Clinicopathologic and prognostic characteristics of tumor budding-like in giant cell tumor of bone.

BACKGROUND: Currently, tumor budding (TB) is defined as an important factor for a poor prognosis in various types of cancers. The authors identified a significant presence of TB-like structures at the tumor invasive front in giant cell tumor of bone (GCTB), which may have the same biologic function as TB. The objective of this report was to describe the distribution of TB in GCTB and investigate its correlation with clinicopathologic characteristics, the immune microenvironment, survival prognosis, and response to denosumab treatment. METHODS: This multicenter cohort study included 426 patients with GCTB who received treatment between 2012 and 2021 at four centers. Two independent pathologists performed visual assessments of TBL structures in hematoxylin-and-eosin-stained tumor sections. Immunohistochemistry was used to evaluate tumor-infiltrating lymphocyte subtypes (CD3-positive, CD4-positive, CD8-positive, CD20-positive, programmed cell death protein-1-positive, programmed cell death-ligand 1positive, and FoxP3-positive) as well as Ki-67 expression levels in 426 tissue samples. These parameters were then analyzed for associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]), clinicopathologic characteristics, and response to denosumab treatment. RESULTS: High-grade TB was associated with poorer LRFS and OS in both patient groups. In addition, TB was correlated with various clinicopathologic features, tumor-infiltrating lymphocyte expression, and response to denosumab treatment. TB outperformed the traditional Enneking and Campanacci staging systems in predicting patient LRFS and OS. CONCLUSIONS: The current data support the assessment of TBL structures as a reliable prognostic tool in GCTB, potentially aiding in the development of personalized treatment strategies for patients.

Micro-CT, Mechanical, and Histological Examination of the Effect of Local Adjuvants on Porcine Cortical Bone Following Intralesional Curettage of Bone Tumors.

BACKGROUND AND OBJECTIVES: Curettage is the removal of a tumor from the bone while preserving the surrounding healthy cortical bone, and is associated with higher rates of local recurrence. To lower these rates, curettage should be combined with local adjuvants, although their use is associated with damage to nearby healthy bone. OBJECTIVE: The purpose of this analysis is to determine the effect of local adjuvants on cortical porcine bone by using micro-computed tomography (micro-CT) along with histological and mechanical examination. METHODS: Local adjuvants were applied to porcine specimens under defined conditions. To assess changes in bone mineral density (BMD), a micro-CT scan was used. The pixel gray values of the volume of interest (VOI) were evaluated per specimen and converted to BMD values. The Vickers hardness test was employed to assess bone hardness (HV). The depth of necrosis was measured histologically using hematoxylin and eosin-stained tissue sections. RESULTS: A noticeable change in BMD was observed on the argon beam coagulation (ABC) sample. Comparable hardness values were measured on samples following electrocautery and ABC, and lowering of bone hardness was obtained in the case of liquid nitrogen. Extensive induced depth of necrosis was registered in the specimen treated with liquid nitrogen. CONCLUSION: This study determined the effect of local adjuvants on cortical bone by using micro-CT along with histological and mechanical examination. Phenolization and liquid nitrogen application caused a decrease in bone hardness. The bone density was affected in the range of single-digit percentage values. Liquid nitrogen induced extensive depth of necrosis with a wide variance of values.

The diagnostic and prognostic value of tartrate-resistant acid phosphatase isoform 5b for giant cell tumor of bone.

