Ewing Sarcoma Research Articles

The use of vascularized fibula flap with allograft in post-oncologic microsurgical bone reconstruction of lower limbs in pediatric patients.

Post-oncologic surgical reconstruction of lower limbs in pediatrics remains a challenging topic. Microsurgical techniques allow reconstructions of large bony defects. The use of vascularized fibular flap with allograft has proven to be an ideal biologic construct. We aim to assess the success rate of this operation, including flap survival, bony union, weight-bearing ambulation, and complications in a long-term follow-up in our case series compared to the literature. Our case-series includes 18 femoral resections (9 osteosarcomas, 8 Ewing sarcoma, and 1 desmoid tumor) and 15 tibial resections (10 osteosarcoma, 4 Ewing sarcoma, and 1 Malignant Fibrous Histiocytoma). We collected patients' demographics, type of tumor, type of resection, defect size, fibula-flap length, method of fixation, anastomosis site, follow-up data, complications, and their management. All survivals were examined by X-ray and CT-scan to evaluate the morphological changes of the vascularized fibula and follow-up. The functional evaluation was performed by the 30-point Musculoskeletal Tumor Society Rating Score (MSTS) for the lower limb (Enneking et al., Clinical Orthopaedics and Related Research 1993(286):241-246). The mean age of the femur resection patients' group was 11.2 years with a mean defect size of 14 cm and a mean length of the fibular flap of 18 cm; for the tibia the mean age was 12 years with a mean defect size of 14 cm and a mean length of the fibular flap of 16.6 cm. The overall survival of the reconstructions at 5 years follow-up was 17 out 18 cases for the femur and 13 out of 15 cases for the tibia. MSTS score was 28.2 for the femur and 23.7 for the tibia. The average time of union of the fibula was seen after 5 months, while allograft consolidation was observed around 19.7 months. The mean time of follow-up was 144.5 months for the femur and 139.2 months for the tibia. The complication rate observed was 7 out of 18 for the femur and 7 out of 15 for the tibia reconstructions. The viability of the fibula is a cornerstone in the success of reconstruction as well as the successful management of complications in intercalary defects after tumor resection in pediatrics to restore good functionality. Our results are in line with those reported in the literature in terms of overall complication rates. The high primary union of allograft, the high MSTS score obtained, and the low rate of severe complications reflect the mechanical role of this reconstructive technique over a long follow-up.

Sarcoma of the uterine cervix: experience of a single center

ObjectivesTo investigate the clinicopathological characteristics and prognosis of patients with primary sarcoma of the uterine cervix.MethodsWe identified all patients with primary cervical sarcomas treated at our institution from 2002 to 2020 and analyzed the clinicopathological characteristics and prognosis.Results34 patients were identified, 7 (20.6%) patients had leiomyosarcoma, 6 (17.6%) had carcinosarcoma, 5 (14.7%) had Ewing sarcoma, 4 (11.8%) had rhabdomyosarcoma, 4 (11.8%) had undifferentiated sarcoma, 2 (5.9%) had adenosarcoma, 2 (5.9%) had endometrial stromal sarcoma, 1 (2.9%) had dermatofibrosarcoma protuberans, 1 (2.9%) had alveolar soft tissue sarcoma and 2 (5.9%) had sarcoma not otherwise specified. The median age of the whole patients was 43.5 years (range, 13–63). The median age of patients with Ewing sarcoma or rhabdomyosarcoma was 22 years (range, 13–39) and 17 years (range, 13–36 years), respectively. The distribution by stage was: stage I in 21 (61.8%) patients, stage II in 4 (11.8%), stage III in 6 (17.6%) and stage IV in 3 (8.8%). Overall, 30 patients (88.2%) received surgical treatment. The median follow-up was 33.3 months (range 3.6–187.3 months). 11 patients died within 2 years after diagnosis, most of them were patients with carcinosarcoma or undifferentiated sarcoma (45.5%, 5/11). In the entire cohort, 2- and 5-year OS were 67.2% and 56.9%, respectively. 5-year OS was 25.0% for undifferentiated sarcoma, 50.0% for rhabdomyosarcoma, 50.0% for carcinosarcoma, 53.3% for Ewing sarcoma, 57.1% for leiomyosarcoma.ConclusionCervical sarcomas are rare neoplasms with multiple histological subtypes and follow an aggressive course. Prognosis may be associated with tumor histology and stage.

