Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations.

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

First-line Anti-GD2 Therapy Combined With Consolidation Chemotherapy in 3 Patients With Newly Diagnosed Metastatic Ewing Sarcoma or Ewing-like Sarcoma.

Despite multimodal therapy, the prognosis of patients with metastatic Ewing sarcoma (ES) remains poor, with new treatments urgently needed. The disialoganglioside GD2, a well-established tumor-associated antigen, is expressed in 40% to 90% of ES cells, making it a suitable therapeutic target. Here we report 3 cases with newly diagnosed, metastatic, GD2-positive ES or Ewing-like sarcoma treated with the anti-GD2 antibody dinutuximab beta in addition to standard chemotherapeutic regimens. Treatment was well-tolerated, and all patients achieved complete remission, without evidence of relapse. First-line anti-GD2 immunotherapy in patients with metastatic, GD2-positive ES or Ewing-like sarcoma represents a promising therapeutic option that warrants further clinical evaluation.

Early Use of Dinutuximab Beta in Patients with High-Risk Neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor in children, accounting for 15% of all pediatric cancer deaths. High-risk neuroblastoma (HRNB) is a particularly difficult-to-treat form of the disease that requires aggressive multimodality therapy, including induction chemotherapy, consolidation therapy with high-dose chemotherapy and autologous stem cell transplant, and maintenance therapy with dinutuximab beta. Despite treatment advances, the prognosis of these patients remains poor. As a better response to induction therapy has been associated with prolonged survival in patients with HRNB, we hypothesized that early use of dinutuximab beta-post-induction chemotherapy-may improve patient outcomes. We describe here our experience of administering at least one cycle of dinutuximab beta post-induction and prior to surgery in three children with HRNB who did not demonstrate a complete response to induction chemotherapy. All three patients achieved complete remission. Early use of dinutuximab beta may therefore have the potential to improve outcomes in patients with HRNB.

Magnetic Resonance Imaging of Hemophilic Joints: Correlations with the Bleeding Phenotype and Physical Examination.

INTRODUCTION: Blood-induced joint damage as a hallmark of haemophilia continues to occur despite the widespread prophylaxis. Pre-cise assessment and follow-up of joint status are crucial for tailoring their treatment. AIM: To study the correlation between the bleeding phenotype, the functional joint status, and the magnetic resonance imaging score in pediatric patients with haemophilia. MATERIALS AND METHODS: Eighty-six joints (ankles, knees, and elbows) in patients aged 10.7±0.5 (range 4 - 20) years with severe/moderate haemophilia A, severe haemophilia B and haemophilia A with inhibitors were included in the study. The joints were assessed by Haemophilia Joint Health Score 2.1 (HJHS2.1) one month after the last hemarthrosis in a non-bleeding state. The magnetic reso-nance imaging was performed on 40 (46.5%) of the examined hemophilic joints (16 ankles, 11 knees and 13 elbows). RESULTS: Joint bleeds were present in 37 (38.9%) of the joints with ankles being the most commonly affected. Sixty joints (69.8%) had normal HJHS2.1 score. Only the loss of flexion score differed significantly between the joints and the ankles had highest score. The cumulative number of hemarthrosis in the joint correlated moderately with hemosiderin deposition and strongly with the formation of subchondral cysts on magnetic resonance imaging. The magnetic resonance imaging scores for soft tissue and osteochondral domains correlated moderately with the cumulative number of hemarthrosis in the joint and only with the presence of pain and crepitus of mo-tion from the physical examination. CONCLUSIONS: Magnetic resonance imaging is more sensitive than the bleeding phenotype and physical examination in detecting early signs of haemophilic arthropathy.

Treatment of Childhood Acute Myeloid Leukemia in Bulgaria.

BACKGROUND: During the last four decades the prognosis of childhood acute myeloid leukemia (AML) has been substantially improved due to an increase in complete remission (CR) rates, event-free survival (EFS) and reduced early mortality. The relapsed AML still remains a therapeutic challenge. AIM: To report the AML treatment results of the Bulgarian pediatric oncohematological centers. MATERIALS AND METHODS: Retrospective analysis of the treatment results of children and adolescents (age from 0 to 20 years) with primary AML. Unified AML BFM- backbone type treatment protocol is used. RESULTS: This study included 97 newly diagnosed patients (44 girls and 53 boys) with AML in Bulgaria between 2003 and 2016. The median age at diagnosis was 10.2 years. The most frequent FAB-morphologic subtype was M2 followed by M4. First complete remission (CR1) was achieved in 83 patients (85.6%). The 13-year EFS was 49%, while the overall survival (OS) was 54.6%. Twenty seven (27.8%) patients relapsed, with only 5 of them being still alive towards the end of the study period. CONCLUSION: The EFS and OS for the children with AML in Bulgaria are comparable with those reported by other European groups. The prognosis of relapsed AML remains still unfavorable for the past 13 years.