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Simple Summary: Ewing sarcoma is a malignant tumor that frequently occurs in adolescents and young adults, primarily originating from bone and rarely from soft tissue. Approximately 25% of patients present with metastatic disease at the time of diagnosis. Ewing sarcoma is considered a systemic disease, with the standard treatment consisting of a multimodal approach that combines surgery, radiotherapy, and chemotherapy. However, the optimal second-line or subsequent-line treatment for patients who progress after first-line chemotherapy remains unclear. Treatment options include high-dose ifosfamide, gemcitabine–docetaxel, topotecan–cyclophosphamide, and vincristine–irinotecan–temozolomide. The aim of this study was to evaluate the efficacy and safety of the topotecan–cyclophosphamide regimen in adult patients with metastatic Ewing sarcoma. The topotecan–cyclophosphamide regimen appears to be a viable treatment option regarding efficacy and safety for patients who progress after first-line therapy. However, further research is needed to better define its role in treatment. Background/Objectives: There is an unmet need to improve outcomes in patients with metastatic Ewing sarcoma (ES). This retrospective, multicenter study aimed to evaluate the efficacy and safety of the topotecan–cyclophosphamide (TC) regimen in adult patients with metastatic ES who had previously been treated with chemotherapy. Methods: This study enrolled 75 patients who were treated at five oncology centers in Turkey between 2011 and 2020. Patients were treated with the TC regimen, consisting of topotecan at 0.75 mg/m2/day and cyclophosphamide at 250 mg/m2/day, given daily for 5 days and repeated every 21 days. Results: The median progression-free survival was 3.06 months (95% CI, 2.91–3.22), and the median overall survival was 6.16 months (95% CI, 5.14–7.18). Patients who received the TC regimen in the second line demonstrated longer OS (7.55 months 95% CI, 5.37–14.17) compared to those who received it in the third line or later (5.70 months 95% CI, 4.07–6.60) (p = 0.005). When the TC regimen was used in the second line, the disease control rate was 50%, whereas in the third line or later, the DCR was 10.8%. In the entire group, the DCR was 30.7%. The most common toxicity was transient cytopenia. Conclusions: This study showed that the use of the TC regimen in the second line resulted in better efficacy and overall survival outcomes compared to its use in the third line or later. However, in the entire population, the TC regimen demonstrated only a modest effect on metastatic ES. TC can be considered one of the palliative treatment options for metastatic ES. [ABSTRACT FROM AUTHOR]

A 23-year-old female patient presented with radicular back pain, perineal numbness, and urinary retention. The patient was diagnosed with cauda equina syndrome and magnetic resonance imaging (MRI) of the spine revealed an enhancing osseous lumbar lesion causing severe central stenosis. A core needle biopsy of the lumbar spine showed microscopic features compatible with a small round blue cell tumor. CD99 and FLI1 were positive in the tumor cells. Next-generation sequencing demonstrated a EWSR1::FLI1 fusion. Given these findings, the spine lesion was diagnosed as Ewing sarcoma. The patient underwent surgical decompression of L2. On further workup, an MRI revealed an ill-defined enhancing mass of the right distal femur. This area was biopsied, demonstrating a fibro-osseous lesion with osteoblast proliferation containing nuclear atypia, low mitotic activity, and SATB2 positivity, diagnosed as low-grade central osteosarcoma (LGCOS). The patient underwent resection, which showed a classic LGCOS by histomorphology. Although fluorescence in-situ hybridization study for MDM2 gene amplification was negative, the overall findings are most consistent with LGCOS. These neoplasms are considered to be synchronous due to the presentation of each entity within 6 months. Considering the aggregate yearly incidence of Ewing sarcoma (approximately 1 case per 750 000 per year) and LGCOS (approximately 1 case per 10 million per year), the aggregate yearly probability of developing both of these genetically unrelated tumors in a single individual is 1 per 7.5 trillion per year, and it is likely such an event has never happened in the past. [ABSTRACT FROM AUTHOR]

Periosteal Ewing sarcoma (ES) is an exceedingly rare topographic subtype of the ES. To our knowledge, only 60 patients have been reported in the medical English language literature. It predominantly affects men in the second decade of life and arises in the long tubular bone diaphysis. Periosteal ES rarely develops distant metastases. We report two patients of this rare ES location that were found on the distal tibial shaft and proximal femoral diaphysis of a 21-year-old man and an 8-year-old boy, respectively. Both patients were treated with neoadjuvant chemotherapy, wide resection, and adjuvant chemotherapy. One of our patients had lung metastases at the time of diagnosis and died 5 years later. The other patient presented intramedullary humeral bone metastasis 19 years after diagnosis. There has been no evidence of disease in the 26 years of follow-up. Close follow-up of periosteal ES is recommended because distant metastases may exceptionally occur, even several years after diagnosis. [ABSTRACT FROM AUTHOR]

CDK12 is essential for cellular processes like RNA processing, transcription, and cell cycle regulation, inhibiting cancer cell growth and facilitating macrophage invasion. CDK12 is a significant oncogenic factor in various cancers, including HER2-positive breast cancer, Anaplastic thyroid carcinoma, Hepatocellular carcinoma, prostate cancer, and Ewing sarcoma. It is also regarded as a potential biomarker, emphasizing its broader significance in oncology. Targeting CDK12 offers a promising strategy to develop therapy. Various monoclonal antibodies have drawn wide attention, but they are expensive compared to small-molecule inhibitors, limiting their accessibility and affordability for patients. Consequently, this research aims to identify effective CDK12 inhibitors using comprehensive high-throughput virtual screening. RASPD protocol has been employed to screen three different databases against the target followed by drug-likeness, molecular docking, ADME, toxicity, Consensus molecular docking, MD Simulation, and in-vitro studies MTT assay. The research conducted yielded one compound ZINC11784547 has demonstrated robust binding affinity, favorable ADME features, less toxicity, remarkable stability, and cytotoxic effect. The identified compound holds promise for promoting cancer cell death through CDK12 inhibition. [ABSTRACT FROM AUTHOR]

