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Giant cell tumor of bone (GCTB) is a rare osteolytic intermediate bone tumor that harbors a pathogenic H3F3A gene mutation and exhibits characteristic histology. The standard curative treatment for GCTB is complete surgical resection, but it frequently results in local recurrence and, more rarely, metastasis. Therefore, effective multidisciplinary treatment is needed. Although patient-derived tumor cell lines are promising tools for preclinical and basic research, there are only four available cell lines for GCTB in public cell banks. Thus, the aim of this study was to establish a novel GCTB cell line. Using surgically resected tumor tissues from a patient with GCTB, we established a cell line named NCC-GCTB4-C1. The cells harbored the typical H3F3A gene mutation and exhibited constant proliferation and invasive capabilities. After characterizing NCC-GCTB4-C1 cell behaviors, we conducted high-throughput screening of 214 anti-tumor drugs and identified seven effective drugs. Comparing the results of high-throughput screening using NCC-GCTB4-C1 cell line with the results using NCC-GCTB1-C1, NCC-GCTB2-C1, and NCC-GCTB3-C1 cell lines that we previously established, four drugs were in common effective. This study showed potential drugs for the treatment of GCTB. These data indicate that NCC-GCTB4-C1 has the potential to be a powerful tool in preclinical and basic research on GCTB.

Microcephaly is characterized by significant clinical and genetic heterogeneity, therefore reaching the genetic diagnosis remains challenging in this group of disorders. We describe a case of a girl with secondary microcephaly, associated with severe developmental delay, intellectual disability, growth retardation and dysmorphic features. For purposes of clinical genetic diagnostic testing, we performed trio whole exome sequencing in the proband and unaffected parents. We found a heterozygous de novo missense variant in the H3F3A gene in the proband (NM_ 002107.4: c.185T>G), which is absent from the gnomAD and from the Slovenian Genome databases. The identified variant affects a highly conserved leucine residue at position 62 of the histone H3 protein (H3.3) and is predicted to affect the physicochemical properties of the affected protein. Mouse models, which demonstrated involvement of H3.3 protein in the control of neuronal- and glial-specific gene expression patterns that control synaptic connectivity and behavioral plasticity. Additionally, we also identified similar cases reported in the ClinVar database. These arguments support the possible pathogenic role of the reported genetic variant and thus suggest a novel molecular mechanism for this syndromic form of microcephaly.

Background: Giant cell tumor of bone is a locally aggressive, rarely metastasizing tumor that accounts for about 5% of bone tumors and generally occurs in patients between 20 and 45 years old. A driver mutation in the histone 3.3 (H3.3) gene H3F3A has been identified in as many as 96% of giant cell tumors of bone. The immunohistochemical expression of H3F3A H3.3 G34 expression was found in 97.8% of cases. In the present study, we describe our series of cases of giant cell tumor of bone in pediatric patients &lt, 16 years old. Methods: All cases of giant cell tumor of bone in pediatric patients &lt, 16 years old treated in our institute between 1982 and 2018 were reviewed. Immunohistochemistry and/or molecular analysis for H3F3A gene mutations was performed to confirm the diagnosis. A group of aneurysmal bone cysts in patients &lt, 16 years old was used as a control group. Results: Fifteen cases were retrieved. A pronounced female predominance (93%) was observed. A pure metaphyseal central location occurs in 2 skeletally immature patients. Conclusions: Giant cell tumor of bone should be distinguished from its mimickers due to differences in prognosis and treatment. Immunohistochemical and molecular detection of H3F3A gene mutation represents a reliable diagnostic tool.

Giant cell tumors (GCTs) are primary bone tumors that occur most commonly in long bones, with half such tumors occurring in the distal femur, proximal tibia, and fibula. Around 12% of patients present with a pathological fracture indicating more aggressive disease. Arthrodesis after tumor resection is a popular choice due to its affordability and early postoperative mobilization, as well as low risks of implant loosening, infections, malignant lesions, or mortality. A free fibular graft is a popular option in limb-sparing surgery for long bone tumors. A bone graft and nail can be used to reconstruct long bones and bridge defects up to 25 cm. In developing countries, the cost of the imported mega prosthesis, around 8,500 US$, means many patients cannot afford the treatment. We describe a case of a GCT of the distal femur treated by excision of the tumor and reconstruction using a fibular bone graft, with knee arthrodesis using a custom-made long intramedullary interlocking nail fixation across the femur to the knee and the tibia. The length was achieved with 1 cm shortening post-surgery. The result was satisfactory, and partial weight-bearing was allowed three months after the surgery. At the one-year follow-up, there was no recurrence, and the patient had the full weight-bearing ability.

Background “Diffuse midline glioma (DMG), H3 K27M-mutant” is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Methods Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan–Meier modeling, and univariate and multivariate analysis. Results Median patient age was 32 years (range 18–71 years). Tumors were centered in the thalamus (n = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the H3F3A gene and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric DMGs. Accompanying mutations in TP53, PPM1D, FGFR1, NF1, and ATRX were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults. Conclusions Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.

Giant Cell Tumor (GCT) represents about 20% of benign bone tumors, is locally aggressive although malignant transformation is extremely rare

Aims Giant cell tumor of soft tissue (GCT-ST) is a primary soft tissue neoplasm histologically similar to GCT of bone (GCT-B). Recently, it has been reported that >90% of GCT-B have a driver mutation in H3F3A gene. Since the relationship between GCT-ST and GCT-B is unclear, we compared a series of GCT-ST and GCT-B for the presence of H3F3A mutations and for several immunophenotypic markers. Methods and Results Eight cases of GCT-ST were retrieved from our institutional archives. Fifteen GCT-B served as controls. Direct sequencing for H3F3A mutations in coding regions between codons 1 and 42, including the hot spot codons (28, 35 and 37) was performed on DNA extracted from formalin-fixed paraffin-embedded tissue. Tumors were studied immunohistochemically for the expression of CD14, CD33, RANKL, RANK, P63 and for the osteoblastic markers SATB2 and RUNX2. None of the 7 cases of GCT-ST that could be analyzed presented H3F3A mutations, whereas 14 GCT-Bs (93.3%) were mutated. All 8 cases of GCT-ST were positive for RANK and RUNX2, while RANKL and SATB2 were detected only in 2 cases (25%). CD14 was detected only in mononuclear elements, while multinucleated giant cells and part of the mononuclear population expressed CD33. Few mononuclear cells of GCT-ST expressed P63. In comparison, GCT-B showed higher expression of p63 (14/15 cases with >50% of positive mononuclear cells), RANKL and SATB2, while CD14, CD33, RANK and RUNX2 were similarly expressed. Conclusions Although similar in the histologic appearance, our results indicate that GCT-ST is immunophenotypically and genetically distinct from GCT-B. This article is protected by copyright. All rights reserved.

Pediatric glioblastomas (GBM) are lethal and fatal tumors and ∼30% of GBM and ∼80% of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. These mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a biomarker and tested an antibody directed specifically against the K27M mutation in 290 samples of 203 pediatric (including 38 pediatric high-grade astrocytomas), 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of K27M by immunohistochemistry showed 100% sensitivity and specificity and was superior to reduction in H3K27me3 as a biomarker. Moreover, cases that stained positive for K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of K27M is a sensitive and specific surrogate for K27M mutations and a prognostic marker.