Search Results (261)

Background/Objectives: Ewing sarcoma (ES), a highly aggressive bone and soft tissue cancer occurring in children and young adults, is defined by the ETS fusion oncoprotein EWS::FLI1. Although event-free survival rates remain high in ES patients with localized disease, those with metastatic or relapsed disease face poor long-term survival odds. Topoisomerase 1 (TOP1) inhibitors are commonly used therapeutics in ES relapse regimens. Methods: In this work, we used a genome-wide CRISPR knockout library screen to identify the deletion of the TOP1 gene as a mechanism for resistance to topoisomerase 1 inhibitors. Using isogenic cell line models, we performed a high-throughput small-molecule screen to discover a small molecule, GNF-7, which had an IC50 that was 10-fold lower in TOP1-deficient cells when compared to the wild-type cells. Results: The characterization of GNF-7 demonstrated the molecule was highly active in the inhibition of CSK, p38α, EphA2, Lyn, and ZAK and specifically downregulated genes induced by the EWS::FLI1 fusion oncoprotein. Conclusions: Together, these results suggest that GNF-7 or small molecules with a similar kinase profile could be effective treatments for ES patients in combination with TOP1 inhibitors or for those patients who have developed resistance to TOP1 inhibitors. Full article

Background: CIC-rearranged sarcoma is a rare and aggressive type of undifferentiated round cell tumor characterized by CIC gene fusion, most commonly CIC::DUX4. This study presents a series of eleven cases, highlighting their clinicopathological features. Methods: Pathology records (2019 to 2024) were searched using “sarcoma with CIC”, identifying eleven cases, of which seven referred cases were initially misdiagnosed. Pathological and clinical analysis was conducted. Treatment was dictated upon multidisciplinary panel discussion based on tumor stage. Follow-up data (1–25 months) was available for all patients. Results: The cohort included six males and five females, with a median age of 43 years (range;14–53), with nine in soft tissue and two in bone. Tumor size ranged from 3.5 cm to 20.0 cm (mean: 9.8 cm). Most cases showed sheets of undifferentiated round- to oval-shaped cells. Two cases showed an Ewing-like pattern, and one case showed spindle cells in a fibrotic stroma transitioning to epithelioid cells. Necrosis was present in nine cases, and mitotic count ranged from 2 to 38/ 10HPFs (mean = 14.2). CD99 was positive in (10/11) cases and WT-1 in (6/9). NKX2.2, S100, and MDM2 were positive in rare cases. CIC::DUX4 fusion was detected in four cases. FISH for CIC gene rearrangement was positive in seven cases, two of them confirmed by methylation analysis. Metastasis at diagnosis was common (n = 8), primarily in the lungs, with later metastasis to the brain and bone. At time of final analysis, eight patients died within a median of 10 months (range: 1–19 months), while three were alive, two with stable disease (for a period of 6 and 25 months) and one with progression after 10 months. Significant correlation was seen between overall survival and the presence of metastasis at diagnosis (p value = 0.03). Conclusions: CIC-rearranged sarcomas are rare, high-grade tumors with predilection for soft tissue. Misdiagnosis is frequent, necessitating molecular confirmation. These tumors are treatment-resistant, often present with lung metastasis, and carry a poor prognosis, especially with initial metastasis. Full article

Background: Primary malignant bone tumors among adolescent patients are most commonly associated with burdensome surgeries that can severely affect young patients’ early life. To this day, despite available autologous tissue donor sites, cement spacers or endoprostheses are still most commonly used as a form of reconstruction of post-resection defects. Methods: The study group includes 20 adolescent patients diagnosed with Osteosarcoma or Ewing Sarcoma involving the upper limbs. The inclusion criteria were as follows: primary malignant bone tumors sensitive to neoadjuvant chemotherapy, tumors not infiltrating major blood vessels and nerves, and the appliance of the microsurgical free flap as a reconstructive method. Poor tumor response to neodajuvant chemotherapy or patients with incomplete follow-up were excluded from this study. To achieve the functional reconstruction of post-resection defects, fibula free flaps were applied. In cases of resection, including the metaphysis of a long bone, a modification of the flap harvest was applied in order to prevent arthrodesis. The MSTS (Musculoskeletal Tumor Society Scoring System) scale was used as a functional outcome measurement tool. Results: The reported outcomes of this study prove the efficiency of the treatment’s approach of combining the resection of the tumor with subsequent microsurgical restoration with the use of autologous tissues. The average score on the MSTS scale, which assesses the functional outcome, was 26.8/30 points, which indicates great motor outcomes. There were no reports of local recurrence during follow-up. Conclusions: Patients with primary malignant bone tumors in the upper limbs can benefit from microsurgical techniques, which are highly customized; effective; and give sufficient functionality following extensive resection. Full article

