Ewing Sarcoma Research Articles

HER2 expression-independent antitumor effect of trastuzumab deruxtecan (T-DXd) on pediatric solid tumors.

e15016 Background: Treatment of pediatric solid tumors shows limited improvement even with intensification of conventional chemotherapy, suggesting novel approaches such as targeted therapies are needed. Trastuzumab Deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate, exhibits significant anti-cancer activity in breast cancers with a broad range of HER2 expression. T-DXd might be a promising agent for refractory or relapsed pediatric solid tumors, but its efficacy in pediatric tumors needs to be studied. Methods: Anti-cancer efficacy of T-DXd and its payload DXd were assessed in vitro by utilizing our in-house cancer cell line models. Cytotoxicity assays were performed for 60 pediatric cancer cell lines, including Neuroblastoma (NB) = 25, Ewing sarcoma / Ewing sarcoma family of tumors (EWS / EWSFT) = 17, Rhabdomyosarcoma (RMS) = 10, Others (Osteosarcoma, Brain tumor, Wilms tumor, Hepatoblastoma, and Malignant rhabdoid tumor (MRT) = 8, and 2 breast cancer cell lines expressing HER2 high or low (IHC score 2+ or 0) as positive or low control, respectively. We analyzed HER2 expression on the cell surface by flow cytometry and evaluated relative mean fluorescence intensity (MFI) values. Results: In the flow cytometric assessment, pediatric cancer cell lines showed smaller median MFI of 1.40 (0.67 - 2.71) compared with breast cancer control with HER2 high expression (33.77). The median MFI of each cell lines were 0.94 in NB, 1.76 in EWS / EWSFT, 1.42 in RMS, 1.52 in other pediatric cancers. Although low or no expression of HER2, certain inhibitory activities to the cell growth were observed for T-DXd against a part of NB, EWS, RMS and MRT cell lines, with the minimum IC50 values of 14.5 nM, 6.5 nM, 10.2 nM, 8.1 nM, respectively. In NB, EWS and RMS, a wide range of sensitivity to T-DXd were seen among different cell lines in the same disease. Most of cell lines showed high sensitivity to DXd (Median IC50 value: 0.90 nM [0.08 - 6.46 nM]), but, among them, cell lines with lower sensitivity to DXd tend to show less sensitivity to T-DXd. There was no clear correlation between sensitivity to T-DXd and HER2 expression among pediatric cancer cell lines, indicating that other mechanism such as intrinsic sensitivity to payload might affect antitumor activity of T-DXd. Conclusions: T-DXd exhibited antitumor efficacy against pediatric solid tumors in vitro irrespective of HER2 expression. Our results suggest that T-DXd might be an alternative therapy for pediatric solid tumor cases for whom conventional chemotherapies and other targeting therapies are ineffective. This study supports further investigation for T-DXd in this population.

Association of elevated ctDNA burden following one cycle of chemotherapy with inferior outcomes for patients with metastatic Ewing sarcoma: A report from the Children’s Oncology Group (COG).