BACKGROUND: Serum level of tartrate-resistant acid phosphatase 5b (TRACP5b) is an excellent serum marker of bone resorption. In patients with giant cell tumor of bone (GCTB), TRACP5b levels are reportedly elevated. This study investigated whether TRACP5b could be a diagnostic serum marker and be useful for detecting postoperative disease progression for GCTB. METHODS: Cohort 1: We abstracted data from 120 patients with TRACP5b measurements from our database: 49 patients with GCTB and 71 patients non-GCTB. We compared serum TRACP5b values between the GCTB and non-GCTB groups. Cohort 2 included 47 patients with GCTB who had more than 6 months of follow-up and multiple TRACP5b values. For patients with local recurrence, TRACP5b change rate was calculated by comparing the TRACP5b value just before progression (a) with the value at the time of progression (b): Change rate = [(b)-(a)]/(a). In the non-progression group, the change rate was calculated from the two consecutive TRACP5b values, (c) and (d): Change rate =[(c)-(d)]/(c). We compared TRACP5b change rates between the progression and non-progression groups. RESULTS: Cohort 1: The GCTB group had a significantly higher mean TRACP5b value (1756 ± 2021 mU/dL) than the non-GCTB group (415 ± 219 mU/dL) (p < 0.0001). Cohort 2: The mean TRACP5b change rate of the progression group was significantly higher than the non-progression group (8.53 ± 8.52 and 0.24 ± 0.27, respectively; p < 0.0001). CONCLUSION: TRACP5b is a useful diagnostic marker in GCTB. The rate of change in serum TRACP5b values is a highly sensitive marker for predicting local recurrence in GCTB.

Giant cell tumor of bone of temporal bone and skull base: report of 6 cases.

OBJECTIVE: Five cases of giant cell tumor of bone (GCTB) in the head and neck region were reported, with a main focus on the radiological findings to identify common characteristics for the diagnosis of GCTB in these sites. MATERIALS AND METHODS: Five consecutive patients diagnosed with GCTB were retrospectively selected. Radiological features on conventional and advanced MR sequences and CT were analyzed. HE staining and immunohistochemical examination were performed using antibodies against p63 and CD68. RESULTS: The common clinical features were local mass (3/5), tinnitus (3/5) and headache (2/5). Radiologically, all the cases were well-circumscribed osteolytic lesion, majority of cases demonstrated an expansile growth pattern and "soap bubble" appearance on CT (4/5). On MRI, the tumors showed predominantly hypointensity both on T1WI and T2WI, and no evidence of restricted diffusion on DWI. Intratumoral hemorrhage (2/5), cystic alternation (2/5) and very low signal on T2WI in the periphery region of the tumor (4/5) was found. Fluid-fluid level was noted in one case, which was eventually verified to be GCTB with secondary aneurysmal bone cyst (ABC). With contrast agent, all the cases showed striking (3/5) or mild to intermediate (2/5) enhancement. CONCLUSIONS: Although the above described radiological findings are not specific for GCTB in head and neck region, a well-defined osteolytic lesion in the bones of head and neck region with "soap bubble" appearance on CT and hypointensity on T2WI with very low signal in the peripheral region of the tumor on MRI highly suggest GCTB for patient ages 20 to 40.

Diagnosis and monitoring denosumab therapy of giant cell tumors of bone: radiologic-pathologic correlation.

OBJECTIVE: To determine the value of CT and dynamic contrast-enhanced (DCE-)MRI for monitoring denosumab therapy of giant cell tumors of bone (GCTB) by correlating it to histopathology. MATERIALS AND METHODS: Patients with GCTB under denosumab treatment and monitored with CT and (DCE-)MRI (2012-2021) were retrospectively included. Imaging and (semi-)quantitative measurements were used to assess response/relapse. Tissue samples were analyzed using computerized segmentation for vascularization and number of neoplastic and giant cells. Pearson's correlation/Spearman's rank coefficient and Kruskal-Wallis tests were used to assess correlations between histopathology and radiology. RESULTS: Six patients (28 ± 8years; five men) were evaluated. On CT, good responders showed progressive re-ossification (+7.8HU/month) and cortical remodeling (woven bone). MRI showed an SI decrease relative to muscle on T1-weighted (-0.01 A.U./month) and on fat-saturated T2-weighted sequences (-0.03 A.U./month). Time-intensity-curves evolved from a type IV with high first pass, high amplitude, and steep wash-out to a slow type II. An increase in time-to-peak (+100%) and a decrease in Ktrans (-71%) were observed. This is consistent with microscopic examination, showing a decrease of giant cells (-76%), neoplastic cells (-63%), and blood vessels (-28%). There was a strong statistical significant inverse correlation between time-to-peak and microvessel density (ρ = -0.9, p = 0.01). Significantly less neoplastic (p = 0.03) and giant cells (p = 0.04) were found with a time-intensity curve type II, compared to a type IV. Two patients showed relapse after initial good response when stopping denosumab. Inverse imaging and pathological findings were observed. CONCLUSION: CT and (DCE-)MRI show a good correlation with pathology and allow adequate evaluation of response to denosumab and detection of therapy failure.

