Unlocking epigenetics for precision treatment of Ewing’s sarcoma

Ewing’s sarcoma(EWS)is a highly aggressive malignant bone tumor primarily affecting adolescents and young adults.Despite the efficacy of chemoradiotherapy in some cases,the cure rate for patients with metastatic and recurrent disease remains low.Therefore,there is an urgent need for innovative therapeutic approaches to address the challenges associated with EWS treatment.Epigenetic regulation,a crucial factor in physiological processes,plays a significant role in controlling cell proliferation,maintaining gene integrity,and regulating transcription.Recent studies highlight the importance of abnormal epigenetic regulation in the initiation and progression of EWS.A comprehensive understanding of the intricate interactions between EWS and aberrant epigenetic regulation is essential for advancing clinical drug development.This review aims to provide a comprehensive overview of both epigenetic targets implicated in EWS,integrating various therapeutic modalities to offer innovative perspectives for the clinical diagnosis and treatment of EWS.

Primary Ewing sarcoma of the kidney mimicking cystic papillary renal cell carcinoma in an older patient:A case repor

BACKGROUND Ewing’s sarcoma(ES)is a neuroectodermal tumor that typically occurs in the bones and soft tissues of children and young adults.Primary renal ES is rare;only a few cases and a small case series have been documented,and only four cases involved primary renal ES in older people(>65 years old).CASE SUMMARY Herein,we describe the radiological and pathological features of primary renal ES in an older person.A 76-year-old man complained of poor oral intake and was found to have a large cystic renal mass with indistinct margins on computed tomography.Ultrasound-guided biopsy revealed that the tumor contained small round blue cells.The patient underwent a right radical nephrectomy.The tumor cells showed diffuse membranous CD99,and nuclear friend leukemia integration 1 transcription factor and NK2 Homeobox 2.Fluorescence in situ hybridization revealed EWSR1 translocation.Postoperatively,18F-fluorodeoxyglucose positron emission tomography revealed no evidence of metastasis.The patient was diagnosed with primary renal ES.Six months following the surgery,local recurrence and distant metastasis were observed.Primary renal ES is rare and often lethal in older individuals.The specific imaging findings are unknown,and treatment protocols have not been standardized.CONCLUSION This case report describes the radiological and pathological features of primary renal ES in an older person.

Bioinformatics Analysis of the Biological Properties of Ewing Sarcoma

Purpose: Bioinformatics-based approach to screen and analyze differentially expressed genes associated with the biological characteristics of Ewing sarcoma. Means: The GSE17674 dataset was selected for analysis, obtained by data retrieval based on the GEO public database. The R language limma toolkit was used to screen DEmRNAs. After the data were normalized, the Metascape online analysis software and the R language clusterProfiler package were used to analyze the GO function and KEGG pathway enrichment of DEmRNAs lines, respectively. The string database was selected for PPI analysis, and the results were imported into Cytoscape software to derive the core modules and predicted core genes. The genes selected above were analyzed for tissue localization specificity. Results: Through the analysis of GSE17674, differentially expressed genes were screened out, and GO and KEGG analyses were performed on the differentially expressed genes. The GO functional enrichment analysis was mainly enriched in the process of muscle system, muscle contraction, myocyte development, contractile fibers, myogenic fibers, myofibers, myofibrillar segments, actin binding, structural composition of muscle, and actin filament binding. KEGG pathway analysis showed that the core pathways associated with the development of ES were the core genes for myocardial contraction, congestive cardiomyopathy, and hypertrophic cardiomyopathy. Five Hub genes were obtained based on Cytoscape prediction. Tissue localization specificity analysis of Hub genes was performed, and a total of 2 Hub genes with tissue specificity were screened;MYH6 was specifically expressed in cardiac cells and MYL1 was specifically expressed in skeletal muscle cells. Conclusions: The differential genes screened will help to understand the molecular mechanisms underlying the highly invasive and metastasis-prone biological characteristics of ES, as well as provide new ideas for clinical drug-targeted treatment of ES.