Ewing sarcoma family tumors (ESFT) pose diagnostic challenges, which largely depend on the primary site of involvement and tumor stage. Despite advancements in treatment, metastatic ESFTs remain associated with poor outcomes. This case describes a 21-year-old woman who, in July 2022, presented with a left breast mass identified through ultrasound and CT scan, along with abdominal distention. A biopsy of the breast mass confirmed metastatic extraskeletal Ewing sarcoma. Further imaging revealed an ovarian mass, with subsequent biopsy confirming ovarian origin as extraskeletal Ewing sarcoma. The breast mass was identified as metastatic based on imaging features, including irregular margins and CT scan confirmation of widespread metastasis. Histopathology and immunohistochemistry confirmed Ewing sarcoma, consistent with the ovarian mass pathology that was the primary site. She underwent 15 cycles of VDC/IE chemotherapy ((vincristine, doxorubicin, and cyclophosphamide) for 2 days and 5 days IE (ifosfamide etoposide)), resulting in tumor cytoreduction. However, in less than 2 years, she developed metastases to the dura, spine, and bone, with optic nerve involvement. Despite treatment with radiotherapy and two cycles of high-dose Ifosfamide chemotherapy, her condition deteriorated, and she passed away in April 2024. This case underscores the complexity of managing metastatic ESFTs. Further research is needed to improve outcomes and establish treatment protocols for this malignancy. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (EWS) is the second most common bone tumor affecting children and young adults, with dismal outcomes for patients with metastasis at diagnosis. Mechanisms leading to metastasis remain poorly understood. To deepen our knowledge on EWS progression, we have profiled tumors and metastases from a spontaneous metastasis mouse model using a multi‐omics approach. Combining transcriptomics, proteomics, and methylomics analyses, we identified signaling cascades and candidate genes enriched in metastases that could be modulating aggressiveness in EWS. Phenotypical validation of two of these candidates, cyclic AMP‐responsive element‐binding protein 1 (CREB1) and lipoxygenase homology domain‐containing protein 1 (LOXHD1), showed an association with migration and clonogenic abilities. Moreover, previously described CREB1 downstream targets were present amongst the metastatic‐enriched results. Combining the different omics datasets, we identified FYVE, RhoGEF, and PH domain‐containing protein 4 (FGD4) as a CREB1 target interconnecting the different EWS biological layers (RNA, protein and methylation status) and whose high expression is associated with worse clinical outcome. Further studies will provide insight into EWS metastasis mechanisms and ultimately improve survival rates for EWS patients. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (ES) is the second most common primary malignant bone tumour in children and adolescents. About 14.5% of primary malignancies develop in pelvic bones, where they typically have worse prognoses than extremity or acral sarcomas. It usually presents with aggressive features on radiology scans, but may also present with different radiological characteristics. In this series, we describe rare appearances of pelvic skeletal Ewing sarcoma, with large extraosseous cystic component on imaging, defined by the presence of fluid-filled spaces in the extraosseous tumour lesion, which distinguishes it from the solid nature of conventional ES. We report 3 cases of cystic presentation of ES, with imaging features supporting diagnosis of a primary malignant bone tumour arising from the superior pubic ramus with associated massive intrapelvic solid and cystic mass. CT-guided biopsy provided diagnosis of ES, with large intrapelvic soft tissue and cystic component. These patients underwent neo-adjuvant chemotherapy and proton beam therapy with significant reduction in size of the solid components, while the cystic components remained relatively unchanged. Two patients underwent surgical resection of the tumour (navigated P3 internal hemipelvectomy and hemipelvis P2/P3 resection, respectively), and one patient died while on treatment. In both who underwent surgery, histology showed ES with margins clear and more than 99% of treatment-induced necrosis. To the authors' 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing sarcomas are rare, aggressive tumors, occurring mostly in children and adolescents. They usually derive from the bone; however, extraskeletal Ewing sarcomas develop in the soft tissue. Ewing sarcoma of the mediastinum is extremely rare; there are only a few cases reported in the literature. The outcome is usually poor with about 30% 5-year survival. We retrieved data from two international, multicenter, prospective, clinical trials investigating the optimal treatment for patients with Ewing sarcoma. We then analyzed the patient and treatment characteristics to gain a better understanding of this rare tumor entity. This study is the first to describe the prevalence of mediastinal Ewing sarcoma in a homogeneously treated patient cohort. Objective: Ewing sarcoma (EWS) of the mediastinum is extremely rare, with only a few cases reported in the literature. We aimed to gain a better understanding of primary mediastinal EWS, describing patients treated within two international, multicenter, prospective, randomized EWS trials. Methods: Data from patients with primary mediastinal EWS were retrieved from the database of the EURO-E.W.I.N.G.99 (ClinicalTrials.gov identifier: NCT00020566) and EWING 2008 (ClinicalTrials.gov identifier: NCT00987636) trials. Patient and treatment characteristics were analyzed. Results: Out of 2969 patients with EWS, 9 (0.3%) had primary mediastinal EWS. The median age at diagnosis was 30.5 years (4 to 49). At the time of diagnosis, n = 3 (33%) patients had synchronous metastases. All patients underwent multiagent chemotherapy. Local therapy for non-metastatic patients was surgery (n = 2, 22%), surgery and radiotherapy (n = 2, 22%) or radiotherapy alone (n = 2, 22%). Surgery consisted of extended resections in most patients (n = 3, 33%). Five-year survival for the whole cohort was 64%. Apart from one patient who was lost to follow-up, all patients (n = 4) who had undergone surgery were alive at the end of follow-up. Conclusions: Primary mediastinal ES is extremely rare, with a prevalence of 0.3% among EWS. Five-year survival was favorable compared to primary mediastinal sarcoma of all histologies and in line with EWS of different origin. [ABSTRACT FROM AUTHOR]

Background: Herein, we present the results of the phase 2 IMMUNOSARC study (NCT03277924), investigating sunitinib and nivolumab in adult patients with advanced bone sarcomas (BS). Methods: Progressing patients with a diagnosis of BS were eligible. Treatment was comprised of sunitinib (37.5 mg/day on days 1–14, 25 mg/day afterword) plus nivolumab (3 mg/kg every 2 weeks). Primary end point was progression‐free survival rate (PFSR) at 6 months based on central radiology review. Secondary end points were overall survival (OS), overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and safety. Results: A total of 46 patients were screened, 40 patients entered the study, and 38 underwent central radiological review and were evaluable for primary end point. Median age was 47 years (range, 21–74). Histologies include 17 (43%) osteosarcoma, 14 chondrosarcoma (35%, 10 conventional, four dedifferentiated [DDCS]), eight (20%) Ewing sarcoma, and one (2%) undifferentiated pleomorphic sarcoma. The PFSR at 6 months was 42% (95% confidence interval [CI], 27–58). With a median follow‐up of 39.8 months (95% CI, 37.9–41.7), the median PFS and OS were 3.8 months (95% CI, 2.7–4.8) and 11.9 months (95% CI, 5.6–18.2). ORR by RECIST was 5%, with two of 38 partial responses (one of four DDCS and one of 17 osteosarcoma), 19 of 38 (50%) stable disease, and 17 of 38 (45%) progressions. Grade ≥3 adverse events were neutropenia (six of 40, 15%), anemia (5/40, hypertension (6/40, 15%), 12.5%), ALT/AST elevation (5/40, 12.5%), and pneumonitis (1/40, 2.5%). Seventeen percent of patients discontinued treatment due to toxicity, including a treatment‐related grade 5 pneumonitis Conclusion: The trial met its primary end point in the BS cohort with >15% of patients progression‐free at 6 months. However, the toxicity profile of this regimen was relevant. With a progression‐free survival of 42% at 6 months, this trial with nivolumab and sunitinib in 40 patients with advanced bone sarcoma met its primary end point. The response rate was high (25%) in patients with dedifferentiated chondrosarcoma (DDCS) and an international expansion phase 2 trial in DDCS is currently enrolling. [ABSTRACT FROM AUTHOR]

