Ewing Sarcoma Research Articles

An Analysis of The Pattern and Frequency of Primary Malignant Bone Tumors in Nassyriah

Bone tumors are uncommon lesions and account for only 0.2% of all malignant tumors. Primary malignant bone tumors develop from bony tissue and are categorized according to their location of origin and the cell type that makes up the tumor. This research aims to report on the prevalence, geographic distribution, and comparison of malignant bone tumors in Nassyriha province. Malignant bone tumors were studied in 182 people (119 men and 63 females) between February 2021 and February 2023. Their ages varied widely (from 5 to 70), with the second decade being the most prevalent. The most common cancer was osteosarcoma, which accounted for 34.62 percent, followed by Ewing's sarcoma (24.73), chondrosarcoma (13.74), multiple myeloma (11.53), malignant giant cell tumors (8.14%), fibrosarcoma (2.74%), and 2 instances of chordoma (1.10%). None of the six instances (3.30%) could be definitively diagnosed. Primary malignant bone tumors are rising, with men being disproportionately impacted. Information gleaned from this study will be useful for both researchers and clinicians.

Mesenchymal Non-Meningothelial Tumors of the CNS: Evolving Molecular Landscape and Implications for Neuroradiologists.

The World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5) significantly revised the terminology and diagnostic criteria of "mesenchymal non-meningothelial" tumors of CNS to better align with the classification of these soft tissue tumors outside the CNS. The CNS chapter only covers the entities with distinct histological or molecular characteristics that occur exclusively or primarily in the CNS. These tumors usually arise from the meninges and are rarely intraparenchymal in origin, mainly in the supratentorial compartment. These tumors are grouped into three main categories: soft tissue, chondro-osseous, and notochordal. Soft tissue tumors, the largest group, are further divided into fibroblastic, vascular, and skeletal muscle subtypes. Notably, a new subcategory for "tumors of uncertain differentiation" has been introduced, encompassing three new histomolecular entities: FET::CREB fusion-positive, CIC-rearranged sarcoma, and primary intracranial sarcoma, DICER1-mutant. Emerging entities like dural angioleiomyomas and spindle cell neoplasms with NTRK-rearrangements have been reviewed, although not introduced in WHO CNS5. Given the often non-specific histology and immunophenotype of mesenchymal nonmeningothelial tumors of uncertain differentiation, molecular techniques have become indispensable for accurate diagnosis. This review provides a comprehensive overview of primary mesenchymal non-meningothelial CNS tumors, including their clinical, radiological, histopathological, and molecular characteristics and treatment strategies.ABBREVIATIONS: ALK: Anaplastic lymphoma kinase; ATF1: activating transcriptase factor-1; CREB: cAMP response element-binding protein; CREM: cAMP response element modulator; CIC: Capicua transcriptional receptor; EWSR1: Ewing sarcoma RNA binding protein; FUS: fused in sarcoma; NAB2: nerve growth factor-inducible protein A binding protein 2; STAT6: signal transducer and activator of transcription 6; WHO: World Health Organization WHO CNS5: World Health Organization Classification of Tumors of the Central Nervous System, fifth edition.

Hijacking the BAF complex: the mechanistic interplay of ARID1A and EWS::FLI1 in Ewing sarcoma.

Ewing sarcoma, an aggressive pediatric cancer, is driven by the EWS::FLI1 fusion protein, which disrupts gene expression by hijacking the BAF chromatin remodeling complex. Central to this mechanism is the formation of biomolecular condensates, mediated by the prion-like domains (PrLDs)of EWS and ARID1A, a core BAF subunit. ARID1A serves as a critical interface between EWS::FLI1 and the BAF complex, with its condensate-forming ability essential for the aberrant gene expression that drives tumor growth. The loss of condensate-competent ARID1A significantly impairs tumor progression, identifying it as a potential therapeutic target. However, targeting condensate formation is challenging due to the transient nature of the interactions involved, complicating the development of effective inhibitors. This work underscores the importance of further investigation into therapeutic strategies aimed at disrupting condensate formation in Ewing sarcoma and other related malignancies.