Cushing's syndrome caused by giant Ewing's sarcoma of the kidney:A case report and review of literature

BACKGROUND Primary renal Ewing’s sarcoma(ES)is extremely rare,and only two cases causing Cushing’s syndrome(CS)have been reported to date.We report that the case of an 18-year-old patient is diagnosed primary renal ES with typical CS characterized by purple stripes,weight gain,and hypertension.CASE SUMMARY CS was first diagnosed by laboratory testing.A huge tumor was revealed in the kidney following an imaging examination.Moreover,brain and bone metastases were observed.After comprehensive treatment,primarily based on surgery,primary renal ES was pathologically diagnosed with a typical EWSR1-FLI1 genetic mutation through genetic testing.Furthermore,the glucocorticoid level returned to normal.By the ninth postoperative month of follow-up,the patient was recovering well.Cushing-related symptoms had improved,and a satisfactory curative effect was achieved.CONCLUSION Primary renal ES,a rare adult malignant tumor,can cause CS and a poor prognosis.

Metastatic peritoneal sarcomatosis from radiation-induced osteosarcoma in a patient with previously treated pelvic Ewing’s sarcoma: Report of a case

Metastatic peritoneal sarcomatosis most commonly occurs from primary soft tissue sarcomas arising either within the abdomen or extremities. Metastatic peritoneal sarcomatosis from an osteosarcoma is extremely rare;only six cases have previously been reported. We report the first case of metastatic peritoneal sarcomatosis originating from radiation-induced osteoblastic osteosarcoma in a 22-year-old woman who had previously been treated for pelvic Ewing’s sarcoma. Abdominal computed tomography, bone scintigraphy and FDG PET/CT demonstrated extensive finely nodular disseminated peritoneal lesions. Histopathologic examination of these peritoneal lesions revealed osteosarcomatosis. In summary, we describe an unusual case of metastatic peritoneal sar comatosis from secondary osteosarcoma arising in a previously irradiated pelvicEwing’s sarcoma.

Imaging-based diagnosis for extraskeletal Ewing sarcoma in pediatrics: A case report

BACKGROUND Extraskeletal Ewing sarcoma(EES)is a member of the Ewing sarcoma family of tumors which is pathologically known as a small,round,blue cell tumor involving bone and soft tissue.The prevalence of EES is only 15%-25%of all Ewing sarcoma and EES often occurs in patients aged from 20-mo-old to 30-yearsold resulting in an unfavorable prognosis.CASE SUMMARY The present case report described a 7-year-old patient with a palpable EES mass of 33 mm×27 mm×28 mm in the deep neck with symptoms of persistent dyspnea over the past 5 mo.After laboratory examinations,abnormal physiological and biochemical indicators were not found.Ultrasound images presented the mass to be complex,solid and fluid-filled with circumscribed margins and posterior acoustic enhancement.The mass also presented with partial internal vascularity.The contrast-enhanced magnetic resonance imaging scan illustrated the outstanding enhancement with fast perfusion mode in the early arterial phase. CONCLUSIONOur study suggested that a quick-growing mass in the pediatric patient is possibly a malignanttumor whether the mass has well-defined margins or not.

Primary extraskeletal Ewing’s sarcoma of the lumbar nerve root:A case report

BACKGROUND Ewing’s sarcoma(ES)is a highly aggressive bone malignancy.Extraskeletal ES(EES)originating in the spinal canal is extremely rare.Herein,we report on a rare case of EES with a primary lumbar spinal nerve root including the complete diagnosis and treatment.CASE SUMMARY A young female patient presented with a complaint of right lower limb pain for 1 mo.Magnetic resonance imaging(MRI)revealed an 11 mm×14 mm×31 mm mass in the lumbar epidural region extending at the fifth lumbar spine(L5)level toward the right L5 neural foramen.Our initial diagnosis was an epidural schwannoma.The patient underwent total laminectomy,tumor resection and pedicle screw internal fixation and the L5 root tumor was found to have been completely removed intraoperatively.Histopathological examination of the lesion showed a typical ES with a large number of small,round cells.Immunohistochemistry analysis indicated positive CD99 and S100.After surgery,the patient received chemotherapy and radiotherapy with a 1 year of follow-up and no recurrent tumors or new lesions were found upon spine MRI and positron emission tomography/computed tomography reexamination.CONCLUSION Clinically,ES outside the bone should be considered when nerve root tumors are encountered inside and outside the spinal canal and the diagnosis should be determined by pathological biopsy.After surgical resection,chemotherapy and radiotherapy should be performed.After treatment,active follow-up and regular review should be completed.

