OBJECTIVE: The primary objective of this study was to determine time to full weight-bearing after the use of a calcium-sulfate-calcium phosphate bone substitute (CaSO4/CaPO4) as a bone void filler in the treatment of primary benign bone tumours following intralesional curettage. The secondary objectives were to determine surgical complications and recurrence rates.
METHODS: Retrospective review of patients identified from a surgeon-specific orthopaedic oncology database, who underwent curettage of benign bone tumours and subsequent bone void filling with CaSO4/CaPO4.
RESULTS: A total of 39 patients (20 males, 19 females) met inclusion criteria with an average age of 31 years (range: 13 to 62 years), a median follow-up of 3.7 years, and a maximum follow-up of 11 years. The most common tumour diagnosis was giant cell tumour of bone (GCT) (n = 19), and the most common location was the proximal tibia (n = 9). The mean volume of tumour excised was 74.1 cm3 including extraosseous bone expansion due to tumour growth, with a mean of volume of 21.4 mL of CaSO4/CaPO4 used to fill the intraosseous cavitary defects to restore normal bone anatomy. None of the lesions required additional internal fixation. The primary outcome measure, average time to full weight-bearing/full range of motion, was 11 weeks and 6 weeks for upper and lower extremity lesions, respectively. Secondary outcomes included tumour recurrence requiring reoperation in five patients and infection requiring reoperation in two patients.
CONCLUSIONS: This study demonstrates that CaSO4/CaPO4 is a viable option as a bone void filler in the reconstruction of cavitary defects following removal of primary benign bone tumours. CaSO4/CaPO4 provides sufficient bone regeneration early in the post-operative period to allow progression to full weight-bearing within weeks without the need for internal fixation. There were no graft-specific complications noted.

A 31-year-old woman was diagnosed with a recurrent and rapidly growing giant cell tumour of distal tibia with skin ulceration after intralesional curettage. The patient started on Denosumab 120 mg subcutaneously, once per month with additional loading doses on Days 8 and 15 attempting to avoid below-knee amputation. Twelve doses of Denosumab were administered in 9 months, resulting in resolution of pain, reduction of tumour size and calcification. Hence, the local surgical treatment was delayed and bisphosphonate maintenance therapy was initiated as skin healing was incomplete. The patient was given Zoledronic acid infusions at a dose of 4 mg. After the third infusion, the skin healed. As tumour remained stable, it was decided to continue maintenance. Overall, six doses of Zoledronic acid at 6 months intervals were administrated over 3 years. At the end of the maintenance, the patient experienced no pain and satisfied with her limb function. Since the lesion remained stable over 3 years after Denosumab discontinuation, it was suggested to stop further medical treatment and proceed to active surveillance. The patient\'s disease is still stable clinical remission with no serious adverse events 41 months after Denosumab cessation and 10 months after the last bisphosphonate infusion. The present case confirmed the high effectiveness of denosumab as induction therapy in advanced recurrent giant cell tumour. We speculate that following the Denosumab-induced tumour ossification, high Zoledronic acid uptake in lesion may prevent tumour reactivation due to its improved pharmacodynamics with an assumed irreversible anti-tumoral effect on residual mutated cells. This hypothesis requires confirmation in future studies.

OBJECTIVE: The advent of denosumab has rendered giant cell tumors (GCT) of the bone amenable. It makes sense to evaluate its effect on the patient\'s symptoms and the histopathological outcomes. The aim of the study is to ascertain the effect of 24-week neoadjuvant denosumab therapy on the following parameters: visual analogue scale (VAS), musculoskeletal tumor society (MSTS) scores, tumor size, and the number of giant and stromal cells.
METHODS: This observational study was conducted from February 2022 to April 2023 at SCB Medical College and Hospital, India. Fifty-four GCT participants had their VAS and MSTS scores assessed at baseline and then every four weeks for the next 24 weeks. At 24 weeks, changes in their tumor size and the number of giant and stromal cells per high-power field (hpf) were also evaluated.
RESULTS: Fifty-four (82%) out of the 66 enrolled participants completed the study. Among those 54, 29 (54%) participants were female. The study population had a mean age of 39.0 ± 4.7 years. The median VAS scores were (female: 7.0, male: 7.0; p = 0.51) at baseline and (female: 2.0, male: 2.0; p = 0.39) at 24 weeks. The median MSTS scores at baseline and 24 weeks were (female: 8.0, male: 8.0; p = 0.41) and (female: 15.0, male: 16.0; p = 0.66), respectively. The median reductions in tumor size, the number of giant, and stromal cells (per hpf) were (female: 6.0 mm, male: 5.0 mm; p = 0.11), (female: 25, male: 27; p = 0.07), and (female: 1200, male: 2100; p < 0.001), respectively.
CONCLUSIONS: After receiving neoadjuvant denosumab for 24 weeks, the study participants\' clinical symptoms and histological indicators improved. With the exception of the stromal cells, there was no statistically significant difference between the male and female participants.