Background: The care of adolescents and young adults (AYAs) with bone sarcomas involves unique challenges. The objectives of this study were to identify challenges and evaluate long‐term outcomes of these patients from India who received treatment with novel protocols. Methods: This prospective cohort study included AYA patients (aged 15–39 years) with osteosarcoma and Ewing sarcoma (ES), who were treated uniformly at the authors' institute using unique protocols (OGS‐12 and EFT‐2001) from 2011 to 2021 and from 2013 to 2018, respectively. Results: The cohorts included 688 of 748 (91.9%) treatment‐naive AYA patients with osteosarcoma and 126 of 142 (88.7%) treatment‐naive AYA patients with ES. Among 481 of 561 patients (85.7%) who had nonmetastatic osteosarcoma treated according to protocol, at a median follow‐up of 59.7 months, the 5‐year event‐free survival (5‐EFS) rate was 58.6% (95% confidence interval, 54.1%–63.5%) and for 142 patients (20.6%) who had metastatic osteosarcoma, the 5‐EFS rate was 18.7%. The 5‐EFS rate was 66.4% and 21.9% for 104 patients (73%) with nonmetastatic ES and 38 patients (27%) with metastatic ES, respectively. Treatment‐naive patients had better outcomes, similar to compliance in the form of protocol completion (hazard ratio, 1.93 [p =.0043] and 2.66 [p <.0001], respectively. Only 230 of 377 (61.0%) male patients and 10 of 134 (7.4%) female patients reached out to fertility specialists. In addition, 17 of 161 (10.6%) eligible male survivors and 14 of 61 (22.9%) eligible female survivors got married posttreatment. Furthermore, 14 of 17 (82.4%) males and 14 of 14 (100%) females conceived. Among 311 patients who were working or attending school during diagnosis, greater than 90% had interruptions. Conclusions: Homogenous treatment with the OGS‐12 and EFT‐2001 protocols resulted in internationally comparable long‐term outcomes in the cohorts with nonmetastatic and metastatic AYA bone sarcomas. Treatment compliance, timely referral to sarcoma reference centers (avoiding prior inadvertent treatment), and streamlining fertility‐preservation practices constitute unmet needs that demand prioritization. Adolescents and young adults who have bone sarcomas receive prior inadvertent treatment at peripheral centers and commonly present with a significant delay, resulting in a high baseline tumor burden and relatively higher stage disease. Superior outcomes with the indigenous OGS‐12 and EFT‐2001 protocols in treatment‐naive and compliant patients who have osteosarcoma and Ewing sarcoma, respectively, compared with inadvertently treated adolescent and young adult patients, underscores the need for the timely referral of these patients to sarcoma reference centers and effective patient navigation systems. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (ES) is a rare malignant tumor, particularly in the head and neck region. Its incidence tends to be higher in pediatric patients than in adults. Occasionally, curative treatment of ES requires extensive resection of the primary lesion, which can result in postoperative aesthetic or functional disorders. In recent years, advances have been made in reconstructive surgery of the maxillofacial region. Broad mandibular defects are a prime indication for several types of vascularized free bone grafts. Similarly, the treatment of ES has progressed in the field of systemic chemotherapy. We report a multidisciplinary surgical case of ES in the mandible of a 12-year-old patient who underwent extensive mandibular resection and fibula free flap (FFF) reconstruction with preoperative and postoperative chemotherapy. In brief, after conducting a multidisciplinary clinical conference, perioperative chemotherapy was planned by pediatric oncologists, and the operation was performed by a head and neck cancer team consisting of head and neck, oral and maxillofacial, and plastic surgeons. Five months after the operation, prosthodontists applied an intraoral prosthesis. The reconstructed mandible demonstrated good development, and the quality of life was maintained both aesthetically and functionally for eight years after treatment. Our efficient multidisciplinary medical collaboration demonstrated that mandibular reconstruction using FFF is a suitable method for treating pediatric patients and leads to long-term survival with satisfactory outcomes. [ABSTRACT FROM AUTHOR]

Intra-neural Ewing sarcoma is an extremely rare tumour and only a few isolated case reports exist in the literature. A 32-year-old South Asian male presented with wrist and finger drops of 3 months duration. Further evaluation with ultrasonography and magnetic resonance imaging revealed a tumour of the radial nerve in the arm. A wide excision of the tumour was performed, and the radial nerve was reconstructed with cabled nerve grafts. A diagnosis of extra-osseous Ewing sarcoma (EES) was made after histopathological evaluation using immunohistochemistry techniques. The patient subsequently received chemotherapy and after 5 months, he is disease-free and pain-free. However, there has been no motor recovery yet. Clinical findings and imaging can help and characterise the tumour, but histopathology and analysis for EWSR1 gene rearrangement are essential to confirm the diagnosis. Wide surgical excision and chemotherapy are the mainstay of managing neural EES. [ABSTRACT FROM AUTHOR]

ABSTRACT Capicua transcriptional repressor (CIC)‐rearranged sarcoma (CRS) is a rare and recently described tumor that most commonly affects patients between 15 and 30 years of age. It is an undifferentiated round cell malignancy, with a disease defining CIC fusion, with double homeobox 4 (DUX4) being the most common partner. Here, we report a 77‐year‐old woman who presented with a cutaneous thigh mass with a clinical morphology suggesting Merkel cell carcinoma. Immunohistochemically, there was positivity for INSM1 (extensive) and synaptophysin (patchy) and granular expression of neurofilament (extensive), CAM5.2, and CK20 (focal, nonspecific). The majority of the tumor showed histopathologic features within the range of what can be seen in Merkel cell carcinoma, but there were divergent features, including a myxoid zone with corded and stranded tumor cells and a Ewing‐sarcoma‐like zone with confluent concentric membranous CD99 expression. WT‐1 was strongly expressed, prompting RNA‐based next generation sequencing for gene fusions, which identified the CIC:DUX4 [t(19;4)(19q13.2;4q35.2)]. A novel IRAK3:HMGA2 fusion was also identified. This example of CRS simulated MCC clinically, histopathologically, and immunohistochemically and represents a likely underrecognized diagnostic pitfall. [ABSTRACT FROM AUTHOR]

