Treatment Of Giant Cell Tumor Of Bone Research Articles

Establishment and characterization of two novel patient-derived cell lines from giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a rare bone tumor with osteolytic features, composed of stromal cells with a monotonous appearance, macrophages, and osteoclast-like giant cells. GCTB is commonly associated with a pathogenic mutation in the H3-3A gene. While complete surgical resection is the standard cure for GCTB, it often results in local recurrence and, rarely, metastasis. Thus, an effective multidisciplinary treatment approach is necessary. Although patient-derived cell lines is an essential tool for investigating novel treatment strategies, there are only four GCTB cell lines available in public cell banks. Therefore, this study aimed to establish novel GCTB cell lines and successfully created NCC-GCTB6-C1 and NCC-GCTB7-C1 cell lines from two patients' surgically removed tumor tissues. These cell lines exhibited H3-3A gene mutations, consistent proliferation, and invasive properties. After characterizing their behaviors, we performed high-throughput screening of 214 anti-cancer drugs for NCC-GCTB6-C1 and NCC-GCTB7-C1 and integrated their screening data with those of NCC-GCTB1-C1, NCC-GCTB2-C1, NCC-GCTB3-C1, NCC-GCTB4-C1, and NCC-GCTB5-C1 that we previously established. We identified histone deacetylase inhibitor romidepsin as a possible treatment for GCTB. These findings suggest that NCC-GCTB6-C1 and NCC-GCTB7-C1 could be valuable tools for preclinical and basic research on GCTB.

Role of Denosumab in the Management of Giant Cell Tumor, a Cross Sectional Study

<strong>Background:</strong> Giant cell tumor (GCT) of bone is a benign lesion which is characterized by presence of multinucleated osteoclasts type giant cells. Nuclear factor kappa B (RANKL) serves as the trigger factor for osteoclasts cells formation. Although surgery is the primary treatment for GCT of bone but recurrence remains the concern. Therefore, the development of denosumab, a monoclonal antibody for treating GCT for both primary and recurrent disease cases. The present study aims to show the role of denosumab along with surgery when given as neo-adjuvant drug to patients of GCT for their treatment. <strong>Methodology:</strong> A total of 23 patients diagnosed with GCT were included in this study from January 2016–December 2019 and all of these patients had received neo adjuvant denosumab dose of 120 mg SC on day 0, 15, 30 &amp; 45. All patients were treated at the section of Orthopedics, department of surgery, Aga Khan University hospital, Karachi. Other benign lesions were excluded from the study. <strong>Results:</strong> Out of 23 patients we had 12 (52.2%) males and 11 (47.8%) females. The mean age of our patients was 34±13.8 years and mean follow up duration of all patients was 20.5 ± 10.7 months. There were 15 (65.2%) primary cases of GCT while 8 (34.8%) were recurrent cases. In 8 (34.8%) of the cases primary site of lesion was distal femur followed by 7(30.4%) proximal tibia cases and 3(13%) distal radius cases. In surgical procedure 20 (87%) patients underwent wide margin excision and only 3 (13%) had intralesional curettage. Reconstruction was performed in 21 patients which consist of bone grafting in 9 patients and mega prosthesis insertion in 12 patients. Only two patients had no reconstruction. On final histopathology, there was no residual GCT and we observed no denosumab induced adverse effects. Post-operative complications included wound infection and peri prosthetic infection in 3 patients. On follow-up we had 4(17.4%) cases of recurrence that were offered revision surgery while 19 (82.6%) were disease free. <strong>Conclusion:</strong> Denosumab has shown successful results in treating patients with GCT along with surgical intervention and it can be a best option for treating recurrent disease as well. <strong>Highlights</strong><ul><li>Giant cell tumor of bones is aggressive non-cancerous tumor.</li><li>Denosumab, a human monoclonal antibody that inhibits RANK-L, has shown good results in its management along with surgery in neo adjuvant setting.</li><li>In our study, most of the patients underwent wide margin excision followed by few treated intralesional curettage ins surgical management.</li><li>Our study reported few cases of recurrence after neoadjuvant Denosumab treatment showing its efficacy inthe disease management.</li></ul> <strong>Research registration no:</strong> researchregistry4695