Osteosarcoma of the Humerus Developing as Second Malignancy in the Irradiation Field Outside the Primary Tumor: 11 Years after Ewing Sarcoma of the Scapula and 29 Years after Breast Cancer

Purpose: Development of sarcoma is a known late rare negative side effect of radiotherapy. We add two cases to emphasize the need for open-end follow-up and critical evaluation to avoid misinterpretation. Patients, Methods, and Results: Two patients developed osteosarcoma as a second malignancy in the humerus after adjuvant radiotherapy of a primary tumor not directly involving the later affected bone. The first patient had a Ewing sarcoma of the scapula at age 13 years. Though after neoadjuvant chemotherapy the resected specimen showed only fibrotic necrotic areas within clear resection margins, the study group indicated adjuvant radiotherapy in a field including the shoulder joint. At age 24 years she developed an osteosarcoma of the humeral head, which was resected and reconstructed with a proximal humerus endoprosthesis. She is alive without disease at age 32 years. The second patient presented with an osteosarcoma of the proximal humerus 29 years after irradiation for breast cancer including the shoulder joint. The sarcoma was misinterpreted as radiation-induced necrosis and the patient was treated with a reverse shoulder endoprosthesis. Pathologic examination of the resected humeral head then showed a typical osteosarcoma. Two years later the humeral reverse shoulder implant was resected and a proximal humerus tumor prosthesis implanted leaving the original glenosphere. Conclusions: In both cases radiation-induced osteosarcoma developed in bone not affected by the primary cancer. Protecting uninvolved structures must be warranted in the planning of radiotherapy. The long latency between the primary and second cancer mandates long-term—best indefinite—follow-up, as with appropriate treatment of a radiation-induced osteosarcoma good healing rates comparable to those of primary osteosarcoma can still be achieved.

Ureteral Ewing’s sarcoma in an elderly woman: A case report

BACKGROUND Ewing’s sarcoma(ES)is regarded as a skeletal tumor,with few instances of extraskeletal ES.A primary ES in the ureter is extremely rare.CASE SUMMARY We report the case of a 69-year-old woman who presented with intermittent flank pain and hematuria and was found to have a mass in the left ureter.Pathology of the excised mass indicated ES.The clinical treatment and pathologic characteristics in this case,and a review of the literature describing ES in the urinary system,are presented.CONCLUSION Due to the rarity and malignancy of ES in ureter,early diagnosis and prompt surgical treatment are critical.

Perigastric extraskeletal Ewing's sarcoma: A case report

Ewing's sarcoma (ES) is a neoplasm of undifferentiated small round cells, which occurs in the bones and deep soft tissues of children and adolescents. We present a rare case of a 44-year-old woman with gastric ES presenting with epigastric pain and weight loss. Ultrasound and computed tomography scans indicated a solid/cystic mass in the pancreatic tail. At laparotomy, the tumor was found attached to the posterior surface of the stomach, completely free from the pancreas, with no lymphadenopathy or local metastases. The polynodal, partly pseudocystic, dark-red soft tumor was excised. Histopathology revealed an anaplastic small-round-cell tumor with strong membranous CD99 immunoexpression. Additionally, there was patchy immunostaining for S-100 protein, vimentin, protein gene product (PGP) 9.5 and neuron-specifi c enolase, and weak focal CD117 cytoplasmic immunoreactivity. The patient had no adjuvant chemotherapy; her postoperative recovery was uneventful, and she remains symptom-free, and without any sign of recurrence at 20 mo. To the best of our knowledge, this is only the third ever case of gastric ES.