Reduced recurrence rate and comparable functionality after wide resection and reverse total shoulder arthroplasty with allograft-prosthetic composite versus curettage for proximal humeral giant cell tumor: a multicenter retrospective study.

BACKGROUND: Giant cell tumors of bone (GCTBs) are rare, aggressive tumors, and the proximal humerus is a relatively rare location for GCTBs; limited evidence exists on which surgical approaches and reconstruction techniques are optimal. In the largest case series to date, we evaluated the recurrence rate of proximal humeral GCTBs and the functional outcomes of different resection and reconstruction options in this multicenter study. METHODS: All 51 patients included in this study received initial surgical treatment for proximal humeral GCTBs from January 2007 to December 2020, with a minimum 2-year follow-up period. Local recurrence and functional outcomes were statistically analyzed in relation to demographic, clinical, and primary surgical variables. Functional outcomes were reported by patients and were assessed by the Musculoskeletal Tumor Society score and QuickDASH instrument (shortened version of the Disabilities of the Arm, Shoulder and Hand instrument). RESULTS: The mean follow-up period was 81.5 months (range, 30-191 months), and the overall recurrence rate was 17.6% (9 of 51 patients). The majority of recurrences (n = 7) occurred in the first 2 years of follow-up. The intralesional curettage group (n = 23) showed a statistically significant difference in the recurrence rate compared with the en bloc resection group (n = 28) (34.8% vs. 3.6%, P = .007). Among shoulders receiving en bloc resection, 16 were reconstructed with hemiarthroplasty; 8, reverse total shoulder arthroplasty (rTSA) with allograft-prosthetic composite (APC) reconstruction; and 4, arthrodesis. On the basis of intention-to-treat analysis, the mean functional Musculoskeletal Tumor Society scores of the groups undergoing curettage, rTSA with APC, hemiarthroplasty, and arthrodesis were 26.0 ± 3.1, 26.0 ± 1.7, 20.3 ± 2.8, and 22.5 ± 1.3, respectively (P < .001 [with P < .001 for curettage vs. hemiarthroplasty and P = .004 for rTSA with APC vs. hemiarthroplasty]) and the mean QuickDASH scores were 14.0 ± 11.0, 11.6 ± 4.5, 33.1 ± 11.8, and 21.6 ± 4.7, respectively (P < .001 [with P < .001 for curettage vs. hemiarthroplasty and P = .003 for rTSA with APC vs. hemiarthroplasty]). CONCLUSIONS: On the basis of our data, en bloc resection followed by reverse shoulder arthroplasty showed a lower recurrence rate and no significant difference in functional outcome scores for proximal humeral GCTBs compared with intralesional curettage. Therefore, we believe that rTSA with APC may be reasonable for the initial treatment of proximal humeral GCTBs.

Denosumab treatment for progressive Enneking stage II cervical giant-cell tumor conservatively.

Cervical giant cell tumor of the bone (GCTB) is a rare, primary benign bone tumor in pediatric patients. Surgery remains the primary choice for treating resectable cervical GCTB. Additional adjuvant therapeutic options are available for patients with unresectable cervical GCTB, including the anti-RANKL monoclonal antibody, denosumab. We represented a case incidentally found in a 7-year-old female, who complained severe craniocervical pain, grade 2-3 dysphagia, dysphonia, hypesthesia, and extremity weakness. The patient showed an impressive clinical response to denosumab, both clinically and radiologically, without adverse events or recurrence. To date, this is the youngest patient ever reported to have a progressive Enneking stage II C3 GCTB treated with denosumab alone. Denosumab can be administered as a single and conservative therapy for pediatric patients with unresectable upper cervical GCTB, avoiding the risks and morbidity of surgical and radiative treatment.

