Research

10 pages, 2500 KiB

Open AccessArticle

Bone Turnover Marker (BTM) Changes after Denosumab in Giant Cell Tumors of Bone (GCTB): A Phase II Trial Correlative Study

by Emanuela Palmerini, Laura Pazzaglia, Luca Cevolani, Loredana Pratelli, Michela Pierini, Irene Quattrini, Elisa Carretta, Maria Cristina Manara, Michela Pasello, Giorgio Frega, Anna Paioli, Alessandra Longhi, Marilena Cesari, Rossella Hakim, Toni Ibrahim, Laura Campanacci, Eric Lodewijk Staals, Davide Maria Donati, Maria Serena Benassi, Katia Scotlandi and Stefano Ferrari Show full author list Hide full author list

Cancers 2022, 14(12), 2863; https://doi.org/10.3390/cancers14122863 - 10 Jun 2022

Cited by 6 | Viewed by 1811

Abstract

Background: Giant cell tumors of bone (GCTB) are osteolytic tumors. Denosumab, a RANK-L inhibitor, is approved for GCTB. Data on serum bone turnover marker (sBTM) changes are lacking. We present a phase II correlative study on sBTMs in GCTB patients treated with denosumab. [...] Read more.

Background: Giant cell tumors of bone (GCTB) are osteolytic tumors. Denosumab, a RANK-L inhibitor, is approved for GCTB. Data on serum bone turnover marker (sBTM) changes are lacking. We present a phase II correlative study on sBTMs in GCTB patients treated with denosumab. Methods: All GCTB patients receiving denosumab within a multicentre, open-label, phase 2 study were enrolled. Serum levels of carboxyterminal-crosslinked-telopeptide of type I collagen (s-CTX), alkaline phosphatase (ALP), bone-alkaline phosphatase (bALP), parathyroid hormone (sPTH), and osteocalcin (OCN) were prospectively assessed (baseline, T0, 3 months, T1, 6 months, T2). The primary endpoint was assessment of sBTM changes after denosumab; the secondary endpoints were disease-free survival (DFS) and sBTM correlation. Results: In 54 cases, sBTMs decreased during denosumab treatment except for sPTH. With a median follow-up of 59 months, 3-year DFS was 65% (%CI 52–79), with a significantly worse outcome for patients with high (≥500 UI/mL) s-CTX at baseline, as compared to low s-CTX (<500 UI/mL) (3-year DFS for high CTX 45% (95%CI 23–67) vs. 75% (95%CI 59–91) for low s-CTX. Higher median ALP and s-CTX were found for patients with tumor size ≥ 5 cm (p = 0.0512; p = 0.0589). Conclusion: Denosumab induces ALP/OCN and s-CTX reduction. High baseline s-CTX identifies a group of patients at higher risk of progression of the disease. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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12 pages, 1555 KiB

Open AccessArticle

Late Local Recurrence of Bone Giant Cell Tumors Associated with an Increased Risk for Malignant Transformation

by Shinji Tsukamoto, Alberto Righi, Andreas F. Mavrogenis, Manabu Akahane, Kanya Honoki, Yasuhito Tanaka, Davide Maria Donati and Costantino Errani

Cancers 2021, 13(14), 3644; https://doi.org/10.3390/cancers13143644 - 20 Jul 2021

Cited by 10 | Viewed by 2333

Abstract

In giant cell tumor of bone (GCTB), an intermediate malignant bone tumor, approximately 4% of all cases undergo malignant transformation. Accordingly, we analyzed risk factors for malignant transformation of GCTB treated without radiotherapy. We retrospectively reviewed medical records of 530 patients with GCTB [...] Read more.

In giant cell tumor of bone (GCTB), an intermediate malignant bone tumor, approximately 4% of all cases undergo malignant transformation. Accordingly, we analyzed risk factors for malignant transformation of GCTB treated without radiotherapy. We retrospectively reviewed medical records of 530 patients with GCTB of the extremities, admitted and treated at two institutions between January 1980 and December 2019. Overall, 4 patients with primary malignant GCTB, 4 patients with missing data, 3 patients with a history of radiotherapy, 22 patients with a follow-up of less than 6 months, and 36 patients who received denosumab were excluded. Accordingly, 461 patients were included for further analysis. Malignant transformation was observed in 15 of 461 patients (3.3%) at a median follow-up period of 192 months. The median follow-up duration was 89.4 months. Multivariate analysis revealed that local recurrence was an independent prognostic factor for unfavorable malignant transformation (Hazard ratio [HR], 11.33; 95% confidence interval [CI] 2.33–55.13; p = 0.003 for once versus none and HR, 11.24; 95% CI, 1.76–71.96; and p = 0.011 for twice or more versus none). The interval between the last surgery to local recurrence and malignant transformation was longer than that to local recurrence of benign GCTB, with a median of 15.2 years (interquartile range [IQR], 5.2–25.4) versus 1.3 months (IQR, 0.8–2.6), respectively (p < 0.001). Late local recurrence of GCTB is associated with a higher risk of malignant transformation. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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15 pages, 3666 KiB

