided surgery (FGS), based on fluorescent tracers binding to tumor-specific biomarkers, could assist surgeons to achieve complete tumor resections. This study evaluated potential biomarkers for FGS in pediatric Ewing sarcoma (ES). Immunohistochemistry (IHC) was performed to assess CD99, CXCR4, CD117, NPY-R-Y1, and IGF-1R expression in ES biopsies and resection specimens. LINGO-1 and GD2 evaluation did not work on the acquired tissue. Based on the immunoreactive scores, anti-CD99 and anti-CD117 were evaluated for binding specificity using flow cytometry and immunofluorescence microscopy. Anti-GD2, a tracer in the developmental phase, was also tested. These three tracers were topically applied to a freshly resected ES tumor and adjacent healthy tissue. IHC demonstrated moderate/strong CD99 and CD117 expression in ES tumor samples, while adjacent healthy tissue had limited expression. Flow cytometry and immunofluorescence microscopy confirmed high CD99 expression, along with low/moderate CD117 and low GD2 expression, in ES cell lines. Topical anti-CD99 and anti-GD2 application on ES tumor showed fluorescence, while anti-CD117 did not show fluorescence for this patient. In conclusion, CD99-targeting tracers hold promise for FGS of ES. CD117 and GD2 tracers could be potential alternatives. The next step towards development of ES-specific FGS tracers could be ex vivo topical application experiments on a large cohort of ES patients.

Cardiac function in pediatric Ewing sarcoma during and after treatment: A longitudinal study.

While anthracycline therapy has been shown to improve outcomes in Ewing sarcoma, it may be associated with severe and even fatal cardiac dysfunction. We evaluated the burden and determinants of cardiac dysfunction in pediatric Ewing sarcoma (pES). This retrospective study included children aged 0-18 years with pES treated at our center with the EFT 2001 protocol (anthracycline and cyclophosphamide containing regimen), with/without radiation therapy from January 2001 to December 2018. Cardiac dysfunction was defined as left ventricular (LV) ejection fraction with an absolute value<50%. Amongst 650 eligible patients (median age at diagnosis 12 years and median follow-up duration 69 months), 85 (13%) developed cardiac dysfunction, at a median 13 months (range: 1-168 months). The cumulative incidence of cardiac dysfunction was 5.7% at 12 months, 12% at 2 years, 13% at 3 years, 14% at 5 years, and 15 % at 10 years. At a median follow-up duration of 25 (range: 3-212) months, 21 (24.7%) patients had normalization of LV function, whereas nine (10.6%) patients died of cardiac causes. Older age at diagnosis (7-12 years OR 5.1, p=.01, 13-18 years, OR 3.9, p=.03), female sex (OR 2.3, p=.004), undernutrition (OR 2.9, p=.001), and chest wall location (OR 8.7, p=.08) were risk factors for cardiac dysfunction. Children with Ewing sarcoma have a high incidence of cardiac dysfunction, which continues to develop even years after therapy, underlining the need for life-long surveillance. Undernourished children are at a higher risk for cardiac dysfunction and need stringent monitoring.

Overall survival comparison between pediatric and adult Ewing sarcoma of bone and adult nomogram construction: a large population-based analysis.

Ewing sarcoma (ES) is a common primary bone tumor in children. Our study aimed to compare overall survival (OS) between pediatric and adult bone ES patients, identify independent prognostic factors and develop a nomogram for predicting OS in adult patients with ES of bone. We retrospectively analyzed data for the 2004-2015 period from the Surveillance, Epidemiology, and End Results (SEER) database. To guarantee well-balanced characteristics between the comparison groups, propensity score matching (PSM) was used. Kaplan-Meier (KM) curves were used to compare OS between pediatric and adult patients with ES of bone. Univariate and multivariate Cox regression analyses were used to screen independent prognostic factors for ES of bone, and a prognostic nomogram was constructed by using the factors identified. The prediction accuracy and clinical benefit were evaluated using receiver operating characteristic (ROC) curves, areas under the curves (AUCs), calibration curves, and decision curve analysis (DCA). Our results showed that adult ES patients had lower OS than younger ES patients. Age, surgery, chemotherapy, and TNM stage were independent risk factors for bone ES in adults and were used to develop a nomogram. AUCs for 3-, 5-, and 10-year OS were 76.4 (67.5, 85.3), 77.3 (68.6, 85.9) and 76.6 (68.6, 84.5), respectively. Calibration curves and DCA results indicated excellent performance for our nomogram. We found that ES pediatric patients have better OS than adult ES patients, and we constructed a practical nomogram to predict the 3-, 5- and 10-year OS of adult patients with ES of bone based on independent prognostic factors (age, surgery, chemotherapy, T stage, N stage and M stage).

