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In situ cell cycle analysis in giant cell tumor of bone reveals patients with elevated risk of reduced progression-free survival.

Abstract

OBJECTIVE

Giant cell tumor of bone (GCTB) is a frequently recurring locally aggressive osteolytic lesion, where pathological osteoclastogenesis and bone destruction are driven by neoplastic stromal cells. Here, we studied if cell cycle fractions within the mononuclear cell compartment of GCTB can predict its progression-free survival (PFS).

METHODS

154 cases (100 primaries and 54 recurrent) from 139 patients of 40 progression events, was studied using tissue microarrays. Ploidy and in situ cell cycle progression related proteins including Ki67 and those linked with replication licensing (mcm2), G1-phase (cyclin D1, Cdk4), and S-G2-M-phase (cyclin A; Cdk2) fractions; cell cycle control (p21waf1) and repression (geminin), were tested. The Prentice-Williams-Peterson (PWP) gap-time models with the Akaike information criterion (AIC) were used for PFS analysis.

RESULTS

Cluster analysis showed good correlation between functionally related marker positive cell fractions indicating no major cell cycle arrested cell populations in GCTB. Increasing hazard of progression was statistically associated with the elevated post-G1/S-phase cell fractions. Univariate analysis revealed significant negative association of poly-/aneuploidy (p < 0.0001), and elevated cyclin A (p < 0.001), geminin (p = 0.015), mcm2 (p = 0.016), cyclin D1 (p = 0.022) and Ki67 (B56: p = 0.0543; and Mib1: p = 0.0564 -strong trend) positive cell fractions with PFS. The highest-ranked multivariate interaction model (AIC = 269.5) also included ploidy (HR 5.68, 95%CI: 2.62-12.31, p < 0.0001), mcm2 (p = 0.609), cyclin D1 (HR 1.89, 95%CI: 0.88-4.09, p = 0.105) and cyclin A (p < 0.0001). The first and second best prognostic models without interaction (AIC = 271.6) and the sensitivity analysis (AIC = 265.7) further confirmed the prognostic relevance of combining these markers.

CONCLUSION

Ploidy and elevated replication licensing (mcm2), G1-phase (cyclin D1) and post-G1 phase (cyclin A) marker positive cell fractions, indicating enhanced cell cycle progression, can assist in identifying GCTB patients with increased risk for a reduced PFS.

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  • Authors+Show Affiliations

    ,

    1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

    ,

    Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.

    ,

    1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

    ,

    1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

    ,

    1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.

    ,

    Department of Orthopedics, Semmelweis University, Budapest, Hungary.

    ,

    Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary.

    ,

    Department of Anatomic Pathology, University of Brussels, Belgium.

    ,

    Laboratory of Experimental Oncology, Institute of Orthopedics Rizzoli, Bologna, Italy.

    1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. Electronic address: krenacst@gmail.com.

    Source

    Bone 127: 2019 Jun 22 pg 188-198

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31233932

    Citation

    Maros E, Mate, et al. "In Situ Cell Cycle Analysis in Giant Cell Tumor of Bone Reveals Patients With Elevated Risk of Reduced Progression-free Survival." Bone, vol. 127, 2019, pp. 188-198.
    Maros E M, Schnaidt S, Balla P, et al. In situ cell cycle analysis in giant cell tumor of bone reveals patients with elevated risk of reduced progression-free survival. Bone. 2019;127:188-198.
    Maros E, M., Schnaidt, S., Balla, P., Kelemen, Z., Sapi, Z., Szendroi, M., ... Krenacs, T. (2019). In situ cell cycle analysis in giant cell tumor of bone reveals patients with elevated risk of reduced progression-free survival. Bone, 127, pp. 188-198. doi:10.1016/j.bone.2019.06.022.
    Maros E M, et al. In Situ Cell Cycle Analysis in Giant Cell Tumor of Bone Reveals Patients With Elevated Risk of Reduced Progression-free Survival. Bone. 2019 Jun 22;127:188-198. PubMed PMID: 31233932.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - In situ cell cycle analysis in giant cell tumor of bone reveals patients with elevated risk of reduced progression-free survival. AU - Maros E,Mate, AU - Schnaidt,Sven, AU - Balla,Peter, AU - Kelemen,Zoltan, AU - Sapi,Zoltan, AU - Szendroi,Miklos, AU - Laszlo,Tamas, AU - Forsyth,Ramses, AU - Picci,Piero, AU - Krenacs,Tibor, Y1 - 2019/06/22/ PY - 2019/02/04/received PY - 2019/05/23/revised PY - 2019/06/21/accepted PY - 2019/6/25/pubmed PY - 2019/6/25/medline PY - 2019/6/25/entrez KW - Cyclin A KW - Cyclin D1 KW - Giant cell tumor of bone KW - Mononuclear cell cycle fractions KW - Neoplastic stromal cells KW - Tumor progression KW - mcm2 KW - ploidy SP - 188 EP - 198 JF - Bone JO - Bone VL - 127 N2 - OBJECTIVE: Giant cell tumor of bone (GCTB) is a frequently recurring locally aggressive osteolytic lesion, where pathological osteoclastogenesis and bone destruction are driven by neoplastic stromal cells. Here, we studied if cell cycle fractions within the mononuclear cell compartment of GCTB can predict its progression-free survival (PFS). METHODS: 154 cases (100 primaries and 54 recurrent) from 139 patients of 40 progression events, was studied using tissue microarrays. Ploidy and in situ cell cycle progression related proteins including Ki67 and those linked with replication licensing (mcm2), G1-phase (cyclin D1, Cdk4), and S-G2-M-phase (cyclin A; Cdk2) fractions; cell cycle control (p21waf1) and repression (geminin), were tested. The Prentice-Williams-Peterson (PWP) gap-time models with the Akaike information criterion (AIC) were used for PFS analysis. RESULTS: Cluster analysis showed good correlation between functionally related marker positive cell fractions indicating no major cell cycle arrested cell populations in GCTB. Increasing hazard of progression was statistically associated with the elevated post-G1/S-phase cell fractions. Univariate analysis revealed significant negative association of poly-/aneuploidy (p < 0.0001), and elevated cyclin A (p < 0.001), geminin (p = 0.015), mcm2 (p = 0.016), cyclin D1 (p = 0.022) and Ki67 (B56: p = 0.0543; and Mib1: p = 0.0564 -strong trend) positive cell fractions with PFS. The highest-ranked multivariate interaction model (AIC = 269.5) also included ploidy (HR 5.68, 95%CI: 2.62-12.31, p < 0.0001), mcm2 (p = 0.609), cyclin D1 (HR 1.89, 95%CI: 0.88-4.09, p = 0.105) and cyclin A (p < 0.0001). The first and second best prognostic models without interaction (AIC = 271.6) and the sensitivity analysis (AIC = 265.7) further confirmed the prognostic relevance of combining these markers. CONCLUSION: Ploidy and elevated replication licensing (mcm2), G1-phase (cyclin D1) and post-G1 phase (cyclin A) marker positive cell fractions, indicating enhanced cell cycle progression, can assist in identifying GCTB patients with increased risk for a reduced PFS. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/31233932/In_situ_cell_cycle_analysis_in_giant_cell_tumor_of_bone_reveals_patients_with_elevated_risk_of_reduced_progression-free_survival L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(19)30254-6 DB - PRIME DP - Unbound Medicine ER -