The utility of FISH analysis in the diagnosis of BCOR-rearranged sarcomas.

Background: A BCL6 corepressor (BCOR) gene alteration is a genetic signature of rare subsets of sarcomas. The identification of this alteration has recently contributed to the definition of new entities in the current WHO (2020) classification of soft tissue and bone tumours. We retrospectively examined cases of BCOR-rearranged sarcoma (BRS) to assess the reliability of the BCOR FISH analysis using an IVD (in vitro diagnostic) probe.

SMARCB1/INI1 loss in skull base conventional chordomas: a clinicopathological and molecular analysis.

Introduction: The loss of SMARCB1/INI1 protein has been recently described in poorly differentiated chordoma, an aggressive and rare disease variant typically arising from the skull base.

Methods: Retrospective study aimed at 1) examining the differential immunohistochemical expression of SMARCB1/INI1 in conventional skull base chordomas, including the chondroid subtype; 2) evaluating SMARCB1 gene deletions/copy number gain; and 3) analyzing the association of SMARCB1/INI1 expression with clinicopathological parameters and patient survival.

Results: 65 patients (35 men and 30 women) affected by conventional skull base chordoma, 15 with chondroid subtype, followed for >48 months after surgery were collected.

Osteogenic sarcomas of the hands: A case series with emphasis in its peculiarities and literature review.

Aim: To present our experience on osteosarcomas of the hands and review the existing literature pertaining osteosarcomas in this extremely rare location.

Methods: and results: Seven cases of osteosarcomas of the hands were reviewed, and a literature search of all primary osteosarcomas of the hands was performed. All tumors occurred in adults (mean age, 41 years) and were located mainly around the metacarpophalangeal joints.

The Efficacy of Molecular Analysis in the Diagnosis of Bone and Soft Tissue Sarcoma: A 15-Year Mono-Institutional Study.

The histological diagnosis of sarcoma can be difficult as it sometimes requires the combination of morphological and immunophenotypic analyses with molecular tests. A total of 2705 tissue samples of sarcoma consecutively collected from 2006 until 2020 that had undergone molecular analysis were assessed to evaluate their diagnostic utility compared with histological assessments. A total of 3051 molecular analyses were performed, including 1484 gene fusions tested by c/qRT-PCR, 992 gene rearrangements analysed by FISH, 433 analyses of the gene status of MDM2, 126 mutational analyses and 16 NGS analysis.

ABCA6 affects the malignancy of Ewing sarcoma cells via cholesterol-guided inhibition of the IGF1R/AKT/MDM2 axis.

Purpose: The relevance of the subfamily A members of ATP-binding cassette (ABCA) transporters as biomarkers of risk and response is emerging in different tumors, but their mechanisms of action have only been partially defined. In this work, we investigated their role in Ewing sarcoma (EWS), a pediatric cancer with unmet clinical issues.

Methods: The expression of ABC members was evaluated by RT-qPCR in patients with localized EWS.

Periosteal chondrosarcoma: A case series in a referral center with survivorship analysis.

Background: Periosteal chondrosarcomas are among the rarest types of chondrosarcomas dealt with in few small series of cases. In this study, we aimed to present our experience with this chondrosarcoma, seek for prognostic factors for OS and DFS and survey the status of IDH1 and IDH2.

Results: 55 periosteal chondrosarcomas were retrospectively identified.

CIC rearranged sarcomas: A single institution experience of the potential pitfalls in interpreting CIC FISH results.

Aim: The aim of this study was to establish how reliable FISH CIC analysis using an IVD (in vitro diagnostic) commercial probe is.

Methods And Results: A series of 19 CIC-DUX4 sarcomas were evaluated. The samples presenting CIC-DUX4 fusion transcript detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Sanger sequencing and/or Next Generation Sequencing were selected for Fluorescent in Situ Hybridization (FISH) CIC analysis with CIC break-apart IVD probe and compared to molecular analysis.

Primary synovial sarcoma of bone: a retrospective analysis of 25 patients.

Aims: To evaluate the diagnostic accuracy of SSX and SSX::SS18 antibodies in decalcified surgical specimens and outcome of synovial sarcomas (SS) of bone.

Methods And Results: Twenty-five cases were classified as bone SS (prevalence 0.32% among malignant primary bone sarcoma).

Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma.

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters.

Giant Cell Tumor of Bone in Patients under 16 Years Old: A Single-Institution Case Series.

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.

Histological response to neoadjuvant chemotherapy in localized Ewing sarcoma of the bone: A retrospective analysis of available scoring tools.

Aim: The aim is to evaluate which of the existing scoring systems of histological response to neoadjuvant chemotherapy best stratifies the clinical outcome of patients with localized Ewing sarcoma of bone.

Methods: 474 patients with diagnosis of localized Ewing sarcoma of bone were included. The median follow-up was 13.

Usefulness of β-catenin expression in the differential diagnosis of osteosarcoma, osteoblastoma, and chondroblastoma.

The aim of this study is to assess the usefulness of beta-catenin immunohistochemical expression in the differential diagnosis of osteoid-producing primary tumors of bone. Seventy cases of osteoid-producing tumors of bone (24 conventional osteosarcomas, 18 osteoblastomas, 13 osteoblastoma-like osteosarcomas, 10 chondroblastomas, and 5 chondroblastoma-like osteosarcomas) diagnosed at Istituto Ortopedico Rizzoli were reviewed and evaluated for the intensity, extension, and subcellular distribution of immunohistochemical expression of beta-catenin. A majority of cases (73%, 51 cases) exhibited cytoplasmic and/or membranous positivity in varied degrees of intensity and proportion of positive cells, in the absence of nuclear staining.

