44 Chapter 3 with a worse prognosis in cases with high PDL-1, may be an argument for adjuvant immunotherapy in patients with residual tumour after trimodality therapy. Previous studies from our group showed that patients with SST who have a pathologic complete response (pCR) in their resection specimen after trimodality therapy, do have a better prognosis when compared to patients with residual tumour43,63. Whether the addition of immunotherapy to chemoradiotherapy results in higher pCR, and its mechanism of action, is currently investigated in a phase II study investigating the role of adding neoadjuvant immunotherapy to CRT in patients with T3-4N0-1 (eg, SST). The fraction of patients with a PD-L1 expression < 1% was lower than expected64,65 and may be explained by preanalytical factors occurring in resections specimen66. In addition, the translational and pathological part of this study will further help in defining the clinical significance of PD-L1 expression and up-regulation in patients treated with chemoradiotherapy and immunotherapy, and its impact on pCR67. In contrast to our previous study43, a significant association between the percentage of vital tumour cells and prognosis was not observed. This is probably due to the selection procedure: in the current study cases with absence of vital tumour cells were not included, since this prohibited a comparison with the biopsies. The R-status and stage were, beside the above-mentioned biomarkers, the clinical parameters most relevant clinical parameters for predicting prognosis. Nuclear enlargement is considered as one of the criteria of cytonuclear atypia in cancer68,69, although it is not specific for cancer and could also be seen in inflammatory processes and after radiation70,71. Enlarged nuclear size seems to be associated with clinical outcome in several tumour types72,73. Increased nuclear size in relationship to the amount of cytoplasm (the nuclear-cell ratio) is one of the criteria for defining cytonuclear atypia and associated with a diagnosis of malignancy. Our findings of a larger nuclear size in tumour cells, both in pre-treatment biopsies and in the resection specimen, compared to normal pneumocytes is therefore not surprising. Although we found the size of tumour cell nuclei in resection specimen was larger after chemoradiotherapy compared to the pre-treatment biopsies, this was not of prognostic value. Radiotherapy for non–small cell lung cancer induces DNA damage response in both irradiated and out-of-field normal tissues74. This could lead to increased cytonuclear atypia, the so-called radiation atypia70, but also to tumour cell shrinkage75. This theoretical dual response may be a reason that we did not confirm the hypothesis that chemoradiation leads to more cytonuclear atypia. Our study did not show relevant associations between the mean nuclear area and survival in patients with residual tumour in the resection specimen. Likewise, postulating that the highest nuclear areas are associated with poorer survival, for the 75th or 90th percentiles of nuclear size we did not find a prognostic relevance. Apparently, nuclear size is too crude a measure for such associations, as many different, partly opposite, functionalities may take place in this cellular component. Examination of individual functions, such as proliferation fraction and escape from immunological surveillance, seem to be more informative.
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