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Purpose: About 30%–35% of nonmetastatic and 60%–80% of metastatic Ewing Sarcoma (ES) will relapse post-treatment and outcomes after relapse continue to be poor over last several decades. Prognostic...

Context.— Molecular diagnostics play an increasing role in the diagnosis of Ewing sarcoma. The type of molecular testing used in clinical practice has been poorly described. Objective.— To describe patterns of translocation testing for newly diagnosed Ewing sarcoma. Design.— Children's Oncology Group (COG) trial AEWS1221 was a phase III randomized trial enrolling patients with newly diagnosed metastatic Ewing sarcoma from 2014 to 2019. Patients were required to have a histologic diagnosis of Ewing sarcoma, but translocation testing was not required. Sites provided types and results of any molecular diagnostics performed. Results.— Data from 305 enrolled patients were available. The most common type of molecular testing was fluorescence in situ hybridization (FISH) performed on the primary tumor (236 of 305 patients; 77.4%), with positive testing for an EWSR1 or FUS translocation in 211 (89.4%). Reverse transcription–polymerase chain reaction (RT-PCR) on the primary tumor was performed in 61 of 305 patients (20%), with positive results in 48 of 61 patients (78.7%). Next-generation sequencing was reported in 7 patients for the primary tumor and in 3 patients for metastatic sites. For all types of testing on either primary or metastatic tumor, 16 of 305 patients (5.2%) had no reported translocation testing. When evaluating all results from all testing, 44 of 305 patients (14.4%) lacked documentation of an abnormality consistent with a molecular diagnosis of Ewing sarcoma. Conclusions.— COG sites enrolling in a Ewing sarcoma trial have high rates of testing by FISH or PCR. A small proportion of patients have no translocation testing on either primary or metastatic sites. Next-generation sequencing techniques are not yet commonly used in this context.

A 26-year-old pregnant woman, with multiple metastatic Ewing sarcoma, presented with a sternal mass that began enlarging during pregnancy. Due to high-risk pregnancy, the patient was discussed in a multidisciplinary meeting and intubation was considered too risky without cardiopulmonary support. Computed tomography showed extrinsic tumor compression of the right ventricle outflow tract. Veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) was initiated before general anesthesia, followed by Cesarean section (C-section). VA ECMO was initiated with the patient in the awake position, ECMO support was discontinued when the patient had stable ventilation and hemodynamics. This case represents a unique indication of VA ECMO, during C-section, with maternal and fetal survival.

Background The use of radiation therapy to treat metastases in patients with metastatic Ewing sarcoma (MES) has been controversial and variable. The authors report outcomes and patterns of failure after metastatic site irradiation (MSI). Procedure A total of 27 pediatric patients with MES were treated with chemotherapy and received radiation therapy to their primary site. Ten patients additionally received MSI, which consisted of whole-lung irradiation (WLI) in patients with lung metastases. Metastatic sites were followed from diagnosis to the first relapse. Results Median follow-up was 29 months. Seventy-eight percent of patients relapsed. Two-year progression-free survival (PFS) and overall survival with and without MSI were 30 versus 29% (log rank P=0.38) and 60 versus 70% (log rank P=0.11), respectively. The median time to relapse among patients who relapsed was 19.5 versus 12.3 months for those receiving MSI versus those who did not (P=0.04).Seven of 20 (35%) patients with lung metastases received WLI±other MSI. Two-year PFS with and without MSI was 43% versus 23% (log rank P=0.02). Among patients with a complete response to computed tomography, 5 of 14 (36%) patients received MSI. Two-year PFS with and without MSI was 60% versus 33% (log rank P=0.04).In the cohort of patients who relapsed, among all metastatic sites at diagnosis, the disease recurred at 15% of irradiated sites and 31% of unirradiated sites. On logistic regression, no factors were statistically associated with increased risk of recurrence at initial sites of metastases. Conclusions Relapses frequently occur at sites of prior unirradiated disease in patients with MES. WLI may improve 2-year PFS, regardless of chemotherapy response. Further investigation of the role of MSI is warranted.

Background Ewing sarcomas are solid tumours of the bone and soft tissue, that usually affect children, adolescents, and young adults. The incidence is about three cases per million a year, with a peak incidence at 12 years of age. Metastatic disease is detected in about 20 % to 30% of people, and is typically found in the lungs, bone, bone marrow, or a combination of these. Presence of metastatic disease at diagnosis (primary metastatic disease) is the most important adverse prognostic factor, and is associated with a five-year survival lower than 30%. High-dose chemotherapy (HDC) followed by autologous haematopoietic cell transplantation (AHCT) is used in various solid tumours with unfavourable prognoses in children, adolescents, and young adults. It has also been used as rescue after multifocal radiation of metastases. The hypothesis is that HDC regimens may overcome the resistance to standard multidrug chemotherapy and improve survival rates. Objectives To assess the effects of high-dose chemotherapy with autologous haematopoietic cell transplantation compared with conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with primary metastatic Ewing sarcoma, and to determine the toxicity of the treatment. Search methods We searched CENTRAL, MEDLINE, Embase, conference proceedings from major international cancer-related conferences, and ongoing trial registers until January 2020. We also searched reference lists of included articles and review articles. Selection criteria We included randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC and AHCT with conventional chemotherapy for children, adolescents, and young adults (younger than 30 years at the date of diagnostic biopsy) with primary metastatic Ewing sarcoma. Data collection and analysis We used standard methodological procedures expected by Cochrane. Main results We identified one RCT, which investigated the effects of HDC with AHCT versus conventional chemotherapy with whole lung irradiation (WLI) in people with Ewing sarcoma metastasised to the lungs only at diagnosis. Only a selection of the participants were eligible for our review (N = 267: HDC with AHCT group N = 134; control group N = 133). There may be no difference in event-free survival between the two treatment groups (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.59 to 1.17; low-certainty evidence). We downgraded one level each because of study limitations and imprecision. Overall survival and toxicity were not reported separately for the participants eligible for this review, while quality-adjusted survival and progression-free survival were not reported at all. We did not identify any studies that addressed children, adolescents, and young adults with Ewing sarcoma with metastases to other locations. Authors' conclusions In people with Ewing sarcoma with primary metastases to locations other than the lungs, there is currently no evidence from RCTs or CCTs to determine the efficacy of HDC with AHCT compared to conventional chemotherapy. Based on low-certainty evidence from one study (267 participants), there may be no difference in event-free survival between children, adolescents, and young adults with primary pulmonary metastatic Ewing sarcoma who receive HDC with AHCT and those who receive conventional chemotherapy with WLI. Further high-quality research is needed. Results are anticipated for the EuroEwing 2008R3 study, in which the effects of HDC with treosulfan and melphalan followed by AHCT on survival, in people with Ewing sarcoma with metastatic disease to bone, other sites, or both were explored. Achieving high-quality studies in a selection of people with rare sarcoma requires long-term, multi-centre, international participant inclusion.