Open AccessArticle

New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling

by Michal Mahdal, Jakub Neradil, Peter Mudry, Silvia Paukovcekova, Iva Staniczkova Zambo, Jiri Urban, Peter Macsek, Lukas Pazourek, Tomas Tomas and Renata Veselska

Cancers 2021, 13(14), 3543; https://doi.org/10.3390/cancers13143543 - 15 Jul 2021

Cited by 8 | Viewed by 3462

Abstract

Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of [...] Read more.

Giant-cell tumor of bone (GCTB) is an intermediate type of primary bone tumor characterized by locally aggressive growth with metastatic potential. The aim of this study was to identify new druggable targets among the cell signaling molecules involved in GCTB tumorigenesis. Profiles of activated signaling proteins in fresh-frozen tumor samples and tumor-derived cell lines were determined using phosphoprotein arrays. Analysis of the obtained data revealed epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor beta (PDGFRβ) as potential targets, but only the PDGFR inhibitor sunitinib caused a considerable decrease in stromal cell viability in vitro. Furthermore, in the case of a 17-year-old patient suffering from GCTB, we showed that the addition of sunitinib to the standard treatment of GCTB with the monoclonal antibody denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal cells in the tumor tissue. To summarize, the obtained data showed that a specific receptor tyrosine kinase (RTK) signaling pattern is activated in GCTB cells and plays an important role in the regulation of cell proliferation. Thus, activated RTKs and their downstream signaling pathways represent useful targets for precision treatment with low-molecular-weight inhibitors or with other types of modern biological therapy. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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10 pages, 13962 KiB

Open AccessArticle

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

by Francesca Ambrosi, Alberto Righi, Stefania Benini, Giovanna Magagnoli, Ilaria Chiaramonte, Marco Manfrini, Alessandro Gasbarrini, Tommaso Frisoni and Marco Gambarotti

Cancers 2021, 13(11), 2585; https://doi.org/10.3390/cancers13112585 - 25 May 2021

Cited by 6 | Viewed by 2953

Abstract

Background: Giant cell tumor of bone is a locally aggressive, rarely metastasizing tumor that accounts for about 5% of bone tumors and generally occurs in patients between 20 and 45 years old. A driver mutation in the histone 3.3 (H3.3) gene H3F3A has [...] Read more.

Background: Giant cell tumor of bone is a locally aggressive, rarely metastasizing tumor that accounts for about 5% of bone tumors and generally occurs in patients between 20 and 45 years old. A driver mutation in the histone 3.3 (H3.3) gene H3F3A has been identified in as many as 96% of giant cell tumors of bone. The immunohistochemical expression of H3F3A H3.3 G34 expression was found in 97.8% of cases. In the present study, we describe our series of cases of giant cell tumor of bone in pediatric patients <16 years old. Methods: All cases of giant cell tumor of bone in pediatric patients <16 years old treated in our institute between 1982 and 2018 were reviewed. Immunohistochemistry and/or molecular analysis for H3F3A gene mutations was performed to confirm the diagnosis. A group of aneurysmal bone cysts in patients <16 years old was used as a control group. Results: Fifteen cases were retrieved. A pronounced female predominance (93%) was observed. A pure metaphyseal central location occurs in 2 skeletally immature patients. Conclusions: Giant cell tumor of bone should be distinguished from its mimickers due to differences in prognosis and treatment. Immunohistochemical and molecular detection of H3F3A gene mutation represents a reliable diagnostic tool. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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Review

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22 pages, 8008 KiB

Open AccessReview

Denosumab in Giant Cell Tumor of Bone: Multidisciplinary Medical Management Based on Pathophysiological Mechanisms and Real-World Evidence

by Aneta Maria Borkowska, Anna Szumera-Ciećkiewicz, Bartłomiej Szostakowski, Andrzej Pieńkowski and Piotr Lukasz Rutkowski

Cancers 2022, 14(9), 2290; https://doi.org/10.3390/cancers14092290 - 04 May 2022

Cited by 12 | Viewed by 4711

Abstract

(1) Despite the benign nature of the giant cell tumor of bone (GCTB), it shows a local recurrence rate of up to 50% and a chance of malignant transformation. The widely accepted local therapy in extremity GCTB is surgery, in the form of [...] Read more.