Risk factors for local recurrence of giant cell tumor of bone of the extremities: a retrospective study

Background: Although considered as a benign tumor, giant cell tumor of bone (GCTB) has an aggressive biological behavior with high tendency for local recurrence (LR). The most commonly used method of treatment of GCTB is intralesional curettage augmented by various types of local adjuvants. The aim of this study was to evaluate the rate of recurrence of GCTB after surgical treatment to detect the risk factors that may influence the rate of LR. Methods: Fifty-two cases of GCTB that had been treated in a university hospital musculoskeletal oncology unit, between 2012 and 2017 were retrospectively reviewed after minimal follow-up of 4 yr and risk factors of LR were determined. Results: All LRs occurred within the first 3 yr (4 to 31 mo). Curettage was used to manage 34 patient cases, from which 11 patients (32.4%) showed LR. Only one patient (5.6%) of the 18 wide local excision patients developed recurrence. The highest recurrence rate was found among the lesions of the proximal femur. Neither the tumor volume nor the pathological grade had a significant impact on the rate of LR. The presence of soft-tissue invasion, occurrence of pathological fracture at presentation and using curettage as a method of treatment were associated with significantly higher rate of LR. Conclusions: Lesions in the proximal femur, occurrence of pathological fracture at presentation, soft-tissue invasion, and curettage as management option were found to be associated with an increased risk of LR of GCTB. Level of Evidence: Level III

Progress on Denosumab Use in Giant Cell Tumor of Bone: Dose and Duration of Therapy.

Giant cell tumor of bone (GCTB) is an aggressive non-cancerous bone tumor associated with risks of sarcoma and metastasis. Once malignancy occurs, the prognosis is generally poor. Surgery remains the main treatment for GCTB. Multidisciplinary management is a feasible option for patients wherein surgical resection is not an option or for those with serious surgery-related complications. Denosumab is an anti-nuclear factor kappa B ligand approved for the treatment of postmenopausal women with osteoporosis, bone metastases, and advanced or inoperable GCTB. However, the guidelines for treating GCTB are unclear; its short-term efficacy and safety in inoperable patients have been demonstrated. Lengthier therapies (high cumulative doses) or pre-operative adjuvant therapy may be associated with severe complications and high local recurrence rates. Short-term administration helps attain satisfactory local control and functionality. As a result, lately, the impact of different doses and lengths of treatment on the efficacy of denosumab in GCTB treatment, the incidence of complications, and recurrence rates have gained attention. The efficacy and safety of denosumab against GCTB, its impact on imaging assessment, related complications, and recurrence of GCTB were previously reviewed. For further research direction, this paper reviews the progress of studies evaluating the impact of the dose and duration of denosumab therapy for GCTB.

Giant cell tumor of bone: Epidemiological profile (fifth version) – A study protocol

The giant cell tumor of bone (GCTB) represents approximately 5% of primary bone tumors, and more than half of cases affect individuals between 20 and 50 years of age. Despite being a benign neoplasm, 3 to 5% of cases may show pulmonary metastases, besides it has high potential for bone destruction at the main site of the lesion, often in the epiphyses of long bones, which may lead to serious functional problems in affected patients. Multidisciplinary treatment of GCTB has been a cause for discussion in the last decade due to the discovery of drugs such as denosumab that prevent tumor progression and may be useful in cases of patients with local recurrences and unresectable tumors. The therapeutic basis of GCTB remains the isolated surgical treatment by intralesional (with adjuvants), marginal or wide resection. Intralesional treatment presents higher rates of recurrence, however it preserves the adjacent joint function and much of the individual bone stock. Resection with wide margins presents lower recurrence rates but has shown worse functional results and frequent complications in bone reconstructions. Current knowledge of GCTB surgical outcomes has been based on major world series - there is a lack of Brazilian epidemiological and surgical data on this specific type of neoplasm, except for a few series of cases. The primary objective of this paper is to identify the epidemiological profile of GCTB; the secondary objectives are to describe the surgical aspects in the main diagnostic centers and treatment of bone tumors, to analyze the clinical and surgical aspects of patients with GCTB of wrist and hand, and to analyze the clinical and surgical aspects of patients with knee GCTB. These findings may help in the maintenance or change of national guidelines for the treatment of GCTB. This study protocol was submitted to ethical assessment under the CAAE (Ethical Appreciation Presentation Certificate) registry No. 94280918.0.0000.5327 (5th version), evaluated through the substantiated opinion No. 4.770.705, and approved by the Institutional Research Ethics Committee on June 12, 2022.