A Systematic Review of the Gonadotoxicity of Osteosarcoma and Ewing's Sarcoma Chemotherapies in Postpubertal Females and Males.

Data on gonadotoxicity of chemotherapies are essential to better counsel young females and males about the risk of infertility and to better indicate fertility preservation measures before cancer therapies. However, such data have not recently been reviewed for bone cancer. Therefore, a systematic literature search was conducted considering papers published since 2000. This study is part of the FertiTOX® project, which aims to improve the lack of data regarding gonadotoxicity of cancer therapies to enable more accurate counseling regarding fertility preservation. Only relapse-free women and men were included. Gonadotoxic therapy-induced suspected infertility was defined as very low anti-mullerian hormone, high gonadotropin concentration, amenorrhea, oligomenorrhea, azoospermia, or oligozoospermia. The quality of the individual studies was assessed using the Newcastle-Ottawa Scale (NOS). In total, 11 out of 831 studies were included in the review. Suspected infertility was found in 10/190 (5.1%, range 0%-66%) of female patients with osteosarcoma (six studies), in 24/46 (52.2%, range 46%-100%) of male patients with osteosarcoma (three studies), in 18/138 (13.0%, range 3%-18%) of female patients with Ewing's sarcoma (three studies), and in 34/38 (89.5%) of male patients with Ewing's sarcoma (one study). A risk calculation in relation to specific chemotherapies was not possible. Risk of suspected infertility tends to be higher in Ewing's sarcoma in which all patients received chemotherapies with alkylating agents. Two of the 11 included studies received a high NOS quality score, whereas the remaining nine studies received a low quality score, mainly because of the lack of a comparator group. Published data are too limited for precise estimation of the gonadotoxicity. However, data indicate clinically relevant risk for infertility, supporting counseling patients before chemotherapy about fertility preservation measures.

Advancing Pediatric Sarcomas through Radiomics: A Systematic Review and Prospective Assessment Using Radiomics Quality Score (RQS) and Methodological Radiomics Score (METRICS).

Pediatric sarcomas, rare malignancies of mesenchymal origin, pose diagnostic and therapeutic challenges. In this review, we explore the role of radiomics in reshaping our understanding of pediatric sarcomas, emphasizing methodological considerations and applications such as diagnostics and predictive modeling. A systematic review conducted up to November 2023 identified 72 papers on radiomics analysis in pediatric sarcoma from PubMed/MEDLINE, Web of Knowledge, and Scopus. Following inclusion and exclusion criteria, 10 reports were included in this review. The studies, predominantly retrospective, focus on Ewing sarcoma and osteosarcoma, utilizing diverse imaging modalities, including CT, MRI, PET/CT, and PET/MRI. Manual segmentation is common, with a median of 35 features extracted. Radiomics Quality Score (RQS) and Methodological Radiomics Score (METRICS) assessments reveal a consistent emphasis on non-radiomic features, validation criteria, and improved methodological rigor in recent publications. Diagnostic applications dominate, with innovative studies exploring prognostic and treatment response aspects. Challenges include feature heterogeneity and sample size variations. The evolving landscape underscores the need for standardized methodologies. Despite challenges, the diagnostic and predictive potential of radiomics in pediatric oncology is evident, paving the way for precision medicine advancements.

An unusual cystic presentation of pelvic skeletal Ewing sarcoma: a case series.