Identification of small extracellular vesicle protein biomarkers for pediatric Ewing Sarcoma.

Ewing Sarcoma (EWS) is the second most common osseous malignancy in children and young adults after osteosarcoma, while it is the fifth common osseous malignancy within adult age population. The clinical presentation of EWS is quite often non-specific, with the most common symptoms at presentation consisting of pain, swelling or general discomfort. The dearth of clinically relevant diagnostic or predictive biomarkers continues to remain a pressing clinical challenge. Identification of tumor specific biomarkers can lend towards an early diagnosis, expedited initiation of therapy, monitoring of therapeutic response, and early detection of recurrence of disease. We carried-out a complex analysis of cell lines and cell line derived small extracellular vesicles (sEVs) using label-free-based Quantitative Proteomic Profiling with an intent to determine shared and distinct features of these tumor cells and their respective sEVs. We analyzed EWS cells with different EWS-ETS fusions (EWS-FLI1 type I, II, and III and EWS-ERG) and their corresponding sEVs. Non-EWS controls included osteosarcoma, rhabdomyosarcoma, and benign cells, i.e., osteoid osteoma and mesenchymal stem cells. Proteomic profiling identified new shared markers between cells and their corresponding cell-derived sEVs and markers which were exclusively enriched in EWS-derived sEVs. These exo-biomarkers identified were validated by in silico approaches of publicly available protein databases and by capillary electrophoresis based western analysis (Wes). Here, we identified a protein biomarker named UGT3A2 and found its expression highly specific to EWS cells and their sEVs compared to control samples. Clinical validation of UGT3A2 expression in patient tumor tissues and plasma derived sEV samples demonstrated its specificity to EWS, indicating its potential as a EWS biomarker.

Perinucleolar Compartment (PNC) Prevalence as an Independent Prognostic Factor in Pediatric Ewing Sarcoma: A Multi-Institutional Study.

The perinucleolar compartment (PNC) is a small nuclear body that plays important role in tumorigenesis. PNC prevalence correlates with poor prognosis and cancer metastasis. Its expression in pediatric Ewing sarcoma (EWS) has not previously been documented. In this study, we analyzed 40 EWS tumor cases from Caucasian and Hispanic patients for PNC prevalence by immunohistochemical detection of polypyrimidine tract binding protein and correlated the prevalence with dysregulated microRNA profiles. EWS cases showed staining ranging from 0 to 100%, which were categorized as diffuse (≥77%, n = 9, high PNC) or not diffuse (<77%, n = 31) for low PNC. High PNC prevalence was significantly higher in Hispanic patients from the US (n = 6, p = 0.017) and in patients who relapsed with metastatic disease (n = 4; p = 0.011). High PNC was associated with significantly shorter disease-free survival and early recurrence compared to those with low PNC. Using NanoString digital profiling, high PNC tumors revealed upregulation of eight and downregulation of 18 microRNAs. Of these, miR-320d and miR-29c-3p had the most significant differential expression in tumors with high PNC. In conclusion, this is the first study that demonstrates the presence of PNC in EWS, reflecting its utility as a predictive biomarker associated with tumor metastasis, specific microRNA profile, Hispanic ethnic origin, and poor prognosis.

Surgical treatment of pediatric thoracic Ewing tumors.