EWS Knockdown and Taxifolin Treatment Induced Differentiation and Removed DNA Methylation from p53 Promoter to Promote Expression of Puma and Noxa for Apoptosis in Ewing’s Sarcoma

Ewing’s sarcoma is a pediatric tumor that mainly occurs in soft tissues and bones. Malignant characteristics of Ewing’s sarcoma are correlated with expression of EWS oncogene. We achieved knockdown of EWS expression using a plasmid vector encoding EWS short hairpin RNA (shRNA) to increase anti-tumor mechanisms of taxifolin (TFL), a new flavonoid, in human Ewing’s sarcoma cells in culture and animal models. Immunofluorescence microscopy and flow cytometric analysis showed high expression of EWS in human Ewing’s sarcoma SK-N-MC and RD-ES cell lines. EWS shRNA plus TFL inhibited 80% cell viability and caused the highest decreases in EWS expression at mRNA and protein levels in both cell lines. Knockdown of EWS expression induced morphological features of differentiation. EWS shRNA plus TFL caused more alterations in molecular markers of differentiation than either agent alone. EWS shRNA plus TFL caused the highest decreases in cell migration with inhibition of survival, angiogenic and invasive factors. Knockdown of EWS expression was associated with removal of DNA methylation from p53 promoter, promoting expression of p53, Puma, and Noxa. EWS shRNA plus TFL induced the highest amounts of apoptosis with activation of extrinsic and intrinsic pathways in both cell lines in culture. EWS shRNA plus TFL also inhibited growth of Ewing’s sarcoma tumors in animal models due to inhibition of differentiation inhibitors and angiogenic and invasive factors and also induction of activation of caspase-3 for apoptosis. Collectively, knockdown of EWS expression increased various anti-tumor mechanisms of TFL in human Ewing’s sarcoma in cell culture and animal models.

Management of Ewing sarcoma family of tumors: Current scenario and unmet need

Ewing sarcoma family tumors(ESFT) are heter ogeneous,aggressive group of disease with peak incidence in adolescent and young adults. The outcome has been improved dramatically from 10% with surgery and radiotherapy alone to 65%-70% now, in localized disease, with the introduction of chemotherapy. Chemotherapy regimen evolved from single agent to multiagent with effort of many cooperative clinical trials over decades. The usual treatment protocol include introduction of multi-agent chemotherapy in neoadjuvant setting to eradicate systemic disease with timely incorporation of surgery and/or radiotherapy as local treatment modality and further adjuvant chemotherapy to prevent recurrence. Risk adapted chemotherapy in neoadjuvant and adjuvant setting along with radiotherapy has been used in many international collaborative trials and has resulted in improved outcome,more so in patients with localized disease. The role of high dose chemotherapy with stem cell rescue is still debatable. The outcome of patients with metastatic disease is dismal with long term outcome ranges from 20%-40% depending on the sites of metastasis and intensity of treatment. There is a huge unmet need to improve outcome further, more so in metastatic setting.Novel therapy targeting the molecular pathways and pathogenesis of ESFT is very much required. Here we have discussed the current standard of management in patients with ESFT, investigational targeted or novel therapies along with future promises.

Prostatic sarcoma of the Ewing family in a 33-year-old male e A case report and review of the literature

Ewing sarcoma is the second most common primary bone tumor seen in children and adolescents,typically presenting between 10 and 20 years of age.Extraosseous sarcomas of the Ewing family in adults are rare.We report a manifestation of this tumor entity in the periprostatic tissue of a 33-year-old male and discuss our treatment approach.Transrectal biopsy is a feasible and simple diagnostic tool for unclear pelvic masses.Multi-modal therapy and central registries are needed to gain knowledge of rare pelvic tumors like Ewing sarcoma.