Ewing sarcoma (ES) is the second mostcommon primarymalignant bone tumour in children and adolescents. About 14.5% of primary malignancies develop in pelvic bones, wherethey typically have worse prognoses than extremity or acral sarcomas. It usually presents with aggressive features onradiology scans, but may also present with different radiological characteristics. In this series, we describe rare appearancesof pelvic skeletal Ewing sarcoma, with large extraosseous cystic component on imaging, defined by the presence of fluid-filledspaces in the extraosseous tumour lesion, which distinguishes it from the solid nature of conventional ES. We report3 cases of cystic presentation of ES, with imaging features supporting diagnosis of a primary malignant bone tumourarising from the superior pubic ramus with associated massive intrapelvic solid and cystic mass. CT-guided biopsy provideddiagnosis of ES, with large intrapelvic soft tissue and cystic component. These patients underwent neo-adjuvantchemotherapy and proton beam therapy with significant reduction in size of the solid components, while the cysticcomponents remained relatively unchanged. Two patients underwent surgical resection of the tumour (navigated P3internal hemipelvectomy and hemipelvis P2/P3 resection, respectively), and one patient died while on treatment. In both whounderwent surgery, histology showed ES with margins clear and more than 99% of treatment-induced necrosis. To theauthors' knowledge, this unusual presentation of pelvic ES is described for the first time in the literature as a case series,with particular reference to atypical extraosseous cystic changes, along with the clinical and radiological characteristics,and their treatment.

Primary intradural Extraosseous Ewing’s sarcoma of the cauda equina: A case report and literature review

Intradural Extraosseous Ewing sarcoma (IEES) is an infrequent occurrence. We report a case of a 66-year-old male who presented with a 2-month history of low back pain and bilateral S1 sciatica, with acute sphincter dysfunction. Imaging studies revealed an intradural extramedullary lesion in the cauda equina spanning from level L4 to S1. The patient underwent partial removal of the intradural lesion. Histopathological examination showed the presence of small round cells, which were consistent with Ewing Sarcoma. The patient was then treated with targeted radiation therapy and chemotherapy.The rarity of IEES in this specific location underscores the significance of evaluating and managing patients with intradural spinal tumors with careful consideration of this diagnosis. To further investigate this condition, we conducted a thorough review of the literature on IEES involving the lumbar spine and cauda equina. Our analysis revealed that patients with this condition frequently exhibit rapidly progressive neurological symptoms likely attributed to hemorrhagic transformation. This characteristic may serve as a distinguishing factor from other lesion types, particularly benign ones. Our study provides a comprehensive summary that can offer direction for clinical management in comparable uncommon and novel cases.

Hyalinizing clear cell carcinoma of the left main bronchus diagnosed with Ewing sarcoma breakpoint region 1::activating transcription factor 1 fusion: A case report

Rationale: Hyalinizing clear cell carcinoma (HCCC) of the bronchus is extremely rare. In addition, its rarity makes an accurate histological diagnosis difficult. Herein, we report a case of HCCC in the left main bronchus diagnosed by the detection of Ewing sarcoma breakpoint region 1::activating transcription factor 1 (EWSR1::ATF1) fusion transcript using reverse transcription-polymerase chain reaction (RT-PCR). Patient concerns: A 56-year-old woman presented with a tumor obstructing the left main bronchus on physical examination computed tomography. A bronchoscopic biopsy confirmed a malignant tumor but did not provide a definitive diagnosis. Interventions: Sleeve resection of the left main bronchus was performed. The intraoperative frozen section was negative for cancer in both the proximal and distal bronchial stumps. Diagnosis: General immunohistochemical staining was performed, and mucoepidermoid carcinoma and HCCC were suspected. RT-PCR revealed positive results for EWSR1::ATF1 fusion transcript, and the tumor was finally diagnosed as HCCC. Outcomes: The patient was discharged without any postoperative complications. Sixty-five months have passed since surgery, and no cancer recurrence has been observed. Lessons: Although hematoxylin and eosin staining and immunostaining alone were not sufficient to distinguish HCCC from mucoepidermoid carcinoma and other malignant tumors, adding genetic testing for EWSR1 rearrangement led to a definitive pathological diagnosis.