Denosumab is a fully humanised monoclonal antibody to RANK ligand, inhibiting the RANK-RANKL pathway. It promotes the apoptosis of osteoclast-like giant cells, a secondary ossification and connective tissue formation. Given its high efficacy, denosumab is the standard treatment of unresectable or metastatic giant cell tumour of bone (GCTB) requiring morbid surgery. Neoadjuvant administration of denosumab may be justified to enable the resection of the tumour in certain cases; it should be considered, however, with caution for joint-saving surgery due to high local recurrence rates. In cases of unresectable or metastatic GCTB, however, denosumab treatment should be administered for years or even as a lifelong therapy. This poses many yet unanswered questions concerning the frequency of denosumab treatment as well as the ratio of the adverse events in the following years. Denosumab suppresses, not directly targets, the neoplastic stromal cells of GCTB. Ongoing in vitro studies suggest that other drugs alone or in combination (e.g. sunitinib) with denosumab may target both the neoplastic and the giant cells. Promising results have been reported regarding the off-label use of denosumab in other giant cell-rich tumours/tumour-like lesions, i.e. aneurysmal bone cysts and central giant cell granulomas. Data are derived, however, mostly from case reports and case series. Large prospective clinical trials are needed to evaluate the role and also the side effects of denosumab in the treatment of these rare diseases.

As the only humanized monoclonal antibody against receptor activator of nuclear factor-κB ligand (RANKL) for giant cell tumour of bone (GCTB) therapy, denosumab has limited antitumour effect on neoplastic stromal cells. Nevertheless, its mechanism of action has not yet been clarified. A previous study has revealed that p62 may play an important role in the antitumour activity of denosumab.
The study aimed to investigate if the mechanism by which denosumab inhibits GCTB neoplastic stromal cells growth is via p62 modulation and other related mechanisms.
p62 expression before and after denosumab therapy was analysed by RT‒qPCR, western blot, ELISA, and immunohistochemical assays. Two primary neoplastic stromal cells were isolated from fresh GCTB tumour tissue (L cell) and metastatic tissue (M cell). Cell proliferation, migration, apoptosis, and autophagy were investigated in p62 knockdown neoplastic stromal cells transfected by short hairpin RNA lentivirus in vitro. Tumor growth was evaluated in the chick chorioallantoic membrane model in vivo.
p62 expression was found to be downregulated following denosumab therapy. The patients with a decrease in p62 expression had lower recurrence-free survival rates. The proliferation of M cells was not inhibited by denosumab therapy, but it was restored by p62 knockdown. Moreover, p62 knockdown inhibited tumour growth in vivo. Denosumab induced M cell apoptosis and arrested the cell cycle at the G1/G0 transition and these effects were also enhanced by p62 knockdown. Autophagic flux assays revealed p62 modulation to be dependent on autophagy following denosumab incubation.
Denosumab induced neoplastic stromal cells apoptosis via p62 downregulation dependent on autophagy pathway. The combination of p62 and RANKL knockdown might be a better strategy than RANKL knockdown alone for GCTB targeted therapy.

Giant cell tumours (GCTs) of the medial epicondyle of the humerus are rare. These are generally benign tumours but have the potential to be locally aggressive. They can invade the adjacent joint or the surrounding soft tissues or, in rare cases, cause distant metastasis. Locally aggressive GCTs are generally treated with wide resection, curettage, and bone grafting, followed by joint reconstructions. Here we present a case of a 49-year-old female with a history of swelling over the medial epicondyle of the humerus for six months. The patient was diagnosed with a locally aggressive GCT and was managed with wide excision of the tumour followed by sandwich bone grafting. A two-year follow-up of the patient shows no signs of recurrence. The patient is pain-free and has decent elbow function.