Incidence trends, overall survival, and metastasis prediction using multiple machine learning and deep learning techniques in pediatric and adolescent population with osteosarcoma and Ewing's sarcoma: nomogram and webpage.

The objective of this study was to analyze the incidence and overall survival (OS) of osteosarcoma (OSC) and Ewing's sarcoma (EWS) in a pediatric and adolescent population, employing machine learning (ML) and deep learning (DL) models to predict the likelihood of metastasis. Involving 2465 OSC and 1373 EWS patients aged 0-19 years, from 2004 to 2020. ML techniques-Lasso, Ridge Regression, Elastic Net, and Random Forest-were used alongside a deep learning model based on TensorFlow and Keras, to construct predictive models for metastasis. These models were optimized using grid search with cross-validation and evaluated on their performance metrics, including AUC, sensitivity, and accuracy. The variables' importance in metastasis prediction was determined using SHAP values. Statistical analysis was performed using R software, and an online nomogram was developed for clinical use. The age-adjusted incidence of OSC and EWS from 2004 to 2020 showed a significant uptrend. The deep learning model, iterated 50 times, outperformed the Random Forest model in both loss and accuracy stabilization. The nomogram created demonstrated accurate survival predictions, as evidenced by its calibration curves and the distinction between high and low-risk groups. The increasing trend in age-adjusted incidence of OSC and EWS highlights the need for continued research and improved therapeutic strategies in this domain. The study employed ML and DL models to predict distant metastasis in pediatric and adolescent patients with OSC and EWS, providing a valuable tool for prognosis. The online nomogram developed as a part of this research enhances the models' clinical utility, offering an accessible means for clinicians to predict survival outcomes effectively.

A phenome-wide association study of polygenic scores for selected childhood cancer: Results from the UK Biobank

The aim of this study was to scan phenotypes in adulthood associated with polygenic risk scores (PRS) for childhood cancers with well-articulated genetic architectures: acute lymphoblastic leukemia (ALL), Ewing sarcoma, and neuroblastoma to examine genetic pleiotropy. Furthermore, we aimed to determine which single nucleotide polymorphisms (SNPs) could drive associations. Per-SNP summary statistics were extracted for PRS calculation. Participants with white British ancestry were exclusively included for analyses. SNPs were queried from the UK biobank genotype imputation data. Records from the cancer registry, death registry, and inpatient diagnoses were abstracted for phenome-wide scans. Firth logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) alongside corresponding p-values, adjusting for age at recruitment and sex. A total of 244,332 unrelated white British participants were included. We observed a significant association between ALL-PRS and ALL (OR: 1.20e+24, 95% CI: 9.08e+14-1.60e+33). In addition, we observed a significant association between high-risk neuroblastoma PRS and nonrheumatic aortic valve disorders (OR: 43.9, 95% CI: 7.42-260). There were no significant phenotype associations with Ewing sarcoma and neuroblastoma PRS. Regarding individual SNPs, rs17607816 increased the risk of ALL (OR: 6.40, 95% CI: 3.26-12.57). For high-risk neuroblastoma, rs80059929 elevated the risk of atrioventricular block (OR: 3.04, 95% CI: 1.85-4.99). Our findings suggest that individuals with genetic susceptibility to ALL may face a lifelong risk for developing ALL, along with a genetic pleiotropic association between high-risk neuroblastoma and circulatory diseases.

ENL mutation and AML: a new model that reveals oncogenic condensate's function in leukemogenesis.