Purpose: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). Methods: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for &lt, 14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. Results: After WLI, grade 1–2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1–79.3), 61.2% (48.4–71.7) and 70.5% (56.3–80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. Conclusions: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor.

PURPOSE: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Ewing sarcoma is a bone tumor most commonly diagnosed in adolescents and young adults. Survival for patients with recurrent or metastatic Ewing sarcoma is dismal and there is a dire need to better understand the mechanisms of cell metastasis specific to this disease. Our recent work demonstrated that microenvironmental stress leads to increased Ewing sarcoma cell invasion through Src activation. Additionally, we have shown that the matricellular protein tenascin C (TNC) promotes metastasis in Ewing sarcoma. A major role of both TNC and Src is mediation of cell–cell and cell-matrix interactions resulting in changes in cell motility, invasion, and adhesion. However, it remains largely unknown, if and how, TNC and Src are linked in these processes. We hypothesized that TNC is a positive regulator of invadopodia formation in Ewing sarcoma through its ability to activate Src. We demonstrate here that both tumor cell endogenous and exogenous TNC can enhance Src activation and invadopodia formation in Ewing sarcoma. We found that microenvironmental stress upregulates TNC expression and this is dampened with application of the Src inhibitor dasatinib, suggesting that TNC expression and Src activation cooperate to promote the invasive phenotype. This work reports the impact of stress-induced TNC expression on enhancing cell invadopodia formation, provides evidence for a feed forward loop between TNC and Src to promote cell metastatic behavior, and highlights a pathway by which microenvironment-driven TNC expression could be therapeutically targeted in Ewing sarcoma.

INTRODUCTION: Intramedullary metastasis of Ewing sarcoma is extremely rare. Here, we report an adult case of cervical intramedullary recurrent Ewing sarcoma after a 10-year disease-free survival after the initial surgery for a thoracic lesion. CASE PRESENTATION: A 39-year-old man with a history of surgery and chemoradiotherapy for thoracic Ewing sarcoma ten years ago presented with neck pain and incomplete motor paralysis in the right upper extremity, which had suddenly appeared three months before. Cervical magnetic resonance imaging revealed a tear-drop-shaped intramedullary lesion at the C3 level accompanied by diffuse edematous change. Because of the rapid progression of his myelopathy, he underwent surgery for this intramedullary lesion. Intraoperatively, the tumor exhibited an orangish exophytic appearance. The unclearness of the tumor boundary compelled us to perform a partial resection. The histopathology showed the tumor comprised small round atypical cells with immunoreactivity for Nkx2.2 and CD99, diagnosing a metastatic Ewing sarcoma. Postoperatively, although his myelopathy improved transiently and adjuvant chemotherapy radiation was undergone, he died of cranial dissemination of the tumor two months and a half later. DISCUSSION: To our knowledge, 31 cases of primary and only 4 cases of recurrent intramedullary spinal Ewing sarcoma have been reported to date; however, this is the first case of recurrent intramedullary Ewing sarcoma with a 10-year disease-free survival. Sadly, the prognosis of the current case was extremely poor. There is no clear treatment guideline for recurrent intramedullary Ewing sarcoma because of its rarity, and further collection of similar cases would be required.

Background: Few models have been used to estimate the survival rate of patients metastatic Ewing sarcoma of bone are scarce. We aimed to develop nomograms for predicting 3-, 5-year survival for these patients.Methods: We extracted 686 cases of metastatic Ewing's sarcoma diagnosed between 1973 and 2016 from the Surveillance, Epidemiological and End Results (SEER) database. Univariate and multivariate Cox analysis were used to determine independent prognostic factors. The nomograms are based on the results of multivariate Cox analysis. We also evaluate the performance of these prediction models through the analysis of time-dependent receiver operating characteristic curve, concordance index, calibration curve and decision curve.Results: Age, surgery, tumor size, treatment method and chemotherapy were considered to be important predictors of overall survival of bone metastatic Ewing's sarcoma. Based on these factors, the nomogram models were established and verified internally. These models have good identification and calibration characteristics. A risk classification system based on nomogram has also been constructed to promote risk stratification of metastatic Ewing's sarcoma and to optimize clinical management.Conclusions: We developed the first nomograms and corresponding risk classification system to predict the survival of patients with bone metastatic Ewing's sarcoma. These easy-to-use tools can help oncologists and surgeons make accurate survival assessments.

[Background] The prognosis of patients with metastatic Ewing sarcoma family of tumors (ESFT) remains poor. [Procedure] We retrospectively analyzed 57 patients diagnosed with metastatic ESFT between 2000 and 2018 to identify prognostic and therapeutic factors affecting the clinical outcome. [Results] The 3-year overall survival (OS) rate of the entire cohort was 46.8% (95% confidence interval [CI], 33.0-59.4%). Treatment-related death was not observed. Multivariate analysis identified stem cell transplantation (SCT), response to first-line chemotherapy, and bone metastasis as independent risk factors for OS. Objective response rate to first-line chemotherapy was 65.1% in the 43 evaluable patients. There was no significant difference in the response to different types of first-line chemotherapy. Among patients with lung metastasis alone, the 3-year OS rate was higher in 13 patients who received local treatment than in four who did not, although the difference was not significant. [Conclusions] One possible reason for the high OS rates was the absence of treatment-related mortality even in patients receiving SCT, which could be attributed to advances in the management of post-SCT complications. Novel first-line chemotherapy strategies need to be established to improve the disease status prior to SCT in a higher proportion of patients.