10018 Background: All patients with Ewing sarcoma (EWS) currently receive the same intensive chemotherapy and novel risk-adapted approaches to therapy are needed. We have previously shown that elevated baseline ctDNA burden is prognostic among patients with EWS. Here we investigate the prognostic impact of on-treatment ctDNA burden in patients with metastatic EWS treated on COG AEWS1221. Methods: AEWS1221 was a randomized phase 3 trial evaluating ganitumab plus interval compressed chemotherapy (vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide given every 2 weeks) for patients with newly diagnosed metastatic EWS. We evaluated 680 serial blood samples and data from 273 patients enrolled to AEWS1221. We utilized a custom NGS hybrid-capture assay for ctDNA quantification that detects EWSR1 and FUSfusions. We used log rank tests to compare event-free survival (EFS) from the designated timepoint according to ctDNA burden post cycle 1 of VDC (planned day 14) and post cycle 2 VDC+IE (planned day 28) of chemotherapy. We dichotomized patients by ≥0.5% ctDNA at each timepoint. A P-value of ≤0.05 was considered evidence of a significant association. Results: Of 298 eligible patients with metastatic EWS, 273 provided blood samples for ctDNA analysis. Three patients had non-FET-ETS family fusions ( CIC::DUX4, EWSR1::WT1 and EWSR1::GTDC1) and were excluded from further analysis. Eighty-five percent of patients were < 21, 56% were male, 33% had pelvic bone primary tumors, and 40% had lung only metastatic disease. ctDNA was ≥0.5% in 86% of patients at baseline (median 25%, range 0-113%, n = 264), in 53% (median 0.53%, range 0-15%, n = 34) after 1 cycle (median day 14, range 11-20), and in 14% (median 0, range 0-53%, n = 130) after 2 cycles (median day 29, range 25-36). Baseline ctDNA burden ≥0.5% was associated with an increased risk of EFS-event (3-year EFS 35% [95% CI 29-41%] vs. 61% [95% CI 43-76%], HR = 2.2, P= 0.002). ctDNA ≥0.5% after cycle 1 was also associated with an increased risk of EFS-event (3-year EFS 6% [95% CI 0.4-22%] vs. 56% [95% CI 29-76%], HR = 6.0, P< 0.0001). ctDNA ≥0.5% after cycle 2 was not associated with an increased risk of EFS-event (28% [95% CI 10-49%] vs. 34% [95% CI 25-43%], HR = 1.2, P= 0.55). Conclusions: ctDNA burden ≥0.5% following one cycle of chemotherapy identifies patients highly likely to relapse, albeit in a small cohort with available data at that timepoint. Conversely, ctDNA at a cutpoint of ≥0.5% after two cycles of chemotherapy was not prognostic, suggesting either more sensitive assays are needed or the prognostic value of ctDNA burden is diminished following additional therapy. These findings will enable novel trials of risk-adapted therapy focused on baseline and early ctDNA burden.

Impact of age on clinical trial availability for AYAs with cancer: A time-trend analysis.

1534 Background: Low participation of adolescents and young adults (AYAs, age 15-39 yrs at diagnosis) in cancer clinical trials (CCT) limits their access to novel therapies and hinders the ability to study disease biology and age-specific toxicities. Patient age may be an important barrier as younger and older AYAs may be excluded depending on the trial’s focus. In 2017, the American Society of Clinical Oncology and Friends of Cancer Research issued a joint statement encouraging removal of age as a CCT eligibility criterion unless there is specific biological rationale. To evaluate the impact of this statement, we undertook this analysis of CCT availability for AYAs. Our primary objective was to compare the number of CCT available for AYAs, overall and by tumor types, from 2019-2023 vs previously published data from 2007-2018. The availability of early phase trials and study sponsor was also assessed. Methods: We identified CCT registered on ClinicalTrials.gov from January 2019 to July 2023 enrolling patients with 10 malignancies relevant for AYAs (Hodgkin lymphoma, anaplastic large cell lymphoma, melanoma, extracranial germ cell tumors [GCT], medulloblastoma, thyroid cancer, Ewing sarcoma, osteosarcoma, rhabdomyosarcoma [RMS], and synovial sarcoma). Trials were categorized as adult (≥18 yrs), transitional (patients < or ≥18 yrs), or pediatric (<18 yrs). Transitional trials with an age range 12-18 to <40 yrs were defined as AYA specific trials. Early phase included phase 1 and 1/2 trials; late phase included phase 2/3 and 3 trials. Trial availability from 2007-2018 was identified from a prior analysis by deRojas et al in 2019 (PMID:32337483). The proportion of trials in each category was compared between 2007-2018 and 2019-2023 using z-tests. Results: There were 1071 eligible trials registered on Clinicaltrials.gov: 840 (78%) adult, 226 (21%) transitional, and 5 (0.5%) pediatric. Four trials were AYA-specific. Compared to the prior 10 years, the proportion of transitional trials did not change overall (19% vs 21%, p=0.24) or within any disease. Whereas the proportion of trials available at age 17 has not significantly changed overall (20% vs 21%; p=0.48) or within any disease, the proportion of trials available at age 18 significantly increased (95% vs 98%; p<0.001) in aggregate and specifically for Ewing sarcoma (93% vs 100%; p=0.003), GCT (96% vs 99%; p=0.002), medulloblastoma (86% vs 98%; p=0.006), RMS (87% vs 98%; p=0.007) and thyroid cancer (92% vs 98%; p=0.01). Time trends for transitional trials by phase and sponsor are summarized (Table). Conclusions: Availability of transitional trials for AYAs has not increased, particularly for those <18 yrs. The 18-yr-old age limit continues to be an obstacle in CCT availability and enrollment. [Table: see text]

Eribulin and irinotecan for refractory or recurrent Ewing sarcoma: A retrospective study.