Histone acetylation is an important epigenetic modification, modulating the development of many tumors. However, the functions of most histone acetylation-related genes (HARGs) and their prognostic values in Ewing sarcoma (EWS) remain unclear. The current study aimed to investigate the prognostic values and potential functions of HARGs in EWS. After collecting EWS patients with mRNA sequencing data from the Gene Expression Omnibus (GEO) database and a list of HARGs from previous studies, Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression were performed to construct a prognostic gene signature based on HARGs. Then, four HARGs (TAF4, ATF2, HDAC2 and OGA) composed a formula to calculate risk score for each patient in the training cohort. Based on median risk score, all patients were classified into low- and high-risk group, and patients with high-risk score had a poor survival outcome (p < 0.001). The 1-, 2-,3- and 5-year AUC (0.853, 0.886,0.909and 0.833, respectively) showed the good ability of this signature to predict the prognoses of EWS patients. In addition, distinct functional enrichment and immune-related pathways were also observed in two risk groups. All results were validated in an external cohort from two dataset in GEO database. Moreover, it was found that silencing HDAC2 expression in EWS cells significantly suppressed the cell viability and migration capability. In conclusion, this is the first study to detect the prognostic values of HARGs in EWS patients, further developing a good prognostic signature based on HARGs, and HDAC2 might be an oncogene in the development of EWS. [ABSTRACT FROM AUTHOR]

Introduction: Pediatric sarcomas, including osteosarcoma (OS), Ewing sarcoma (EwS) and rhabdomyosarcoma (RMS) carry low somatic mutational burden and low MHC-I expression, posing a challenge for T cell therapies. Our previous study showed that mediators of monocyte maturation sensitized the EwS cell line A673 to lysis by HLA-A*02:01/CHM1319-specific allorestricted T cell receptor (TCR) transgenic CD8+ T cells (CHM1319 CD8+ T cells). Methods: In this study, we tested a panel of monocyte maturation cytokines for their ability to upregulate immunogenic cell surface markers on OS, EwS and RMS cell lines, using flow cytometry. xCELLigence, SRB and ELISpot assays were used to assess whether TNF pretreatment increases CD8+ T cell cytotoxicity. Results: We observed that TNF and IL-1β upregulated MHC class I, ICAM-1 as well as CD83 and PD-L1 on the surface of pediatric sarcoma cell lines, while IL-4, GM-CSF, IL-6 and PGE2 failed to induce respective effects. Although pretreatment of pediatric sarcoma cell lines with TNF did not improve unspecific peripheral blood mononuclear cells (PBMCs) cytotoxicity, TNF enhanced specific lysis of 1/3 HLA-A2+ EwS cell lines by CHM1319 CD8+ T cells depending on MHC-I expression and ICAM-1 upregulation. Discussion: Our study supports utilization of TNF or TNF-inducing regimens for upregulation of MHC-I and costimulatory surface molecules on pediatric sarcoma cells and for enhancing recognition of responsive HLA-A2+ EwS tumor cells by antigen-specific CD8+ T cells. [ABSTRACT FROM AUTHOR]

Background: Ewing sarcoma (ES), the second main pediatric bone sarcoma, is characterised by a chromosomal translocation leading to the formation of fusion proteins like EWS::FLI1. While several studies have shown that potassium channels drive the development of many tumours, limited data exist on ES. This work therefore aimed to study the transcriptional regulation of KCNA2 and define the involvement of the Kv1.2 channel encoded by KCNA2 in a key function of ES development, cell proliferation. Methods: KCNA2 expression in patients and cell lines was measured via bioinformatic analysis (RNA-Seq). The presence of a functional Kv1.2 channel was shown using patch-clamp experiments. Molecular biology approaches were used after EWS::FLI1 silencing to study the transcriptional regulation of KCNA2. Proliferation and cell count assessment were performed using cell biology approaches. KCNA2 silencing (siRNA) and RNA-Seq were performed to identify the signalling pathways involved in the ability of KCNA2 to drive cell proliferation. The regulation of the Hippo signalling pathway by KCNA2 was studied by measuring Hippo/YAP target genes expression, while YAP protein expression was studied with Western-Blot and immunofluorescence approaches. Results: This research identified KCNA2 (encoding for a functional Kv1.2 channel) as highly expressed in ES biopsies and cell lines. The results indicated a correlation between KCNA2 expression and patient survival. The data also demonstrated that KCNA2/Kv1.2 is a direct target of EWS::FLI1, and identified the molecular mechanisms by which this chimeric protein regulates KCNA2 gene expression at the transcriptional level. Furthermore, the results indicated that KCNA2 expression and Kv1.2 activity regulate ES cell proliferation and that KCNA2 expression drives the Hippo/YAP signalling pathway. Using the specific Kv1.2 channel inhibitor (κ-Conotoxin), the results suggested that two complementary mechanisms are involved in this process, both dependently and independently of Kv1.2 functional channels at the plasma membrane. Conclusion: This study is the first to describe the involvement of KCNA2 expression and Kv1.2 channel in cancer development. The study also unveiled the involvement of KCNA2 in the regulation of the Hippo/YAP signalling cascade. Thus, this work suggests that KCNA2/Kv1.2 could be a potential therapeutic target in ES. [ABSTRACT FROM AUTHOR]

Prognosis remains poor for patients with relapsed or refractory Ewing sarcoma, with limited treatment options after first‐line therapy. Oral etoposide has efficacy in the paediatric setting; however, data are limited in adults. A retrospective analysis was conducted on 33 patients with relapsed or refractory Ewing sarcoma who completed at least one cycle of oral etoposide at the Peter MacCallum Cancer Centre from 2005 to 2020. The median age at diagnosis and first relapse was 21 and 23 years, respectively. All patients had prior exposure to intravenous etoposide. Nine patients (27%) had stable disease for at least 6 months, and six patients (18%) had a partial response. The clinical benefit rate was 45%. The median PFS was 3.6 months (95% CI: 1.7–5.5), and OS was 8.5 months (95% CI: 4.1–13.0). Despite prior exposure, oral etoposide demonstrated antitumour activity and durable responses in the relapsed or refractory setting for adult patients with Ewing sarcoma. [ABSTRACT FROM AUTHOR]