Single-cell RNA sequencing reveals differential expression of EGFL7 and VEGF in giant-cell tumor of bone and osteosarcoma.

Dysregulation of angiogenesis is associated with tumor development and is accompanied by altered expression of pro-angiogenic factors. EGFL7 is a newly identified antigenic factor that plays a role in various cancers such as breast cancer, lung cancer, and acute myeloid leukemia. We have recently found that EGFL7 is expressed in the bone microenvironment, but its role in giant-cell tumor of bone (GCTB) and osteosarcoma (OS) is unknown. The aims of this study are to examine the gene expression profile of EGFL7 in GCTB and OS and compare with that of VEGF-A-D and TNFSF11 using single-cell RNA sequencing data. In-depth differential expression analyses were employed to characterize their expression in the constituent cell types of GCTB and OS. Notably, EGFL7 in GCTB was expressed at highest levels in the endothelial cell (EC) cluster followed by osteoblasts, myeloid cells, and chondrocytes, respectively. In OS, EGFL7 exhibited highest expression in EC cell cluster followed by osteoblastic OS cells, myeloid cells 1, and carcinoma associated fibroblasts (CAFs), respectively. In comparison, VEGF-A is expressed at highest levels in myeloid cells followed by OCs in GCTB, and in myeloid cells, and OCs in OS. VEGF-B is expressed at highest levels in chondrocytes in GCTB and in OCs in OS. VEGF-C is strongly enriched in ECs and VEGF-D is expressed at weak levels in all cell types in both GCTB and OS. TNFSF11 (or RANKL) shows high expression in CAFs and osteoblastic OS cells in OS, and osteoblasts in GCTB. This study investigates pro-angiogenic genes in GCTB and OS and suggests that these genes and their expression patterns are cell-type specific and could provide potential prognostic biomarkers and cell type target treatment for GCTB and OS.

A biomechanical comparison between cement packing combined with extra fixation and three-dimensional printed strut-type prosthetic reconstruction for giant cell tumor of bone in distal femur

BackgroundThe most common reconstruction method for bone defects caused by giant cell tumor of bone (GCTB) is cement packing combined with subchondral bone grafting and extra fixation. However, this method has several limitations involving bone cement and bone graft, which may lead to poor prognosis and joint function. A titanium-based 3D-printed strut-type prosthesis, featured with excellent biocompatibility and osseointegration ability, was developed for this bone defect in our institution. The goal of this study is to comparatively analyze the biomechanical performance of reconstruction methods aimed at the identification of better operative strategy.MethodsFour different 3D finite element models were created. Model #1: Normal femur; Model #2: Femur with tumorous cavity bone defects in the distal femur; Model #3: Cavity bone defects reconstructed by cement packing combined with subchondral bone grafting and extra fixation; Model #4: Cavity bone defects reconstructed by 3D-printed strut-type prosthesis combined with subchondral bone grafting. The femoral muscle multiple forces were applied to analyze the mechanical difference among these models by finite element analysis.ResultsOptimal stress and displacement distribution were observed in the normal femur. Both reconstruction methods could provide good initial stability and mechanical support. Stress distributed unevenly on the femur repaired by cement packing combined with subchondral bone grafting and extra fixation, and obvious stress concentration was found around the articular surface of this femur. However, the femur repaired by 3D-printed strut-type prosthetic reconstruction showed better performance both in displacement and stress distribution, particularly in terms of the protection of articular surface and subchondral bone.Conclusions3D-printed strut-type prosthesis is outstanding in precise shape matching and better osseointegration. Compared to cement packing and extra fixation, it can provide the almost same support and fixation stiffness, but better biomechanical performance and protection of subchondral bone and articular cartilage. Therefore, 3D-printed strut-type prosthetic reconstruction combined with subchondral bone grafting may be evaluated as an alternative for the treatment of GCTBs in distal femur.