Analysis of 41 cases of non-metastatic Ewing's sarcoma in children

To summarize the clinical characteristics, treatment outcomes, and prognostic factors of children with non-metastatic Ewing's sarcoma (ES). A retrospective analysis was conducted on the clinical data of 41 children with non-metastatic ES diagnosed and treated at the Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine from January 2010 to December 2018. All patients underwent chemotherapy based on the RMS-2009 protocol of the center, and local treatment such as surgery and/or radiotherapy was performed according to risk grouping. The Kaplan-Meier method was used to calculate the overall survival (OS) and event-free survival (EFS) rates. Univariate prognostic analysis was performed using the log-rank test, and multivariate analysis was conducted with Cox regression. Of the 41 children, 21 were male and 20 were female. The median age at diagnosis was 7.7 years (range: 1.2-14.6 years). The median follow-up time for patients with event-free survival was 68.1 months (range: 8.1-151.7 months). As of the last follow-up, 33 patients were in complete remission, and the overall 5-year EFS and OS rates were (78±6)% and (82±6)%, respectively. Univariate analysis by the log-rank test showed that a tumor diameter ≥8 cm, time from diagnosis to start of local treatment ≥16 weeks, and incomplete surgical resection were associated with poor prognosis (P<0.05). Multivariate Cox regression analysis indicated that incomplete surgical resection (HR=8.381, 95%CI: 1.681-41.801, P=0.010) was an independent risk factor for poor prognosis in children with ES. Secondary tumors occurred in 2 cases. A comprehensive treatment strategy incorporating chemotherapy, surgery, and radiotherapy can improve the prognosis of children with ES. Poor prognosis is associated with an initial tumor diameter ≥8 cm, while complete surgical resection and early initiation of local treatment can improve outcomes.

Primary intracranial peripheral primitive neuroectodermal tumor: lessons from an exceptionally rare neoplasm. Illustrative case.

The primary intracranial peripheral primitive neuroectodermal tumor (pPNET) is a lesion subtype within the Ewing sarcoma family of tumors. pPNETs are extremely uncommon pathologies, accounting for 0.03% of intracranial tumors and 1% to 2% of Ewing sarcoma cases. Given its histological aspect similar to other highly proliferative malignant neuroectodermal neoplasms, pPNET merits extensive workup for accurate diagnosis and treatment. A 36-year-old male presented to the emergency department with a 1-year history of headaches in the right frontoparietal area, generalized tonic-clonic seizures, and a history of the resection of a tumor labeled as a meningioma 5 years before admission. He was neurologically intact. Brain magnetic resonance imaging revealed a heterogeneous focal lesion of 25 × 35 × 23 mm with a necrotic center and neoformative appearance in the right frontal cortex. The patient underwent multimodal treatment with gross-total resection, radiotherapy, and chemotherapy. Histopathological examination results supported the diagnosis of pPNET. At the 2-year follow-up, the patient had no new-onset symptoms, and brain imaging revealed absent signs of tumor recurrence. The present case describes an extraordinary pPNET case, initially confounded as a clear cell meningioma. Managing pPNET requires thorough investigation, careful differentiation from similar neuroectodermal lesions, and multimodal treatment to improve the patient's prognosis.

Cell Context Is the Third Axis of Synergy for the Combination of ATR Inhibition and Cisplatin in Ewing Sarcoma.

The importance of cellular context to the synergy of DNA damage response (DDR)-targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR-targeted combination therapy for Ewing sarcoma. We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for Ewing sarcoma selectivity, and optimized for in vivo schedule. Berzosertib combined with cisplatin demonstrates profound synergy in multiple Ewing sarcoma cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell-cycle check-points, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of CHEK1 expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of Ewing sarcoma models, leading to durable complete responses in 50% of animals bearing two different Ewing sarcoma xenografts. These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule. See related commentary by Ohmura and Grünewald, p. 3358.

Surgical Outcomes and Complications of Custom-Made Prostheses in Upper Limb Oncological Reconstruction: A Systematic Review.

