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.

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.

Primary extraosseous Ewing's sarcoma of the lung in a 36-year-old female patient:clinical,imaging,and pathologic findings

Primary extraosseous Ewing's sarcoma is a very rare clinical entity. In the report, we present the case of a 36year-old female patient who underwent resection of lung mass and was diagnosed as having Ewing's sarcoma by pathological examination. The clinical, imaging, and pathologic features of the case are described and discussed.

Extraskeletal Ewing sarcoma of the stomach:A rare case report

BACKGROUND Extraskeletal Ewing sarcoma(EES)is a rare and highly malignant small round cell tumor associated with a poor clinical outcome.Ewing sarcoma(ES)involving the stomach is an uncommon presentation and can be easily confused with other small round cell tumors.We herein present a rare case of ES involving the gastric area.CASE SUMMARY We report a case of gastric ES in a 19-year-old female patient who initially presented with a complaint of a tender epigastric mass for 5 d.Contrast-enhanced abdominal computed tomography revealed a soft-tissue-density mass with a diameter of 8.5 cm between the liver and stomach;the mass was connected to the gastric antrum.Then,the mass was surgically excised completely.Upon histopathological,immunophenotype and molecular analysis,the mass was identified to be a primary gastric ES.CONCLUSION EES is an aggressive tumor with poor prognosis.Therefore,early diagnosis and timely intervention are essential for a good prognosis.It is imperative for us to raise awareness about this rare tumor.Surgical resection is still the best treatment option.

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.

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.

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.

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.

Anesthesia and perioperative management for giant adrenal Ewing’s sarcoma with inferior vena cava and right atrium tumor thrombus:A case report

BACKGROUND Ewing’s sarcoma of the adrenal gland with inferior vena cava(IVC)and right atrium thrombus is extremely rare.Here,we report a case of giant adrenal Ewing’s sarcoma with IVC and right atrium tumor thrombus and summarize the anesthesia and perioperative management.CASE SUMMARY A young female was admitted to the Department of Urology with intermittent pain under the right costal arch for four months.Enhanced abdominal computed tomography revealed a large retroperitoneal mass(22 cm in diameter),which may have originated from the right adrenal gland and was closely related to the liver.Transthoracic echocardiography showed a strong echogenic filling measuring 70 mm extended from the IVC into the right atrium and ventricle.After preoperative preparation with cardiopulmonary bypass,sufficient blood products,transesophageal echocardiography and multiple monitoring,tumor and thrombus resection by IVC exploration and right atriotomy were successfully performed by a multidisciplinary team.Intraoperative hemodynamic stability was the major concern of anesthesiologists and the status of tumor thrombus and pulmonary embolism were monitored continuously.During transfer of the patient to the intensive care unit(ICU),cardiac arrest occurred without external stimulus.Cardiopulmonary resuscitation was performed immediately and cardiac function was restored after 1 min.In the ICU,extracorporeal membrane oxygenation(ECMO)and continuous renal replacement therapy(CRRT)were provided to maintain cardiac,liver and kidney function.Histopathologic examination confirmed the diagnosis of Ewing’s sarcoma.After postoperative treatments and rehabilitation,the patient was discharged from the urology ward.CONCLUSION An adrenal Ewing’s sarcoma with IVC and right atrium thrombus is extremely rare,and its anesthesia and perioperative management have not been reported.Thus,this report provides significant insights in the perioperative management of patients with adrenal Ewing’s sarcoma and IVC tumor thrombus.Intraoperative circulation fluctuations and sudden cardiovascular events are the major challenges during surgery.In addition,postoperative treatments including ECMO and CRRT provide essential support in critically ill patients.Moreover,this case report also highlights the importance of multidisciplinary cooperation during treatment of the disease.