e23502 Background: The effectiveness of eribulin and irinotecan in treatment of xenograft models of Ewing sarcoma is well-established but little clinical data has been reported. Encouraging results from preclinical models and a shortage of temozolomide in our hospital have prompted the administration of the eribulin as substitute for temozolomide and vincristine in combination of irinotecan at our institution from 2022 to 2023 in an off-label way. Methods: We retrospectively reviewed the medical records of patients treated for refractory or recurrent Ewing sarcoma with 1.4mg/m2 D1,8 eribulin and 20mg/m2/d D1-5,8-12 irinotecan at 21 day intervals (ERII) at Peking University People’s Hospital. Results: Finally, a total of 17 patients with median age 18.6 years were treated with a total of 77 courses of ERII between February 2022 and February 2023. The objective response rate was 35.3%, the disease control rate 58.9% and the median event-free survival (EFS) 2.07 months. 35.3% patients had 6 months EFS and overall survival was 66.9%. Grade 3 or 4 toxicities were observed in 37.6% courses and in 64.7% of the patients, with myelosuppression, especially neutropenia, being the most common and diarrhea / abdominal pain the second most common. In the dx5x2 VIT protocol the later portion was given two days after the end of early portion. However, in this substitute regimen of eribulin, the median time interval between the end of the early portion to the start of later portion was 5 days. The dose intensity of the regimen was reduced by 21% per cycle. The later portion was delayed mostly because of unrecovered myelosuppression. Conclusions: The efficacy and safety of eribulin and irinotecan as a second-line regimen was inferior to historical reports of temozolomide and irinotecan in the same institute. There was no need for further prospective trials on this combination unless mechanisms of synergy and biomarkers are identified. [Table: see text]

Feasibility of tumor-informed circulating tumor DNA (ctDNA) for molecular residual disease (MRD) assessment in pediatric patients with solid tumors.

10058 Background: Circulating Tumor DNA (ctDNA) is a noninvasive biomarker which has been validated as a prognostic tool in multiple adult cancers. There is evolving evidence that ctDNA may be prognostic in pediatric solid tumors, but experience with commercially available assays in pediatric patients is scarce. Signatera is a ctDNA assay which utilizes whole exome sequencing of tumor and whole blood to identify 16 tumor-specific, clonal, somatic variants. These variants are then monitored in plasma as a molecular residual disease (MRD) assessment. Methods: From November 2021 through August 2023, 30 patients were enrolled on a single center study evaluating the feasibility and utility of Signatera MRD monitoring in pediatric patients with solid tumors. Patients 6 months to 25 years of age with any malignant extracranial solid tumor including lymphoma were eligible. Peripheral blood has been collected every 3 weeks to 3 months while on therapy and every 3 to 6 months while off therapy for up to 2 years. A minimum of 22mL of blood was required for the first draw, and 16mL for subsequent draws. Timing of blood draws was aligned with standard of care blood draws when possible. Results of ctDNA MRD were compared with imaging obtained for disease response and surveillance as standard of care. Results: The cohort consisted of 6 cases of neuroblastoma, 6 osteosarcomas, 4 Wilms tumors, 4 carcinomas, 3 soft tissue sarcomas, 2 Ewing sarcomas, 2 germ cell tumors, 2 lymphomas, and one hepatoblastoma. Of 30 patients enrolled, a tumor-informed ctDNA assay was successfully created for 27 (90%). Of 25 patients who had radiographic evidence of disease at any time of monitoring, 23 (92%) had simultaneous detectable ctDNA. Seven patients have had disease recurrence, of whom all seven had detectable ctDNA at or preceding time of recurrence. Conclusions: Signatera tumor-informed ctDNA assay is a feasible noninvasive tool which may be utilized in parallel with standard of care imaging to monitor for disease recurrence in pediatric patients with extracranial solid tumors. Additional analysis of a larger patient cohort is needed to identify tumor types and clinical scenarios for which its application is most useful.

SARC037: Phase II results of trabectedin given as a 1-hour (h) infusion in combination with low dose irinotecan in patients (pts) with relapsed/refractory Ewing sarcoma (ES).

SARC037: Phase II results of trabectedin given as a 1-hour (h) infusion in combination with low dose irinotecan in patients (pts) with relapsed/refractory Ewing sarcoma (ES).

Results of a randomized phase II trial of 2nd-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib: Japan Clinical Oncology Group study JCOG1802 (2ND-STEP).