Objetivo. Presentar los resultados perinatales de dos pacientes con diagnóstico de sarcoma de Ewing y rabdomiosarcoma alveolar. Metodología. Se revisaron dos casos de pacientes con diagnóstico de sarcoma atendidas en el Instituto Nacional de Perinatología de la Ciudad de México. Resultados. Caso 1 femenino de 22 años, con embarazo de 23,0 semanas y tumoración en región glútea izquierda de 20 cm, dolor y dificultad para deambular. La radiografía de tórax informó múltiples nódulos pulmonares y la resonancia magnética, tumor en región glútea con compromiso extenso. El diagnóstico fue sarcoma de Ewing metastático en etapa IV. El manejo consistió en tratamiento sintomático con resolución del embarazo a las 28 semanas. Caso 2 femenino de 22 años con embarazo de 12,0 semanas y diagnóstico de síndrome medular metastásico. Se realizó descompresión T9-11. Se evidenció ausencia de frecuencia cardiaca fetal, por lo que se realizó manejo médico de aborto diferido.

A 49-year-old male with Ewing sarcoma and bone, pleural, lung and mediastinal lymph node metastasis was treated with cabozantinib after four lines of previous systemic treatments. He responded objectively and subjectively well for 8 months. In this heavily pretreated patient, the daily starting dose of 60 mg had to be reduced to 30 mg because of adverse events. We conclude that treatment with cabozantinib administered in further-line was active in this particular patient with metastatic Ewing sarcoma. The underlying mechanism of action remains unclear. Because of a stable disease on a long-term treatment with pazopanib targeting an anti-angiogenic pathway common to both drugs previously administered in this patient, it is hypothesized that the action of cabozantinib could be ascribed to its action on the non-common receptors AXL and c-Met. The potential of cabozantinib should be further investigated more upfront in this disease either alone or in combination with other systemic treatments.

BACKGROUND Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response. MATERIALS AND METHODS We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes. RESULTS Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P

Ewing sarcoma (ES) is an undifferentiated small round blue cell tumor most commonly originating in the bone of adolescents 10-20 years of age, although 30% are diagnosed in adults. The most important prognostic factor is the presence of metastatic disease. Results of the EURO-EWING 99 trial of ES patients showed that local treatment of not only the primary, but also of the sites of metastatic disease should be considered to improve event-free survival. The use of stereotactic body radiotherapy (SBRT) has been extensively reported for tumors of lung, liver, pancreas, and spine. The use of SBRT in these sites is well-accepted. Here, we report a detailed case of SBRT to multisite metastatic ES. We demonstrate the feasibility, safety, and efficacy of aggressive local control with multisite SBRT for the treatment of metastatic ES.

Highlights • The incidence of ES of the bone is very low, reaching a peak in adolescence. • We assessed the patterns of DM and the prognostic factors in this patient subset. • Lung and bone are the most frequently distant metastatic sites. • Bone metastasis is an independent risk factor for inferior survival., Background Ewing sarcoma (ES) of bone is accounting for the second most common type of primary bone cancer in children and adolescents. However, the patterns of distant metastasis (DM) and the effect of the sites of DM on survival outcomes were not investigated. Aims This study aimed to investigate the patterns of DM and the prognostic factors related to outcomes in primary metastatic ES of the bone. Methods Patients who were diagnosed with primary metastatic ES between 2010 and 2018 were identified from the Surveillance, Epidemiology, and End Results database. Kaplan–Meier analysis, log-rank tests, and Cox proportional-hazards regression models were used for statistical analyses. Results We identified 277 patients in this study and 95.3% of them (n = 264) receiving chemotherapy. A total of 371 sites of DM were observed. Lung was the most common distant metastatic site (n = 182, 49.1%), followed by bone (n = 139, 37.5%), distant lymph node (n = 26, 7.0%), liver (n = 14, 3.8%), and brain (n = 10, 2.7%). Three-year cause-specific survival (CSS) was 56.1% in the entire cohort. Older age (hazard ratio [HR] 2.210, P

A 45-year-old male with recurrent metastatic Ewing sarcoma presented to Memorial Sloan Kettering Cancer Center for potential enrollment in a clinical trial. Initial laboratory results were notable for increased alkaline phosphatase levels [(ALP2, 495 U/L; (reference interval: 33–97 U/L); Abbott Architect C8000] and γ-glutamyl transferase levels [GGT, 393 U/L (reference interval: 0–73 U/L); Abbott Architect C8000] but were otherwise unremarkable, including normal levels of aspartate aminotransferase (AST) and alanine transaminase (ALT). Elevations in ALP and GGT levels suggested liver disease, although the patient had no previous history of liver abnormalities. Given the patient's history of metastatic bone disease, it was suspected that the observed elevation in ALP was due to increased bone ALP isoenzyme. However, it was important to document the origin of the increased ALP as the patient was to be enrolled in an investigational trial that would define drug dosage and side effects. Elevations in ALP over the course of the trial that were attributable to liver-specific isoenzymes would be reported as a dose-limiting toxicity and could delay treatment or potentially exclude the patient from the clinical trial. Conversely, elevations in ALP originating from bone and secondary to disease would not be reported as toxicity. The laboratory was consulted regarding testing options to identify the specific isoenzyme(s) responsible …

Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS‐275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically, MS‐275 inhibits YB‐1 deacetylation, decreasing its binding to 5′‐UTRs of NFE2L2 encoding the antioxidant factor NRF2, thereby reducing NFE2L2 translation and synthesis of NRF2 to increase cellular ROS. By global acetylomics, MS‐275 promotes rapid acetylation of the YB‐1 RNA‐binding protein at lysine‐81, blocking binding and translational activation of NFE2L2, as well as known YB‐1 mRNA targets, HIF1A, and the stress granule nucleator, G3BP1. MS‐275 dramatically reduces sarcoma metastasis in vivo, but an MS‐275‐resistant YB‐1K81‐to‐alanine mutant restores metastatic capacity and NRF2, HIF1α, and G3BP1 synthesis in MS‐275‐treated mice. These studies describe a novel function for MS‐275 through enhanced YB‐1 acetylation, thus inhibiting YB‐1 translational control of key cytoprotective factors and its pro‐metastatic activity., Class 1 HDAC inhibitors including MS‐275 inhibit the RNA binding protein YB‐1 by enhancing its acetylation. This reduces its affinity to mRNA targets under cellular stress, and decreases tumor cell fitness and metastatic capacity.