This study aims to determine the thoracic surgery techniques, surgical indications, the role and effectiveness of surgical treatment in multimodal treatment applied to pediatric Ewing sarcoma patients. Between A pril 2004 a nd November 2020, a total of 15 pediatric patients ( 9 males, 6 females; mean age: 10.1±4.5 years; range, 3 to 18 years) who were diagnosed with primary thoracic Ewing sarcoma and operated were retrospectively analyzed. Tumor-related factors and treatment modalities for Ewing sarcoma originating from the chest wall and mediastinum were examined. The most common complaint was pain in nine patients. While the tumor originated from the ribs in nine patients, it originated from the soft tissue (n=2), mediastinum (n=2), and extra-thoracic tissue (n=2) in six patients. Complete resection was achieved in 10 patients. While neoadjuvant chemotherapy was applied to eight patients, chemotherapy and radiotherapy was applied to 14 and five patients, respectively. Bone marrow transplantation was performed in one patient. The mean follow-up was 54.2±44.9 months. Recurrence was seen in six patients in a mean duration of 17.8±7.4 months. The most effective treatment for thoracic Ewing sarcoma is complete resection. Multimodal therapy in the form of surgical resection, chemotherapy and/or radiotherapy provides optimal efficacy and the most favorable survival. The follow-up period should be kept short, since recurrences are common.

Equivocal end-of-therapy imaging findings do not predict a higher risk of local relapse after definitive radiotherapy in pediatric Ewing sarcoma and rhabdomyosarcoma.

Posttherapy imaging studies can provide reassurance or induce anxiety regarding risk of recurrence for patients and their families. In some cases, it is difficult to determine if imaging findings represent posttreatment changes or residual disease. Equivocal radiographic findings can occur due to therapy-related inflammation or residual, inactive soft tissue masses, but it is unknown if such findings indicate an increased likelihood of local recurrence. The aim of this study was to assess the value of initial posttherapy scans for predicting local relapse in patients with Ewing sarcoma (EWS) or rhabdomyosarcoma (RMS) who received radiotherapy (RT) for local control. These findings are critical to inform clinicians' surveillance recommendations and ability to accurately counsel patients and their families. The primary endpoint was time to local progression (LP). Patients were classified as having posttherapy scans that were "positive" (residual disease within the RT field), "negative" (no evidence of residual disease within the RT field), or "equivocal" (no determination could be made). The value of initial posttreatment scans for predicting LP was assessed using positive predictive value (PPV) and negative predictive value (NPV). Negative imaging findings (n=51) had an NPV of 88%, and positive imaging findings (n=1) had a PPV of 100%. When equivocal findings (n=16) were categorized with negative results (i.e., positive vs. equivocal/negative), the NPV was 90%. When equivocal findings were categorized with positive results (equivocal/positive vs. negative), the PPV was 12%. Equivocal findings within the RT field on end-of-therapy imaging studies indicate no higher risk of local recurrence than negative findings. These results may contribute to appropriate surveillance schedules and accurate counseling of patients with RMS and EWS who have received RT for local control.

Comprehensive Radiotherapy for Pediatric Ewing Sarcoma: Outcomes of a Prospective Proton Study