Precise regulation of gene expression is essential for proper development and the maintenance of homeostasis in organisms. Studies have shown that some transcriptional regulatory proteins influence gene expression through the formation of dynamic, locally concentrated assemblies known as condensates, while dysregulation of transcriptional condensates was associated with several cancers, such as Ewing sarcoma and AML [Wang Y etal. (2023) Nat Chem Biol 19, 1223-1234; Chandra B etal. (2022) Cancer Discov 12, 1152-1169]. Mutations in the histone acetylation "reader" eleven-nineteen-leukemia (ENL) have been shown to form discrete condensates at endogenous genomic targets, but it remains unclear how ENL mutations drive tumorigenesis and whether it is correlated with their condensate formation property. Liu etal. now show, using a conditional knock-in mouse model, that ENL YEATS domain mutation is a bona fide oncogenic driver for AML. This mutant ENL forms condensates in hematopoietic stem/progenitor cells at the genomic loci of key leukemogenic genes, including Meis1 and Hoxa cluster genes, and disrupting condensate formation via mutagenesis impairs its chromatin and oncogenic function. Furthermore, they show that small-molecule inhibition of the acetyl-binding activity displaces ENL mutant condensates from oncogenic target loci, and this inhibitor significantly impairs the onset and progression of AML driven by mutant ENL in vivo.

Guidance for Circumflex Scapular Artery Flap Utilization in Pediatric Reconstruction.

The circumflex scapular artery (CSA) flap system, consisting of scapular, parascapular, and chimeric flaps, is useful for pediatric reconstruction in many anatomical locations. The objectives of this case series are to offer insights into our decision-making process for selecting the CSA flap in particular pediatric reconstructive cases and to establish a framework for choosing a scapular or parascapular skin paddle. We also aim to emphasize important technical considerations of CSA flap utilization in pediatric patients. Pediatric reconstruction with CSA flaps performed at our institution between 2006-2022 was retrospectively reviewed. Patient demographics, indications, flap characteristics, complications, and operative data were abstracted. Functional donor site morbidity was assessed through postoperative physical examinations. Unpaired t test analyzed scapular versus parascapular flap size. Eleven CSA flaps were successfully performed in 10 patients (6 scapular and 5 parascapular flaps). Patient ages ranged from 2 to 17 years. Scapular fasciocutaneous free flaps (n = 4) were performed in patients' ages 2-5 years for hand and forearm scar contractures. Two pedicled scapular flaps were performed for a single patient for bilateral axillary hidradenitis suppurativa. The 5 parascapular flaps were performed in patients' ages 2-14 years for calcaneus and forearm avulsion wounds and reconstruction after resection of hidradenitis suppurativa, nevus sebaceous, and Ewing sarcoma. In the sarcoma resection case, a chimeric flap with latissimus dorsi was employed. Average flap size was 101.6 ± 87.3 cm2 (range: 18-300 cm2). Parascapular flaps were significantly larger than scapular flaps (156.60 ± 105.84 cm2 vs 55.83 ± 26.97 cm2, P = 0.0495). Overall, 3 complications occurred (27.3% of cases) including venous congestion (n = 2) and wound dehiscence (n = 1). There were no reported cases of compromised shoulder function at 1.9 ± 2.5-year follow-up. The successful reconstruction rate for scapular, parascapular, and chimeric flaps was 100%. The CSA flap treated a wide variety of indications demonstrating the flap's attributes: large vessel caliber, wide arc of rotation, reliable vascular anatomy, minimal donor site morbidity, and ability to incorporate bone and muscle. Our cases also highlight important pediatric considerations such as vascular mismatch and limited scapular bone stock. We recommend selection of the parascapular over the scapular flap with reconstruction of larger, complex defects given its ability to be harvested with a large skin paddle.

18 F-FDG PET Metabolic Parameters for the Prediction of Histological Response to Induction Chemotherapy in Osteosarcoma and Ewing Sarcoma : A Systematic Review and Network Meta-analysis.