Purpose: We present our single-institution experience of sarcomatous brain metastasis patients who underwent stereotactic radiosurgery (SRS) over the past 35 years. Methods: In total, 31 patients (16 males) who underwent SRS for sarcoma brain metastases were identified. Median age at presentation to SRS was 47 (range: 4–78) months. Common histopathologies included leiomyosarcoma (eight patients), osteosarcoma (six patients), alveolar sarcoma (three patients), Ewing sarcoma (three patients), and undifferentiated/unclassified sarcoma (three patients). The median Karnofsky Performance Score (KPS) was 90. Nine patients underwent pre-SRS craniotomy. The median dose prescribed was 18 Gy. The median cumulative tumor volume was 1.4 cc. Results: Median patient overall survival (OS) after SRS was 7 (range: 0–155) months. Local tumor control (LTC) was achieved in 105 out of 113 tumors, at a median time of 3 (range: 0–17) months between SRS and progression. LTC rates per patient and per tumor were 74.2% and 92.9%, respectively. Following SRS, 10 patients (32.3%) developed new tumors at a median time of 6 (range: 1–25) months. Four patients experienced adverse radiation effects (AREs). At the last follow-up, all patients died, one patient from intracranial progression, 27 from systemic disease progression, and the remaining from unrelated medical conditions. Conclusions: Given high LTC and low ARE rates, this suggests SRS as a strong candidate for the non-invasive management of sarcomatous brain metastases, which typically present late following initial presentation of the primary disease. Full article

In children without Down syndrome who have acute megakaryoblastic leukemia (AMKL), inv(16)(p13q24)/CBFA2T3::GLIS2 is the most frequent genetic aberration. Pediatric CBFA2T3::GLIS2-positive AMKL is strongly associated with a poor prognosis and a high cumulative incidence of relapse. One of the key laboratory signs of CBFA2T3::GLIS2-positive AMKL is the RAM immunophenotype, which looks very similar to that of solid-tumor bone marrow (BM) infiltration. For this reason, in cases of isolated extramedullary involvement of CBFA2T3::GLIS2-positive AMKL, excluding solid tumors may be challenging. We report a case of a girl with isolated extramedullary CBFA2T3::GLIS2-positive AMKL relapse, which was misdiagnosed as secondary Ewing sarcoma. The morphological differential diagnosis between Ewing sarcoma and AMKL presented significant challenges owing to their overlapping histological features (small, round blue-cell morphology and similar growth patterns). The tumor cells’ immunophenotype completely mirrored that at the initial diagnosis of AMKL. Additional cytogenetic and molecular studies confirmed the presence of the CBFA2T3::GLIS2 fusion, but no Ewing sarcoma-specific EWSR1, FUS and CIC fusion transcripts were found. Thus, extramedullary CBFA2T3::GLIS2-positive AMKL relapse was confirmed. The presented case demonstrates the difficulties in differential diagnosis between AMKL relapse and the development of a secondary tumor. Full article