11551 Background: Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD) are the candidates of second-line chemotherapy for advanced soft tissue sarcomas (STS), although there is no clear evidence showing which is better among those agents. This clinical trial aims to determine the most promising regimen among trabectedin, eribulin, and pazopanib as the test arm regimen in the future phase III trial of the second-line treatment for patients with advanced STS. Methods: This study, JCOG1802, is a multicenter randomized phase II selection design trial comparing trabectedin (1.2 mg/m2 IV, every 3 weeks), eribulin (1.4 mg/m2 IV, days 1 and 8, every 3 weeks) and pazopanib (800 mg PO, everyday) for patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. Eligibility criteria include 16 years old or older, ECOG performance status of 0–2, unresectable and/or metastatic STS, an exacerbation within 6 months prior to registration, histological diagnosis of STS other than Ewing sarcoma, well-differentiated liposarcoma and myxoid liposarcoma, a history of chemotherapy of doxorubicin-based regimen for STS, and sufficient organ function. Primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival (OS), disease-control rate (DCR), response rate (RR), and adverse events. The planned total sample size was set at 120 patients to select the most promising regimen with a probability of at least 80%, assuming a median PFS of 3 months in the worst regimen and 4 months in the best regimen. The regimen demonstrating the most favorable point estimate of hazard ratio for PFS is chosen for the subsequent phase III trial. Results: From December 2019 to March 2023, 120 patients with advanced STS were enrolled (31 with leiomyosarcomas, 26 with liposarcomas, 18 with translocation-related sarcomas, and 45 with others) and randomized. Median PFS for trabectedin was 2.9 months (95% CI 1.3-5.3), for eribulin was 2.2 months (1.5-3.8), and for pazopanib was 3.7 months (2.6-5.2), respectively. The hazard ratios for eribulin and pazopanib compared to trabectedin were 1.22 (0.77-1.94) and 0.99 (0.63-1.56), respectively. Median OS for trabectedin was 14.8 months (10.8-29.1), for eribulin was 13.3 months (7.6-20.1), and for pazopanib was 15.7 months (9.8-not estimable). DCR for trabectedin was 50.0% (32.4-67.6), for eribulin was 34.3% (19.1-52.2), and for pazopanib was 64.9% (47.5-79.8). Conclusions: Pazopanib showed the best PFS and OS as the second-line treatment for patients with advanced STS among trabectedin, eribulin, and pazopanib. A phase III trial comparing GD with pazopanib is planned as the next step. Clinical trial information: jRCTs031190152 .

Prevalence of neurotrophic tropomyosin receptor kinase (NTRK) fusion gene positivity in patients with solid tumors in Japan.

Members of the neurotrophic tropomyosin receptor kinase (NTRK) gene family, NTRK1, NTRK2, and NTRK3 encode TRK receptor tyrosine kinases. Intra- or inter-chromosomal gene rearrangements produce NTRK gene fusions encoding fusion proteins which are oncogenic drivers in various solid tumors. This study investigated the prevalence of NTRK fusion genes and identified fusion partners in Japanese patients with solid tumors recorded in the Center for Cancer Genomics and Advanced Therapeutics database of comprehensive genomic profiling test. In the analysis population (n = 46,621), NTRK fusion genes were detected in 91 patients (0.20%). The rate was higher in pediatric cases (<18 years; 1.69%) than in adults (0.16%). NTRK gene fusions were identified in 21 different solid tumor types involving 38 different partner genes including 22 (57.9%) previously unreported NTRK gene fusions. The highest frequency of NTRK gene fusions was head and neck cancer (1.31%) and thyroid cancer (1.31%), followed by soft tissue sarcoma (STS; 0.91%). A total of 97 NTRK fusion gene partners were analyzed involving mainly NTRK1 (49.5%) or NTRK3 (44.2%) gene fusions. The only fusion gene detected in head and neck cancer was ETV6::NTRK3 (n = 22); in STS, ETV6::NTRK3 (n = 7) and LMNA::NTRK1 (n = 5) were common. Statistically significant mutual exclusivity of NTRK fusions with alterations was confirmed in TP53, KRAS, and APC. NTRK gene fusion was detected from 11 STS cases: seven unclassified sarcoma, three sarcoma NOS, and one Ewing sarcoma. NTRK gene fusion identification in solid tumors enables accurate diagnosis and potential TRK inhibitor therapy.