Giant cell tumor of bone with secondary aneurysmal bone cyst does not have a higher risk of local recurrence.

BACKGROUND: Fluid-fluid levels (FFLs) is found in 10%-16% of giant cell tumor of bone (GCTB), and the presence of FFLs raises the suspicion of GCTB with secondary aneurysmal bone cyst (ABC), which can lead to increased intraoperative bleeding and, blurring the operative field, be associated with a risk of local recurrence. The first objective of this study is to determine whether secondary ABC is associated with a higher risk of local recurrence after curettage in patients with GCTB of the extremities. The second objective of this study is to investigate the sensitivity, specificity, positive predictive value, and negative predictive value of the presence of FFLs detected on magnetic resonance imaging (MRI) to diagnose secondary ABC associated with GCTB. METHODS: Two hundred and eighty patients with GCTB of the extremities who underwent curettage at the authors' institutions between 1980 and 2021 were included in this study. RESULTS: Secondary ABC was found in 36 of 280 patients (12.9%) and local recurrence occurred in 66 of 280 patients (23.6%). Multivariate analysis showed no significant correlation between secondary ABC and local recurrence (hazard ratio [HR]: 1.87 (95% confidence interval [CI]: 1.00-3.53]; p = 0.051). Preoperative MRI revealed FFLs in 13 of 82 patients (15.9%). Sensitivity, specificity, positive predictive value, and negative predictive value of FFLs detected on preoperative MRI to diagnose secondary ABC were 36.8%, 90.5%, 53.8%, and 82.6%, respectively. CONCLUSION: The results of this study showed that secondary ABC does not increase the risk of local recurrence after curettage in patients with GCTB of the extremities. Although rare, FFLs were present in patients with GCTB and half of those with FFLs detected on preoperative MRI had secondary ABC.

The efficacy and safety of short-course neoadjuvant denosumab for en bloc spondylectomy in spinal giant cell tumor of bone: a preliminary report.

PURPOSE: This study aimed to investigate whether short course of neoadjuvant denosumab treatment for spinal GCTB could (1) Induce radiological and histological response? (2) Facilitate en bloc resection? (3) Achieve satisfactory oncological and functional outcomes? METHODS: The clinical information of ten consecutive patients between 2018 and 2022 with spinal GCTB treated with short course of neoadjuvant denosumab (≤ 5 doses) and en bloc spondylectomy was retrospectively reviewed. The radiological and histological response, operative data, oncological and functional outcomes were analyzed. RESULTS: The mean doses of neoadjuvant denosumab were 4.2 (range 3-5 doses). After neoadjuvant denosumab, there were 9 cases showing new ossification and 5 cases with reappearance of cortical integrity. The values of Hounsfield units (HU) of the soft tissue component were increased by > 50% in 7 cases. The signal intensity (SI) ratios of tumor/muscle in T2WI of plain MRI were decreased by > 10% in 60% of the cases. Shrinkage of soft tissue mass by > 10% was observed in 4 cases. The mean duration of operation was 575 ± 174 min, and the mean estimated blood loss (EBL) was 2790 ± 1934 ml. No obvious adhesion to dura mater or major vessels was encounter intraoperatively. There is no tumor collapse or breakage during surgery. Multinucleated giant cells were decreased in 6 cases (60%) with the remaining 4 cases showing absence of multinucleated giant cells. Mononuclear stromal cells existed in most of the cases (8 cases, 80%). New bone formation was noticed in 8 cases (80%). No patient had a worsening of neurologic function after surgery. No tumor recurrence was noticed within the mean follow-up of 24 ± 20 months. CONCLUSION: Short-term neoadjuvant denosumab could yield radiological and histological responses and might facilitate en bloc spondylectomy by hardening the tumor and causing less adhesion to segmental vessels, major vessels and nerve roots, which was beneficial to achieve the optimal oncological and functional outcomes.