Though having been discovered in one third of sarcomas, gene fusions are less studied in their roles as potential therapeutic targets, making conventional modalities the mainstream treatment options for sarcoma patients. Recent decades have witnessed encouraging progress in basic research delving into mechanisms underlying how gene fusions drive sarcomas; nevertheless, further translation to clinical application fails to keep abreast with the advances achieved in basic science. In this review, we will focus on key chromosomal translocation-driven sarcomas defined by characteristic hallmark fusion oncoproteins, including Ewing sarcoma with EWSR1–FLI1/ERG fusion, epithelioid hemangioendothelioma with WWTR1–CAMTA1/YAP1–TFE1 fusion, and others, to discuss the potential of directly targeting these fusion proteins as therapeutic targets in preclinical and clinical contexts. Full article

Background: Mithramycin (MTM) is a polyketide anti-cancer natural product previously identified as an EWS-FLI1 inhibitor. This oncogenic transcription factor is a canonical target for drug development in Ewing sarcoma. However, poor pharmacokinetics have been identified as a critical liability of MTM, preventing its further development. Through semisynthetic chemical modifications, we identified mithramycin SA-Trp (MTMSA-Trp) as being a pharmacologically superior congener. To explore their pharmacokinetic (PK) differences, this study examined the plasma PKs and plasma protein binding (PPB) of MTM and MTMSA-Trp in mice, rats, and monkeys. Methods: Protein binding was investigated by rapid equilibrium dialysis in plasma from mice, rats, monkeys, and humans. The pharmacokinetics were investigated at milligram- and microgram-level doses in mice and rats. The pharmacokinetics in monkeys were investigated using the cassette dosing approach at two microgram-level doses. The MTMSA-Trp pharmacokinetic linearity was evaluated in mice at 0.3, 1, 3, and 10 mg/kg doses. All samples were analyzed using LC-MS/MS. Results: Plasma protein binding was higher for MTMSA-Trp (1–4% unbound) than for MTM (10–30% unbound) across species, except in athymic nude mice (1–4% unbound and <1% for mithramycin and MTMSA-Trp, respectively). In mice and rats, MTMSA-Trp had significantly lower clearance than MTM at both milligram and microgram doses; however, the difference in plasma exposure was more pronounced at milligram doses. Consistent with the rodent PK results, cassette microdosing in monkeys showed that the clearance of MTMSA-Trp was lower than that of MTM, but the differences were less pronounced. In the dose proportionality study, MTMSA-Trp showed linear pharmacokinetics at 1, 3, and 10 mg/kg doses. Conclusions: MTMSA-Trp has significantly lower clearance than MTM in rodent models. This is a significant improvement compared to the parent drug, MTM, and warrants further evaluation of PKs in non-rodent models to enable the prediction of MTMSA-Trp PK in humans. Full article

Background: Internal hemipelvectomies are rare procedures for primary musculoskeletal sarcomas of the bony pelvis. There is a sparse amount of data on functional outcomes and activity levels in postoperative patients. The aim of this study was to investigate functional outcomes, including sport activity levels, and the impact of tumor grade, resection margins, adjuvant therapies, pelvic reconstruction, and patient age at the time of surgery. Methods: Patients who underwent internal hemipelvectomy at our clinic between 1995 and 2019, with a minimum follow-up of 12 months, were assessed using the Musculoskeletal Tumor Society Score (MSTS), the Toronto Extremity Salvage Score (TESS), the Oxford Hip Score (OHS), and the University of Los Angeles Activity Scale (UCLA AS). Results: Our cross-sectional study included 29 patients (14 male, 15 female; 15 with chondrosarcoma, 8 with Ewing’s sarcoma, 2 with osteosarcoma, 2 with chordoma, and 2 with other sarcomas) with a median follow-up of 8.7 years (range: 12 months to 25.4 years; interquartile range (IQR): 13.1 years). The median MSTS was 16 (range: 1–30; IQR: 9), median TESS was 75.8% (range: 12.9–100%; IQR: 31.7%), median OHS was 35 (range: 10–48; IQR: 16), and median UCLA AS was 5 (range: 1–9; IQR: 3). Tumor grade, resection margins, chemotherapy, radiation therapy, and pelvic reconstruction had no significant effect on functional outcomes. Patient age at the time of surgery had a statistically significant effect on all measured outcome parameters, although all parameters exhibited a wide range and large IQR, likely reflecting the small, heterogeneous patient cohort. Conclusions: Surviving patients who underwent internal hemipelvectomy for primary musculoskeletal sarcomas of the pelvic bone demonstrated overall moderate to good functional outcomes and moderate sport activity levels. Full article