<h3>Purpose/Objective(s)</h3> Patients with Ewing Sarcoma (EWS) are treated with multimodal therapy, with radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) for localized and metastatic EWS. <h3>Materials/Methods</h3> Fifty children with EWS (39 localized, 11 metastatic) treated between 2007 and 2020 were enrolled on a prospective IRB-approved protocol for pediatric patients undergoing PRT. Median age at time of PRT was 11.5 years (range 0.9-19.6 years); 62% were male. Median tumor size was 6.4cm (range 2.5-21cm). All patients received induction chemotherapy prior to PRT; 38 patients had definitive PRT and 12 had surgery followed by PRT. PRT was delivered by passive scatter (74%), pencil-beam scanning (12%) or mixed technique (14%). Treated sites included the spine (40%), pelvis/sacrum (26%), skull (18%), extraosseous (10%), and axial-skeleton (6%). Median radiation dose was 54Gy-RBE (range 36.9-55.8Gy-RBE). All patients with metastatic disease (n=11) received consolidative RT to metastatic sites (5 at the time of local control [LC], 6 after completion of chemotherapy). Long-term follow-up data was available for 41 patients which comprise the subjects included in this report. Local failures were classified as in-field (>80% of relapse volume within the 95% isodose line [IDL]), marginal (>20% to ≤80% within the 95% IDL), or out-of-field (≤20% within the 95% IDL). Median follow-up time was 47 months after PRT. <h3>Results</h3> The 4-year LC, progression-free survival (PFS), and overall survival (OS) rates were 83.2%, 71.4%, and 86.3%, respectively. All local failures (n=6) were in-field failures. Tumor size ≥8cm predicted both inferior 4-year LC and PFS (69% vs 95%, p=0.04; 55% vs 86%, p=0.03, respectively). The 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72% vs 67%, p=0.70; 89% vs 78%, p=0.38, respectively). Long-term toxicity included a grade 3 esophageal stricture in 1 patient. <h3>Conclusion</h3> We report one of the largest series of pediatric patients with EWS treated with PRT. LC was comparable to that of historical patients who received photon-RT and there were no marginal failures. Larger initial tumor size predicted increased risk of local failure and disease progression, which supports current efforts to dose-escalate treatment of tumors ≥8cm. Finally, patients with metastatic disease received radiation therapy to all metastatic sites and had survival outcomes comparable to those of patients with localized disease, suggesting a benefit to using RT for consolidation in metastatic EWS.

Mitochondrial DNA haplogroup, genetic ancestry, and susceptibility to Ewing sarcoma

Based on current studies, the incidence of Ewing sarcoma (ES) varies significantly by race and ethnicity, with the disease being most common in patients of European ancestry. However, race/ethnicity has generally been self-reported rather than formally evaluated at a population level using DNA evidence. Additionally, mitochondrial dysfunction is a hallmark of ES, yet there have been no reported studies of mitochondrial genetics in ES. Thus, we evaluated both the mitochondrial and nuclear ancestries of 420 pediatric ES patients in the United States using whole-genome sequencing. We found that the mitochondrial DNA (mtDNA) genomes of only six (1.4 %) patients belonged to African L haplogroups, while those of 90 % of the patients belonged to macrohaplogroup R, which includes haplogroup H, the most common maternal lineage in Europe. Compared to the general US population, European haplogroups were significantly enriched in ES patients (p < 2.2e-16) and the African haplogroups are significantly impoverished (p < 4.6e-16). Using the ancestry informative markers defined in a National Genographic study, the vast majority of patients exhibited significant nuclear ancestry originating from the Mediterranean, Northern Europe, and Southwest Asia, including all six patients with African L mtDNAs. Very few had primarily African nuclear ancestry. This is the first genomic epidemiology study to simultaneously interrogate the mitochondrial and nuclear ancestries of ES patients. While supporting previous findings of enriched European ancestry in ES patients, these results also suggest alternative hypotheses for the significant contribution of mitochondrial ancestry in ES patients, as well as the protective role of African ancestry.

Clinical implementation of plasma cell-free circulating tumor DNA quantification by digital droplet PCR for the monitoring of Ewing sarcoma in children and adolescents.