Ewing sarcoma is a rare type of cancer that typically arises in the bones or soft tissues of children and young adults. However, Ewing sarcoma can also occur in other body parts, including the pancreas. Ewing sarcoma of the pancreas is rare and often affects children or young adults. We reported a 33-year-old male with no medical illness who presented with worsening epigastric pain and vomiting for one-week duration. CT scan of the abdomen showed an obstructive duodenal mass complicated with perforation. The biopsy of the duodenal mass showed sheets of small round blue cells with immunohistochemical features favouring Ewing sarcoma. Pancreatoduodenectomy procedure (Whipple resection) was performed, which revealed an ill-defined whitish solid tumour at the head of the pancreas measuring 80x50x65mm. Histologically, the tumour is composed of sheets of malignant cells displaying uniform small round to oval nuclei containing fine chromatin, inconspicuous nucleoli, scanty cytoplasm, and indistinct cell membrane. A few mitoses are seen (4/10HPF). Areas of tumour necrosis are observed. Scattered lymphovascular invasion is also present. The malignant cells are infiltrating into the duodenal mucosa. The malignant cells are diffuse and strongly positive towards CD99, FLI-1 and NK2.2 (Figure 3). A diagnosis of primary pancreatic Ewing sarcoma was made. [ABSTRACT FROM AUTHOR]

Objective: No consensus exists for tumor volume response criteria in patients with Ewing sarcoma. This study aimed to identify an optimal cutoff for predicting a good histological response by analyzing tumor volume changes and tumor necrosis after neoadjuvant chemotherapy. Materials and methods: We performed a retrospective analysis of 184 Ewing sarcoma patients, analyzing tumor volume changes before and after neoadjuvant chemotherapy. Patients were divided into two groups based on histological response: good (tumor necrosis ≥ 95%) and poor (tumor necrosis < 95%) responders. The receiver operating characteristic (ROC) area under the curve (AUC) method was used to determine the optimal thresholds for predicting the histological response. Additionally, the prognostic value of this cutoff for relapse-free survival was assessed. Results: Out of 184 patients, 83 (45%) had tumor necrosis ≥ 95%, while 101 (55%) had tumor necrosis < 95%. ROC analysis identified the optimal cutoff for a good histological response as over 65% tumor volume reduction (AUC = 0.69; p < 0.001). Patients with volume reduction of ≥ 65% had a higher likelihood of a good histological response than those with lesser reductions (p = 0.004; odds ratio = 2.61). Multivariable analysis indicated a correlation between poor histological response and reduced relapse-free survival (hazard ratio = 2.17; p = 0.01), while tumor volume reduction itself did not impact survival. Conclusion: We reported that a tumor volume reduction of ≥ 65% was able to predict a good histological response in Ewing sarcoma patients. We recommend preoperative tumor volume assessment to identify patients at greater risk for poor histological response who could benefit from more intensive chemotherapy protocols or additional radiotherapy. [ABSTRACT FROM AUTHOR]

Ewing sarcomas are rare tumors arising mainly in the bones and the surrounding soft tissues. Primary extraosseous Ewing sarcomas have also been described in several other organs and locations other than bones, including the pancreas. These tumors have well-defined histological, immunohistochemical, and molecular characteristics. In this manuscript, we present a case of primary Ewing sarcoma of the pancreas in a 29-year-old patient, and we systematically review the literature on both primary and metastatic Ewing sarcomas of the pancreas, describing their clinicopathological characteristics. We also discuss the differential diagnosis and the treatment of this rare entity. [ABSTRACT FROM AUTHOR]

Simple Summary: Desmoplastic small round cell tumors (DSRCTs) are rare, aggressive malignant neoplasms that typically affect the abdominal region. The challenge in diagnosing those tumors is rendered to their histopathologic resemblance to other small round cell tumors, such as Ewing sarcoma and rhabdomyosarcoma. Our review aims to provide a better understanding of the key histomorphologic and genetic features that make DSRCTs unique, including specific gene fusions. We highlight the importance of ancillary tests, including immunohistochemical staining and molecular profiling, in making an accurate diagnosis. By improving the way these tumors are identified and treated, we hope this review will help guide both pathologists and clinicians and improve outcomes for patients with DSRCTs. Desmoplastic small round cell tumors (DSRCTs) of the gastrointestinal (GI) tract are a rare and highly aggressive variant of soft tissue sarcomas, predominantly affecting the abdominal region. These tumors are believed to originate from multipotent mesenchymal stem cells or primitive progenitor cells. They are composed of small round tumor cells associated with prominent stromal desmoplasia, polyphenotypic differentiation, and EWSR1::WT1 gene fusion. Diagnostically, DSRCTs present a significant challenge due to their histological resemblance to other small round cell tumors, such as Ewing sarcoma and rhabdomyosarcoma, necessitating the use of ancillary tests, including immunopanels and molecular analysis, to reach a definitive diagnosis. Immunohistochemical staining, including markers like cytokeratin, vimentin, desmin, and WT1, has proven valuable in differentiating DSRCTs from their mimickers. The prognosis of these tumors is highly dependent on factors such as tumor location and stage at diagnosis, and given their aggressive nature, a multidisciplinary approach may be required that combines surgical resection, chemotherapy, and radiation therapy, among other options. In this review, we provide a synopsis of the pathophysiology of DSRCTs and the latest diagnostic advancements, including the utility of molecular profiling and novel biomarkers. [ABSTRACT FROM AUTHOR]

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR‐ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR‐ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high‐dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR‐ES. Plain Language Summary: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults.This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi‐institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES.Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs. Debates remain in defining the standard of care for treating patients with relapsed Ewing sarcoma. This set of consensus recommendations from the National Ewing Sarcoma Tumor Board are intended to provide some clarity and recommendations for the management of patients with recurrent disease. [ABSTRACT FROM AUTHOR]

The Ewing sarcoma family of tumors (ESFT) stands for a group of rare and aggressive malignancies consisting of high grade poorly differentiated small round blue cells. In our case report, we aim to describe the clinical presentation, diagnosis and the treatment plan for our patient. A 16-year-old girl presented to the ENT outpatient department of the Mayo Hospital Lahore with the complaints of right nasal obstruction, epistaxis from right nose, swelling on the right cheek and headaches. Examination revealed a soft, tender swelling on her right cheek below the right eye. Imaging revealed a heterogeneous opacity in the right nose and right maxillary sinus with erosion of the sinus walls.Very few such cases have been reported in international literature. Being a rare case, our article will add insights to the literature regarding complex clinical presentation, diagnostic evaluation and treatment of the sinonasal Ewing sarcoma. [ABSTRACT FROM AUTHOR]