Benign Brain and Spinal Tumors Originating from Bone or Cartilage.

Benign osseocartilaginous tumors of the spine are overall uncommon, representing between 1 and 13% of all primary bone tumors and less than 10% of all spinal tumors. Tumors in this category include osteoblastic lesions such as the related osteoid osteoma and osteoblastoma, and cartilage-forming lesions including osteochondroma, chondroma, and chondroblastoma. Aneurysmal bone cysts, giant cell tumors of bone, and eosinophilic granulomas also comprise benign tumors of the spine arising from bone. There is significant heterogeneity in the epidemiology, molecular biology, imaging features, and optimal treatment of these lesions. For example, osteoid osteoma is characterized by high expression of the cyclooxygenase enzymes, making it amenable to treatment with anti-inflammatory drugs initially, whereas other lesions such as osteoblastoma may require intralesional curettage or en bloc resection sooner. Generally, en bloc resection is preferred when possible to minimize risk of recurrence. Further, some tumors may arise in the setting of syndromic conditions, such as multiple chondromas arising in Ollier disease or Maffucci syndrome, or as part of genetic disorders, such as osteochondromas in the context of hereditary multiple exostosis. These lesions may present with local pain, cause neurological compromise or be discovered incidentally on routine imaging. The Enneking classification and Weinstein-Boriani-Biagini system are routinely used to classify lesions and assist in surgical planning. More novel techniques such as radiofrequency ablation and laser photocoagulation have been applied for the treatment of osteoid osteoma and may have utility in the treatment of other lesion types. A multidisciplinary approach is critical in the management of benign lesions of the spine, and both chemotherapeutic and surgical approaches are routinely used.

Giant-cell-poor giant cell tumor of bone: report of two cases and literature review.

Giant cell tumor of bone (GCTB) is a locally aggressive tumor that shows predilection for the metaphysis/epiphysis of long bones, with an incidence of 4-5% of primary bone tumors. GCTB shows two main populations of cells: mononuclear cells and non-neoplastic multi-nucleated giant cells, with or without fibrous background. On the other hand, giant-cell-poor GCTB are rare with only few reports in the literature. These cases offer a diagnostic challenge, given the absence of giant cells and such cases have consistently been shown to harbor the H3F3A gene mutation by sequencing. The H3.3 G34W mutation-specific monoclonal antibody has shown high specificity in the diagnosis of GCTB. Two cases of giant-cell-poor GCTB are presented in this study, in which giant cells were absent or sparse and the diagnosis of GCTB was confirmed by the expression of H3.3 G34W monoclonal antibody in the mononuclear cells by immunohistochemistry. Whether this represents a histologic variant of GCTB or partial involution of GCTB is not yet fully understood; however, an immune response, infectious/inflammatory reaction, and/or anti-tumor cytokine production have been purported to be factors inciting disease regression in GCTB.

Comparing clinical outcomes between extended curettage and wide resection in Enneking stage 3 giant cell tumor of bone.

