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journal article 
Eckstein, Markus; Wirtz, Ralph M; Pfannstil, Carolin; Wach, Sven; Stoehr, Robert; Breyer, Johannes; Erlmeier, Franziska; Günes, Cagatay; Nitschke, Katja; Weichert, Wilko; Otto, Wolfgang; Keck, Bastian; Eidt, Sebastian; Burger, Maximilian; Taubert, Helge; Wullich, Bernd; Bolenz, Christian; Hartmann, Arndt; Erben, Philipp 
A multicenter round robin test of PD-L1 expression assessment in urothelial bladder cancer by immunohistochemistry and RT-qPCR with emphasis on prognosis prediction after radical cystectomy. 
Immunohistochemical PD-L1 assessment is currently used to identify responders towards checkpoint inhibitors although it is limited by inter-observer effects. Here, we conducted a multi-center round robin test to prove the possibility of assessing the PD-L1 status by gene expression to avoid inter-observer effects.Gene expression of PD-L1 was analyzed in a total of 294 samples (14 cases non-muscle invasive and muscle-invasive bladder cancer; MIBC) in seven centers by a RT-qPCR kit and compared with immunohistochemical scoring of three pathologists (DAKO, 22c3). Both assays were compared towards prognosis prediction in a cohort of 88 patients with MIBC.PD-L1 gene expression revealed very high inter center correlation (centrally extracted RNA:= 0.68-0.98,<= 0.0076; locally extracted RNA:0.81-0.98,<= 0.0014). IHC Inter-observer concordance was moderate to substantial for immune cells (IC), fair for combined IC/ tumor cell (TC) (IC: ? = 0.50-0.61; IC + TC: ? = 0.50), and fair for TC scoring (? = 0.26-0.35). Gene expression assessment resulted in more positive cases (9/14 cases positive vs. 6/14 cases [IHC]) which could be validated in the independent cohort. Positive mRNA status was associated with significantly better overall and disease-specific survival (5-year OS: 50% vs. 26%,0.0042, HR0.48; 5 year DSS: 65% vs. 40%,= 0.012, HR0.49). The 1% IHC IC cut-off also revealed significant better OS (5 year OS: 58% vs. 31%,0.036, HR0.62).Gene expression showed very high inter-center agreement. Gene expression assessment also resulted in more positive cases and revealed better prognosis prediction. PD-L1 mRNA expression seems to be a reproducible and robust tool for PD-L1 assessment. 
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Institut für Allgemeine Pathologie und pathologische Anatomie