Posterior fossa primary intracranial extraosseous Ewing’s sarcoma: case report

BackgroundPrimary intracranial Ewing’s sarcoma (ES) is a type of primitive neuroectodermal tumour and is a rare malignant tumour in children and adolescents. The imaging features of ES overlap with other central nervous system embryonal tumours, making it difficult to pinpoint a specific diagnosis. We aim to explore the clinical, neuroimaging and differential diagnoses of this entity.Case presentationWe describe a 6-month-old infant who presented with complaints of enlarging the head size and poor feeding. Imaging revealed a contrast-enhancing large solid-cystic mass lesion with internal calcification, focal bone erosion and haemorrhage in the posterior fossa. Histopathological examinations, immunohistochemistry, and molecular analysis confirmed ES.ConclusionsThe confirmative diagnosis of primary intracranial ES requires histological examination, immunohistochemical analysis, and genetic detection, along with radiological findings. Surgical excision followed by combined radiotherapy and chemotherapy is the treatment of choice.

Non-Wilms renal tumors: Twenty years experience in a referral center

BackgroundNon-Wilms Renal Tumors (NWRT) constitute less than 10% of all renal tumors diagnosed in childhood. We studied our experience in the diagnosis and management of these tumors to compare our results with the current literature. Study designThis is a retrospective observational study which includes all patients aged 0-18 years with histopathological diagnosis of NWRT treated in our center during the period 2000-2022. ResultsWe identified 10 patients with diagnosis of: cystic nephroma(3), congenital mesoblastic nephroma(1), renal cell carcinoma(2), clear cell sarcoma of the kidney (2), renal Ewing's sarcoma(1) and malignant rhabdoid tumor of the kidney(1). Sixty percent (60%) were female. The median age at diagnosis was 3.25 years (IQR 1.5-10). Median age at diagnosis excluding CN was 6 years old (IQR 2.62-10.75). Molecular alterations were detected in 60% of the cases. Hematuria (40%) and palpable abdominal mass (40%) were the most frequent presenting symptoms. In total, 62.5% patients were misdiagnosed during the preoperative period as Wilms' tumor (WT), based on imaging data. A Radical nephroureterectomy was performed in all cases and staging lymphadenectomy in 70%. We recorded a major complication in one patient, who suffered a contralateral lower renal pole infarction due to section of a polar vessel during surgery. This patient had no preoperative vascular study. The recurrence-free survival rate was 90% with a median follow-up of 6.4 years (IQR 2-13.9). DiscussionRadiological imaging has fundamental importance in the diagnosis of renal tumors, especially to identify children who might benefit from initial surgical treatment or the indication of biopsy for preoperative histopathological confirmation before initiating cytotoxic treatment. However, there are no pathognomonic imaging findings that clearly differentiate between WT and other renal tumors, nor among the heterogeneous group of NWRT[3]. In our series, 62.5% of patients were misdiagnosed as WT based on imaging features.We found different molecular alterations in 60% of our patients (Table 1). None of them predispose to the development of bilateral tumors nor correlates with predisposing syndromes of metachronous tumors.Apart from its retrospective design, this study is limited by small number of cases and a long study period. ConclusionsCorrect differential diagnosis of NWRT is necessary for an adequate therapeutic approach. The molecular-genetic profile is an important step in the diagnosis of NWRT that allows for the use of targeted therapies in refractory patients. Detailed anatomical study by vascular mapping minimizes the risk of iatrogenic damage during tumor resection.

PULMONARY EWING SARCOMA/PRIMITIVE NEUROECTODERMAL TUMOR : A CASE REPORT

Extraosseous Ewings sarcoma is an extremely rare neuroectodermal tumor,Although thoracic Ewing sarcoma/primitive neuroectodermal tumor (PNET) usually developson the chest wall, there have been reports of primary Ewing sarcoma/PNET of the lung Wereport the case of a 30-year-old manwho presented with right-sided pulmonary mass.Radiology, histopathology, and immunohistochemistry confirmed the diagnosis of primarypulmonary Ewings sarcoma, the patient wastreated by chemotherapy ( regimen ofvincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, etoposide ) andradiotherapy.

Lumbar functional evaluation of pelvic bone sarcomas after surgical resection and spinal pelvic fixation: A clinical study of 304 cases.