This study aimed to evaluate the ability of 18 F-FDG PET/CT metabolic parameters to predict the histological response to neoadjuvant chemotherapy in patients with osteosarcoma and Ewing sarcoma. This systematic review and network meta-analysis adhered to the PRISMA-NMA and Cochrane guidelines. Electronic databases were searched from January 2008 to January 2024; this search was supplemented by snowballing methods. The risk of bias was evaluated with QUADAS-2, and evidence certainty was assessed using the GRADE approach. The prognostic value of 18 F-FDG PET/CT parameters, including pretreatment and posttreatment SUVs (SUV1, SUV2 and the SUV2/SUV1 ratio), metabolic tumor volume (MTV1, MTV2, ΔMTV), and total lesion glycolysis (TLG1, TLG2, ΔTLG), was examined. The meta-analysis of 18 studies (714 patients) identified the ΔTLG, ΔMTV, and SUV ratio as superior predictors of histological response. The changes in metabolic activity, as indicated by these parameters, provided a robust indication of treatment effectiveness. Baseline parameters showed limited predictive value compared with posttreatment assessments. The study's robustness was confirmed through meta-regression, which revealed that the predictive value of the SUV2 and SUV ratio was consistent across various cutoff thresholds. 18 F-FDG PET/CT metabolic parameters, particularly those measuring changes posttherapy, are effective in predicting the histological response in patients with osteosarcoma and Ewing sarcoma. These findings underscore the potential of 18 F-FDG PET/CT in guiding early treatment decisions, thereby enhancing personalized therapeutic approaches.

Is Information About Musculoskeletal Malignancies From Large Language Models or Web Resources at a Suitable Reading Level for Patients?

Patients and caregivers may experience immense distress when receiving the diagnosis of a primary musculoskeletal malignancy and subsequently turn to internet resources for more information. It is not clear whether these resources, including Google and ChatGPT, offer patients information that is readable, a measure of how easy text is to understand. Since many patients turn to Google and artificial intelligence resources for healthcare information, we thought it was important to ascertain whether the information they find is readable and easy to understand. The objective of this study was to compare readability of Google search results and ChatGPT answers to frequently asked questions and assess whether these sources meet NIH recommendations for readability. (1) What is the readability of ChatGPT-3.5 as a source of patient information for the three most common primary bone malignancies compared with top online resources from Google search? (2) Do ChatGPT-3.5 responses and online resources meet NIH readability guidelines for patient education materials? This was a cross-sectional analysis of the 12 most common online questions about osteosarcoma, chondrosarcoma, and Ewing sarcoma. To be consistent with other studies of similar design that utilized national society frequently asked questions lists, questions were selected from the American Cancer Society and categorized based on content, including diagnosis, treatment, and recovery and prognosis. Google was queried using all 36 questions, and top responses were recorded. Author types, such as hospital systems, national health organizations, or independent researchers, were recorded. ChatGPT-3.5 was provided each question in independent queries without further prompting. Responses were assessed with validated reading indices to determine readability by grade level. An independent t-test was performed with significance set at p < 0.05. Google (n = 36) and ChatGPT-3.5 (n = 36) answers were recorded, 12 for each of the three cancer types. Reading grade levels based on mean readability scores were 11.0 ± 2.9 and 16.1 ± 3.6, respectively. This corresponds to the eleventh grade reading level for Google and a fourth-year undergraduate student level for ChatGPT-3.5. Google answers were more readable across all individual indices, without differences in word count. No difference in readability was present across author type, question category, or cancer type. Of 72 total responses across both search modalities, none met NIH readability criteria at the sixth-grade level. Google material was presented at a high school reading level, whereas ChatGPT-3.5 was at an undergraduate reading level. The readability of both resources was inadequate based on NIH recommendations. Improving readability is crucial for better patient understanding during cancer treatment. Physicians should assess patients' needs, offer them tailored materials, and guide them to reliable resources to prevent reliance on online information that is hard to understand. Level III, prognostic study.

Ewing Sarcoma of Temporal bone Presentation as Chronic Otitis Media: A rare Clinical Confusion

Ewing Sarcoma of Temporal bone Presentation as Chronic Otitis Media: A rare Clinical Confusion

Identification of ENO-1 positive extracellular vesicles as a circulating biomarker for monitoring of Ewing sarcoma.