With the increasing use of next generation sequencing in soft tissue pathology, particularly in neoplasms not fitting any World Health Organization (WHO) category, the spectrum of EWSR1 fusion-associated soft tissue neoplasms has been expanding significantly. Although recurrent EWSR1::ATF1 fusions were initially limited to a triad of mesenchymal neoplasms including clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma and malignant gastrointestinal neuroectodermal tumor (MGNET), this family has been expanding. We herein describe 4 unclassified extra-abdominal soft tissue (n = 3) and bone (n = 1) neoplasms displaying epithelioid and round cell morphology and carrying an EWSR1::ATF1 fusion. Affected were 3 males and 1 female aged 20–56 years. All primary tumors were extra-abdominal and deep-seated (chest wall, mediastinum, deltoid, and parapharyngeal soft tissue). Their size ranged 4.4–7.5 cm (median, 6.2). One patient presented with constitutional symptoms. Surgery with (2) or without (1) neo/adjuvant therapy was the treatment. At last follow-up (8–21 months), 2 patients developed progressive disease (1 recurrence; 1 distant metastasis). The immunophenotype of these tumors is potentially misleading with variable expression of EMA (2 of 3), pankeratin (2 of 4), synaptophysin (2 of 3), MUC4 (1 of 3), and ALK (1 of 3). All tumors were negative for S100 and SOX10. These observations point to the existence of heretofore under-recognized group of epithelioid and round cell neoplasms of soft tissue and bone, driven by EWSR1::ATF1 fusions, but distinct from established EWSR1::ATF1-associated soft tissue entities. Their overall morphology and immunophenotype recapitulate that of the emerging EWSR1/FUS::CREB fusion associated intra-abdominal epithelioid/round cell neoplasms. Our cases point to a potentially aggressive clinical behavior. Recognizing this tumor type is mandatory to delineate any inherent biological and/or therapeutic distinctness from other, better-known sarcomas in the differential diagnosis including sclerosing epithelioid fibrosarcoma. [ABSTRACT FROM AUTHOR]

With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET(EWSR1/FUS)::CREB(CREM/ATF1) fused unclassified neoplasms has been reported followed by recent recognition of an analogous extra-abdominal category of unclassified neoplasms carrying EWSR1::ATF1 fusions. We describe 9 additional tumors (5 extra-abdominal and 4 abdominal) carrying an EWSR1::CREM (n = 8) and FUS::CREM (n = 1) fusion. Patients were 7 females and 2 males aged 10 to 75 years (median, 34). Extra-abdominal tumors originated in the head and neck (2 sinonasal, 1 orbital) and soft tissues (1 gluteal, 1 inguinal). Abdominal tumors involved stomach (2), mesentery (1), and kidney (1). Tumor size ranged from 3.5 to 11 cm (median, 6). Treatment was radical surgery with (5) or without (2) neo/adjuvant radio/chemotherapy. Extended follow-up of 5 patients (21–52 months; median, 24) showed an aggressive course in two (40%); one died of disseminated metastases 52 months after several intensified chemotherapy regimens, and one was alive with progressive abdominal disease at 21 months. The immunophenotype of the two subcohorts was significantly overlapping with variable expression of EMA (7 of 8), keratin AE1/AE3 (5 of 9), CD99 (4 of 7), MUC4 (2 of 8), ALK (3 of 8), synaptophysin (3 of 9), chromogranin (1 of 8), CD34 (3 of 6), CD30 (1 of 6), PAX8 (1 of 7), and inhibin (1 of 7), but no reactivity with desmin (0 of 8), S100 (0 of 8), and SOX10 (0 of 8). This series further solidifies the notion that FET::CREB fusions are not limited to the triad of angiomatoid fibrous histiocytoma, clear cell sarcoma, and malignant gastrointestinal neuroectodermal tumor, but characterize an emerging family of potentially aggressive neoplasms occurring at both intra- and extra-abdominal sites. These tumors underscore the promiscuity of the FET::CREB fusions and highlight the pivotal role of phenotype-oriented classification of these neoplasms that share the same genotype, still featuring significant biological and behavioral distinctness. [ABSTRACT FROM AUTHOR]

This case report details a rare presentation of cervical Ewing's sarcoma in a 4-year-old female, emphasizing its clinical presentation, diagnostic process, and treatment challenges. The patient initially presented with a rapidly growing neck mass and neurological symptoms; MRI confirmed a well-defined mass at the C5-C6 vertebral level, and histopathological examination verified the diagnosis of Ewing's sarcoma. Treatment involved neoadjuvant chemotherapy, followed by surgical resection with clear margins, and the patient is currently being monitored for recurrence with a guarded prognosis. This case underscores the need for a multidisciplinary approach, early intervention, and thorough surgical planning in managing rare and aggressive tumors in complex anatomical locations, contributing valuable insights to the limited literature on this uncommon malignancy.

Abstract Histone acetylation is an important epigenetic modification, modulating the development of many tumors. However, the functions of most histone acetylation-related genes (HARGs) and their prognostic values in Ewing sarcoma (EWS) remain unclear. The current study aimed to investigate the prognostic values and potential functions of HARGs in EWS. After collecting EWS patients with mRNA sequencing data from the Gene Expression Omnibus (GEO) database and a list of HARGs from previous studies, Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression were performed to construct a prognostic gene signature based on HARGs. Then, four HARGs (TAF4, ATF2, HDAC2 and OGA) composed a formula to calculate risk score for each patient in the training cohort. Based on median risk score, all patients were classified into low- and high-risk group, and patients with high-risk score had a poor survival outcome (p

BCOR-rearranged sarcomas (BRS) constitute relatively newly described sarcomas, which, within the musculoskeletal sites, usually occur in the bones, followed by soft tissues. Primary BRS involving the visceral organs is very rare, and only a single case is reported in the lung. These tumors share overlapping morphological and immunohistochemical (IHC) features with other neoplasms, such as synovial sarcoma, Ewing sarcoma, as well as carcinosarcoma, the latter especially when occurring in the visceral organs. BCOR immunostaining is useful in triaging a tumor for molecular diagnosis, which constitutes the “essential” diagnostic criterion for these tumors. To report an extremely rare case of a BRS, confirmed by BCOR-rearrangement by fluorescence in situ hybridization (FISH), primarily occurring in the lung, emphasizing the diagnostic approach and management, along with review of literature. An18-year-old boy presented with complaints of left-sided chest pain, along with cough, fever, loss of appetite, and weight. On radio imaging, there was a complete collapse of the left lower lobe of lung with moderate pleural effusion. The biopsy showed a biphasic tumor comprising primitive round cells admixed with spindle cells. Immunohistochemically, the tumor cells were positive for BCOR, TLE1, and p53. FISH showed BCOR gene rearrangement. A diagnosis of primary BRS of lung was offered. The patient had a favorable response to the chemotherapy regime. BRS is an ultra-rare tumor, which rarely involves visceral organs. The lung is an exceptionally rare site, with only single reported case previously. An exact confirmation by molecular testing has treatment-associated implications. A review of similar reported cases is presented herewith.