Musculoskeletal tumors present a diagnostic challenge due to their rarity, histological diversity, and overlapping imaging features. Accurate characterization is essential for effective treatment planning and prognosis, yet current diagnostic workflows rely heavily on invasive biopsy and subjective radiologic interpretation. This review explores the evolving role of radiogenomics and machine learning in improving diagnostic accuracy for bone and soft tissue tumors. We examine integrating quantitative imaging features from MRI, CT, and PET with genomic and transcriptomic data to enable non-invasive tumor profiling. AI-powered platforms employing convolutional neural networks (CNNs) and radiomic texture analysis show promising results in tumor grading, subtype differentiation (e.g., Osteosarcoma vs. Ewing sarcoma), and predicting mutation signatures (e.g., TP53, RB1). Moreover, we highlight the use of liquid biopsy and circulating tumor DNA (ctDNA) as emerging diagnostic biomarkers, coupled with point-of-care molecular assays, to enable early and accurate detection in low-resource settings. The review concludes by discussing translational barriers, including data harmonization, regulatory challenges, and the need for multi-institutional datasets to validate AI-based diagnostic frameworks. This article synthesizes current advancements and provides a forward-looking view of precision diagnostics in musculoskeletal oncology. Full article

A histological evaluation remains the cornerstone of diagnosing highly malignant osteosarcoma, having demonstrated its efficacy and reliability over several decades. However, despite these advancements, misdiagnoses with severe consequences, including inadequate surgical procedures, continue to occur. Consequently, there is a pressing need to further enhance diagnostic security. Adjunct immunohistochemical approaches have demonstrated significant effectiveness in regard to cancer diagnostics, generally. However, their utility for identifying highly malignant osteosarcoma is limited. Molecular genetic findings have significantly improved the diagnosis of Ewing’s sarcoma by identifying specific translocations and have been used to detect specific IDH gene mutations in chondrosarcoma. Nevertheless, molecular genetic alterations in highly malignant osteosarcoma exhibit a high degree of complexity, thereby limiting their diagnostic utility. Given that only 1–2% of the human genome comprises protein-coding sequences, the growing number of non-coding regulatory RNAs, which are increasingly being elucidated, has garnered substantial attention in the field of clinical cancer diagnostics. Over the past several years, patterns of altered non-coding RNA expression have been identified that facilitate the distinction between benign and malignant tumors in various organs. In the field of bone tumors, the experience of this approach has been limited thus far. The divergent expression of microRNAs has demonstrated utility for differentiating osteosarcoma from osteoblastoma and discriminating between osteosarcoma and giant-cell tumors of bone and fibrous dysplasia. However, the application of non-coding RNA expression patterns for the differential diagnosis of osteosarcoma is still in its preliminary stages. This review provides an overview of the current status of non-coding RNAs in osteosarcoma diagnostics, in conjunction with a histological evaluation. The potential of this approach is discussed comprehensively. Full article

Objectives: To evaluate the clinical heterogeneity of sarcomas by examining associations between histological subtypes, metastatic patterns, treatment modalities, and survival outcomes. Methods: We analyzed data from 97,062 adult patients diagnosed with sarcoma between 2000 and 2020, using the Surveillance, Epidemiology, and End Results (SEER) database. Fourteen histological subtypes were included. Propensity score matching (PSM) was employed to adjust for baseline differences, and Cox proportional hazards models were used to identify prognostic variables. Results: The most prevalent subtypes were sarcoma not otherwise specified (31.9%), leiomyosarcoma (17.1%), and liposarcoma (13.9%). Metastatic patterns differed significantly by subtype; liver metastases were most common in sarcomas with small blue round cell (SBRC) features (8.9%) and stromal sarcoma (6.1%), while lung metastases were frequently observed in Ewing sarcoma (10.0%) and rhabdomyosarcoma (9.7%). Median overall survival (mOS) varied widely, ranging from 234 months in chondrosarcoma to 16–20 months in rhabdomyosarcoma and SBRC sarcoma. Overall, patients with primary sarcoma had significantly better survival than those with treatment-related disease (119.0 vs. 45.0 months, p < 0.0001), with this trend consistent across most subtypes. Treatment responses were subtype- and size-dependent. For instance, surgery plus radiotherapy improved outcomes in giant cell sarcoma regardless of tumor size, whereas chemotherapy provided benefit only in tumors larger than 5 cm. Combined surgery and radiotherapy offered additional survival benefit in select subtypes, including chordoma, leiomyosarcoma (>5 cm), and synovial sarcoma (<5 cm). Conclusions: Sarcomas exhibit substantial clinical and prognostic heterogeneity across histological subtypes. These findings underscore the importance of subtype-specific, individualized treatment strategies in optimizing patient outcomes. Full article