We endeavored to introduce a novel scoring system (Lumbar Functional Index, LFI) capable of evaluating lumbar function in pelvic bone sarcoma patients who underwent surgical resection and spinal pelvic fixation, while simultaneously identifying the incidence, outcomes, and risk factors of lumbar function impairment among these populations. A cohort of 304 primary bone sarcoma patients were recruited. The LFI was created based on the Oswestry Dysfunction Index (ODI) and Japanese Orthopaedic Association (JOA) scores. Lumbar function impairment was defined as LFI score ≥ 18 points, which was identified as high LFI. Demographic data, clinical characteristics, and oncological outcomes were analyzed. The cohort included chondrosarcoma (39.8%), osteosarcoma (29.9%), Ewing sarcoma (8.6%), bone-derived undifferentiated pleomorphic sarcoma (7.2%), giant cell tumor of bone (7.2%), chordoma (2.3%), and other bone sarcomas (5.0%). The LFI score exhibited significant negative correlation with common scoring systems of bone sarcoma. The incidence of high LFI was 23.0%. Patients with high LFI demonstrated a higher prevalence of type I + II + III + IV pelvic tumor, more sacrificed nerve roots and bilateral lumbar spine fixation during surgery, while lower percentage of R0 resection and local control of pelvic tumor. Decreased median overall survival (30 vs. 52 months, p < 0.001) and recurrence-free survival (14 vs. 24 months, p < 0.001) time were observed in these patients. Type I + II + III + IV pelvic tumor and sacrificed nerve roots≥2 were identified as risk factors for high LFI, while R0 resection and local control were identified as protective factors. The LFI scoring system exhibited a significant negative correlation to current scoring systems. High LFI patients had worse prognosis and distinct characteristics. The risk factors of high LFI included type I + II + III + IV pelvic tumor and sacrificed nerve roots≥2, and the protective factors included R0 resection and local control.

Disease Control and Toxicity Outcomes after Stereotactic Ablative Radiation Therapy for Recurrent and/or Metastatic Cancers in Young-Adult and Pediatric Patients.

Pediatric patients with metastatic and/or recurrent solid tumors have poor survival outcomes despite standard-of-care systemic therapy. Stereotactic ablative radiation therapy (SABR) may improve tumor control. We report the outcomes with the use of SABR in our pediatric solid tumor population. This was a single-institutional study in patients < 30 years treated with SABR. The primary endpoint was local control (LC), while the secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. The survival analysis was performed using Kaplan-Meier estimates in R v4.2.3. In total, 48 patients receiving 135 SABR courses were included. The median age was 15.6 years (interquartile range, IQR 14-23 y) and the median follow-up was 18.1 months (IQR: 7.7-29.1). The median SABR dose was 30 Gy (IQR 25-35 Gy). The most common primary histologies were Ewing sarcoma (25%), rhabdomyosarcoma (17%), osteosarcoma (13%), and central nervous system (CNS) gliomas (13%). Furthermore, 57% of patients had oligometastatic disease (≤5 lesions) at the time of SABR. The one-year LC, PFS, and OS rates were 94%, 22%, and 70%, respectively. No grade 4 or higher toxicities were observed, while the rates of any grade 1, 2, and 3 toxicities were 11.8%, 3.7%, and 4.4%, respectively. Patients with oligometastatic disease, lung, or brain metastases and those who underwent surgery for a metastatic site had a significantly longer PFS. LC at 1-year was significantly higher for patients with a sarcoma histology (95.7% vs. 86.5%, p = 0.01) and for those who received a biological equivalent dose (BED10) > 48 Gy (100% vs. 91.2%, p = 0.001). SABR is well tolerated in pediatric patients with 1-year local failure and OS rates of <10% and 70%, respectively. Future studies evaluating SABR in combination with systemic therapy are needed to address progression outside of the irradiated field.

Ganglioside SSEA-4 in Ewing sarcoma marks a tumor cell population with aggressive features and is a potential cell-surface immune target

Carbohydrate markers of immature cells during prenatal human development can be aberrantly expressed in cancers and deserve evaluation as immune targets. A candidate target in Ewing sarcoma is the globo-series ganglioside stage-specific embryonic antigen-4 (SSEA-4). We detected SSEA-4 expression on the cell surface of all of 14 EwS cell lines and in 21 of 31 (68%) primary EwS tumor biopsies. Among paired subpopulations of tumor cells with low versus high SSEA-4 expression, SSEA-4high expression was significantly and consistently associated with functional characteristics of tumor aggressiveness, including higher cell proliferation, colony formation, chemoresistance and propensity to migrate. SSEA-4low versus SSEA-4high expression was not related to expression levels of the EWSR1-FLI1 fusion transcript or markers of epithelial/mesenchymal plasticity. SSEA-4low cells selected from bulk populations regained higher SSEA-4 expression in vitro and during in vivo tumor growth in a murine xenograft model. T cells engineered to express SSEA-4-specific chimeric antigen receptors (CARs) specifically interacted with SSEA-4 positive EwS cells and exerted effective antigen-specific tumor cell lysis in vitro. In conclusion, with its stable expression and functional significance in EwS, SSEA-4 is an attractive therapeutic immune target in this cancer that deserves further evaluation for clinical translation.