Objective: Aim of study was to describe the clinical characteristics and short-term survival of adult patients diagnosed with skeletal Ewing sarcoma. Methods: This descriptive study included 15 patients who underwent surgical treatment after being diagnosed with skeletal Ewing sarcoma and received perioperative treatment between January 2017 and February 2023. Patients were retrospectively evaluated for tumor recurrence, metastasis development, and survival. Results: Of the 15 patients, 10 were men and 5 were women. At the time of diagnosis, 11 (73.33%) patients were found to be non-metastatic. Bone marrow transplantation was performed in 12 (80%) patients. Metastasis was detected during the follow-up period in 6 (40%) patients. Local recurrence developed in 10 (66.7%) patients, and additional surgeries were planned due to recurrence in 5 (33.3%). Second recurrence developed in 4 (26.67%) patients and 2 (13.3%) patients who required additional surgery. Overall, survival after surgical treatment was 4 years in 11 (73.33%) patients. Conclusion: Treatment protocols applied to adult patients with Ewing sarcoma are often adapted from pediatric clinical studies or have been developed based on the experiences of the centers. Therefore, to achieve better outcomes, it is crucial to report the treatment protocols and patient outcomes of centers providing care for adult Ewing sarcoma patients and contribute these findings to the literature in order to develop an optimal treatment strategy.

The Ewing sarcoma family of tumors (ESFT) stands for a group of rare and aggressive malignancies consisting of high grade poorly differentiated small round blue cells. In our case report, we aim to describe the clinical presentation, diagnosis and the treatment plan for our patient. A 16-year-old girl presented to the ENT outpatient department of the Mayo Hospital Lahore with the complaints of right nasal obstruction, epistaxis from right nose, swelling on the right cheek and headaches. Examination revealed a soft, tender swelling on her right cheek below the right eye. Imaging revealed a heterogeneous opacity in the right nose and right maxillary sinus with erosion of the sinus walls.Very few such cases have been reported in international literature. Being a rare case, our article will add insights to the literature regarding complex clinical presentation, diagnostic evaluation and treatment of the sinonasal Ewing sarcoma.

We report an uncommon case of primitive neuroectodermal tumor/ Ewing's sarcoma of the lumbar and sacral nerve plexus in a 17years old boy who presented with an intense pain in the lower back radiating to legs. Magnetic resonance imaging showed a soft tissue mass with thickening of lumbar and sacral spinal nerve roots (L5-S3 level), along with widening of the corresponding foramina. There was also posterior scalloping of L5/S1 vertebrae and invasion of the sacral bone. A Partial resection has been performed, and the ensuing histopathology confirmed the diagnosis of PNET/Ewing's sarcoma. MRI in conjunction with histopathology are the key to narrow down the differential diagnoses list. PNET of lumbosacral area remain scarce, and only few cases have been reported nowadays. Given to the aggressivity of these tumors, the prognosis is poor despite appropriate treatment.

Abstract Ewing sarcoma (ES) poses a significant therapeutic challenge due to the difficulty in targeting its main oncodriver, EWS::FLI1. We show that pharmacological targeting of the EWS::FLI1 transcriptional complex via inhibition of P300/CBP drives a global transcriptional outcome similar to direct knockdown of EWS::FLI1, and furthermore yields prognostic risk factors for ES patient outcome. We find that EWS::FLI1 upregulates LMNB1 via repetitive GGAA motif recognition and acetylation codes in ES cells and EWS::FLI1-permissive mesenchymal stem cells, which when reversed by P300 inhibition leads to senescence of ES cells. P300-inhibited senescent ES cells can then be eliminated by senolytics targeting the PI3K signaling pathway. The vulnerability of ES cells to this combination therapy suggests an appealing synergistic strategy for future therapeutic exploration.

Extra-skeletal Ewing sarcoma (EWS) occurs in about 12% of EWS patients; at the same time, primary involvement of the kidneys remains extremely rare. Since it was first described in 1975, only a small case series have been reported worldwide. About 95% of surgically treated patients with EWS of the kidney described in the literature underwent nephrectomy, and the remaining patients only had a tumor biopsy. Nephron-sparing surgery (NSS) has not been sufficiently investigated as an alternative in the local surgical treatment of localized disease, mostly as a result of technically unfeasible provisions of negative surgical margins. In this report, we present a unique case of primary EWS of the kidney with an asymptomatic course without radiographic signs that suggest a highly aggressive disease, successfully locally treated with robotic-assisted NSS. This report showcases that robotic-assisted NSS could be a feasible alternative in treatment of localized disease yielding equally good oncological results while, at the same time, creating better prerequisites for necessary adjuvant chemotherapy.

Ewing sarcoma (EWS) is an invasive and primary bone tumor with a high incidence in children and adolescents. The presence and extent of metastases at the time of diagnosis remains the most important prognostic factor in determining a patient’s prognosis. Up now, considerable ambiguity exists regarding the optimal modality for detecting bone marrow metastases. Bone marrow biopsy and/or aspiration (BMBA) is the gold standard for determining bone marrow metastases. This invasive and painful procedure may be amenable to being replaced by 18F-FDG PET/CT because of its high sensitivity in detecting EWS bone and extraosseous metastases. This review provides an overview of the current literature, concludes that there is no longer a systematic consensus on the implementation of BMAB criteria for the diagnosis of bone marrow metastases in EWS, and summarizes the current practical strategies and clinical practices for the diagnosis of EWS bone marrow metastases accordingly.

Abstract Background Ewing sarcoma (EwS) is a highly malignant and heterogeneous tumor. Exploring clinicopathological characteristics and genetic features of EwS is critical for prognosis and treatment regimen. Methods Clinicopathological characteristics and genetic features of young (≤ 30y) and senior (> 30y) EwS patients were analyzed based on histology, phenotype, and next-generation sequencing (NGS) detection. Results The young group (18/36) presented nontypical EwS histological morphology, whereas the senior group (18/36) presented typical morphology. The prognosis of the young group was found to be worse compared with the senior group for patients without metastasis at the initial diagnosis. DNA- and RNA-based NGS was conducted on 20 extraosseous EwS patients. 16/20 samples demonstrated EWSR1-FLI1 fusion and 4/20 demonstrated EWSR1-ERG fusion. However, 13/16 EWSR1-FLI1fusions were detected both in DNA- and RNA-based NGS, 1/16 was detected only at the DNA level, and 2/16 were detected only at the RNA level. An analysis of the genetic profiles of the EWSR1-FLI1 cases revealed that the young group was inclined to couple with more copy number variations (CNV), such as CCND1, CDK4 amplification, and fusion variations, such as CHEK1-EWSR1, SLIT2-EWSR1, and EWSR1-FAM76B fusion. The senior group was more likely to have SNV or Indel mutations, such as EPHA3 and STAG2 mutations. Moreover, patients with more CNV abnormalities had a worse prognosis than those with predominantly SNP variants. In addition, compared with the senior group, the young group had significantly higher CyclinD1 protein expression. Conclusion Clinicopathological characteristics and genetic features in young and senior EwS patients differed significantly. Targeting cell cycle dysregulation based on age subgroup may be a potential therapeutic strategy for Ewing sarcoma.