Sporadic giant cell granulomas (GCGs) of the jaws and cherubism-associated giant cell lesions share histopathological features and microscopic diagnosis alone can be challenging. Additionally, GCG can morphologically closely resemble other giant cell-rich lesions, including non-ossifying fibroma (NOF), aneurysmal bone cyst (ABC), giant cell tumour of bone (GCTB), and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and DNA methylation profiling has been shown to be clinically useful for the diagnosis of other tumour types. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic GCG and cherubism to test whether DNA methylation patterns can help to distinguish them. Additionally, we compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. DNA methylation analysis was performed for central (n = 10) and peripheral (n = 10) GCG, cherubism (n = 6), NOF (n = 10), ABC (n = 16), GCTB (n = 9), and chondroblastoma (n = 10) using the Infinium Human Methylation EPIC Chip. Central and peripheral sporadic GCG and cherubism share a related DNA methylation pattern, with those of peripheral GCG and cherubism appearing slightly distinct, while central GCG shows overlap with both of the former. NOF, ABC, GCTB, and chondroblastoma, on the other hand, have distinct methylation patterns. The global and enhancer-associated CpG DNA methylation values showed a similar distribution pattern among central and peripheral GCG and cherubism, with cherubism showing the lowest and peripheral GCG having the highest median values. By contrast, promoter regions showed a different methylation distribution pattern, with cherubism showing the highest median values. 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).

Paget disease of bone is a metabolic disorder with a strong genetic component, characterised by pronounced disorganised bone remodelling. Complications of this disease include an increased risk of developing bone neoplasms. Here, we describe the case of a 60-year-old Italian patient with Paget disease of bone, presenting with an osteoclast-rich tumour. Our analysis of this entity, based on the clinical, morphological and genetic data (whole exome sequencing), suggests that osteoclast-rich lesions in Paget disease of bone are genetically distinct from classical giant cell tumour of bone. We discuss the importance of differentiating these osteoclast-rich lesions.

A giant cell tumour of bone presented in the os sacrum of a prepubertal girl. Surgery with reconstruction was performed, but total resection was impossible. Zoledronate failed to avoid tumour regrowth, and treatment was changed to denosumab, despite not being recommended for use in growing children. Denosumab treatment for 21 months reduced and stabilized tumour size, the girl became pain free with asymptomatic side effects as mild hypocalcemia, hypophosphatemia and sclerosis of newly formed bone.

UNASSIGNED: A 10-year-old male neutered domestic shorthair cat was presented with a 5-month history of progressive non-ambulatory paraparesis. Initial vertebral column radiographs revealed an L2-L3 expansile osteolytic lesion. Spinal MRI showed a well-demarcated, compressive expansile extradural mass lesion affecting the caudal lamina, caudal articular processes and right pedicle of the second lumbar vertebra. The mass was hypointense/isointense on T2-weighted images, isointense on T1-weighted images and had mild homogeneous contrast enhancement after gadolinium administration. MRI of the remaining neuroaxis and CT of the neck, thorax and abdomen with ioversol contrast revealed no additional neoplastic foci. The lesion was removed by en bloc resection via a dorsal L2-L3 laminectomy, including the articular process joints and pedicles. Vertebral stabilisation was performed with titanium screws placed within L1, L2, L3 and L4 pedicles with polymethylmethacrylate cement embedding. Histopathology revealed an osteoproductive neoplasm composed of spindle and multinucleated giant cells without detectable cellular atypia or mitotic activity. On immunohistochemical evaluation, osterix, ionised calcium-binding adaptor molecule 1 and vimentin labelling were observed. Based on the clinical and histological features, a giant cell tumour of bone was considered most likely. Follow-up at 3 and 24 weeks postoperatively demonstrated significant neurological improvement. Postoperative full-body CT at 6 months showed instability of the stabilisation construct but absence of local recurrence or metastasis.
UNASSIGNED: This is the first reported case of a giant cell tumour of bone in the vertebra of a cat. We present the imaging findings, surgical treatment, histopathology, immunohistochemistry and outcome of this rare neoplasm.