Emerging therapies in Ewing sarcoma.

There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy and local therapy, but despite intensification of treatment, those with metastases at diagnosis and recurrent disease have poor outcomes. Improved understanding of Ewing sarcoma biology has identified novel targets with promising activity in Ewing sarcoma patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination and maintenance therapy. Other emerging therapies include those that target the EWSR1::FLI1 fusion oncoprotein, and act on DNA damage, cell cycle and apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell therapy directed at GD2, also hold promise. Recent collaborative clinical trials that have defined an international standard of care for patients with newly diagnosed Ewing sarcoma and novel platform studies with adaptive designs offer unique opportunities to investigate these therapies inclusive of all ages. Close international collaboration between clinicians and biologists will allow us to prioritize promising emerging therapies and develop biomarkers to facilitate their incorporation into standard of care and more rapidly translate into benefit for Ewing sarcoma patients.

Extraskeletal Ewing Sarcoma of the Gastrointestinal and Hepatobiliary Tract: Deceptive Immunophenotype Commonly Leads to Misdiagnosis.

Ewing sarcoma (ES) is an uncommon mesenchymal neoplasm that typically develops as a bone mass, although up to 30% arise in extraskeletal sites. ES of the gastrointestinal (GI) and hepatobiliary tract is rare and may be misdiagnosed as other, more common neoplasms that occur in these sites. However, the correct classification of extraskeletal ES is important for timely clinical management and prognostication. We reviewed our experience of ES in the GI and hepatobiliary tract in order to further highlight the clinicopathologic features of these neoplasms and document the potential for misdiagnosis in this setting. The archives and consultation files of 6 academic institutions were retrospectively queried for cases of ES occurring in the GI and hepatobiliary tract. The histologic slides and ancillary studies were reviewed and clinical data were retrieved for each case through the electronic medical records, when available. Twenty-three patients with ES in the GI and/or hepatobiliary tract were identified from 2000 to 2022. Of these, 11 were women and 12 were men with a median age of 38 years (range, 2 to 64). Tumor locations included the pancreas (n=5), liver (n=2), stomach (n=3), colorectum (n=3), and small intestine (n=5), as well as tumors involving multiple organs, pelvis and retroperitoneum (n=5). Tumor size varied between 2cm and 18cm. Twenty were primary and 3 were metastases. Of the 23 cases, only 17% were initially diagnosed as ES. The most common misdiagnoses involved various forms of neuroendocrine neoplasia due to expression of synaptophysin and other neuroendocrine markers (22%). A wide variety of diagnoses including GI stromal tumor was considered due to aberrant CD117 expression (4%). The diagnosis of ES was ultimately confirmed by detection of the EWSR1 rearrangement in 22 cases. The remaining case was diagnosed using traditional immunohistochemistry. Follow-up information was available in 20 cases, with follow-up time varying between 2 and 256 months. Six patients with follow-up died of disease between 6 and 60 months following initial presentation. Our data indicate ES in the GI and hepatobiliary tract is commonly misdiagnosed leading to a delay in therapy. In light of the attendant therapeutic and prognostic implications, ES should be considered in the differential diagnosis of any GI or hepatobiliary tumor with epithelioid and/or small round cell morphology.

Anticancer Drugs of Lysine Specific Histone Demethylase-1 (LSD1) Display Variable Inhibition on Nucleosome Substrates.