Bone tumors of the upper limb are a common cause of bone pain and pathological fractures in both old and young populations. Surgical reconstruction and limb salvage have become valid options for these patients despite this kind of surgery being challenging due to the need for wide bone resection and the involvement of surrounding soft tissues. Computer-assisted technology helps the surgeon in pre-operative planning and in designing customized implants. The aim of this study was to investigate the surgical outcomes and complications of custom-made prostheses in oncologic reconstruction of the upper limb and if they are reliable options for patients suffering from aggressive tumors. An electronic search on PubMed, Google Scholar, and Web of Knowledge was conducted to identify all available articles on the use of custom-made prostheses in oncological resections of the upper limb. Twenty-one studies were included in the review, comprising a total of 145 patients with a mean age of 33.68 years. The bone involved was the humerus in 93 patients, and the radius was involved in 36 patients. There were only six cases involving proximal ulna, three cases involving the scapula, and seven cases involving the elbow as well as soft tissues around it. The most frequent primary tumor was the giant cell tumor, with 36 cases, followed by osteosarcoma with 25 cases, Ewing Sarcoma with 17 cases, and Chondrosarcoma with 7 total cases. Forty patients were affected by bone metastases (such as renal cell cancer, breast cancer, melanoma, and rectal cancer) or hematologic diseases involving bone (lymphoma, myeloma, or non-Hodgkin disease). Custom-made prostheses are a viable option for patients who suffer from malignant tumors in their upper limbs. They are a reliable aid for surgeons in cases of extensive resections.

ETS1, a Target Gene of the EWSR1::FLI1 Fusion Oncoprotein, Regulates the Expression of the Focal Adhesion Protein TENSIN3.

The mechanistic basis for the metastasis of Ewing sarcomas remains poorly understood, as these tumors harbor few mutations beyond the chromosomal translocation that initiates the disease. Instead, the epigenome of Ewing sarcoma cells reflects the regulatory state of genes associated with the DNA-binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the EWSR1::FLI1/ERG's repression of transcription factor genes, concentrating on those that exhibit a broader range of expression in tumors than in Ewing sarcoma cell lines. Focusing on one of these target genes, ETS1, we detected EWSR1::FLI1 binding and an H3K27me3-repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1's binding of promoter regions, substantially altering the transcriptome of Ewing sarcoma cells, including the upregulation of the gene encoding TENSIN3 (TNS3), a focal adhesion protein. Ewing sarcoma cell lines expressing ETS1 (CRISPRa) exhibited increased TNS3 expression and enhanced movement compared with control cells. Visualization of control Ewing sarcoma cells showed a distributed vinculin signal and a network-like organization of F-actin; in contrast, ETS1-activated Ewing sarcoma cells showed an accumulation of vinculin and F-actin toward the plasma membrane. Interestingly, the phenotype of ETS1-activated Ewing sarcoma cell lines depleted of TNS3 resembled the phenotype of the control cells. Critically, these findings have clinical relevance as TNS3 expression in Ewing sarcoma tumors positively correlates with that of ETS1. Implications: ETS1's transcriptional regulation of the gene encoding the focal adhesion protein TENSIN3 in Ewing sarcoma cells promotes cell movement, a critical step in the evolution of metastasis.

