Giant Cell Tumor of Bone

P3, N=128, Not yet recruiting, SynOx Therapeutics Limited | Trial completion date: Sep 2025 --> Sep 2027 | Trial primary completion date: Dec 2023 --> Sep 2027

P3, N=40, Active, not recruiting, Daiichi Sankyo Co., Ltd. | Trial completion date: Mar 2024 --> Feb 2026

P3, N=90, Active, not recruiting, Abbisko Therapeutics Co, Ltd | Recruiting --> Active, not recruiting

Our research supports the concept that Xanthomatous giant cell renal cell carcinoma (XGC RCC) shares clinicopathological and molecular characteristics with ESC RCC and shows a relatively positive prognosis, providing further support for a close morphologic spectrum between the two. We propose considering XGC RCC as a distinct subtype of ESC RCC.

Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma.

TRPS1 was mostly negative (18/23) and variably positive in ovarian (4/9) and intrahepatic bile duct (1/1) tumors. The diagnosis of breast needle core biopsy specimen should be combined with clinical history, imaging study, and careful examination of histological features, such as presence of in situ component, morphological similarity between the primary and metastatic tumors, and using appropriate markers to differentiate the primary from metastatic tumors.

P3, N=120, Active, not recruiting, Deciphera Pharmaceuticals LLC | Trial primary completion date: Mar 2024 --> Aug 2023

The significance of this case lies in its rarity, the challenge of preoperative clinical diagnosis, and the differential diagnosis with other malignancies.

P=N/A, N=145, Completed, Changye Zou

These two fusion genes may be detected in resembling tumors, which contain giant cells, apart from malignant GCTB. The real-world data used herein provide a unique perspective on genomic alterations in clinicopathologically diagnosed malignant GCTB.

Among the 214 antitumor agents tested, romidepsin, a histone deacetylase inhibitor, and mitoxantrone, a topoisomerase inhibitor, were identified as potential therapeutic agents against GCTB. Conclusively, the establishment of NCC-GCTB8-C1 and NCC-GCTB9-C1 provides novel and crucial resources that are expected to advance GCTB research and potentially revolutionize treatment strategies.

EWSR1 or FUS rearrangement is most commonly identified in SBC, suggesting that SBC might be a neoplastic disease. In cases where the radiologic appearance and histomorphology are difficult to differentiate from aneurysmal bone cyst, FISH detection can aid in the definitive diagnosis.

The interpretation criteria for FISH detection of MDM2 amplification are currently not unified. The signal characteristics need more attention when interpreting.

The diagnostic sensitivity and specificity of H3.3 G34W for GCTB were 88.1% and 100%, respectively. This constitutes one of the first reports from our country, further validating the diagnostic value of H3.3 G34W in differentiating GCTB, including metastatic and malignant forms from its mimics, including small biopsy samples. Its value in various diagnostic dilemmas is presented and utility in identifying residual tumor cells in post-denosumab treated GCTBs is worth exploring.

Additionally, we proved that changes in DNA methylation contribute to upregulating the expression of RANKL and downregulating the expression of OPG, which are critical for bone homeostasis and GCTB development. Our results suggest that the overexpression of RANKL/RUNX2 and the lower expression of OPG are associated with recurrence in GCTB patients.

Bone sarcomas associated with infarcts exhibit genomic instability, with pronounced copy number variations, especially in Chromosome 12. CDKN2A/B homozygous deletion is highly prevalent, whereas TP53 alterations appear less frequent than in osteosarcomas. MDM2 amplification and H3.3-G34 mutations are recurrent (33%).

Together with defective cell cycle checkpoints reported previously, this DNA repair deficiency in H3.3-G34W cells led to accumulation of micronuclei and cytosolic DNA following IR, which subsequently led to activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immune-stimulatory cytokines. These findings suggest a potential for radiotherapy for tumors expressing H3.3-G34W, which can be further improved by combination with STING agonists to induce immune-mediated therapeutic efficacy.

However, with the discovery of the driver histone mutations in giant cell tumor of bone (GCTB) and chondroblastoma, as well as USP6 rearrangements in aneurysmal bone cyst, pathologists now have objective ancillary tools to aid in the separation of several histologically similar giant cell-rich neoplasms. Furthermore, the recognition of histone mutations has allowed pathologists to revisit several entities, such as "malignant chondroblastoma," and furthered our understanding of phenomena such as "aneurysmal bone cyst-like change," formerly recognized as "secondary aneurysmal bone cyst." Herein, the evolution of testing for histone mutations in bone tumors is considered; the sensitivity and specificity of the histone antibodies is reviewed; and a practical guide for the use of these ancillary tests is offered.