BackgroundTreatment stratification and response assessment in pediatric sarcomas has relied on imaging studies and surgical/histopathological evidence of vital tumor cells. Such studies and evidence collection processes often involve radiation and/or general anesthesia in children. Cell-free circulating tumor DNA (ctDNA) detection in blood plasma is one available method of so-called liquid biopsies that has been shown to correlate qualitatively and quantitatively with the existence of vital tumor cells in the body. Our clinical observational study focused on the utility and feasibility of ctDNA detection in pediatric Ewing sarcoma (EWS) as a marker of minimal residual disease (MRD).Patients and methodsWe performed whole genome sequencing (WGS) to identify the exact breakpoints in tumors known to carry the EWS-FLI1 fusion gene. Patient-specific fusion breakpoints were tracked in peripheral blood plasma using digital droplet PCR (ddPCR) before, during, and after therapy in six children and young adults with EWS. Presence and levels of fusion breakpoints were correlated with clinical disease courses.ResultsWe show that the detection of ctDNA in the peripheral blood of EWS patients (i) is feasible in the clinical routine and (ii) allows for the longitudinal real-time monitoring of MRD activity in children and young adults. Although changing ctDNA levels correlated well with clinical outcome within patients, between patients, a high variability was observed (inter-individually).ConclusionctDNA detection by ddPCR is a highly sensitive, specific, feasible, and highly accurate method that can be applied in EWS for follow-up assessments as an additional surrogate parameter for clinical MRD monitoring and, potentially, also for treatment stratification in the near future.

Multimodality treatment of pediatric Ewing sarcoma: A single-center 10-year analysis of outcomes

BackgroundEwing sarcoma, a malignancy originating from the bone or soft tissues most commonly diagnosed in adolescents, requires multimodality therapy. Although both surgical resection and radiation therapy are effective local control modalities, there are limited data comparing outcomes in patients treated with surgery versus radiation. We sought to determine whether there were differences in 5-year local failure-free survival, event-free survival, and overall survival based on the modality used for local control. MethodsPatients treated for Ewing sarcoma at a single tertiary pediatric hospital between 2010 and 2020 were included for retrospective analysis. Patient and tumor demographics, treatment information, and patient response to therapies were collected from the medical record. Outcome measures were local failure-free survival, event-free survival, and overall survival at 5 years from diagnosis. ResultsSixty-one patients met inclusion criteria. All patients received chemotherapy, and 68.9% of patients presented with localized disease. Of these, 23.8% were treated with radiation alone; the remaining 76.2% underwent resection ± radiation. A total of 52.4% of patients with localized disease achieved R0 resection. Only 3 patients experienced local progression; there was no difference between treatment groups. There was no significant association between local control modality and event-free survival or overall survival in patients with localized disease, regardless of margin status. ConclusionThere was no significant difference in 5-year local failure-free survival, event-free survival, or overall survival in Ewing sarcoma patients treated with radiation versus surgery ± radiation, regardless of whether or not R0 resection was achieved. Future directions include a multi-institutional study to allow for further subgroup analysis and increased sample size.

High-dose chemotherapy followed by whole lung irradiation in pulmonary relapse Ewing's sarcomas: a retrospective multicenter study.

Regarding the efficiency of Bu-Mel-based high-dose-chemotherapy (Bu-Mel-HDCT) and whole lung irradiation (WLI), the objective was to evaluate the efficiency and safety of this salvage sequence in Ewing sarcoma (ES) lung relapses. All eligible pediatric ES patients (1991-2020) identified in SFCE departments were retrospectively reviewed. Seven patients were (1) diagnosed with a pulmonary relapse, isolated or not, (2) naïve from both HCDT and WLI (3) treated by the salvage sequence of conventional chemotherapy, Bu-Mel-HDCT and WLI. The main endpoint was OS evaluation. WLI toxicities were scored using CTC-V5. With a 13 years median follow-up (FU), 5/7 patients are alive and in complete remission. 10y-EFS is 71.4%. Three patients experienced transitory radio-induced pneumopathy (RIP). A patient developed RIP (gr.3) and finally progressive lung fibrosis leading to death. This study reports seven ES patients treated for lung metastatic relapses, using an aggressive strategy, with favorable survival long-term results which should be balanced with the risk of lung toxicity. The approach of surgery, Bu-Mel HDCT followed by WLI can be discussed in selected ES patients with lung relapse, naive from HDCT or WLI, providing an optimal chemosensitivity. A special vigilance is necessary regarding the incidence rate of lung toxicity which can be mitigated by limiting the radiotherapy dose, and observing optimal timing of radiotherapy after HDCT.

