253 General discussion and future perspectives this trimodality approach. In a case report, Tang et al. reported a complete pathologic response after neoadjuvant chemo-immunotherapy followed by surgery359. In chapter 2, we investigated in one of the first more detailed retrospective studies on the pathologic response in a series of 46 patients who underwent tri-modality therapy for a sulcus superior tumor. To estimate the pathologic response, we used a modification of the cut-off points suggested by Junker et al27, creating a four-tiered grading system, similar to the one used by Dworak for colorectal cancers33. A cut-off point of less than 10% viable tumor cells in our study confirmed the favorable prognosis. This was later-on suggested as the cut-off for a major pathologic response (MPR) in the IASLC multidisciplinary recommendations for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy45. They formulated 11 recommendations concerning among others the necessary clinical information, such as the type of neoadjuvant therapy and the way the specimen has to be sampled to optimize comprehensive gross and histologic assessment of the lung tumor bed for pathologic response. Subsequently, another group described a major pathologic response calculator tool, and proposed this for standardized, comprehensive collection of percentages of viable tumor, necrosis, and stroma in the tumor bed. MPR and pathologic complete response (pCR), defined as less than or equal to 10% and 0% viable tumor cells, respectively, are investigated in NSCLC clinical trials to examine if they can be used as surrogate end points for efficacy to shorten time to outcome360 361. An interesting aspect of estimating the pathologic response after neoadjuvant therapy, is whether this is also applicable in cases where immunotherapy was added to the neoadjuvant scheme. The question is whether there should be a different way to estimate the residual viable tumor (RVT) by including the tumor bed with its inflammatory response362. The Checkmate 816 results showed at least a significant increase in the number of cases with an complete pathologic response (CPR) in those that received immunotherapy as part of their neoadjuvant treatment compared to those who received chemotherapy only (24.0% vs 2.2%)358. When comparing the recommendations as proposed by the IASLC committee45 and Saqi et al360 to our study, we would in hindsight more explicitly describe and illustrate how the handling of the resection specimen was performed and from what areas slides were taken as well as taken more slides than was done, maintaining the 3-dimensional orientation198. This could lead to an even more reliable estimation of the viable tumor rest. With the current data of our study, the major pathologic response calculator tool can’t be used. A small nest was really a small nest, and probably marked lower than the 10% of the gross size. We also experienced that when initial sampling for microscopy (roughly one block per 1-2 cm) did not reveal vital tumor cells, subsequent additional sampling occasionally resulted in areas with vital tumor cells, emphasizing that generous sampling for estimating MPR may aid in the reliability of MPR assessment. Further studies are needed to establish reliable criteria for the pathologic response associated with various types of adjuvant therapy. Artificial intelligence may potentially 17
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