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.

Angiogenesis,Kaposi’s Sarcoma and Kaposi’s Sarcoma-associated Herpesvirus

Tumor angiogenesis is the uncontrolled growth of blood vessels in tumors,serving to supply nutrients and oxygen,and remove metabolic wastes. Kaposi’s sarcoma (KS),a multifocal angioproliferative disorder characterized by spindle cell proliferation,neo-angiogenesis,inflammation,and edema,is associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV). Recent studies indicate that KSHV infection directly promotes angiogenesis and inflammation through an autocrine and paracrine mechanism by inducing pro-angiogenic and pro-inflammatory cytokines. Many of these cytokines are also expressed in KS lesions,implicating a direct role of KSHV in the pathogenesis of this malignancy. Several KSHV genes are involved in KSHV-induced angiogenesis. These studies have provided insights into the pathogenesis of KS,and identified potential therapeutic targets for this malignancy.

Genotypic analysis on the ORF-K1 gene of human herpesvirus 8 from patients with Kaposi's sarcoma in Xinjiang,China

Human herpesvirus 8 （HHV-8） is thought to be essential for the development of all forms of Kaposi＇s sarcoma （KS）. HHV-8 DNA is present virtually in all KS tumor biopsy samples. Genes at both ends of the HHV-8 genome have been shown to vary considerably. Seven major molecular subtypes of HHV-8 were defined based on the amino acid sequence of the open reading frame K1 （ORF-K1）, generally known as A, B, C, D, E, F, and Z. Most strains collected worldwide were clustered into two subtypes （A and C）. Here, the K1/VRI region of HHV-8 was amplified by nested PCR in 22 （81.48%） of 27 cases from Xinjiang Uygur Autonomous Region, a province in northwestern China. Phylogenetic analysis on the basis of the K1/VR1 amino acid sequence indicated that the majority of these KS patients were infected by subtype C HHV-8 （n = 18, including 15 belonging to the C2 group）, and several by subtype A （n = 4, including 3 being the A1 group）. This is the first report of subtype A HHV-8 in China. Furthermore, the correlations between different forms and lesions of KS and different subtypes of HHV-8 were analyzed. The findings showed that subtype A HHV-8 resulted in significantly more frequent mucosal KS lesions than subtype C. However, there was no obvious correlation between different forms of KS and different subtypes of HHV-8.

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.

The effect of ABV regimen on CD4 lymphocyte count in patients with advanced HIV related Kaposi’s sarcoma

Objective: The combination of highly active antiretroviral therapy (HAART) and chemotherapy with ABV regimen (doxorubicin, bleomycin and vincristine) is a promising approach for the treatment of advanced HIV-related Kaposi's sarcoma (KS). Here we analyzed the relationship between the CD4 lymphocyte cell count and the clinical response to chemotherapy. Methods: The 176 HIV infected patients with advanced KS who failed to respond to prior HAART were selected. All these patients were then preceded to chemotherapy with ABV regimen which was administered at 3 weekly intervals for 6 cycles. For each patient CD4 cell count was done before starting chemotherapy and after finishing 6 cycles of chemotherapy. The difference of CD4 cell counts pre chemotherapy and post chemotherapy was compared with the clinical progress of the patients after 6 cycles of chemotherapy. Results: The overall clinical remission was shown in 93.7% patients. Progressive disease (PD) and no change in clinical condition (NC) was shown in 6.3% patients. The increase in CD4 cell count post chemotherapy was found in 89.8% patients and the decrease in CD4 cell count was seen in 10.2% patients. The difference of the mean CD4 cell counts for patients in group CR + PR (complete relief + partial relief) before and after chemotherapy was highly significant. The difference of the mean CD4 cell counts for patients in group NC + PD before and after chemotherapy was not significant. The difference in CD4 cell counts in CR + PR and NC + PD groups before and after chemotherapy was highly significant. Conclusion: The HIV related KS patients on HAART benefit from the chemotherapy as it increases the CD4 cell count and it has positive impact on clinical remission of KS.