The outcomes for relapsed and metastatic Ewing sarcoma (EWS) is extremely poor. Therefore, it is important to identify the tumor‐specific targets in these intractable diseases. High focal adhesion kinase (FAK) transcript expression levels in EWS cell lines are known. TAE226 is a dual inhibitor of FAK and insulin‐like growth factor‐I receptor (IGF‐IR), while PF‐562,271 is a dual inhibitor of FAK and proline‐rich tyrosine kinase 2. We compared the cytotoxicity of TAE226 and PF‐562,271 toward three EWS cell lines. TAE226 strongly inhibited proliferation of three cell lines when compared with PF‐562,271. Furthermore, we investigated the efficacy of TAE226 as well as its mechanism of action against EWS. A stable EWS cell line with FAK and IGF‐IR knocked down was established, and microarray analysis revealed dysregulated expression in various pathways. TAE226 treatment of EWS cell lines induced cell cycle arrest, apoptosis, AKT dephosphorylation, and inhibition of invasion. We demonstrated that TAE226 drastically inhibits the local growth of primary tumors and metastasis in EWS using mouse models. Furthermore, the combination of TAE226 and conventional chemotherapy proved to exert synergistic effects. TAE226 may be a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future., Systemic TAE226 treatment potently reduced the size of local tumors and inhibited micrometastasis in vivo through cell cycle inhibition, induction of apoptosis, and inhibition of AKT signaling. Furthermore, combined therapy with TAE226 and conventional anticancer drugs for EWS has synergistic anticancer effects. Overall, the results of the present study suggest that TAE226 is a candidate single agent or combined therapy drug to be developed for patients who have relapse and metastatic EWS tumors in future.

OBJECTIVEThere are limited data on spine stereotactic radiosurgery (SRS) in treating adolescent and young adult (AYA) patients. SRS has the advantages of highly conformal radiation dose delivery in the upfront and retreatment settings, means for dose intensification, and administration over a limited number of sessions leading to a decreased treatment burden. In this study, the authors report the oncological and toxicity outcomes for AYA patients with metastatic sarcoma treated with spine radiosurgery and provide clinicians a guide for considerations in dose, volume, and fractionation.METHODSAn institutional review board–approved database of patients treated with SRS in the period from October 2014 through December 2018 was queried. AYA patients, defined by ages 15–29 years, who had been treated with SRS for spine metastases from Ewing sarcoma or osteosarcoma were included in this analysis. Patients with follow-ups shorter than 6 months after SRS were excluded. Local control, overall survival, and toxicity were reported.RESULTSSeven patients with a total of 11 treated lesions were included in this study. Median patient age was 20.3 years (range 15.1–26.1 years). Three patients had Ewing sarcoma (6 lesions) and 4 patients had osteosarcoma (5 lesions). The median dose delivered was 35 Gy in 5 fractions (range 16–40 Gy, 1–5 fractions). The median follow-up was 11.1 months (range 6.8–26.0 months). Three local failures were observed within the follow-up period. No acute grade 3 or greater toxicity was observed. One patient developed late grade 3 toxicity consisting of radiation enteritis. This patient had previously received radiation to an overlapping volume with conventional fractionation. SRS re-irradiation for this patient was also performed concurrently with chemotherapy administration. No late grade 4 or higher toxicities were observed. No pain flare or vertebral compression fracture was observed. Three patients died within the follow-up period.CONCLUSIONSSRS for spine metastases from Ewing sarcoma and osteosarcoma can be considered as a treatment option in AYA patients and is associated with acceptable toxicity rates. Further studies must be conducted to determine long-term local control and toxicity for this treatment modality.

Ewing Sarcoma is a highly lethal undifferentiated tumor of bone. ES is a small round cell tumor with etiological and characteristic chromosomal translocations between TET/FET (TLS/FUS, EWSR1, and TAF15) and ETS (E26 transformation-specific) family genes. Generally, therapeutic approach for metastatic Ewing Sarcoma includes both local (surgery and radiotherapy) and systemic (chemotherapy) disease control with an overall cure rate of 20%. For extra-osseous tumors, the most common primary sites of disease are trunk, extremities, head and neck, retroperitoneum. Among other sites, Ewing Sarcoma/PNET may also rarely arise in colon and rectum. Even if colonic Ewing Sarcoma/PNET have been previously reported in 5 cases, none of those reports came from right side of the colon. In this article, we report the first case of right-sided Ewing Sarcoma with synchronous liver metastases completely responding to first line chemotherapy. Furthermore, we provide a systematic qualitative review of the current literature on adult colorectal Ewing Sarcoma using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