Resection with limb salvage in an Asian male adolescent withEwing’s sarcoma: A case report

BACKGROUNDEwing’s sarcoma is a highly malignant primary bone tumor that commonly affectschildren. For young patients, multidisciplinary treatment and limb salvage arerecommended, and surgical plans considering the growth potential and boneactivity after tumor resection are essential.CASE SUMMARYAn 11-year-old Asian boy had a 1-mo history of a right-sided limping gait.Imaging revealed a proximal tumor with bone destruction and physealinvolvement over the right femoral neck. He was diagnosed with stage IV(T1N0M1aG3) Ewing’s sarcoma with bilateral lung metastases. Neoadjuvantchemotherapy decreased the tumor size and confined it to the metaphysealregion. The patient underwent four stages of surgery: wide tumor excision plusreconstruction with vascular fibular bone graft plus internal fixation;repeat openreduction and internal fixation;femoral lengthening with orthosis after physealmaturity;and orthosis removal and bone elongation (approximately 6 cm).Following surgery, he could walk without discomfort and had almost equal-sizedbilateral femoral heads, indicating physis preservation. The surgery wassuccessful, and normal femoral head growth was achieved after completeremission. The patient was able to resume normal activities with equal length ofthe bilateral lower limbs.CONCLUSIONTumor treatment and reconstruction following resection are important in skeletally immature patients with Ewing’s sarcoma to improve quality of life.

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.

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.

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.

Diagnostic Strategies and Treatment for Ewing’s Sarcoma

Ewing’s sarcoma is an enigmatic malignancy of progenitor cell origin, driven by transcription factor oncogenic fusions. About 85% of ESFT cases harbor the t(11;22) translocation and express the fusion protein EWS-FLI. Both bone marrow-derived human Mesenchymal stem cells and Neural crest stem cells are permissive for EWS-FLI1 expression that initiates transition to ESFT-like cellular phenotype. Diagnosis of Ewing’s tumor is based on pathologic and molecular findings. The hypoxia enhances the malignancy of ESFT invasive capacity. An ALDHhigh subpopulation of Ewing’s sarcoma cells, capable of self-renewal, tumor initiation and resistant to chemotherapy in vitro, are not resistant to YK-4-279. Intensive high-dose chemotherapy followed by stem-cell reconstitution was used for ESFT patients in second remission. Plerixafor in combination with G-CSF is an effective enhance stem cell mobilization regimen for stem cell collection with lowest success rate in patients with neuroblastoma. The ESFT-derived antigens EZH2(666) and CHM1(319) are suitable targets for protective allo-restricted human CD8(+) T-cell responses against non-immunogenic ESFT. Primitive neuroectodermal features and MSC origin are both compatible with G(D2) aberrant expression and explore G(D2) immune targeting in ESFT.

EWING’S SARCOMA CAN EXPRESS BONE MORPHOGENETIC PROTEIN

Paraffin sections from 6 cases of Ewing's sarcoma were immunostained by ABC method using BMP -McAb for investigating the existence of BMP in Ewing' s sarcoma. All cases were positive. The result was coincided with human tumor transplants in athymic nude mouse by Bauer. It is shown that Ewing' s sarcoma can express BMP. So we support the hypothesis that Ewing' s sarcoma originates from primitive multipotential cells and can pluripotentially differentiate.

A Case of Ewing’s Sarcoma Arising in the Cervical Spine with an Elevation of Serum ProGRP

We experienced a case of small, round-cell malignant neoplasm diagnosed by touch smear cytology and histopathology when an open biopsy was performed in a 50-year-old Japanese woman. She was suspected of having a cervical spine tumor after surgery for cervical spine foraminal stenosis. After consent, the cervical spine tumor histologically diagnosed by an open biopsy was confirmed to be Ewing sarcoma (EWS) by genetic testing. EWS belongs to a group of small, round-cell tumors that are morphologically similar and often difficult to differentiate. After the open biopsy, the present patient received radiotherapy, and her plasma level of Pro-Gastrin-Releasing-Peptide was decreased (217.2 pg/ml before surgery to 30.3 pg/ml;reference value: 0 - 80 pg/ml). We herein report the process for making the final diagnosis by focusing on the intraoperative cytology, histopathology, and immunohistochemical findings. Our diagnosis was validated by karyotyping and a fluorescence in-situ hybridization analysis.