The lack of circulating biomarkers for tumor monitoring is a major problem in Ewing sarcoma management. The development of methods for accurate tumor monitoring is required, considering the high recurrence rate of drug-resistant Ewing sarcoma. Here, we describe a sensitive analytical technique for tumor monitoring of Ewing sarcoma by detecting circulating extracellular vesicles secreted from Ewing sarcoma cells. Proteomic analysis of Ewing sarcoma cell-derived extracellular vesicles identified 564 proteins prominently observed in extracellular vesicles from three Ewing sarcoma cell lines. Among these, CD99, SLC1A5, and ENO-1 were identified on extracellular vesicles purified from sera of patients with Ewing sarcoma before treatment but not on extracellular vesicles from those after treatment and healthy individuals. Notably, not only Ewing sarcoma-derived extracellular vesicles but also Ewing sarcoma cells demonstrated proteomic expression of CD99 and ENO-1 on their surface membranes. ENO-1+CD63+ extracellular vesicle detection was reduced after tumor resection while both CD99+CD63+ and ENO-1+CD63+ extracellular vesicles were detected in serum from Ewing sarcoma-bearing mice. Finally, the accuracy of liquid biopsy targeting these candidates was assessed using extracellular vesicles from the sera of patients with Ewing sarcoma. Elevated ENO-1+CD81+ extracellular vesicles in the serum of patients before treatments distinguished patients with Ewing sarcoma from healthy individuals with an area under the curve value of 0.92 (P < 0.001) and reflected the tumor burden in patients with Ewing sarcoma during multidisciplinary treatments. Collectively, circulating ENO-1+CD81+ extracellular vesicle detection could represent a novel tool for tumor monitoring of Ewing sarcoma.

Primary Ewing Sarcoma of Kidney in an Adult: An Oddball

Ewing sarcoma (ES) is a malignant bone and soft-tissue tumor derived from neuroectoderm. It occurs, mostly, in pediatric adolescentswith the histopathological features of invasiveness. The occurrence of ES of the kidney is rare, comprising only 1% of all renal tumorswhich are limited to case reports and small case series. Herein, we report a case of a 44-year-old male patient, presenting with the rightflank pain and hematuria. Computed tomography scan demonstrated a right midpolar exophytic renal mass with intraluminal right renalvein and inferior vena cava (IVC) thrombus without visceral metastasis suggesting the diagnosis of renal cell carcinoma (T3BN0M0).The patient underwent the right radical nephrectomy with IVC thrombectomy. In view of the aggressiveness of the tumor, the patientreceived adjuvant chemotherapy (i.e., four cycles of vincristine, adriamycin, and cyclophosphamide alternating every 3 weeks with fourcycles of ifosphamide and etoposide). The patient had near-complete resolution of the tumor with no thrombus seen in the follow-upscan. We could not complete six cycles of chemotherapy which were planned initially due to recurrent cytopenias. Six months postchemotherapy,the patient is clinically and radiologically disease-free and is in close follow-up. We are reporting this case to highlightthe rarity of this entity and its challenging clinicopathological diagnosis when presenting as a renal tumor.

Menin in Cancer.

The protein menin is encoded by the MEN1 gene and primarily serves as a nuclear scaffold protein, regulating gene expression through its interaction with and regulation of chromatin modifiers and transcription factors. While the scope of menin's functions continues to expand, one area of growing investigation is the role of menin in cancer. Menin is increasingly recognized for its dual function as either a tumor suppressor or a tumor promoter in a highly tumor-dependent and context-specific manner. While menin serves as a suppressor of neuroendocrine tumor growth, as seen in the cancer risk syndrome multiple endocrine neoplasia type 1 (MEN1) syndrome caused by pathogenic germline variants in MEN1, recent data demonstrate that menin also suppresses cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, and melanoma. On the other hand, menin can also serve as a tumor promoter in leukemia, colorectal cancer, ovarian and endometrial cancers, Ewing sarcoma, and gliomas. Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin's function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation.