Introduction: Ewing sarcoma is a rare and highly aggressive malignancy, mostly involving the axial skeleton. Ewing sarcoma usually affects children and young adults under 20. Usually presenting as a painful swelling and discomfort worsening over time. Case report: We present a case of a 19-year-old female with no known co-morbidities presenting in the Emergency Department with complaints of fever and backache for the past 2 weeks and bilateral lower limb weakness for more than a week. She was started on steroids and broad-spectrum antibiotics and packed cell volume due to low hemoglobin. The screening MRI of the cervical and dorsal spine without contrast revealed signal abnormalities in the vertebral bodies at multiple levels (C2, C5, C6, C7, T1, and T3), as well as within the spinous processes and interspinous musculature. Further evaluation with contrast-enhanced MRI was recommended. The contrast-enhanced MRI showed straightening of the cervical and dorsal spine due to muscular spasm. Additionally, there were small soft tissue components in the left paravertebral region at the level of D3, extending into the epidural space, and epidural components encasing the thecal sac at the levels of D5, D9, and D10 suggestive of neoplastic lesions, most likely metastasis. The morphological and immunohistochemical correlation established the diagnosis of Ewing Sarcoma of the left thigh with nodal, para-spinal, and soft tissue metastatic lesions. Conclusion: Ewing Sarcoma is generally reported in the pediatric population and may come into clinical view based on a plethora of signs and symptoms. Appropriate imaging in the form of X-rays, CT scans, and MRI must be employed to correctly diagnose, and stage the condition. [ABSTRACT FROM AUTHOR]

Ewing sarcoma is the second most common primary malignant bone cancer in children and adolescents. This rare type of cancer is characterized by its high malignancy and therefore high risk of metastases. Typically, Ewing sarcomas originate from bones. However, extraosseous Ewing sarcoma such as pulmonary Ewing sarcoma can also be found. In this case report, we present a 55-year old male patient who was initially diagnosed with non-small cell lung cancer at his local district hospital. However, the diagnosis was changed to one of pulmonary Ewing sarcoma after subsequent histopathological and molecular pathological analysis performed in a reference pathology laboratory. After patient referral to a certified (according to the German Cancer Society) high-volume sarcoma center, multimodal chemotherapy was initiated based on recently published clinical data as opposed to the more commonly used treatment regimen in Europe. The patient responded well to treatment and underwent a complete surgical tumor resection followed by radiotherapy. In summary, this case report highlights the importance of a rigorous and timely histopathological examination of biopsy samples by a specialized cancer center to enable a correct diagnosis of the cancer type. Additionally, molecular pathology plays a crucial part in this analysis and allows the necessary differentiation between cancer types. Up to now, there is no international treatment guideline available for the treatment of Ewing sarcoma. Patients should be referred to specialist centers to allow the best possible treatment of the cancer type in view of current published clinical data. In the case of Ewing sarcoma, and in accordance with the most recent research, patients should be treated with vincristine, doxorubicin and cyclophosphamide plus ifosfamide and etoposide in combination with local treatment such as surgery and/or radiotherapy because this has been demonstrated to be the more effective therapy. [ABSTRACT FROM AUTHOR]

Ewing sarcoma is a rare malignant neoplasm that primarily affects bone in children. Extraskeletal location is less common, while intradural extramedullary Ewing sarcoma (IEES) in adults is a casuistic phenomenon. Due to its rarity, a standardized treatment strategy for IEES has not been established. The clinical use of proton beam therapy (PBT) for craniospinal irradiation (CSI) in the treatment of IEES has not been reported in the literature. A 41-year-old previously healthy man presented with disabling gluteal and lower extremity pain, decreased sensation, and progressive paraparesis without sphincter dysfunction. Imaging showed intradural extramedullary spinal lesions. The patient underwent urgent surgery. Histology and immunohistochemistry suggested a poorly differentiated neuroendocrine tumor. Negative chromogranin staining and a high Ki67 index prompted further investigation. Next-generation sequencing later confirmed an EWSR1/FLI1 translocation, leading to the diagnosis of extraskeletal Ewing sarcoma. The patient received standardized chemotherapy with marked clinical improvement. PBT CSI was initiated but was interrupted due to COVID-19 and other complications. At 20 months follow-up, no recurrence was observed, and the patient reported an active life. Despite intra-spinal spread and multiple complications, intensive chemotherapy combined with PBT CSI led to a favorable outcome. CSI rather than focal radiotherapy should be considered for patients with IEES limited to the cerebrospinal axis. PBT may be used as an alternative to photon radiotherapy to better spare organs at risk. [ABSTRACT FROM AUTHOR]

Introduction: The topoisomerase 1 (TOP1) inhibitor irinotecan is a standard-of-care agent for relapsed Ewing sarcoma (EWS), but its efficacy is limited by chemical instability, rapid clearance and reversibility, and dose-limiting toxicities, such as diarrhea. Indenoisoquinolines (IIQs) represent a new class of clinical TOP1 inhibitors designed to address these limitations. Methods: In this study, we evaluated the preclinical efficacy of three IIQs (LMP400, LMP744, and LMP776) in relevant models of EWS. We characterized the pharmacokinetics of IIQs in orthotopic xenograft models of EWS, optimized the dosing regimen through tolerability studies, and tested the efficacy of IIQs in a panel of six molecularly heterogeneous EWS patient-derived xenograft (PDX) models. For each PDX, we conducted whole genome and RNA sequencing, and methylation analysis. Results: We show that IIQs potently inhibit the proliferation of EWS cells in vitro, inducing complete cell growth inhibition at nanomolar concentrations via induction of DNA damage and apoptotic cell death. LMP400 treatment induced ≥30% tumor regression in two of six PDX models, with more durable regression compared to irinotecan treatment in one of these models. RNA sequencing of PDX models identified a candidate predictive biomarker gene signature for LMP400 response. These data, along with pharmacogenomic data on IIQs in sarcoma cell lines, are available at a new interactive public website: https://discover.nci.nih.gov/rsconnect/EwingSarcomaMinerCDB/. Discussion: Our findings suggest that IIQs may be promising new agents for a subset of EWS patients. [ABSTRACT FROM AUTHOR]