Ultra-Short Course of Neo-Adjuvant Denosumab for Nerve-Sparing Surgery for Giant Cell Tumor of Bone in Sacrum.

This was a retrospective study about sacral giant cell tumor of bone (GCTB). This study aimed to investigate whether ultra-short course of neo-adjuvant denosumab treatment for sacral GCTB could (1) induce radiological and histological response? (2) Facilitate nerve-sparing surgery? (3) Achieve satisfactory oncological and functional outcomes? Previous reports on long course of neo-adjuvant denosumab treatment for GCTB showed significant tumor response and a relatively high recurrent rate after curettage. Sixty-six patients with sacral GCTB treated with neoadjuvant denosumab and nerve-sparing surgery were categorized into ultra-short course group (≤3 doses and operation within D21 since 1st dose, 41 patients) or conventional group (>3 doses or operation after D21 since 1st dose, 25 patients). The radiological and histological response, operative data, oncological and functional outcomes were compared. The ultra-short course group demonstrated fewer doses of neo-adjuvant denosumab (mean: 2.1 vs. 4.8, P < 0.001) and shorter time to surgery (12.2 days vs. 72.3 days, P < 0.001). Similar patterns of radiological and histological response were observed in the two groups with less fibrosis and ossification in the ultra-short course group. The operative duration (199.9 min vs. 187.8 min, P = 0.364) and estimated blood loss (1552.4 mL vs. 1474.0 mL, P = 0.740) were comparable. Most (94.8%) of the patients received adjuvant denosumab. After a mean follow-up of 29.4 months, three cases (8.8%) and five cases (20.8%) showed local recurrence in each group (P = 0.255). The estimated recurrence-free survival (56.2 vs. 51.2 months, P = 0.210) and the functional status [Motor-Urination-Defecation scores: 25.9 vs. 25.7, P = 0.762] did not differ between the two groups. Ultra-short course of neo-adjuvant denosumab for sacral GCTB could elicit radiological and histological responses as conventional course did. The less degree of fibrosis and ossification might facilitate nerve-sparing surgery and help to achieve satisfactory local control and functional status.Level of Evidence: 4.

Establishment and characterization of the NCC-GCTB4-C1 cell line: a novel patient-derived cell line from giant cell tumor of bone.

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.

Combination of Melatonin and Zoledronic Acid Suppressed the Giant Cell Tumor of Bone in vitro and in vivo.

Melatonin (Mlt) confers potential antitumor effects in various types of cancer. However, to the best of our knowledge, the role of Mlt in the giant cell tumor of bone (GCTB) remains unknown. Moreover, further research is required to assess whether Mlt can enhance the therapeutic effect of zoledronic acid (Zol), a commonly used anti-GCTB drug. In this research, we investigated the effects of Mlt, Zol, and the combination of these two drugs on GCTB cells’ characteristics, including cell proliferation, apoptosis, osteogenic differentiation, migration, and invasion. The cell counting kit-8 (CCK-8) assay, colony formation assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay (TUNEL), alkaline phosphatase (ALP) staining, alizarin red staining (ARS), scratch wound healing assay, and transwell experiment were performed, respectively. Our results showed that Mlt could effectively inhibit the proliferation, migration, and invasion of GCTB cells, as well as promote the apoptosis and osteogenic differentiation of tumor cells. Of note, a stronger antitumor effect was observed when Mlt was combined with Zol treatment. This therapeutic effect might be achieved by inhibiting the activation of both the Hippo and NF-κB pathways. In conclusion, our study suggests that Mlt can be a new treatment for GCTB, which could further enhance the antitumor effect of Zol.