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.

Intestinal Kaposi's sarcoma may mimic gastrointestinal stromal tumor in HIV infection

Diffuse intestinal Kaposi＇s sarcoma shares macroscopic and histopathologic features with gastrointestinal stromal tumors. Correct diagnosis may pose a clinical challenge. We describe the case of a young HIV-1-infected African lady without advanced immunodeficiency, who presented with a diffuse spindle cell tumor of the gut. Initial diagnosis was of a gastrointestinal stromal tumor, based on endoscopy and histopathology. Further evaluation revealed evidence for human herpesvirus 8 （HHV8） and the diagnosis had to be changed to diffuse intestinal Kaposi＇s sarcoma. Antiretroviral triple therapy together with chemotherapy was commenced, and has led to the rapid remission of intestinal lesions. With a background of HIV infection, the presence of HHV8 as the causative agent of Kaposi＇s sarcoma should be determined, as distinct treatment is indicated.

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.

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.

Splenic Kaposi’s sarcoma in a human immunodeficiency virusnegative patient:A case report

BACKGROUND Kaposi’s sarcoma(KS)is a malignancy that usually affects the skin of the lower extremities,and may involve internal organs.It originates from the vascular endothelium.It is well known that the development of KS is associated with human herpes virus 8(i.e.HHV8)infections.Sporadic KS cases have mainly been found in Africa.Isolated splenic KS in Asia has rarely been reported.We present here a case of KS primarily involving the spleen in a human immunodeficiency virus(HIV)-negative Chinese patient.CASE SUMMARY A 50-year-old male patient was admitted to hospital due to abdominal distension and discomfort,reduced food intake and weight loss.Medical examination revealed that the patient had moderate anemia,a low platelet count,slight fatty liver and a huge mass in the spleen.Spleen lymphoma was considered.An anti-HIV test was negative.The whole spleen was surgically excised.The final pathological diagnosis was nodular stage spleen KS,and the patient underwent total splenectomy.He recovered well and was discharged from hospital 12 d after surgery.Two weeks later,the patient developed liver metastasis and died within 1 mo after surgery.CONCLUSION KS is difficult to diagnose and pathological examination is necessary.KS has a poor prognosis and should be diagnosed and treated early to improve survival.

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.

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.

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.

Mathematical Model of Classical Kaposi’s Sarcoma

In this paper, the global properties of a classical Kaposi’s sarcoma model are investigated. Lyapunov functions are constructed to establish the global asymptotic stability of the virus free and virus (or infection) present steady states. The model considers the interaction of B and progenitor cells in the presence of HHV-8 virus. And how this interaction ultimately culminates in the development of this cancer. We have proved that if the basic reproduction number, R0 is less than unity, the virus free equilibrium point, ε0, is globally asymptotically stable (GAS). We further show that if R0 is greater than unity, then both the immune absent and infection persistent steady states are GAS.

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.

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.

Primary Ewing＇s sarcoma/primitive neuroectodermal tumor of the urogenital tract in children

Background Primary Ewing＇s sarcoma/primitive neuroectodermal tumor （ES/PNET） of urogenital tract is a rare condition with non-specific clinical presentations, which can make it difficult to diagnose. In this study, we summarize the clinical presentation, pathological features, therapeutic strategies, and prognosis of ES/PNET.