Infiltration of Round Blue Cell Tumors in Bone Marrow

Objective: To identify different types of round blue cell tumors on bone marrow biopsy and their pattern of marrow infiltration. Methodology: This cross-sectional descriptive study was conducted at the Department of Hematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, from July 2021 to December 2021. A total of 60 diagnosed cases of round blue cell tumors were included. Patients with acute lymphoblastic leukemia (ALL) and those receiving treatment for round blue cell tumors were excluded. Bone marrow aspiration and biopsy were performed. Peripheral film results, clinical observations, and patterns of marrow infiltration of round blue cell malignancies were analyzed using Statistical Package for the Social Sciences (SPSS) version 23. Results: The study revealed a male to female ratio of 2:1, with 40 (66.6%) males and 20 (33.3%) females. The overall average age was 5.69 ± 5.0 years. Ewing sarcoma and rhabdomyosarcoma patients did not exhibit infiltration, while three instances of retinoblastoma (9.37%) and two cases of neuroblastoma (10.52%) did. Immunohistochemistry (IHC) results for synaptophysin and chromogranin were positive for retinoblastoma and neuroblastoma, while S100 results were positive for neuroblastoma infiltration and negative for retinoblastoma. Both retinoblastoma and neuroblastoma showed diffuse, focal, and interstitial patterns of infiltration on trephine biopsy. Conclusion: Small round blue cell tumors were noted in bone marrow infiltration in 5 (8.33%) cases. Early detection of malignant cancers necessitates appropriate medical care, and in more severe cases, the need for neoadjuvant chemotherapy.

Comparing the Efficacy of Palonosetron versus Ondansetron in the Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients; A Randomized Controlled Trial

Objectives: To compare the efficacy of Palonosetron and Ondansetron as premedication in the prevention of early and delayed chemotherapy-induced nausea and vomiting (CINV) in pediatric patients with cancer receiving moderately or highly emetogenic chemotherapy. Methodology: This randomized controlled trial study was conducted at the Oncology Department of Children’s Hospital, PIMS Islamabad, on patients aged 6 months to 12 years undergoing chemotherapy. Patients were divided in 2 groups by stratified random sampling and random allocation. Patients in Group 1 received a single intravenous dose of 20 microgram/kg Palonosetron and dexamethasone before chemotherapy, while Group 2 received intravenous Ondansetron 8 hourly along with dexamethasone. Nausea and vomiting severity were assessed from 0–120-hour interval using the CTCAE V 5.0 grading system. Data analysis was performed using SPSS version 23, employing chi-square and Fisher exact tests to compare outcomes between the two groups. Result: 218 pediatric oncology patients were included who received moderate or high intensity chemotherapy with the mean age of 5.25 ± 2.96 years. The majority of the participants were male (58.7%). The most common diagnosis was Wilms tumor (37.6%), followed by acute lymphoblastic leukemia (21.1%) and Ewing sarcoma (9.6%). Complete response to antiemetics was significantly more in Group 1 as compared to group 2, on day 1 and 2 with p value of 0.004 and 0.001 respectively. Grade of vomiting was significantly less on day in Group 1 study participants. Conclusion: Pediatric oncology patient receiving moderately or highly emetogenic chemotherapy showed effective response to palonosetron as compared to ondansetron in prevention and control of early and delayed chemotherapy induced nausea and vomiting.

Ewing sarcoma of the mandible: A rare case report and literature review.

Ewing sarcoma (ES) usually arises from long bones and affects the head and neck region in only 1%-4% of cases. We reported clinical, radiographic, cytomorphologic, and histomorphologic findings of the ES in the mandible, because of its rarity and radiologically misinterpreted as a parotid gland tumor. A 26-year-old male patient presented with a history of painfull cheek swelling. On magnetic resonance imaging, a mass measuring 50 × 48 × 45 mm was found eroding mandible and pushing back the parotid gland. Aspiration cytology was performed with suspicion of parotid gland tumor. Small, nucleated cells with nuclear indentation, inconspicuous nucleoli, and occasionally rosette-like arrangement were observed. Neuroendocrine immune markers were positive on cell block. It was diagnosed as small round cell neoplasm with neuroendocrine differentiation and biopsy was suggested. The differential diagnosis considered soft tissue and parotid gland tumors. The small round cell tumor morphology was seen on biopsy specimen and immunostaining was applied. The diagnosis for this case was ES of the mandible. ES of the mandible is unusual. Although the histogenesis is still unknown, various cells have been proposed as cells of origin namely, endothelial, hematopoietic, fibroblastic, mesenchymal stem cells or neural derived mesenchymal stem cells. Small cell morphology, CD99, CD56, neuron specific enolase, and synaptophysin expressions confirmed the diagnosis of ES. The differentiation of the ES from other small cell tumors may be difficult and requires awareness for histological and immunohistochemical features. It should be kept in mind that the diagnosis can be challenging due to uncommon locations and radiological misinterpreted.