Lysine specific demethylase-1 (LSD1) serves as a regulator of transcription and represents a promising epigenetic target for anticancer treatment. LSD1 inhibitors are in clinical trials for the treatment of Ewing's sarcoma (EWS), acute myeloid leukemia, and small cell lung cancer, and the development of robust inhibitors requires accurate methods for probing demethylation, potency, and selectivity. Here, the inhibition kinetics on the H3K4me2 peptide and nucleosome substrates was examined, comparing the rates of demethylation in the presence of reversible [CC-90011 (PD) and SP-2577 (SD)] and irreversible [ORY-1001 (ID) and tranylcypromine (TCP)] inhibitors. Inhibitors were also subject to viability studies in three human cell lines and Western blot assays to monitor H3K4me2 nucleosome levels in EWS (TC-32) cells, enabling a correlation of drug potency, inhibition in vitro, and cell-based studies. For example, SP-2577, a drug in clinical trials for EWS, inhibits activity on small peptide substrates (Ki = 60 ± 20 nM) using an indirect coupled assay but does not inhibit demethylation on H3K4me2 peptides or nucleosomes using direct Western blot approaches. In addition, the drug has no effect on H3K4me2 levels in TC-32 cells. These data show that SP-2577 is not an LSD1 enzyme inhibitor, although the drug may function independent of demethylation due to its cytotoxic selectivity in TC-32 cells. Taken together, this work highlights the pitfalls of using coupled assays to ascribe a drug's mode of action, emphasizes the use of physiologically relevant substrates in epigenetic drug targeting strategies, and provides insight into the development of substrate-selective inhibitors of LSD1.

Synchronous Ewing sarcoma of the fibula with involvement of the orbit and abducens nerve palsy

Simultaneous or synchronous Ewing sarcoma (ES) is the occurrence of multifocal lesions without pulmonary involvement. This is a very rare condition. We present a case of multifocal synchronous ES of the fibula with orbital involvement and adducens nerve palsy. A 17-year-old boy presented with pain and swelling in both legs for 6 weeks. He was unable to walk due to pain. He was pale and cachexic. There was proptosis and ptosis in the right eye. His investigations were consistent with a multifocal malignant tumor. There were lesions in the left fibula, tibia, right tibia, and right orbit. The histopathological diagnosis was Ewing sarcoma (ES). This is the first report of synchronous ES involving the orbit and abducens nerve.

Outcomes of ilium and iliosacral Ewing's sarcoma resection reconstructed with tibial strut allograft.

Ilium is the most common site of pelvic Ewing's sarcoma (ES). Resection of the ilium and iliosacral joint causes pelvic disruption. However, the outcomes of resection and reconstruction are not well described. In this study, we report patients' outcomes after resection of the ilium and iliosacral ES and reconstruction with a tibial strut allograft. Medical files of 43 patients with ilium and iliosacral ES who underwent surgical resection and reconstruction with a tibial strut allograft between January 2010 and October 2021 were reviewed. The lesions were classified into four resection zones: I1, I2, I3, and I4, based on the extent of resection. Functional outcomes, oncological outcomes, and surgical complications for each resection zone were of interest. Functional outcomes were assessed using a Musculoskeletal Tumor Society (MSTS) score and Toronto Extremity Salvage Score (TESS). The mean age of the patients was 17 years (SD 9.1). At a mean follow-up of 70.8 months (SD 50), the mean functional outcomes were 24.2 points (SD 6.3) for MSTS and 81 points (SD 11) for TESS. The mean MSTS and TESS scores were associated with the iliac resection zone (< 0.001). Nine patients (20.9%) had local recurrence. The recurrence was not associated with the zone of iliac resection (p = 0.324). The two-year disease-free survival of the patients was 69.4%. The mean time to graft union was longer in patients with the I4 resection zone (p < 0.001). The complication rate was 34.9%, and nerve palsy (11.6%) was the most common. The rate of surgical complications was not associated with the resection zone. Reconstruction using tibial strut allograft is an efficient procedure after the resection of the ilium and iliosacral ES. Functional outcomes and complications of iliac ES depend on the resection zone, and inferior outcomes could be generally expected when more segments of the pelvic ring are resected, even if it is reconstructed.

Ewing's Sarcoma of the Scapula in an Infant: About a Case

Ewing sarcoma (ES)/primary neuroectodermal tumor (PNET) is the second most common malignant bone tumor of childhood and adolescence. It can occur at central or peripheral sites, at skeletal or extraskeletal sites, and is more common at the femurs, ilium, and tibia. We report a rare case of Ewing's sarcoma of the scapula in a 2-year-old infant diagnosed with pain and swelling of the left shoulder. Histopathological confirmation of Ewing's sarcoma was possible following ultrasound-guided biopsy. Treatment consisted of initial chemotherapy, followed by surgical tumor resection after good initial response, followed by adjuvant therapy. The current post-treatment follow-up is 2 years without incident. This case is reported to highlight the rarity of localization and therapeutic modalities, particularly surgical.