Prevalence of Kaposi's sarcoma-associated herpesvirus in Uygur and Han populations from the Urumqi and Kashgar regions of Xinjiang, China

Kaposi's sarcoma-associated herpesvirus(KSHV) is the infectious etiologic agent associated with Kaposi's sarcoma(KS), primary effusion lymphoma, and multicentric Castleman disease. It has been shown that high KSHV prevalence and high incidence of both classic KS and AIDSassociated KS are found mostly among people of Uygur ethnicity in Xinjiang, while people of Han ethnicity in Xinjiang have a higher KSHV seroprevalence than those of other Han populations in China's Mainland. However, it is still unclear why there is such geographical and population variation in KSHV distribution in China. In this work, we focused on the populations in the Kashgar region and Urumqi area, where a total of 1294 research subjects were randomly selected to investigate the potential correlation between KSHV prevalence and different ethnicities in endemic areas of Xinjiang, and to determine risk factors that may affect KSHV infection rates or KS incidence. We identified a high seroprevalence of KSHV and high peripheral blood DNA infection in the general Uygur and Han populations in both Urumqi and Kashgar regions of Xinjiang, and determined that advancing age, low education level, and stationary population status affect KSHV infection rates. Further, KSHV-positive Uygur participants were shown to have higher prevalence of neutralizing antibodies and neutralizing antibody titers than KSHV-positive Han participants.

Molecular detection of EWS-Ets fusion transcripts and their clinicopathologic significance in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor

Background Ewing＇s sarcoma/peripheral primitive neuroectodermal tumor （ES/pPNET） is often difficuh to distinguish from other small round cell tumors. The EWS-Ets gene fusions that result from chromosomal translocations in this tumor provide potential molecular diagnostic markers. To apply these molecular markers to commonly available archival materials, we evaluated the feasibility of detecting EWS-Ets including EWS-Flil and EWS-ERG fusion transcripts in paraffin-embedded tissues and its diagnostic value for detecting ES/pPNET. Methods Thirteen paraffin-embedded samples of ES/pPNETs were retrieved from archives. Thirteen cases of other tumors with small round cell features （including rhabdomyosarcoma, neuroblastoma, lymphoma, small ceil carcinoma, and desmoplastic small round cell tumor ） were used as negative controls. β-actin and β2- microglobulin were used as internal controls. A nested reverse transcriptase-polymerase chain reaction （RT- PCR）-based assay was performed to detect the EWS-Flil and EWS-ERG fusion transcripts. Results β-aetin and β2-mieroglobulin were detected in 10/13 and 13/13 ES/pPNETs, respectively. EWS- Flil fusion transcripts were detected in 11 of 13 （85%） ES/pPNETs. Three chimeric transcripts, all EWS-Flil, were detected in ES/pPNET samples. Among 11 EWS-Flil-positive cases, 7 eases had a type Ⅰ fusion transcript involving fusion of EWS exon 7 with Flil exon 6, 2 eases had a type Ⅱ fusion transcript involving EWS exon 7 with Flil exon 5, and 2 eases expressed fusion transcripts involving EWS exon 7 and Flil exon 8. Type Ⅰ EWS- Flil fusion predominated over other types. Fusion types could not be distinguished in the remaining 2 eases. Thirteen negative controls did not show detectable chimeric messages. There was a significant relationship between EWS-Flil fusion transcripts and CD99 expression. Conclusions Molecular detection of EWS-Flil fusion transcripts in formalin-fixed paraffin-embedded material by nested RT-PCR is feasible and is useful for the diagnosis and differential diagnosis of ES/pPNETs.

Imaging Findings of Hepatic Ewing’s Sarcoma on Computed Tomography and Gadobenate Dimeglumine-enhanced Magnetic Resonance Imaging: A Case Report and Literature Review

Ewing’s sarcoma(ES)is a tumor that often occurs in the long bones and rarely arises from visceral organs primarily.Here,we report a case of primary hepatic ES,discuss its computed tomography(CT)and gadobenate dimeglumineenhanced magnetic resonance(MRI)features.This is the first Chinese and fifth primary hepatic ES case reported,based on a literature review.Imaging examinations showed that the tumor was solid,with necrosis and hemorrhage.Contrast-enhanced images showed that the tumor was hypervascular and especially had heterogeneous signal intensity on hepatobiliary phase MRI images.Intratumoral vessels and vascular invasion were also present.