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

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

HSR24-151: Oncological Outcome of Multimodality Treatment in Ewing Sarcoma.

HSR24-151: Oncological Outcome of Multimodality Treatment in Ewing Sarcoma.

Abstract CT058: A multicenter phase 1-2a clinical study of Orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors

Abstract Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. An off-label regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5-10 days, bi-weekly in combination with other agents such as temozolomide has been recommended for use in treating children with solid tumors (Blaney. ClinCanRes, 2001; Slotkin. PedBloodCan, 2023). While this regimen has shown promise in published clinical trials across a range of pediatric cancers including Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, hepatoblastoma and medulloblastoma, the protracted administration schedule of IRN-IV is costly and inconvenient thereby negatively impacting patients’ quality of life. Oral regimens utilizing IRN-IV have been developed and implemented with favorable tumor responses (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the IRN-IV is poor, leading to reduced compliance. Development of an advanced oral formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve the palatability of oral irinotecan. This Phase 1-2a multi-center clinical trial seeks to examine the safety and tolerability of this novel formulation and assess pharmacokinetics compared to the already established oral regimen. This trial is ongoing (CT.gov: NCT04337177) and currently enrolling the 110mg/m2/day cohort, with no dose limiting toxicity observed to date. Initial pharmacokinetic observations demonstrate similarity for the VAL-413 formulation and i.v. irinotecan given orally for both the parent compound and SN38 active metabolite. TABLE 1. NAND Methods Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day are being studied in combination with fixed-dose temozolomide (100mg/m2/day) using a standard 3 + 3 phase I design. In the event a dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A taste survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites is assessed. Citation Format: James Geller, Patrick Thompson, Javier Oesterheld, Aerang Kim, Meghann McManus, Jeffrey Bacha, Dennis M. Brown, Markos Leggas, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars M. Wagner. A multicenter phase 1-2a clinical study of Orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT058.

A Single-center Experience of Radiotherapy in Pediatric Ewing Sarcoma/Primitive Neuroectodermal Tumor of the Chest Wall.

To evaluate the treatment results, prognostic parameters, and treatment-related toxicity in patients with Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET) of the chest wall who underwent surgery, chemotherapy, and radiotherapy (RT) in a tertiary referral center. The data of 24 patients under 18 years of age with a histologic diagnosis of ES/PNET in the chest wall that received RT in our department between February 2003 and July 2020 were retrospectively evaluated. RT was applied to the primary site±whole involved chest wall and to the whole lung in patients with lung metastasis. The median age was 8.5 years (range: 1.5 to 17y), 15 (63%) patients were female and 9 were male (37%). The tumor localization was extrathoracic in 18 (75%) and intrathoracic in 6 (25%) patients. Mediastinal lymph node and distant metastasis (DM) was present in 5 (21%) and 4 (16%) cases at diagnosis, respectively. The median follow-up after RT was 47 months (range: 11 to 162mo). The 2-year and 5-year overall survival, event-free survival, local recurrence-free survival, and pleural recurrence-free survival were 83% and 48%, 48% and 42%, 74% and 48%, and 61% and 52%, respectively. The overall local control rate was 83% and the pleural control rate was 67%. RT was well tolerated, with 1 case of grade 3 acute dermatitis and 1 case of grade 3 subacute radiation pneumonitis. Late toxicity was observed in 3 (13%) cases. Long-term survival can be achieved with extended-field RT even in patients with ES/PNET of the chest wall with DM. The low toxicity rates allow us to draw the conclusion that RT with modern techniques is an effective and safe treatment modality for these patients.

Wernicke Encephalopathy in a Child Treated for Ewing Sarcoma.

Wernicke Encephalopathy in a Child Treated for Ewing Sarcoma.