A Case of Ewing’s Sarcoma of the Clavicle in Adults

The Clavicle is a rare primary site for Ewing sarcoma (ES). We report one case of patient with clavicular ES under our tracking and review the related literatures on management of this rare tumor. The patient was age of 35 years and were non metastaticat presentation. The patient received chemotherapy before and after the surgery. Claviculectomy was used. The patient had good functional outcomes with no pain of the shoulder at the follow-up of ten months. In conclusion, Ewing sarcoma of clavicle is a very rare tumor and different methods of surgical treatment can be used. Clavicle often can be resected without a need of reconstruction.

CT and multimodal imaging findings of primary orbital Ewing＇s sarcoma involving the middle cranial fossa： a case report

This report details the CT and MR imaging findings of a primary orbital Ewing＇s sarcoma case involving the middle cranial fossa in a 13-year old boy. CT showed an ill-circumscribed homogeneous soft-tissue density mass with needle-like bone reaction. On MRI, the mass showed homogeneous iso-intensity on T1WI, heterogeneous hyper- intensity on T2WI, and marked homogeneous enhancement. Meanwhile, the mass was hyper-intense on DWI, and ADC alue was 575x10-6 mm2/s. The mass showed as high rCBV and rCBF, prolonged MTT based on DCS- PWI, and wash-out pattern of TIC derived from the DCE-MRI. Our case suggests that functional MRI modalities, including DWI, DSC-PWI or DCE-MR, could provide additional information for differential diagnoses. Both CT and MRI should be performed and comprehensively analyzed for limiting differential diagnoses, determining lesion extension and facilitating operative approach.

Accelerated Hyper Fractionated Radiotherapy in Localized Ewing’s Sarcoma with or without Surgery: What’s New? A Phase II Study

Background and aim of work: We aimed from this study to determine the response and local relapse free survival (RFS) of pediatric patients with localized Ewing’s sarcoma treated with accelerated hyper-fractionated RT. Patient and methods: This study was a nonrandomized uncontrolled phase II study and was conducted at clinical oncology department and south Egypt cancer institute;it involved 28 patients with histologically confirmed Ewing’s sarcoma;all of them were subjected to PET/CT whenever possible or MRI with contrast of the primary site, MSCT chest, bone scan, and LDH to ensure absence of metastasis followed by the protocol of accelerated hyper fractionated RT. Results: The overall response rate (ORR) was 92.9% by MRI with significant effect of the type of response on local RFS (P 0.002). The median local RFS of 28 patients with localized Ewing’s sarcoma was 30 ± 8.599 months with 95% CI = 13.147 - 46.853;the 3-year local control was 35%. Conclusion: Accelerated hyper fractionated RT didn’t achieve better results than standard fractionation RT, but it is recommended to be done on a large sample size, and multiple centers, and continued follow up is also recommended to evaluate 5-year LRFS, 5-year OS.

Extraosseous Ewing's sarcoma arising from the pterygomandibular space

Extraosseous Ewing’s sarcoma (EES) arising in head and neck is extremely rare. We report on a rare case of EES originating from the pterygomandibular space. A 15-year-old boy was seen with a rapidly growing mass in the right upper neck, difficulty in opening mouth, dysphagia, numbness in the right lower lip and buccal skin. Clinical and radiological examinations indicated that a soft tissue mass origi-nated from the pterygomandibular space with the submandibular space and mouth floor extension. Histological and immunohistochemical evaluations of the biopsy specimen revealed poorly differentiated small blue round cells with positive stains for CD99 and neuron-specific enolase. According to the clinical manifestation, CT and MRI findings, histological pattern and the results of the immunohistochemical studies, the final diagnosis was EES. Our patient was treated with chemotherapy and radiotherapy. The lesion recurred locally after 10 months and he died of multiple distant metastases 22 months later. Early and confident diagnosis coupled with combined surgical excision and modern chemotherapy/radiotherapy appears to be the most effective treatment plan.