PURPOSE: Our objectives were (1) to compare the recurrence, metastases, and complication rates of patients with Enneking stage 3 GCTB who underwent extended curettage vs wide resection and (2) examine the factors which might influence surgical options for each patient. METHODS: We retrospectively reviewed the records of patients with Enneking stage 3 GCTB from January 2006-December 2015. Extended curettage was performed in patients in whom there was a moderate expansile lesion, minimal/no articular cartilage damage, and less than 50% of cortical deformation compared to its circumference from a CT scan/MRI. The percentages of cortical deformation were collected. Surgical complications, recurrence, and metastatic rates were analyzed. RESULTS: There were 28 extended curettage and 41 wide resections. The mean percentages of cortical deformation compared to circumference were 52.6% (range, 23.9-81.9%) and 91.6% (range, 52.1-100%)(P < 0.01) for the curettage and wide resection groups, respectively. There were three recurrences, 2/28 (7.1%) from the curettage group and 1/41 (2.4%) from the resection group (P = 0.56). There were no cases of pulmonary metastasis. There were two complications in the curettage group and five complications in the resection group. CONCLUSION: Both extended curettage and wide resection are useful methods to treat Enneking stage 3 GCTB. Extended curettage with proper technique is a viable option showing no difference in local recurrence rate and potentially fewer complications. Preference to do extended curettage in patients in whom when the articular cartilage has minimal or no destruction, a moderate expansile lesion and the cortical deformation is less than 50% of the circumference.

Giant Cell Tumor of Bone: Effect of Longer Dosing Intervals of Denosumab on Tumor Control and Bone-related Complications.

BACKGROUND: Denosumab is an effective treatment for giant cell tumor of the bone (GCTB) but can cause clinically significant adverse effects. Current approved dosing is every 4 weeks after 3 weekly loading doses. We assessed whether alternative, longer dosing intervals are associated with differences in efficacy or bone toxicity. METHODS: Single institution retrospective chart review was conducted on patients with GCTB over 18 years old who received at least 1 year of standard denosumab dosing. Patients identified using a free-text search engine with keywords "giant cell tumor" and "denosumab" from January 1998 to August 2020. RESULTS: Approximately 37 patients with GCTB (19F, 18M) were identified with median age of 37 years (range 22-73). Dosing interval was increased in 38% (n = 14), with the most common final dosing interval 12 weeks (n = 8). Six patients (16%) had bone complications: osteonecrosis of the jaw (n =5), atypical fracture (n = 1), and nonhealing dental wounds (n = 2). All patients with bone complications were on the monthly dosing schedule, but there was no statistically significant difference compared to longer dosing intervals (P = .22). No statistically significant difference in median PFS was noted (P = .97). However, 5-year PFS was superior in patients treated with less frequent versus standard dosing of denosumab (P = .036). CONCLUSIONS: Increasing the interval of denosumab dosing for GCTB provided similar tumor control compared to standard dosing and lower absolute number of bone toxicity events. Larger studies are needed to better define the optimal interval of denosumab administration and the effect on efficacy, toxicity, and associated healthcare expense.

Sclerostin immunohistochemical staining in surgically treated giant cell tumor of bone.

BACKGROUND: Giant cell tumor of bone (GCTB) is a destructive lesion with a high potential for recurrence. RANK-ligand targeted therapy has provided promising, yet mixed results. Sclerostin (SOST) inhibition results in a net anabolic response and is currently used in the treatment of osteoporosis. The application to GCTB is unknown. OBJECTIVES: We sought to determine if GCTB stained for SOST on immunohistochemistry and correlate its expression with predictor variables. METHODS: All patients at a single institution undergoing surgery for GCTB between 1993 and 2008 with a minimum of 6 months follow-up were included. Primary outcomes included the presence of SOST staining, secondary outcomes included the correlation of patient and tumor-specific predictor variables. RESULTS: SOST antibody staining of any cell type was present in 47 of 48 cases (97.9%). Positivity of the stromal cells was present in 39 of 48 cases (81.3%) and was associated with radiographic aggressiveness (p = 0.023), symptomatic presentation (p = 0.032), prior surgery (p = 0.005), and patient age (p = 0.034). Positivity of giant cells was present in 41 of 48 cases (85.4%) and was not significant with predictive factors. CONCLUSIONS: Sclerostin staining in GCTB is a novel finding and warrants further research to define the role of sclerostin as a prognostic factor and therapeutic target.

Treatment of giant cell tumors of the distal radius: A long-term patient-reported outcomes study.