It is necessary to identify this subset of lung adenocarcinoma by carrying out BRG1 stain routinely on lung adenocarcinoma. These patients can then be identified and benefit from targeted therapies.

P2, N=17, Active, not recruiting, Andrew J. Wagner, MD, PhD | Trial completion date: Jul 2024 --> Jan 2025

We identified a new differentiation stage of osteoclast maturation, intermediate cell, by comparing histological findings before and after denosumab treatment. We demonstrated that discrepancies exist between histological and molecular data and highlight the need for establishing an integrated definition of osteoclasts considering morphology and marker expression.

No abstract available

HCG restrained the Smad signaling pathway by antagonizing TGF-β signaling in GCTB. HCG may serve as a useful patent to treat GCTB.

Furthermore, FRS2 played a role in repressing osteosarcoma advancement influenced by miR-429 or miR-206. In summary, FRS2, influenced by miR-429 and miR-206, emerges as a promising therapeutic candidate for antiangiogenic osteosarcoma treatments.

P3, N=90, Recruiting, Abbisko Therapeutics Co, Ltd

P2, N=818, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> May 2026 | Trial primary completion date: Oct 2024 --> May 2026

P=N/A, N=12, Completed, University Hospital, Strasbourg, France | Recruiting --> Completed

The results of immunoblotting assays suggested that silybinin as well as compound glycyrrhizin inhibited the protein expression of CYP3A4 and CYP2C9 in rats. Therefore, the combination of pexidartinib with silybinin and compound glycyrrhizin should be monitored to avoid clinical adverse effects.

In conclusion, this study systematically explored the significance of COPS6 across different tumor types, providing a solid foundation for considering COPS6 as a novel biomarker in cancer research.

MMP9, SPP1, and TYROBP were identified as osteoclast-specific up-regulated genes of the tenosynovial giant cell tumour via bioinformatic analysis, which had a reasonable diagnostic efficiency and served as potential drug targets.

Our findings provide additional evidence that the CSF1/CSF1R pathway is involved in the pathogenesis of XGET/KPGCT. These findings suggest a possible role for CSF1R inhibition in the treatment of unresectable or metastatic XGET/KPGCT.

On the one hand, the detection of the highly characteristic histone mutation in the H3F3A gene in GCTB is becoming increasingly important in diagnostics in differentiating GCTB from other giant cell-rich lesions of bone as well as for defining rare variants of GCTB without osteoclastic giant cells. On the other hand, the effects of the H3F3A mutation were shown to have an impact on the epigenetic profile of tumor-driving stromal cells, providing new insights into tumorigenesis of GCTB.

These findings suggest that ICS I can inhibit breast cancer proliferation, apoptosis, invasion and metastasis probably via targeting IL-6/STAT3 pathway. Therefore, ICS I has the potential to become an innovative therapeutic candidate to breast cancer prevention and treatment.

No abstract available

We identified the risk indicators and developed a nomogram in this study to forecast the likelihood of local recurrence-free survival in patients with diffused-tenosynovial giant cell tumor from temporomandibular joint.

We report a familial case in which father and daughter were diagnosed to have brown tumors due to parathyroid adenoma and ectopic parathyroid adenoma, and genetic testing revealed CDC73 gene mutations in both. Therefore, in the diagnostic and differential process of young patients having bone disease, clinicians should not only focus on the clinical manifestations of the skeleton, but also implement a comprehensive analysis of systemic symptoms, considering the possibility that the patient has familial PHPT.

Interestingly, two of these rare variants (p.Pro937His and p.Arg939Cys) were clustering in the nuclear localization signal of the encoded ZNF687 protein, also harboring the p.Pro937Arg variant, a previously reported disease-causing variant. In conclusion, our findings support the involvement of genetic variation in ZNF687 in the pathogenesis of classical PDB, thereby expanding its mutational spectrum.

P2, N=818, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

The most effective therapy for renal and retroperitoneal sarcomas is the gross total resection of the tumor. Increased rates of necrosis, poor differentiation, mitotic activity and increased histological grade are associated with a poor prognosis.

Our findings support previously reported hypotheses that KPGCT-ST is a spectrum of the same entity as the recently described xanthogranulomatous epithelial tumor. Although follow-up data are limited, to date, KPGCT-ST appears to follow an indolent course.

In conclusion, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions. Conversely, it could discriminate sporadic GCG of the jaws from their giant cell-rich mimics (NOF, ABC, GCTB, and chondroblastoma).