Ewing′s瘤的X线、CT和MRI影像学表现及其意义

目的 探讨Ewing′s瘤的X线、CT及MRI影像表现及其意义。资料与方法 回顾性对比分析 2 1例经穿刺及手术病理证实Ewing′s瘤的X线、CT及MRI的影像学改变。结果 管状骨骨质破坏主要表现为筛孔样、虫蚀样溶骨性破坏 ,并出现层状、葱皮样骨膜新生骨 ,放射样针状骨 ,具有一定的特征性。 13例管状骨外骨及 1例骨外Ewing′s瘤骨质破坏表现多样 ,仍以溶骨为主 ,且 2 0例骨Ewing′s瘤均伴有周围软组织肿块。结论 Ewing′s瘤在不同部位有不同的影像学表现 ,具有相对的特征性表现 ;CT及MRI在确定Ewing′s瘤软组织肿块的大小、骨皮质的破坏、骨髓腔的完整性、骨膜反应及病理性骨折优于X线平片 。

18例骨外Ewing肉瘤的临床分析并文献复习

背景与目的:骨外Ewing肉瘤是指原发于骨组织外的尤文氏肉瘤,发病率低。本研究旨在通过对骨外Ewing肉瘤进行临床分析,探讨其临床特点、诊断和治疗方法。方法:回顾分析中山大学肿瘤防治中心1995年1月～2007年7月确诊并接受治疗的18例骨外Ewing肉瘤患者的临床资料,同时结合文献加以讨论。结果:18例患者中,男性13例,女性5例;年龄8个月～60岁,中位年龄17岁,其中12例患者(66.7%)年龄为5～25岁。肿瘤原发于下肢8例(44.4%),椎旁5例(27.8%),胸壁2例(11.1%)。临床症状表现为肿块16例(88.9%)。16例患者接受了综合治疗,2例接受了非综合治疗。1、3、5年生存率分别为82.4%、64.2%和32.1%。单因素分析显示有无远处转移及治疗模式与预后相关。结论:该肿瘤好发于青少年,主要表现为局部肿块,采取积极的综合治疗方案是主要治疗方法,预后与有无远处转移及治疗模式相关。

EWS易位分离探针荧光原位杂交和免疫组织化学抗体(FLI-1和CD99)在尤文肉瘤/原始神经外胚层肿瘤诊断中的价值

目的:评价EWS易位分离探针荧光原位杂交(fluorescence in situ hybridization,FISH)与免疫组化抗体CD99、FLI-1对尤文肉瘤/原始神经外胚层肿瘤(Ewing’s sarcoma/primitive neuroectodermal tumor,EWS/PNET)的诊断价值。方法:收集35例EWS/PNET和其他小圆细胞肿瘤24例,应用FISH检测EWS基因易位、免疫组化抗体CD99和FLI-1的表达,进行对比研究,评价各自及联合应用的诊断价值。结果:FISH检测在EWS/PNET的敏感性、特异性、阳性预期值和阴性预期值分别为93.8%(30/32)、81.8%(18/22)、88.2%(30/34)和90%(18/20);CD99分别为100%(35/35)、58.3%(14/24)、77.8%(35/45)和100%(14/14);FLI-1分别为71.4%(25/35)、62.5%(15/24)、73.5%(25/34)和60%(15/25)。不同指标两两联合应用敏感性、特异性和阳性预期值、阴性预期值为:CD99+FLI-1分别为71.4%(25/35)、75%(18/24)、80.6%(25/31)和64.3%(18/28);FLI-1+FISH分别为68.7%(22/32)、86.4%(19/22)、88%(22/25)和65.5%(19/29),CD99+FISH分别为93.8%(30/32)、95.5%(21/22)、96.8%(30/31)和91.3%(21/23)。结论:应用EWS基因易位分离探针FISH检测染色体易位,是辅助诊断EWS/PNET非常敏感和特异的分子指标,与CD99联合应用诊断价值最大。在缺乏FISH结果的情况下,FLI-1和CD99联合应用能够提高诊断的特异性。