INTRODUCTION: The distal radius is a common location for giant cell tumors (GCTs) of bone. Management includes intralesional curettage or wide excision, however, long-term comparisons of treatment options are limited. The purpose of the current study was to evaluate our institutions' outcomes of treatment of these tumors. METHODS: We reviewed 24 GCT of the distal radius in 23 patients (12 males: 11 females) with a mean age of 42 years at the time of surgery. Functional outcomes were collected including the Musculoskeletal Tumor Society Score (MSTS), QuickDash, the Visual Analog Scale (VAS), and the Patient Rated Wrist Evaluation (PRWE). The mean follow-up was 13 years. RESULTS: Tumor grade included Campanacci Grade II (n = 14) and Grade III (n = 10). Treatment included extended intralesional curettage (n = 16) and wide excision (n = 8). Reconstruction mainly included bone grafting/cement (n = 16) or free vascularized fibula radiocarpal arthrodesis (n = 5). At most recent follow-up, there was no difference in MSTS, VAS, and PRWE (p > 0.05) between patients undergoing a joint sparing or arthrodesis. Patients undergoing arthrodesis had a lower QuickDASH score (13.7 vs. 20.8, p = 0.04) CONCLUSIONS: Treatment for GCT of the distal radius is individualized however in the setting of articular surface involvement, arthrodesis can lead to superior functional results at long-term follow-up.

Combined fibrinogen and neutrophil-lymphocyte ratio as a biomarker in predicting recurrence of giant cell tumor of bone.

Aims: The present study investigated the combined clinical significance of fibrinogen and neutrophil-lymphocyte ratio (F-NLR) in predicting postoperative recurrence of giant cell tumor of bone. Methods: A total of 113 participants were included in this retrospective study to examine the effects of inflammatory factors on postoperative tumor recurrence. Results: The high-score F-NLR group was significantly associated with larger tumor size (p = 0.001), advanced tumor stage (p = 0.018), wide resection (p = 0.004) and greater local recurrence (p = 0.014). Univariate and multivariate survival analyses revealed that F-NLR (p = 0.035) remained an independent factor influencing tumor recurrence rates. Conclusions: This study reveals that the F-NLR score is a promising blood biomarker for predicting giant cell tumor recurrence.

Giant cell tumor of bone (GCT) is predominantly regarded as an intermediate, locally destructive but rarely metastasizing tumor with recurrence potential and peak incidence in the second to fourth decades of life. The treatment of GCT is often difficult due to local recurrence. Therefore, a new indicator is urgently needed to predict postoperative recurrence more accurately in patients with GCT. The preoperative combined fibrinogen and neutrophil­lymphocyte ratio as a predictor of tumor recurrence and prognosis in GCT patients has been assessed. The present study is the first to demonstrate that a grading system based on the fibrinogen and neutrophil­lymphocyte ratio score is an easily determined, meaningful and reproducible biomarker for predicting recurrence in GCT patients.

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone. JCOG1610.

OBJECTIVES: The aim of JCOG1610 (randomized controlled phase III trial) was to confirm the superiority of preoperative denosumab to curettage with adjuvant local therapy for patients with giant cell tumor of bone without possible post-operative large bone defect. METHODS: The primary endpoint was relapse-free survival and the total sample size was set at 106 patients. Patient accrual began in October 2017. However, the accrual was terminated in December 2020 due to a recommendation from the Data and Safety Monitoring Committee because of poor patient accrual. Now, we report the descriptive results obtained in this study. RESULTS: A total of 18 patients had been registered from 13 Japanese institutions at the time of termination on December 2020. Eleven patients were assigned to Arm A (curettage and adjuvant local therapy) and 7 to Arm B (preoperative denosumab, curettage and adjuvant local therapy). Median follow-up period was 1.6 (range: 0.5-2.8) years. Protocol treatment was completed in all but one patient in Arm A who had a pathological fracture before surgery. All patients in Arm B were treated with five courses of preoperative denosumab. Relapse-free survival proportions in Arm A and B were 90.0% (95% confidence interval: 47.3-98.5) and 100% (100-100) at 1 year, and 60.0% (19.0-85.5) and 62.5% (14.2-89.3) at 2 years, respectively [hazard ratio (95% confidence interval): 1.51 (0.24-9.41)]. CONCLUSION: In terms of relapse-free survival, the superiority of preoperative denosumab was not observed in patients with giant cell tumor of bone without possible post-operative large bone defect.