(1) Despite the benign nature of the giant cell tumor of bone (GCTB), it shows a local recurrence rate of up to 50% and a chance of malignant transformation. The widely accepted local therapy in extremity GCTB is surgery, in the form of extended intralesional curettage with adequate disease clearance and retention of the limb, wherever possible. Denosumab, a human monoclonal antibody directed against the RANKL and associated inhibition of the RANKL pathway, is a relevant therapy option for advanced GCTB, to benefit tumor response and surgical down-staging. (2) The literature review of patients with GCTB treated with denosumab is performed via PubMed, using suitable keywords from January 2009 to January 2021. (3) Current indications for denosumab use are not definitively clear and unambiguous. Most GCTB patients with localized disease can be successfully treated with surgical curettage, and the role of denosumab in preoperative therapy in this patient population remains unclear. (4) However, patients with primary unresectable lesions or metastases may experience long-term clinical and radiological remission and pain control with denosumab treatment, and in this clinical situation, denosumab is currently the treatment of choice. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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17 pages, 2533 KiB

Open AccessReview

State of the Art and New Concepts in Giant Cell Tumor of Bone: Imaging Features and Tumor Characteristics

by Anna Parmeggiani, Marco Miceli, Costantino Errani and Giancarlo Facchini

Cancers 2021, 13(24), 6298; https://doi.org/10.3390/cancers13246298 - 15 Dec 2021

Cited by 12 | Viewed by 3733

Abstract

Giant cell tumor of bone (GCTB) is classified as an intermediate malignant tumor due to its locally aggressive behavior, burdened by high local recurrence rate. GCTB accounts for about 4–5% of all primary bone tumors and typically arises in the metaphysis and epiphyses [...] Read more.

Giant cell tumor of bone (GCTB) is classified as an intermediate malignant tumor due to its locally aggressive behavior, burdened by high local recurrence rate. GCTB accounts for about 4–5% of all primary bone tumors and typically arises in the metaphysis and epiphyses of the long tubular bones. Mutation of gene H3F3A is at the basis of GCTB etiopathogenesis, and its immunohistochemical expression is a valuable method for practical diagnosis, even if new biomarkers have been identified for early diagnosis and for potential tumor recurrence prediction. In the era of computer-aided diagnosis, imaging plays a key role in the assessment of GCTB for surgical planning, patients’ prognosis prediction and post treatment evaluation. Cystic changes, penetrating irregular margins and adjacent soft tissue invasion on preoperative Magnetic Resonance Imaging (MRI) have been associated with a higher rate of local recurrence. Distance from the tumor edge to the articular surface and thickness of unaffected cortical bone around the tumor should be evaluated on Computed Tomography (CT) as related to local recurrence. Main features associated with local recurrence after curettage are bone resorption around the graft or cement, soft tissue mass formation and expansile destruction of bone. A denosumab positive response is represented by a peripherical well-defined osteosclerosis around the lesion and intralesional ossification. Radiomics has proved to offer a valuable contribution in aiding GCTB pre-operative diagnosis through clinical-radiomics models based on CT scans and multiparametric MR imaging, possibly guiding the choice of a patient-tailored treatment. Moreover, radiomics models based on texture analysis demonstrated to be a promising alternative solution for the assessment of GCTB response to denosumab both on conventional radiography and CT since the quantitative variation of some radiomics features after therapy has been correlated with tumor response, suggesting they might facilitate disease monitoring during post-denosumab surveillance. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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18 pages, 2594 KiB

Open AccessReview

Cell Biology of Giant Cell Tumour of Bone: Crosstalk between m/wt Nucleosome H3.3, Telomeres and Osteoclastogenesis

by Ramses G. Forsyth, Tibor Krenács, Nicholas Athanasou and Pancras C. W. Hogendoorn

Cancers 2021, 13(20), 5119; https://doi.org/10.3390/cancers13205119 - 13 Oct 2021

Cited by 13 | Viewed by 2559

Abstract

Giant cell tumour of bone (GCTB) is a rare and intriguing primary bone neoplasm. Worrisome clinical features are its local destructive behaviour, its high tendency to recur after surgical therapy and its ability to create so-called benign lung metastases (lung ‘plugs’). GCTB displays [...] Read more.