Analysis of the Density Characteristics of Giant Cell Bone Tumors Treated with Denosumab According to CT Findings

Background: Giant cell tumor of bone (GCTB) is a relatively common benign bone tumor, accounting for 4–9.5 % of all primary bone neoplasms. Localization of GCTB is one of the most important differential diagnostic criteria, since the tumor affects certain parts of the skeleton. Until now, surgical treatment was considered the method of choice in the treatment of GCTB. However, in recent years, denosumab, a genetically engineered drug, has been widely used to treat this tumor. Denosumab treatment of GCTB prevents further tumor progression and reduces tumor size. Histological examination of the surgical specimen is undoubtedly the most objective method for assessing the effectiveness of the treatment. However, it is sometimes necessary to get information regarding the effectiveness of conservative therapy.Purpose: To analyze the density characteristics of denosumab-treated GCTB using CT densitometry.Material and methods: The study included 15 patients aged 28–59 years with histologically verified giantcell tumor, who received denosumab treatment followed by surgery. Tumor structure was assessed before starting denosumab therapy, after 3 and 6 courses of denosumab therapy.Results: Changes in the density parameters (the mean tumor density, standard deviation of density, increase in the median tumor density and standard deviation of density, index of the relative density of the tumor) measured by CT images were analyzed. These changes were statistically significant in GCTB patients before initiating therapy with denosumab, and after 3 and 6 courses of denosumab therapy.Conclusion: Thus, CT densitometry is a useful tool for assessing the density characteristics of the tumor in GCS patients treated denosumab.

Utility of intraoperative magnetic resonance imaging for giant cell tumor of bone after denosumab treatment: a pilot study.

Giant cell tumor of bone (GCTB) is an intermediate but locally aggressive neoplasm. Current treatment of high-risk GCTB involves administration of denosumab, which inhibits bone destruction and promotes osteosclerosis. However, denosumab monotherapy is not a curative treatment for GCTB and surgical treatment remains required. Denosumab treatment complicates surgery, and the recurrence rate of GCTB is high (20%-30%). To examine the utility of intraoperative magnetic resonance imaging (iMRI) for detection and reduction of residual tumor after denosumab treatment and to investigate the utility of iMRI, which is not yet widely used. We enrolled five patients who received denosumab for a median period of eight months (range 6-12 months). Surgery was performed when the degree of osteosclerosis around the articular surface was deemed appropriate. We performed iMRI using a modified operation table to identify residual tumor after initial curettage and evaluated the rate of detection of residual tumor by iMRI, intraoperative and postoperative complications, exposure time of iMRI, and operation time. Suspected residual tumor tissue was identified in all five cases and was confirmed by histopathology after additional curettage. The rate of detection of residual tumor by iMRI was 100%. Residual tumor was located in sites which were difficult to remove due to osteosclerosis. The iMRI was performed safely and without trouble. During the median follow-up period of 10 months (range 6-24 months), no adverse events or recurrences occurred. Intraoperative MRI could contribute to the reduction of residual tumor tissue and it may prevent recurrence of GCTB after denosumab therapy.

Preoperative denosumab treatment with curettage may be a risk factor for recurrence of giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a local aggressive bone tumor, histologically classified as intermediate malignancy. Recently, the RANKL inhibitor, denosumab, was developed as a novel and effective treatment option for GCTB. Since the risk of preoperative use of denosumab with curettage had been previously reported, this study aimed to investigate the relationship between recurrences and clinicopathological features associated with adjuvant denosumab treatment in GCTB. A total of 87 GCTB cases were treated at our institution. We reviewed 66 patients with conventional-type GCTB occurring in the extremities and analyzed 78 surgical treatments, including curettages and resections, with clinicopathological features and denosumab treatment. GCTB lesions, including 66 primary and 12 recurring, underwent surgical treatment like curettage and resection. Recurrence-free survivals in 78 GCTB surgeries were 78.7% in 3 years and 71.9% in 5 years. In the resected cases of GCTBs, there was no recurrence either with or without denosumab. In curettage cases, 3-year recurrence-free survivals were 0.0% (n = 3) in preoperative treatment of denosumab, 66.7% (n = 6) in postoperative treatment, and 76.6% (n = 43) in no treatment. Interestingly, three preoperative treatment cases demonstrated low MIB-1 index despite 100% recurrence. The other clinicopathological factors did not contribute much to the risk of recurrence in curettage cases. Our findings revealed the use of denosumab in GCTB, prior to curettage, to possibly increase the risk of local recurrence. Together with previous reports, our finding might provide information for beneficial treatment of GCTB.