Current management of giant-cell tumor of bone in the denosumab era.

Giant-cell tumor of bone is a rare, locally aggressive and rarely metastasizing primary bone tumor. The mainstay of treatment remains controversial and is decided by the balance between adequate surgical margin and sufficient adjacent joint function. Although curettage with a high-speed burr and local adjuvants can maintain normal joint function, many reports have revealed a high local recurrence rate. Conversely, en bloc resection and reconstruction with prostheses for highly aggressive lesions have reportedly lower local recurrence rates and poorer functional outcomes. Denosumab-a full human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa ß ligand-was approved by the Food and Drug Authority in 2013 for use in surgically unresectable or when resection is likely to result in severe morbidity for skeletally mature adolescents and adults with giant-cell tumor of bone. However, subsequent studies have suggested that the local recurrence rate would be increased by preoperative use of denosumab. In systematic reviews of the local recurrence rate after preoperative use of denosumab, conclusions vary due to the small sample sizes of the studies reviewed. Therefore, controversy regarding the treatment of giant-cell tumor of bone is ongoing. Here, this review elucidates the management of giant-cell tumor of bone, especially with the local adjuvant and neoadjuvant use of denosumab, and presents the current, evidence-based treatment for giant-cell tumor of bone.

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

BACKGROUND: 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%). PURPOSE: 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. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: Intraoperative MRI could contribute to the reduction of residual tumor tissue and it may prevent recurrence of GCTB after denosumab therapy.

Risk factors of fracture following curettage for bone giant cell tumors of the extremities.

BACKGROUND: Following curettage of giant cell tumor of bone (GCTB), it is common to fill the cavity with polymethylmethacrylate (PMMA) bone cement, bone allograft, or artificial bone to maintain bone strength; however, there is a 2-14% risk of postoperative fractures. We conducted this retrospective study to clarify the risk factors for fractures after curettage for GCTB of the extremities. METHODS: This study included 284 patients with GCTBs of the extremities who underwent curettage at our institutions between 1980 and 2018 after excluding patients whose cavities were not filled with anything or who had additional plate fixation. The tumor cavity was filled with PMMA bone cement alone (n = 124), PMMA bone cement and bone allograft (n = 81), bone allograft alone (n = 63), or hydroxyapatite graft alone (n = 16). RESULTS: Fractures after curettage occurred in 10 (3.5%) patients, and the median time from the curettage to fracture was 3.5 months (interquartile range [IQR], 1.8-8.3 months). The median postoperative follow-up period was 86.5 months (IQR, 50.3-118.8 months). On univariate analysis, patients who had GCTB of the proximal or distal femur (1-year fracture-free survival, 92.5%; 95% confidence interval [CI]: 85.8-96.2) presented a higher risk for postoperative fracture than those who had GCTB at another site (100%; p = 0.0005). Patients with a pathological fracture at presentation (1-year fracture-free survival, 88.2%; 95% CI: 63.2-97.0) presented a higher risk for postoperative fracture than those without a pathological fracture at presentation (97.8%; 95% CI: 95.1-99.0; p = 0.048). Patients who received bone grafting (1-year fracture-free survival, 99.4%; 95% CI: 95.7-99.9) had a lower risk of postoperative fracture than those who did not receive bone grafting (94.4%; 95% CI: 88.7-97.3; p = 0.003). CONCLUSIONS: For GCTBs of the femur, especially those with pathological fracture at presentation, bone grafting after curettage is recommended to reduce the risk of postoperative fracture. Additional plate fixation should be considered when curettage and cement filling without bone grafting are performed in patients with GCTB of the femur. This should be specially performed for those patients with a pathological fracture at presentation.