e23510 Background: The purpose of the study was to evaluate the efficacy of vincristine, irinotecan, and temozolomide (VIT) combination in heavily pretreated adult patients with metastatic Ewing sarcoma. Methods: We evaluated data of the patients with metastatic Ewing sarcoma retrospectively. We recorded clinical, pathological, radiological, and treatment features of the patients and used SPSS 25. version for statistical analysis. Kaplan-Meier and Cox regression analysis were used for survival analysis. Results: Sixteen patients were included in the study. The median age was 25 (range, 20-42) years. Eleven (68.8%) of the patients were male. The origin of the tumor was bone (75%) and soft tissue (25%). The most common primary tumor localization was pelvic (41.7%), extremity (33.3%), and other sites (25%), respectively. Six (37.5%) patients were de-novo metastatic at diagnosis. The most common metastatic site was the lung (75%). Before the vincristine, irinotecan, and temozolomide (VIT) combination, patients had received at least two different chemotherapy regimens (87.5%) and palliative radiotherapy (37.5%). Median progression-free survival was 3.4 (95% CI, 1.8-4.9) months. The partial response was observed in five (31.3%) patients, and all other patients (68.7%) had progressive disease. Grade 1-2 adverse events were observed in thirteen (81.3%) patients and grade 3-4 in five (31.3%) patients. The most common adverse events were hematological (87.5%). Median overall survival was 5.6 (95% CI, 3.6-7.5) months. Conclusions: In this study, we showed real-life efficacy of vincristine, irinotecan, and temozolomide (VIT) combination in adult patients with metastatic osteosarcoma. Toxicities were concern about in these heavily pretreated patients. Treatment options of metastatic Ewing sarcoma are limited. VIT regimen may be considered in patients who have a good performance.

Despite the advances in oncology, the survival of children with Ewing Sarcoma metastatic at diagnosis continues to be 27% 3-year event-free survival and 34% 3-year overall survival. In other words, 7 of 10 children die within 3 years of their initial diagnosis despite intense chemotherapy, local treatment (radiation/surgery), and/or high dose busulfan-melphalan and autologous stem-cell transplantation. A chief contributor to this morbidity and mortality is the difficulty eradicating the tumor using present therapeutic modalities. Despite the extensive surgery, intensive chemotherapy and radiation, those left with a significant bulk of residual tumor relapse within a year of completing treatment. This case report suggests that in children left with a significant tumor burden after completing chemotherapy, a prolonged period of stability can be achieved with biological agents targeting the underlying molecular drivers. In this particular case we used figitumumab, an antibody targeting the insulin-like growth factor type 1 receptor pathway, a documented target in Ewing Sarcoma. Although not curative, these agents provide a better quality of life.

Metastatic Ewing sarcoma has a very poor prognosis and therefore new investigations into the biologic drivers of metastatic progression are key to finding new therapeutic approaches. The tumor microenvironment is highly dynamic, leading to exposure of different regions of a growing solid tumor to changes in oxygen and nutrient availability. Tumor cells must adapt to such stress in order to survive and propagate. In the current study, we investigate how Ewing sarcoma cells respond to the stress of growth factor deprivation and hypoxia. Our findings reveal that serum deprivation leads to a reversible change in Ewing cell cytoskeletal phenotypes. Using an array of migration and invasion techniques, including gelatin matrix degradation invadopodia assays, we show that exposure of Ewing sarcoma cells to serum deprivation and hypoxia triggers enhanced migration, invadopodia formation, matrix degradation and invasion. Further, these functional changes are accompanied by and dependent on activation of Src kinase. Activation of Src, and the associated invasive cell phenotype, were blocked by exposing hypoxia and serum-deprived cells to the Src inhibitor dasatinib. These results indicate that Ewing sarcoma cells demonstrate significant plasticity in response to rapidly changing micro-environmental stresses that can result from rapid tumor growth and from necrosis-causing therapies. In response to these stresses, Ewing cells transition to a more migratory and invasive state and our data show that Src is an important mediator of this stress response. Our data support exploration of clinically available Src inhibitors as adjuvant agents for metastasis prevention in Ewing sarcoma.

Receptor tyrosine kinases (RTKs) have provided molecular targets for the development of novel, prognosis‐improving agents in many cancers; however, resistances to these therapies occur. On the cellular level, one resistance mechanism is attributed to functional RTK redundancies and compensatory cross‐signaling, leading to perception of RTKs as signaling and target networks. To provide a basis for better exploitation of this network in Ewing sarcoma, we generated comprehensive qPCR gene expression profiles of RTKs in Ewing sarcoma cell lines and 21 untreated primary tumors. Key findings confirm broad‐spectrum RTK expressions with potential for signaling redundancy. Profile analyses with regard to patient risk‐group further revealed several individual RTKs of interest. Among them, VEGFR3 and TIE1 showed high‐level expressions and also were suggestive of poor prognosis in localized tumors; underscoring the relevance of angiogenic signaling pathways and tumor‐stroma interactions in Ewing sarcoma. Of note, compared to localized disease, tumors derived from metastatic disease were marked by global high‐level RTK expressions. Nine individual RTKs were significantly over‐expressed, suggesting contributions to molecular mechanisms of metastasis. Of these, ROR1 is being pursued as therapeutic target in leukemias and carcinomas, but un‐characterized in sarcomas. We demonstrate expression of ROR1 and its putative ligand Wnt5a in Ewing sarcomas, and of an active ROR1 protein variant in cell lines. ROR1 silencing impaired cell migration in vitro. Therefore, ROR1 calls for further evaluation as a therapeutic target in metastatic Ewing sarcoma; and described as a pseudo‐kinase with several isoforms, underlines these additional complexities arising in our understanding of RTK signaling networks.

Ewing sarcoma (ES) is a poorly differentiated bone and soft tissue tumor of high metastatic potential. ES mainly affects children, adolescents, and young adults (AYAs) at a frequency of ~1.5 cases per million globally. Ewing neoplasms strikingly converge on a single recurrent initiating event, which is a chromosomal translocation that generates a fusion transcript between the EWSR1 gene and a gene of the ETS family of transcription factors, most commonly FLi1 (85%). After 20 years since the discovery of the EWS-FLi1 fusion, ES remains a clinical challenge with unacceptably low survival rates, primarily due to metastasis. The bulk of research conducted to date (>95%) being focused on the primary tumor has resulted in a critical knowledge gap. To address this issue and unravel the dysregulated pathways in ES tumor evolution and metastatic dissemination, we harnessed the genome-wide insertional mechanism of transposons and the transduction efficiency of lentiviruses to engineer ES cell models. Human mesenchymal stem cells (hMSC), the putative cells of origin of ES, were engineered to constitutively express EWS-Fli1 accompanied by the inducible expression of a highly active transposase. Upon activation of the former, transposon-mediated mutagenesis will activate oncogenes and inactivate tumor suppressor genes, to mediate transformation of the transduced that can now engraft when implanted in recipient mice. Xenografted tumors are resected and the mice observed for development of distant metastases. Matching primary and metastatic tumors are sequenced to uncover the genes commonly affected by transposition in the two compartments. Pathway-oriented bioinformatic analysis will further reveal candidate metastatic driver genes. Matching of the targeted pathways with drugs will be used to validate the candidates by in vitro and in vivo metastasis assays. Citation Format: Wajih Jawhar, Paul Waterhouse, Rama Khokha, Takeaki Ishii, Robert Turcotte, Nada Jabado, Livia Garzia. Functional genomics of metastatic Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A64.

