43 Prognostic value of MIB-1, PD-L1 and nuclear size in SST after CRT Table 4. Median (and range) nuclear size (µm2) of normal pneumocytes in resection specimen, and tumour cells in pre-operative biopsy and in resection specimen for patients with and without recurrent disease No recurrent disease n=11 Recurrent disease n=21 p-value Tumour biopsy 61.7 (31.9 – 128.0) 58.2 (41.8 – 95.5) 0.82 Pneumocytes resection 31.2 (16.3 – 39.8) 32.0 (14.5 – 48.0) 0.21 Tumour resection 65.1 (20.9 – 93.0) 69.9 (47.6 – 152.2) 0.43 n number of patients Discussion The International Association Lung Cancer (IASLC) recently published multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy, stating that future studies to explore the role of immunohistochemistry on resected tumours in the neoadjuvant setting are encouraged45. Following these recommendations, this study demonstrates that high tumour cell proliferation (MIB-1 > 20%) and PD-L1 score of >1% are associated with a worse prognosis in patients with SST treated with trimodality therapy, including chemotherapy, radiotherapy and surgery. This finding is in line with the finding of Corzani et al.51, who report a low proliferation index determined with MIB-1 (cut-off point of 50%) associated with favorable outcome in resection specimen after neoadjuvant chemotherapy of surgically resected IIIA-N2 NSCLC. In resected NSCLC, however, several studies report conflicting results regarding the prognostic value of Ki67 or MIB-1 expression as an independent prognostic factor52–54. From a theoretical point of view, one would expect that an absent PD-L1 staining in tumour cells would be associated with a better prognosis, since the tumour is more susceptible for the patient’s own immune system55–58. In line with this theory, our study reports a better outcome in patients with <1% PD-L1 positive cells in the residual tumour. On the other hand, several studies did show an upregulation of PD-L1 after chemoradiation58,59, suggesting it would be beneficial to add PD-L1 inhibitors to the chemoradiation therapy, hereby priming the immuno-microenvironment60. We could not reproduce these results, since there was not enough tumour tissue left in our pretreatment biopsies to compare pretreatment and posttreatment PD-L1 expression, but adding immunotherapy to induction CRT seems promising. Furthermore, we found a relative low number of cases (4 out of 33; 12%) with a PDL1 score of >50%. This is lower than the 23% in the Keynote 010 study61, but in line with other studies, that also contained more adenocarcinomas than squamous cell carcinomas62. Our current results 3
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