Simvastatin Possesses Antitumor and Differentiation‐Promoting Properties That Affect Stromal Cells in Giant Cell Tumor of Bone

Giant cell tumor of bone (GCTB) is a locally aggressive destructive bone lesion. The management of pulmonary metastasis and local recurrence after the surgical treatment of GCTB remains a challenge. Pathologically, stromal cells in GCTB are known as primary neoplastic cells and are recognized as incompletely differentiated preosteoblasts. Therefore, inducing GCTB stromal cells to differentiate into cells with a mature osteoblastic phenotype may stop tumor growth and recurrence. In this study, we aimed to investigate how simvastatin, a clinically approved and commonly used statin that has been known to promote the maturation of cells of the osteogenic lineage, affects GCTB stromal cells. We found that simvastatin effectively inhibited cell viability by suppressing proliferation and by inducing apoptosis in GCTB stromal cells. Moreover, simvastatin treatment upregulated the expression of genes related to osteogenic maturation, such as runt-related transcription factor 2, osteopontin, and osteocalcin, and increased the mineralization of the extracellular matrix in GCTB stromal cells. Ingenuity pathway analysis was used to discover that the vitamin D receptor pathway was involved in the simvastatin-induced osteogenic differentiation of GCTB stromal cells by upregulating the 1,25-dihydroxyvitamin D metabolism. Taken together, this in vitro study demonstrates the antitumor and differentiation-promoting effects of simvastatin on GCTB stromal cells and suggests the possibility of using simvastatin as an adjuvant therapy for GCTB. These findings support further clinical investigation of the efficacy of using simvastatin as an adjuvant therapy for GCTB to reduce recurrence and distant metastasis after surgical treatment. © 2019 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:297-310, 2020.

Denosumab treatment for giant-cell tumor of bone: a systematic review of the literature.

Denosumab is a human monoclonal antibody (mAb) that specifically inhibits tumor-associated bone lysis through the RANKL pathway and has been used as neoadjuvant therapy for giant-cell tumor of bone (GCTB) in surgical as well as non-surgical cases. The purpose of this systematic review of the literature, therefore, is to investigate: (1) demographic characteristics of patients affected by GCTBs treated with denosumab and the clinical impact, as well as, possible complications associated with its use (2) oncological outcomes in terms of local recurrence rate (LRR) and development of lung metastasis, and (3) characteristics of its treatment effect in terms of clinical, radiological, and histological response. A systematic review of the literature was conducted using PubMed, EMBASE, and COCHRANE search including the following terms and Boolean operators: "Denosumab" AND "primary bone tumor", "denosumab" AND "giant cell tumor", "denosumab" AND "treatment", and finally, "denosumab" AND "giant cell tumor" AND "treatment" since 2000. After applying inclusion and exclusion criteria, a total of 19 articles were included. The quality of the included studies was assessed using STROBE for the assessment of observational studies. A total of 1095 patients were included across all 19 studies. Across all the studies included, there were 615 females and 480 males. The mean patient age was 33.7 ± 8.3years when starting the denosumab treatment. The pooled weighted local recurrence rate was 9% (95% CI 6-12%) and the pooled weighted metastases rate was 3% (95% CI 1-7%). The most common adverse event was fatigue and muscular pain. Radiologic response was estimated to occur in 66-100% of the patients. A significant reduction in pain under denosumab treatment was reported in seven studies and additional improvement in function and mobility was reported by several authors. Only two studies reported musculoskeletal tumor society (MSTS) scores which were better after denosumab treatment. The use of denosumab as an adjuvant treatment of GCTB has shown a positive but variable histological response with consistent radiological changes and several types of adverse effects. There is a positive clinical response in terms of pain relief with decrease on the morbidity of surgical procedures to be performed. Finally, oncological outcomes are disparate with neither effect on metastatic disease nor local recurrence rates. IV.