Oncolytic virotherapy is associated with immunogenic cell death and antitumor inflammatory immune responses. Thereby, a local as well as systemic immunosuppressive microenvironment might be abrogated, resulting in efficient phagocytic and antigen-presenting properties. Consecutively, priming of naive T cells against a multitude of de-repressed tumor and viral antigens is claimed to elicit strong antitumor immune responses accompanied by tumor-infiltrating T cells, especially in combination with immune checkpoint blockade. These features might be beneficial for patients with relapsed and metastatic Ewing sarcoma, who have poor prognosis and lack innovative therapy concepts, and whose tumor biopsies are characterized by low or absent T-cell infiltration. Here, we explore the efficacy of the oncolytic YB-1-selective adenovirus XVir-N-31 in combination with the CDK4/6-inhibitor abemaciclib (LY2835219) in established Ewing sarcoma cell lines. We demonstrate enhanced viral replication, particle formation, and oncolysis when combined with abemaciclib in vitro. Priming of tumor cells with abemaciclib before viral infection leads to cell cycle arrest in G1 phase, with consecutive decrease in Rb, pRb, and E2F1 protein levels. Interestingly, in the Rb-mutated hence CDK4/6-inhibitor-resistant cell line SK-N-MC, the combination with abemaciclib does not result in enhanced viral replication oor oncolysis. However, the same effects as for CDK4/6-inhibitor sensitive cell lines can be induced by siRNA-mediated E2F1 knockdown, indicating the crucial role of E2F1 as a repressor for initiation of viral replication. In summary, our results further support the hypothesis of E2F1 being a repressor of adenoviral replication (Holm et al., manuscript in preparation) and suggest the use of CDK4/6-inhibitors to boost oncolytic adenoviral efficacy. Further in vivo confirmation is planned in order to prepare a clinical phase I study of XVir-N-31 in combination with a CDK4/6-inhibitor and immune checkpoint blockade for treatment-refractory pediatric sarcoma patients. Citation Format: Sebastian J. Schober, Uwe Thiel, Melanie Thiede, Maximilian Ehrenfeld, Roman Nawroth, Guenther HS Richter, Stefan E.G. Burdach, Per Sonne Holm. YB-1-based oncolytic virotherapy in combination with CDK4/6-inhibitors against Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A48.

10516 Background: The prognosis of patients with primary multifocal metastatic Ewing sarcoma (PMES) remains dismal. So far, combination with temozolomide and irinotecan (TEMIRI) was tested in patients with refractory or relapsed disease. This study evaluates the activity and the tolerability of TEMIRI as front-line treatment in PMES. Methods: In the study-period 2012-2018, a front-line window therapy with 2 courses TEMIRI (temozolomide 100 mg/sqm/day + irinotecan 50 mg/sqm/day for 5 days every three weeks) was introduced as amendment to the ISG/AIEOP EW-2 protocol ( EUDRACT#2009-011197-15, Vers. 1.02 ) for patients with PMES. Main objective was to test the activity of TEMIRI evaluated by RECIST 1.1 criteria, with centralized revision of the radiological response. Secondary objectives included assessment of the toxicity profile and clinical benefit of the combination. A two-step study design by Simon was planned. Results: Thirty-four patients were enrolled. Median age at diagnosis was 19 years (range 3-55); males/females ratio was 2.4. Primary axial tumour was present in 24 (70%). After TEMIRI, RECIST response was as follows: partial response -20 (59%), stable disease -11 (32%), progression disease -3 (9%). After TEMIRI, amelioration in ECOG/Lansky score was achieved in 25/34 (73,5%), and reduction or disappearance of pain was observed in 31/34 patients (91%). TEMIRI toxicity was manageable: incidence of grade 3-4 nonhaematological and haematological toxicity was 3% and 3%, respectively (67/68 evaluable courses). At the time of the present analysis, 11 patients are alive; 7 of them are in complete remission and completed their treatment program (5-drug standard chemotherapy). With a median follow-up of 31 months (range 23-75), the 3-year survival estimate is 36,5%±0.09. Conclusions: Upfront TEMIRI x 2 courses showed an encouraging activity, with response rate 59% and deserves further evaluation combined with conventional treatments also in non-metastatic patients. In PMES new treatment strategies are urgently needed. Clinical trial information: NCT02727387.