Ten‐year follow‐up of outcomes, patterns of care, and psychosocial burden in adolescent and young adult patients with bone sarcomas from a large cohort in a low‐income and middle‐income country

AbstractBackgroundThe 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.MethodsThis 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.ResultsThe 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 &lt; .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.ConclusionsHomogenous 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.

Safety and effectiveness of controlled ovarian stimulation and oocyte retrieval during prepubertal and peripubertal period.

Is itsafe and effective to perform controlled ovarian stimulation (COS) and oocyte retrieval (OR) in prepubertal and peripubertal patients? In this retrospective cohort study, data of 20 pre-/peripubertal patients who underwent COS and OR for the purpose of oocyte cryopreservation (OC) between 2008 and 2023 were reviewed.Following COS, all OR procedures were performed transabdominally using a vaginal ultrasound probe. Ovarian reserve was assessed by serum FSH, LH, estradiol, AMH, and antral follicle counts (AFC) in all subjects. All mature oocytes were vitrified. Mean age of the patients was 15.05 ± 1.87, mean AMH was 0.84 ± 0.8ng/ml, mean FSH was 6.39 ± 3.95IU/L, mean estradiol was 61.6 ± 51.9pg/ml, mean LH was 4.69 ± 3.46IU/L, and mean AFC was 5.5 ± 5.82. Among the patients, 12 had regular menstrual cycle, 5 had irregular menstrual cycle, whereas 3 patients still did not have their menarche yet. The indications for OC were as follows: primary ovarian insufficiency (n = 7), ovarian surgery for ovarian tumors (n = 5) or ovarian torsion (n = 1), mosaic Turner syndrome (n = 2), acute lymphoblastic leukemia (n = 1) anaplastic B-cell lymphoma (n = 1), Ewing's sarcoma (n = 1), Noonan syndrome (n = 1), and Thalassemia (n = 1). The mean number of oocytes retrieved, MII oocytes frozen, and maturation rate were 5.11 ± 5.0, 3.92 ± 4.48, and 75.1 ± 25.6%, respectively.Stepwise linear regression analysis demonstrated a positive correlation between AFC and number of total oocytes retrieved and number of MII oocytes. In the case diagnosed with Noonan syndrome, all 7 retrieved oocytes were MI and all frozen at MI phase. No patient had any complication related to COS or OR. Even though number of the enrolled subjects is limited and mean AMH is lower in our cohort, we demonstrated that performing COS and OR is safe in pre-/peripubertal patients. If required, transabdominal route can be performed in this age group for OR. AFC appears as a prognostic factor for stimulation outcome in this age group. Pediatric patients or young adolescents at risk for primary ovarian insufficiency should not bediscouragedfrom utilizing OC.

Primary Ewing Sarcoma in the Sphenoidal Sinus: A Case Report.

Ewing's sarcoma (EWS) is a rare malignant bone tumor that primarily affects children and young adults. While it typically affects long bones, it can occur in the head and neck region, including the paranasal sinuses in rare cases. We present a challenging case of a 45-year-old female diagnosed with an EWS of the sphenoidal and the right nasal fossa. A subtotal removal of the mass was performed on the patient followed by combined adjuvant radiotherapy and chemotherapy. Due to its rarity, the diagnosis and management of EWS in the paranasal sinuses are challenging.

Clinicopathological characteristics and genetic features of young and senior Ewing sarcoma patients

BackgroundEwing sarcoma (EwS) is a highly malignant and heterogeneous tumor. Exploring clinicopathological characteristics and genetic features of EwS is critical for prognosis and treatment regimen.MethodsClinicopathological characteristics and genetic features of young (≤ 30y) and senior (> 30y) EwS patients were analyzed based on histology, phenotype, and next-generation sequencing (NGS) detection.ResultsThe 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.ConclusionClinicopathological 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.