Outcome of Treatment of Giant-Cell Tumor of Bone: a Single-Institutional Retrospective Study

Background: Giant-cell tumor of bone (GCTB) is a locally aggressive tumor which metastasizes infrequently to the lungs. The standard treatment of GCTB was surgery until the approval of denosumab. Aim: To describe the outcome of treatment of this rare tumor and to determine factors that influence survival. Methods: Retrospective review of the medical records of GCTB patients treated at our institution. Collected data includes: clinicopathological data, treatment modalities and possible prognostic factors. Results: Forty-two patients were identified between May 2008 and November 2017. Their median age was 31 years, and the majority (62%) were females. The commonest primary sites were the upper and lower limbs (50% and 43%, respectively). Eight (19%) patients initially presented with lung metastases. Thirteen (31%) patients received denosumab as first line treatment before surgery and 12 of them underwent surgery post-denosumab. Denosumab was given after recurrence in 12 (29%) patients [8 (19%) with lung metastasis and 4 (10%) with localized disease]. The objective response rate to denosumab after recurrence was 50%. Four (10%) patients achieved complete response and 2 (5%) partial response. After a median follow up of 4.7 years, 6 (14%) patients had local recurrence and 8 (19%) had lung metastasis with no recorded deaths. The 5-year progression-free survival rate was 61%. Conclusion: Denosumab is effective and tolerable in the management of GCTB preoperatively in localized disease to facilitate surgery and in the management of metastatic disease. Multi-institutional prospective studies are needed for further assessment.

Tumor immunohistochemistry and preoperative magnetic resonance imaging features predict local recurrence of giant cell tumor of bone following intralesional curettage.

Giant cell tumor of bone (GCTB) is among the most prevalent types of tumor of the bone in East and Southeast Asia. The high rate of local recurrence following intralesional curettage poses a challenge for the clinical treatment of GCTB. In the present study, the expression of matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) in GCTB was investigated by immunohistochemical staining. A correlation between expression and preoperative magnetic resonance imaging (MRI) features was identified. The patients were followed up for ≥2 years after intralesional curettage. The rates of local recurrence were compared among different groups. A total of 74 cases of GCTB in the proximal tibia or distal femur were investigated. MRI features were retrospectively examined by correlation analysis. The expression of MMP-9 was demonstrated to be associated with cystic changes and the ‘paint brush borders’ sign (P<0.05), and positively associated with the expression of RANKL (P<0.05) and VEGF (P<0.05). Cystic changes, the ‘paint brush borders’ sign and adjacent soft tissue invasion were associated with high rates of local recurrence (P<0.05) and were therefore identified as significant risk factors. Pathologically, the ‘paint brush borders’ sign was demonstrated to be indicative of local invasion of the bone. These findings may be useful for predicting local recurrence of GCTB, and may provide important insight into the preoperative MRI features and molecular expression patterns of GCTB tumors.

Norcantharidin modulates the miR-30a/Metadherin/AKT signaling axis to suppress proliferation and metastasis of stromal tumor cells in giant cell tumor of bone

Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor, which can cause significant bone destruction at the epiphysis of long bones. Recent studies have demonstrated that norcantharidin (NCTD) can inhibit the proliferation and migration of various human cancer cells, but the role of NCTD in GCTB has not previously been evaluated. The aim of this study was to explore the nature of the anti-cancer effects of NCTD in GCTB and to elucidate the biomolecular mechanisms responsible for these effects. Primary stromal cell cultures, representing the main neoplastic component of GCTB, were used for cell-based experiments. Firstly, the anti-cancer effects of NCTD on GCTB stromal tumor cells were investigated by CCK-8 assay, flow cytometry and transwell invasion assay. Next, microRNA (miRNA) microarray and quantitative reverse transcription PCR (qRT-PCR) analyses were performed to examine and verify altered expression of miRNAs associated with NCTD treatment. Subsequently, the GCTB stromal cells were transfected with miR-30a inhibitor to confirm its involvement in the observed anti-cancer effects of NCTD. Luciferase reporter assays were carried out to identify the target gene of miR-30a. Moreover, changes in the expression of protein markers of AKT signaling were measured by Western Blot analysis. The results demonstrated that NCTD treatment could inhibit cell proliferation, block the cell cycle process and induce cell apoptosis in GCTB stromal cells. An inhibitory effect of NCTD on GCTB stromal cell invasion through inhibition of epithelial mesenchymal transition (EMT) was also observed. Expression of miR-30a was significantly upregulated by NCTD treatment and miR-30a knockdown significantly reversed the anti-tumor effects of NCTD against GCTB stromal cells. Of note, metadherin (MTDH), a novel oncogene which modulates the AKT pathway, was identified as a direct target of miR-30a in GCTB stromal cells. Further data showed that miR-30a could negatively regulate the expression of MTDH and the AKT pathway in GCTB stromal cells. Importantly, MTDH expression was found to be inversely correlated with miR-30a expression in clinical GCTB specimens. Moreover, NCTD treatment effectively suppressed the AKT signaling pathway as demonstrated by downregulation of phosphorylated-Akt S473 (p-Akt S473), p-Akt (T308), phosphorylated-glycogen synthase kinase (GSK)3β (p-GSK3β) and c-Myc, whilst miR-30a inhibition re-activated the AKT signaling pathway in GCTB stromal cells. Our findings demonstrate that NCTD can inhibit cell proliferation and metastasis of GCTB stromal cells in vitro, via modulating the miR-30a/MTDH/AKT signaling axis. This suggests that NCTD has potential as a novel therapeutic treatment for GCTB.

