Mate E Maros1, Sven Schnaidt2, Peter Balla3, Zoltan Kelemen3, Zoltan Sapi3, Miklos Szendroi4, Tamas Laszlo5, Ramses Forsyth6, Piero Picci7, Tibor Krenacs8. 1. 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary; Department of Neuroradiology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 2. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany. 3. 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. 4. Department of Orthopedics, Semmelweis University, Budapest, Hungary. 5. Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Semmelweis University, Budapest, Hungary. 6. Department of Anatomic Pathology, University of Brussels, Belgium. 7. Laboratory of Experimental Oncology, Institute of Orthopedics Rizzoli, Bologna, Italy. 8. 1(st) Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. Electronic address: krenacst@gmail.com.
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.
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.
Authors: Fabian Flottmann; Caspar Brekenfeld; Gabriel Broocks; Hannes Leischner; Rosalie McDonough; Tobias D Faizy; Milani Deb-Chatterji; Anna Alegiani; Götz Thomalla; Anastasios Mpotsaris; Christian H Nolte; Jens Fiehler; Máté E Maros Journal: Stroke Date: 2021-01-20 Impact factor: 7.914
Authors: Mate E Maros; Peter Balla; Tamas Micsik; Zoltan Sapi; Miklos Szendroi; Holger Wenz; Christoph Groden; Ramses G Forsyth; Piero Picci; Tibor Krenacs Journal: Pathol Oncol Res Date: 2021-05-03 Impact factor: 3.201