Long-Term Results of Ewing’s Sarcoma—In a Single Institution

Purpose: This study analyzed oncological and functional outcomes of treatment for Ewing’s sarcoma, as well as its significant risk factors through long-term follow up. Objective and Method: Between September 1990 and April 2009, 20 cases that were diagnosed and treated as Ewing’s sarcoma in Kosin University Gospel Hospital were entered onto the study. Mean follow-up period was 45.4 (12 - 108) months. There were 7 cases of male and 13 cases of female, and mean age was 19.9 (5 - 48) years old. Retrospective review was done about treatment outcomes, complications, and significant risk factors. Results: In terms of oncologic results, there were 9 cases of CDF (continuous disease free), 1 case of NED (no evidence of disease), 4 cases of AWD (alive with disease), 5 cases of DOD (dead of disease), and 1 case of DWOD (dead with other disease). Five-year overall survival rate of all the patients was 70.0% and event-free survival rate was 50.0%. The mean MSTS (Musculoskeletal Tumor Society) score was 15.9 (53%) points at last follow-up. Among prognostic factors of age at diagnosis, Enneking stage, size of tumor, site of primary lesion, and distant metastasis, 5-year survival rate of groups without metastasis were 90.9%, nevertheless 44.4% in other group with the metastasis showing statistical significance (p = 0.020). Postoperative complications were 3 cases of infection, each 2 cases of ankylosis and metal failure, and each 1 case of leg length discrepancy, periprosthetic fracture, and local recurrence. Conclusion: Five-year survival rate of this study was similar to that of multicenter studies in America and Europe. Among the prognostic factors, distant metastasis was proven to be most significant. Enneking stage, size of tumor and site of primary lesion are also important and could be statistically significant if with more cases.

Comparison between Different Modalities of Treatment of Ewing Sarcoma

Background: Ewing sarcoma is the most common primary malignant tumour in patients younger than 10 years of age. The incidence is less than 1 per 1 million per year. Usually it is located in the diaphysis of long bones. Prognosis of these tumours has improved dramatically since the introduction of multi-agent chemotherapy, from an erstwhile 10% survival rate to the current 70% for patients with non-metastatic Ewing sarcoma. Method: A retrospective review of patients with histologically confirmed Ewing sarcoma who were treated in the Department of Orthopaedics, B.S. Medical College during the time period from April 2000 to March 2012 was performed. Patients were divided into two groups: Group A included those treated by External Beam Radiotherapy (EBRT) + chemotherapy while Group B included the patients treated with surgery + chemotherapy. Results were analysed depending on the survival rates. Kaplan-Meier survival curves were compared using log-rank test and a multivariate Cox proportional hazards model was calculated. Result: The survival curves of both the groups were not found to be significantly different. Conclusion: Treatment of Ewing tumour has multiple options. No one treatment modality is superior. Survival rates of patients treated by radiation + chemotherapy are not significantly different from those treated with surgery + chemotherapy.

Prognosis and Outcome of Adult Patients with Ewing Sarcoma (Local Experience)

Objective: Aim of this work is to assess clinical features, outcome and prognosis of adult patients diagnosed with Ewing Sarcoma (ES). Patients, Methods and Results: The records of 53 adult patients treated with Euro-Ewing protocol at Kuwait cancer control center (KCCC) over a period of 5 years were reviewed. Mean age was 26.9 ± 1.25 years. Thirty percent of patients presented with metastatic disease, and 65% of tumors were centrally located and 50% were ≥ 8 cm. All patients received initially VIDE protocol. 13.5% achieved complete remission (CR), and 57.7% achieved partial response (PR). Approximately 1/3 of patients underwent surgery which was adequate in 76% of them, and all patients received local radiotherapy. Post local treatment 56% of patients received VAC and 44% received VAI protocol. Mean treatment duration was 11 months ± 0.54. Median follow-up duration was 38.39 (33.49 - 43.28) months At the end of follow up 20% of patients relapsed locally and 36% distally. Median PFS was 46.9 months (95% CI 41.42 - 52.39), Median OS was 55.43 ms (95% CI 30.71 - 75.74);survivals at 3 and 5 years were 88%, 46% respectively. Conclusion: In this series metastases at presentation and wide surgical margins were the most important prognostic factors. Multimodality therapy is necessary for this rare disease.