10517 Background: The prognosis of patients with metastatic Ewing sarcoma remains poor. The primary aim of the ISG/AIEOP EW2 Study (EUDRACT# 2009-011197-15) was to evaluate the feasibility and efficacy of maintenance therapy with oral cyclophosphamide plus celecoxib. Methods: From June 1st 2009 to Nov 22nd 2019, 112 patients with metastatic Ewing sarcoma at onset entered the ISG/AIEOP EW2 study, consisting of induction chemotherapy, radiotherapy and/or surgery at the site of the primary tumor, a consolidation phase with high-dose busulphan/melphalan + autologous stem cell rescue, whole-lung irradiation (12-15Gy), and a maintenance phase of 180 days with cyclophosphamide 50 mg daily (35 mg/mq daily if age < 14 years) plus celecoxib 400 mg twice daily (250 mg/mq twice daily if age < 14 years). Exclusion criteria from the maintenance phase were disease progression, cardiac or gastro-intestinal comorbidity. For CTCAE v4.0 grade 3-4 toxicities a temporary interruption was planned. Results: Seventy-one patients were eligible and entered the maintenance phase. Median age was 16 years (range 13-41); sites of metastases were lung or single bone (n = 56) and multicentric metastatic spread (n = 15). Sixty-one patients terminated the maintenance phase, 4 patients are still on treatment, 1 patient interrupted the treatment due to auto-immune thrombocytopenia at 4 months, 5 patients were withdrawn throughout maintenance due to disease progression/relapse. The duration of maintenance therapy was 89% of the scheduled days, with a median suspension length of 12 days (range 1-44 days). Causes of temporary suspension were hematological toxicity (19 episodes), infections (12 episodes), gastrointestinal disorders (9 episodes), fluid retention/distal oedema (3 episodes), renal disorders (3 episodes). Median follow-up was 42 months. The 3-year EFS of patients who entered the maintenance phase was 0.79 ± 0.09 for lung or single bone, and 0.19 ± 0.11 for those with multicentric metastatic spread. Conclusions: This schedule of maintenance phase is feasible, despite previous intensive treatment. A longer follow-up is needed to monitor side effects and to evaluate clinical outcome of patients with lung or single bone metastases, while the outcome remains dismal for multicentric metastatic Ewing sarcoma. Clinical trial information: NCT02727387.

e23501 Background: Ewing sarcoma family of tumors (ESFT) is a rare malignancy among adults. Most studies from western countries have reported improvement in outcomes following multi-agent chemotherapy. We report our experience in the management of this disease among Arab ethnicity. The aim of this study is to assess the outcome of VAIA combination as a first-line treatment in Adult-patients with metastatic Ewing sarcoma. Methods: Patients who were newly diagnosed as metastatic Ewing sarcoma between 03/1997 and 11/2016 at King Faisal Specialist Hospital and Research Center, who received VAIA as first-line therapy were eligible. The patient's characteristics were summarized using Medians with interquartile ranges (IQR) and frequencies for continuous and categorical variables, respectively. Variables including age, sex, primary tumor size, site (skeletal vs extraskeletal) and extent of metastasis in correlation with progression and overall survival were analyzed using the Kaplan–Meier method and Cox proportional hazards regression. Results: Thirty-nine patients were identified. Male (26, 66.7%), Female (13, 33.3%). Skeletal (27, 69.2%), Extraskeletal (12, 30.8%). The median longest diameter of the primary tumor 9.75 (IQR 8-15). The most common metastatic sites were Lungs (22, 56.4%) & Bone (10, 25.6%), however, the least common sites were Bone Marrow (3, 7.7%) and liver (2, 5.1%). The median number of VAIA cycles was 10 cycles (IQR 5-14). Objective response rate (ORR) was noticed in 20 patients (51.2%) (Complete Remission (7, 17.9%), Partial Remission (13, 33.3%). One patient had stable disease and 12 (30.8%) patients had progressive disease. The assessment was not feasible in 3 (7.7%) patients. With a median follow up duration of 18 months (1-44).20 patients died (62.5%). The median PFS and OS was 10,18 months respectively with 3,5 years overall survival rate of;35.7%,26.9% respectively. Univariate analysis correlation among different variables were insignificant. Conclusions: VAIA chemotherapy combination showed poor outcomes among our patients in comparison to literature further improvement is needed in this aggressive malignancy in our region.

Background The long-term morbidity of childhood cancer survivors is an emerging field as more patients are now expected to live through adulthood. Case We describe 2 adolescent patients with permanent premature ovarian failure and failure of endometrium to respond to estrogen after they received a combination of chemotherapy and pelvic radiation for metastatic Ewing sarcoma. Both girls were prepubertal at diagnosis of Ewing sarcoma. Puberty was induced with high-dose estrogen and progesterone; however, none of the patients had withdrawal bleeding. Summary and Conclusion It is critical to counsel these patients that menstruation might not be possible even with hormone replacement therapy.

The prognosis of adolescent and young adult patients battling metastatic Ewing Sarcoma Family of Tumours (ESFT) remains less than 30% despite the development of systemic therapies. In the era of personalized medicine, novel molecular targets have been tested in preclinical or clinical settings in ESFT. In this review, we focus on early clinical and translational research that identified multiple molecular targets, including IGF-1R; mTOR; tyrosine kinase inhibitors; EWS-FLI1-related targets, and others. Overall, novel targeted therapies demonstrated modest efficacy; however pronounced and durable antineoplastic responses have been observed in small subsets of treated patients, for example with IGF-1R antibodies. Identifying outcome-predicting biomarkers and overcoming treatment resistance remain major challenges. Due to the rarity of ESFT, multi-institutional collaboration efforts of clinicians, basic and translational scientists are needed in order to understand biology of therapeutic response or resistance, which can lead to development of novel therapeutic methods and improved patient outcomes.

Background Outcomes for patients with metastatic Ewing sarcoma (ES) remain poor. We investigated whether the intensification of ifosfamide improved survival for patients with metastatic ES. Procedure We conducted a retrospective chart review of 30 patients with metastatic ES treated with the MSKCC “EFT regimen.” The regimen included an intensification of ifosfamide dosing from 1,800 mg/m2/day × 5 days per cycle to 2,800 mg/m2/day × 5 days per cycle. Results Twenty six of the 30 patients completed planned chemotherapy. Two patients experienced disease progression during therapy. There were no toxic deaths. One patient developed secondary leukemia. The 4-year event free survival (EFS) was 27% and the overall survival (OS) was 39%. Conclusions Intensification of ifosfamide was tolerated and did not increase toxicity in patients with metastatic ES. The intensification did not improve outcomes for these patients with metastatic disease. Pediatr Blood Cancer 2015;62:594–597. © 2015 Wiley Periodicals, Inc.