Efficacy of replacing actinomycin-D with carboplatin in Ewing sarcoma consolidation treatment: Single-center experience

BackgroundTreatment of Ewing sarcoma (ES) requires multidisciplinary approach and deficiencies in treatment adversely affect the results. This study included patients diagnosed with ES and aimed to determine the factors affecting prognosis and investigate the efficacy of replacing actinomycin-D with carboplatin in consolidation treatment. MethodsEighty-two pediatric ES patients diagnosed at a single institution between 2005 and 2020 were retrospectively evaluated. Clinical and epidemiological features, treatment modalities, prognostic criteria, and overall survival (OS) rates of patients revieved. In consolidation treatment, 22 patients were treated with actinomycin-D and 32 patients with carboplatin (500 mg/m2/dose), 24 patients could not receive consolidation treatment. The 5- and 10-year OS rates of the patients were compared. ResultsThe 5- and 10-year OS rates of the 82 patients with ES were 46% and 40%, respectively. The 5-year OS rates in the group with localized disease (n = 55) and metastasis (n = 27) at diagnosis were 54% and 26%, respectively (p = 0.006). When evaluated according to the consolidation treatment administered both the 5- and 10-year OS rates of the patients receiving actinomycin-D were 50%. The 5-year OS rate was 58% in the carboplatin group, and the 5- and 10-year OS rates of patients that did not receive consolidation treatment was 20%. ConclusionsSurvival was significantly worse in the group that did not receive consolidation treatment. Furthermore, our results suggested that carboplatin could be used effectively as an alternative to actinomycin-D in ES consolidation treatment.

Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes

SummaryMore knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused and pan-ancestry case-control analyses to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1,147 individuals with pediatric sarcoma diagnoses (226 Ewing sarcoma, 438 osteosarcoma, 180 rhabdomyosarcoma, and 303 other sarcoma) relative to identically processed cancer-free control individuals. Findings in Ewing sarcoma were validated with an additional cohort of 430 individuals, and a subset of 301 Ewing sarcoma parent-proband trios was analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the European Ewing sarcoma discovery cohort (three individuals, OR 12.6, 95% CI 3.0–43.2, p = 0.003, FDR = 0.40). This enrichment in FANCC heterozygous pathogenic variants was again observed in the European Ewing sarcoma validation cohort (three individuals, OR 7.0, 95% CI 1.7–23.6, p = 0.014), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in individuals with Ewing sarcoma. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.

Feasibility and safety of outpatient administration of ifosfamide and etoposide for pediatric patients with Ewing sarcoma in a resource-limited setting amid the COVID-19 pandemic.

BackgroundTo assess feasibility and safety of outpatient administration of ifosfamide and etoposide (IE) for pediatric Ewing sarcoma (EWS) patients in a resource‐limited setting amid the COVID‐19 pandemic.Materials and MethodsRetrospective study of patients with EWS who received outpatient IE from January 2020 until January 2021 at our institution. Ifosfamide 1800 mg/m2 was given for 5 days with MESNA (2‐mercaptoethane sulfonate sodium) infusion and additional boluses before and after 9 hours of hydration. Patients >10 years of age with the ability to drink orally at home, no pre‐existing renal dysfunction or history of hematuria were included. They were monitored for hemorrhagic cystitis with a urine dipstick before, midway, and at end of infusion. A urine analysis was done 24 hours after the last dose of ifosfamide.ResultsForty‐seven (100%) cycles were given as outpatient during the study period. Thirty‐five (74%) cycles were given on time, two (4%) cycles were delayed due to mucositis, two (4%) due to delayed count recovery, and eight (18%) due to unavailability of outpatient appointments. The median interval between these cycles was 15 days (range 14–44 days). No episode of hemorrhagic cystitis was reported. Urine analysis was not done at 24 hours for 27 (58%) cycles, so microscopic hematuria may have been missed. This outpatient protocol saved 32% (USD 299) per cycle in cost and 282 days of hospitalization.ConclusionOutpatient administration of IE for pediatric patients with EWS is feasible, safe, and cost‐effective during the COVID‐19 pandemic.