Lipoblastoma-like tumor of the spermatic cord: case report and review of the literature.

Lipoblastoma-like tumor is a very rare mesenchymal tumor believed to be restricted to female patients and only recently reported in the spermatic cord of a male patient. We describe herein an additional case of lipoblastoma-like tumor occurring in the spermatic cord, describing its histopathological, immunohistochemical, and molecular features.

Circulating Candidate Biomarkers in Giant Cell Tumors of Bone.

Purpose: Approximately 5% of giant cell tumors (GCT) of bone develop pulmonary metastases. Although many biomarkers have been proposed, identification of circulating low abundance molecules may be useful to predict malignant progression.

Experimental Design: The hydrogel nanoparticle technique followed by MS was used to detect low molecular weight serum proteins or protein fragments in serum of 20 GCT patients with different clinical course and in ten healthy sera used as control.

Detection of H3F3A p.G35W and p.G35R in giant cell tumor of bone by Allele Specific Locked Nucleic Acid quantitative PCR (ASLNAqPCR).

Giant Cell Tumor (GCT) represents about 20% of benign bone tumors, is locally aggressive although malignant transformation is extremely rare, <1% of cases but 2-3% give pulmonary metastasis. Age at onset is between 20 and 40 years with a slight predominance for the female gender. GCT is characterized by specific mutations in H3F3A gene encoding the protein histone 3.

Tissue and serum IGFBP7 protein as biomarker in high-grade soft tissue sarcoma.

Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal tumors whose classification and treatment is complicated by molecular heterogeneity within the histological subtypes and by the lack of prognostic/therapeutic biomarkers. This study analyses expression of target proteins involved in insulin-like growth factor pathway (IGF1Rβ, IRS1 S612 and IGFBP7) in high-grade STS to stratify patients with the worst prognosis. Tissue microarray analysis performed on 145 high-grade STS samples revealed a uniform expression of IGF1Rβ and IRS1 S612, while IGFBP7 was more strongly expressed in metastatic than in metastasis-free patients.

Identification of novel candidate circulating biomarkers for malignant soft tissue sarcomas: Correlation with metastatic progression.

Soft tissue sarcomas (STS) are a heterogeneous group of rare tumors for which identification and validation of biological markers may improve clinical management. The fraction of low-molecular-weight (LMW) circulating proteins and fragments of proteins is a rich source of new potential biomarkers. To identify circulating biomarkers useful for STS early diagnosis and prognosis, we analyzed 53 high-grade STS sera using hydrogel core-shell nanoparticles that selectively entrap LMW proteins by size exclusion and affinity chromatography, protect them from degradation and amplify their concentration for mass spectrometry detection.

Excision repair cross-complementation group 1 protein expression predicts survival in patients with high-grade, non-metastatic osteosarcoma treated with neoadjuvant chemotherapy.

Aims: To evaluate the clinical impact of excision repair cross-complementation group 1 (ERCC1) expression in high-grade osteosarcoma (OS).

Methods And Results: Immunohistochemistry was performed on biopsies from 99 OS patients enrolled in the ISG/OS-Oss training set or ISG/SSG1 validation set neoadjuvant chemotherapy protocols, based on the use of cisplatin, adriamycin, methotrexate, and ifosfamide. In the training set, ERCC1 positivity was found in eight of 31 (26%) patients, and was significantly associated with worse event-free survival (EFS) (P = 0.

Diagnostic utility of molecular investigation in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma is characterized by the reciprocal chromosomal translocation t(9;22) and the resultant fused gene EWS RNA-binding protein 1 and nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3). A second cytogenetic rearrangement t(9;17) involves the genes NR4A3 and TAF 15 RNA polymerase II, TATA box binding protein (TBP)-associated factor (TAF15). Less frequent fusion transcript variants of the NR4A3 gene, transcription factor 12 (TCF12)-NR4A3 and TRK-fused gene (TFG)-NR4A3, are associated with t(9;15) and t(9;3) respectively.

Mapping protein signal pathway interaction in sarcoma bone metastasis: linkage between rank, metalloproteinases turnover and growth factor signaling pathways.

We applied reverse phase protein microarrays technology to map signal pathway interactions in a discovery set of 34 soft tissue sarcoma (STS) bone metastases compared to healthy bone. Proteins associated with matrix remodeling (MMP), adhesion (FAK Y576/577, Syndecan-1), and growth/survival (IGF1R Y1135/1136, PI3K, EGFR) were elevated in metastasis compared to normal bone. Linkage between Syndecan-1, FAK Y576/577, Shc Y317, and EGFR, IGF Y1135/1136, PI3K/AKT was a prominent feature of STS bone metastasis.

Elevated TNFR1 and serotonin in bone metastasis are correlated with poor survival following bone metastasis diagnosis for both carcinoma and sarcoma primary tumors.

Purpose: There is an urgent need for therapies that will reduce the mortality of patients with bone metastasis. In this study, we profiled the protein signal pathway networks of the human bone metastasis microenvironment. The goal was to identify sets of interacting proteins that correlate with survival time following the first diagnosis of bone metastasis.

The role of imaging for translational research in bone tumors.

Sarcomas are a heterogeneous group of rare connective tissue tumors, representing 1% of adult and 15% of childhood cancers for which biological and pathological information is still incomplete. In bone tumors patients with metastatic disease at onset, those who relapse and those with post-surgical secondary lesions still have a dismal outcome because of poor response to current therapies. Different molecular biology approaches have identified activated cell signalling pathways or specific molecular endpoints that may be considered potential drug targets or markers useful for diagnosis/prognosis in musculoskeletal pathology.