Background. Whole lung irradiation (WLI) is a standard treatment component for children with metastatic Ewing Sarcoma (ES), but data on WLI for adults are sparse.Design. An email survey was sent to expert sarcoma-dedicated oncologists worldwide:An adult with excellent performance status presents with primary ES in the leg and multiple pulmonary metastases. The patient achieves complete radiographic response after chemotherapy and resection of the primary. Would you give bilateral WLI to (1) this adult patient?, (2) this patient if 20 years old (yo)?, (3) this patient if 45 yo?, or (4) this patient if 60 yo? Results. 38 experts responded, including 24 adult, 1 adolescent young adult, and 13 pediatric oncologists. 63%, 63%, 62%, and 50% of respondents offered WLI to the adult, 20-year-old, 45-year-old, and 60-year-old, respectively. Pediatric oncologists more likely endorsed WLI across all ages including the adult (P=0.01), 20-year-old (P=0.005), 45-year-old (P=0.01), and 60-year-old (P=0.08). There were no significant differences between medical and radiation oncologists or between European/Australian and American providers.Conclusions. Almost two-thirds of experts surveyed supported WLI for adults with metastatic ES up to age 45 and half supported WLI for a 60-year-old. Continued collaboration across adult and pediatric oncology is needed to define evidence-based strategies across the age spectrum.

Complementary and alternative medicine (CAM) therapies are commonly incorporated into the care of patients with paediatric cancer. Many modalities are safe and effective during cancer treatment and have proved beneficial for symptom relief and quality of life. However, situations where alternative therapy is provided without allopathic medical care supportive care resources can pose a safety risk to patients. This report describes the case of a 16-year-old Chinese girl with metastatic Ewing sarcoma who sought treatment with alternative treatment in Mexico. When her disease progressed with an ensuing significant loss of function, the centre personnel were unable to respond to her acute deterioration or provide necessary medical care. This resulted in her being stranded in a foreign country paralysed, isolated, and with large unanticipated financial expenditures.

25-year-old woman with history of metastatic Ewing sarcoma to the spine underwent routine follow-up imaging.

The developmental receptor NOTCH plays an important role in various human cancers as a consequence of oncogenic mutations. Here we describe a novel mechanism of NOTCH-induced tumor suppression involving modulation of the deacetylase SIRT1, providing a rationale for the use of SIRT1 inhibitors to treat cancers where this mechanism is inactivated because of SIRT1 overexpression. In Ewing sarcoma cells, NOTCH signaling is abrogated by the driver oncogene EWS-FLI1. Restoration of NOTCH signaling caused growth arrest due to activation of the NOTCH effector HEY1, directly suppressing SIRT1 and thereby activating p53. This mechanism of tumor suppression was validated in Ewing sarcoma cells, B-cell tumors, and human keratinocytes where NOTCH dysregulation has been implicated pathogenically. Notably, the SIRT1/2 inhibitor Tenovin-6 killed Ewing sarcoma cells in vitro and prohibited tumor growth and spread in an established xenograft model in zebrafish. Using immunohistochemistry to analyze primary tissue specimens, we found that high SIRT1 expression was associated with Ewing sarcoma metastasis and poor prognosis. Our findings suggest a mechanistic rationale for the use of SIRT1 inhibitors being developed to treat metastatic disease in patients with Ewing sarcoma. Cancer Res; 74(22); 6578–88. ©2014 AACR.

We report the case of a patient who presented with a large pelvic mass, which was biopsy-proven to be Ewing sarcoma. The patient was also found to have 18 pulmonary lesions on a staging CT that were presumed to represent metastatic disease. After induction chemotherapy, a PET/CT scan revealed a marked reduction in his pelvic mass along with improvement in nearly all his pulmonary lesions except 2, which increased in size. The mixed response to chemotherapy was unusual and the decision was made to resect one of the growing lesions. Fungal culture from the excised lesion grew Coccidioides immitis.

Metastatic Ewing sarcoma (EWS) is often resistant to current multimodal chemotherapeutic regimens. Oncolytic virus therapy (OV) is a novel therapeutic platform whereby viruses can selectively infect as well as replicate in and kill tumor cells, while sparing normal tissues. The purpose of this study is to investigate the efficacy of the biotherapeutic oncolytic agent, vesicular stomatitis virus (VSVΔM51), to kill EWS cells that are resistant to conventional therapy. Our hypothesis is that systemic delivery of VSVΔM51 can demonstrate tumor-specific killing of resistant EWS cells, as well as a significant decrease of tumor burden in EWS bearing mice.Methods. A biopsy sample was obtained from a patient with metastatic EWS and was used to establish a novel EWS cell line.In vitroassays evaluated the oncolytic effect of vesicular stomatitis virus (VSVΔM51) on this cell line. EWS xenograft mice model bearing either lung or subcutaneous tumors was established to evaluate the antitumor specific oncolytic effect of VSVΔM51 after local and systemic delivery.Results. The established EWS cell line shared similar molecular and genetic traits to the patient’s original tumor specimen. VSVΔM51 effectively infected and killed EWS cellsin vitro. In vivo,VSVΔM51 selectively infected and killed EWS and led to significant delay in tumor growth.Conclusion. This study has been designed to implement a translational link between the bedside and the bench, where a specific challenging clinical scenario guided this basic science research. This research demonstrated that a sarcoma, which is resistant to current conventional standard therapies, is still susceptible to an alternative therapeutic platform, such as OV. Adding OV to the armamentarium of sarcoma treatment can enhance the future therapeutic approach towards these cancer patients.

An 18-year-old male with a history of Charcot-Marie-Tooth disease (CMT) presented with metastatic Ewing sarcoma to the lungs. He had been followed by several healthcare professionals who ascribed his enlarging 23 cm gluteal mass to his CMT. The patient experienced a significant delay in diagnosis, not uncommon in sarcoma. This case explores the various system and cognitive errors that contributed to this delay.

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma.

The improvement in outcome for patients with localized and metastatic Ewing sarcoma since the development of cytotoxic chemotherapy remains one of the most profound advances in oncology and one of the proudest achievements of sarcoma researchers. Identification of molecular targets for new treatments has become an intense area within Ewing sarcoma research. The development of improved preclinical Ewing sarcoma models and advanced molecular techniques will build on knowledge of EWS/FLI1 function, EWS/FLI1 transcription targets, and the other critical driver events in these tumors.