Giant cell tumour of bone (GCTB) is a rare and intriguing primary bone neoplasm. Worrisome clinical features are its local destructive behaviour, its high tendency to recur after surgical therapy and its ability to create so-called benign lung metastases (lung ‘plugs’). GCTB displays a complex and difficult-to-understand cell biological behaviour because of its heterogenous morphology. Recently, a driver mutation in histone H3.3 was found. This mutation is highly conserved in GCTB but can also be detected in glioblastoma. Denosumab was recently introduced as an extra option of medical treatment next to traditional surgical and in rare cases, radiotherapy. Despite these new insights, many ‘old’ questions about the key features of GCTB remain unanswered, such as the presence of telomeric associations (TAs), the reactivation of hTERT, and its slight genomic instability. This review summarises the recent relevant literature of histone H3.3 in relation to the GCTB-specific G34W mutation and pays specific attention to the G34W mutation in relation to the development of TAs, genomic instability, and the characteristic morphology of GCTB. As pieces of an etiogenetic puzzle, this review tries fitting all these molecular features and the unique H3.3 G34W mutation together in GCTB. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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17 pages, 1292 KiB

Open AccessReview

Current Concepts in the Treatment of Giant Cell Tumors of Bone

by Shinji Tsukamoto, Andreas F. Mavrogenis, Akira Kido and Costantino Errani

Cancers 2021, 13(15), 3647; https://doi.org/10.3390/cancers13153647 - 21 Jul 2021

Cited by 33 | Viewed by 6113

Abstract

The 2020 World Health Organization classification defined giant cell tumors of bone (GCTBs) as intermediate malignant tumors. Since the mutated H3F3A was found to be a specific marker for GCTB, it has become very useful in diagnosing GCTB. Curettage is the most common [...] Read more.

The 2020 World Health Organization classification defined giant cell tumors of bone (GCTBs) as intermediate malignant tumors. Since the mutated H3F3A was found to be a specific marker for GCTB, it has become very useful in diagnosing GCTB. Curettage is the most common treatment for GCTBs. Preoperative administration of denosumab makes curettage difficult and increases the risk of local recurrence. Curettage is recommended to achieve good functional outcomes, even for local recurrence. For pathological fractures, joints should be preserved as much as possible and curettage should be attempted. Preoperative administration of denosumab for pelvic and spinal GCTBs reduces extraosseous lesions, hardens the tumor, and facilitates en bloc resection. Nerve-sparing surgery after embolization is a possible treatment for sacral GCTBS. Denosumab therapy with or without embolization is indicated for inoperable pelvic, spinal, and sacral GCTBs. It is recommended to first observe lung metastases, then administer denosumab for growing lesions. Radiotherapy is associated with a risk of malignant transformation and should be limited to cases where surgery is impossible and denosumab, zoledronic acid, or embolization is not available. Local recurrence after 2 years or more should be indicative of malignant transformation. This review summarizes the treatment approaches for non-malignant and malignant GCTBs. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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Other

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12 pages, 4579 KiB

Open AccessSystematic Review

Effect of Adjuvant Chemotherapy on Localized Malignant Giant Cell Tumor of Bone: A Systematic Review

by Rokuro Morii, Shinji Tsukamoto, Alberto Righi, Kanya Honoki, Yuu Tanaka, Akira Kido, Hiromasa Fujii, Andreas F. Mavrogenis, Yasuhito Tanaka and Costantino Errani

Cancers 2021, 13(21), 5410; https://doi.org/10.3390/cancers13215410 - 28 Oct 2021

Cited by 2 | Viewed by 1644

Abstract

A malignant giant cell tumor of the bone (GCTB) is a rare primary malignant tumor classified as primary or secondary. Wide resection of the primary tumor is recommended for localized malignant GCTB, but the effect of adjuvant chemotherapy is unclear. A systematic review [...] Read more.

A malignant giant cell tumor of the bone (GCTB) is a rare primary malignant tumor classified as primary or secondary. Wide resection of the primary tumor is recommended for localized malignant GCTB, but the effect of adjuvant chemotherapy is unclear. A systematic review was performed to compare the mortality associated with wide resection with that of wide resection plus adjuvant chemotherapy for primary and secondary localized malignant GCTB. Among the 745 studies identified, 9 were included. A total of 112 cases of localized malignant GCTB were included, with 39 and 73 cases being primary and secondary malignant GCTB. In primary localized malignant GCTB, the mortality rates were 40% (6/15 patients) and 33% (8/24 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. Overall pooled odds ratio was 1.07 (95% confidence interval, 0.26–4.37; p = 0.92). In secondary localized malignant GCTB, the mortality rates were 30.6% (11/36 patients) and 62.2% (23/37 patients) in the surgery plus adjuvant chemotherapy and surgery-only groups, respectively. The overall pooled odds ratio was 0.31 (95% confidence interval, 0.10–0.95; p = 0.04). The effect of adjuvant chemotherapy remains unclear for primary localized malignant GCTB, but adjuvant chemotherapy improved the survival of patients with secondary localized malignant GCTB. Full article

(This article belongs to the Special Issue Research Advances in Giant Cell Tumor of Bone)

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