Bone sarcomas, including Osteosarcoma, Ewing’s sarcoma, and Chondrosarcoma, are rare yet aggressive tumors with high metastatic potential and poor survival outcomes. Despite advances in surgical and chemotherapeutic techniques, these malignancies remain difficult to treat. They often exhibit resistance to conventional therapies and are associated with a limited prognosis for patients. MicroRNAs (miRNAs) have emerged as pivotal regulators of cancer biology, orchestrating crucial processes such as cell proliferation, apoptosis, and metastasis. Their double life as oncogenes or tumor suppressors underscores their significance in the pathogenesis of bone sarcomas. This review examines the multifaceted roles of miRNAs in these malignancies. By elucidating the complex networks affected by miRNA dysregulation, we seek to identify novel avenues for miRNA-based interventions. It is the intention of this work to stimulate future research and clinical strategies that exploit the potential of miRNAs to transform the management and outcomes of bone sarcomas. Full article

CD99 is a membrane protein critical for various immunological functions, including T-cell activation, protein trafficking, cell apoptosis, and leukocyte movement. It is also highly expressed in certain malignant tumors, contributing to the development, invasion, immune evasion, and adaptation of tumor cells to stress stimuli, including drug resistance. CD99 is crucial at the intersection of normal biological processes and pathological conditions like cancer. While research indicates that CD99 may interact homotypically, there is evidence of some heterotypic ligands that align with its roles. The development of multiple anti-CD99 antibodies has shed light on its functions, particularly regarding interactions between tumor cells that overexpress CD99 and immune cells expressing the same protein within the microenvironment. Anti-CD99 antibodies effectively eliminate tumors and attract immune cells to the tumor area. Additionally, CD99 influences the expression of specific immune checkpoint molecules, such as CD47, paving the way for potential combinations of anti-CD99 with immune checkpoint inhibitors. This review explores CD99’s role in normal physiology and cancer biology, focusing on how monoclonal antibodies affect CD99 expression and activity, thereby influencing cancer cells’ interactions with their microenvironment. It summarizes key findings about how these changes impact cancer cell behavior and the effectiveness of treatments. Full article

Primary malignant bone tumours can pose significant diagnostic and therapeutic challenges due to inter-tumour heterogeneity. While traditional imaging modalities such as radiography, MRI (magnetic resonance imaging), and CT (computed tomography) remain essential for initial evaluation and staging, emerging evidence underscores the evolving role of positron emission tomography (PET), particularly PET/CT with Fluorodeoxyglucose ([18F] FDG), in the comprehensive management of bone sarcomas. This narrative review aims to critically summarise the available literature on PET imaging’s utility in the management of primary bone tumours including osteosarcoma, chondrosarcoma, and Ewing sarcoma. Despite limitations like inconsistencies in standard uptake value (SUV) cutoffs and reduced pulmonary resolution, PET/CT is valuable for staging, assessing response to neoadjuvant chemotherapy, predicting histological outcomes, detecting recurrence, and guiding biopsy in metabolically active tumour sites. Further large-scale, prospective studies are warranted to standardise protocols and establish PET’s definitive role in sarcoma management. Full article