Denosumab treatment of inoperable or locally advanced giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is an osteolytic, locally aggressive tumor that rarely metastasizes and typically occurs in the bones. At present, the primary treatment for GCTB is curettage with local adjuvants. Giant cells express receptor activator of nuclear factor-κB ligand (RANKL). Denosumab, a RANKL inhibitor appears to present an effective therapeutic option in advanced cases of GCTB. The aim of the present study was to confirm the efficacy of denosumab in large group of patients with locally advanced GCTB. A total of 35 patients with histologically confirmed GCTB that were treated with denosumab with no participation in clinical trials between May 2013 and September 2015 were included in the present study. Denosumab treatment was administered until complete tumor resection was feasible or tumor progression or unacceptable toxicity had occurred. The mean denosumab treatment duration was 7.4 months. A total of 17 patients received surgery following denosumab treatment: 11 patients underwent wide en bloc resection with prosthesis implantation in 10 cases and 6 patients were treated with intralesional curettage. Tumor progression was observed in 2 patients that underwent intralesional curettage without prosthesis implantation. In addition, tumor progression was observed during denosumab treatment in 2 patients that had previously undergone radiotherapy. The overall 1-year progression-free survival rate was 92.8%. Thus, for patients with advanced, unresectable, progressive or symptomatic pretreated GCTB, denosumab provides a therapeutic option not previously available, which has become the standard therapy in multidisciplinary management of GCTB.

Bortezomib Inhibits Giant Cell Tumor of Bone through Induction of Cell Apoptosis and Inhibition of Osteoclast Recruitment, Giant Cell Formation, and Bone Resorption.

Giant cell tumor of bone (GCTB) is a rare and highly osteolytic bone tumor that usually leads to an extensive bone lesion. The purpose of this study was to discover novel therapeutic targets and identify potential agents for treating GCTB. After screening the serum cytokine profiles in 52 GCTB patients and 10 normal individuals using the ELISA assay, we found that NF-κB signaling-related cytokines, including TNFα, MCP-1, IL1α, and IL17A, were significantly increased in GCTB patients. The results were confirmed by IHC that the expression and activity of p65 were significantly increased in GCTB patients. Moreover, all of the NF-κB inhibitors tested suppressed GCTB cell growth, and bortezomib (Velcade), a well-known proteasome inhibitor, was the most potent inhibitor in blocking GCTB cells growth. Our results showed that bortezomib not only induced GCTB neoplastic stromal cell (NSC) apoptosis, but also suppressed GCTB NSC-induced giant cell differentiation, formation, and resorption. Moreover, bortezomib specifically suppressed GCTB NSC-induced preosteoclast recruitment. Furthermore, bortezomib ameliorated GCTB cell-induced bone destruction in vivo As a result, bortezomib suppressed NF-κB-regulated gene expression in GCTB NSC apoptosis, monocyte migration, angiogenesis, and osteoclastogenesis. Particularly, the inhibitory effects of bortezomib were much better than zoledronic acid, a drug currently used in treating GCTB, in our in vitro experimental paradigms. Together, our results demonstrated that NF-κB signaling pathway is highly activated in GCTB, and bortezomib could suppress GCTB and osteolysis in vivo and in vitro, indicating that bortezomib is a potential agent in the treatment of GCTB. Mol Cancer Ther; 15(5); 854-65. ©2016 AACR.