Abstract A084: CDK12 inhibition drives mitotic catastrophe, triggering genome instability and innate immune response in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited therapies. In our screening using patient-derived organoids, we identified cyclin-dependent kinase 12 (CDK12) as a promising target in a subset of PDAC. Both pharmacological and genetic inhibition of CDK12 exerted potent antitumor activity in vitro and in vivo, inducing double-strand DNA breaks and apoptosis. CDK12 is a member of cyclin-dependent kinases that is involved in gene expression regulations at multiple levels. Recently, CDK12 has gained attention as a therapeutic target in several types of cancers including triple-negative breast cancer and Ewing sarcoma. However, little is known about the impact and possibility of CDK12 inhibition in pancreatic cancer treatment. As the lack of specific inhibitors that selectively target CDK12, studying CDK12 has long been challenging. To overcome this, we used CRISPR-Cas9 mediated genome editing to generate FKBP12F36V (dTAG) knock-in PDAC cell lines, enabling rapid elimination of endogenous CDK12 using a degrader against dTAG (dTAG-13). Quantitative-image-based cytometry and time lapse imaging showed that CDK12 ablation induces mitotic arrest, DNA damage and apoptosis (mitotic catastrophe). Specifically, loss of CDK12 kinase activity in the S phase was sufficient to slow DNA replication speed, leading to spindle assembly checkpoint activation and mitotic catastrophe. Importantly, cells that escaped mitotic death accumulate micronuclei, triggering immune response signaling that is mediated by the cGAS-STING-type I interferon pathway. Our results suggest that CDK12 is a promising target in a subset of PDAC patients, where CDK12 inhibition exerts antitumor activity both in cell autonomous and non-cell autonomous ways through inducing mitotic catastrophe as well as triggering immune response. Citation Format: Dosuke Iwadate, Keisuke Yamamoto, Hiroyuki Kato, Keisuke Tateishi, Mitsuhiro Fujishiro. CDK12 inhibition drives mitotic catastrophe, triggering genome instability and innate immune response in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A084.

Central Nervous System Fungal Diseases in Children with Malignancies: A 16-Year Study from the Infection Working Group of the Hellenic Society of Pediatric Hematology Oncology.

We analyzed data on pediatric invasive fungal diseases of the central nervous system (CNS-IFDs) reported by five of a total of eight Pediatric Hematology-Oncology Departments in Greece for 16 years (2007-2022). A total of twelve patients (11 boys, median age: 9.5 years, range: 2-16) were reported suffering from CNS-IFDs. The underlying malignancy was acute lymphoblastic leukemia in 9/12 and acute myeloid leukemia, Ewing sarcoma, and rhabdomyosarcoma in one each. Eleven patients presented with CNS-related symptoms (i.e., seizures, headache, cerebral palsy, ataxia, hallucination, seizures, blurred vision, amaurosis). All patients had pathological MRI findings. Multifocal fungal disease was observed in 6/12 patients. Nine proven and three probable CNS-IFD cases were diagnosed. Causative pathogens in proven cases were Aspergillus spp. and Candida albicans (n = 2 each), Mucor spp., Rhizopus arrhizus, Absidia spp., Fusarium oxysporum and Cryptococcus neoformans (n = 1 each). Causative pathogens in probable cases were Aspergillus spp. (n = 2) and Candida spp. (n = 1). All patients received appropriate antifungal therapy (median duration: 69.5 days, range 19-364). Two patients underwent additional surgical treatment. Six patients were admitted to the Intensive Care Unit due to complications. Three patients (25%) died, two due to IFD and one due to an underlying disease. Early recognition and prompt intervention of CNS-IFDs may rescue the patients and improve overall survival.

The BCOR-rearranged sarcoma involving the lung: Diagnosis with clinical outcome and literature review.

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.