## 3 Discussion
### RecIST Criteria
iRECIST is based on RECIST 1.1, where the prefix \"i\" stands for \"immune\"; similarly, the response scenarios also have the \"i\" prefix--complete response (iCR), partial response (iPR), unconfirmed progressive disease (iUPD), or confirmed progressive disease (iCDD)--to differentiate them from the RECIST 1.1 criteria. The principles used to evaluate objective tumor response are largely unchanged from the RECIST 1.1 criteria; the main difference is the zeroing of the bar if the next assessment with tumor shrinkage follows the RECIST 1.1 progression. iRECIST introduces immune unconfirmed progressive disease (iUPD), which is related to atypical responses such as the delayed ones that occur with pseudoprogression [27]. Data collected at each time point on target and non-target lesion responses, new lesion responses, and overall response were used for the iRECIST criteria. As lymph nodes are classified as organs, the longest diameter was scored as lesions of other organs as defined by the RECIST 1.1 criteria. Of the 21 mRCC patients enrolled in the study, 10 were responders and 11 were non-responders. In accordance with the iRECIST criteria, 10 patients experienced iPD, 3 patients experienced iPR, and 8 patients experienced iSD. During ICI therapy, three patients died (one from a cardiac event and two from immune confirmed progressive illness). Other complications were ICIs pneumonia (n = 1), metastatic inferior vena cava thrombosis (n = 1), duodenal hemorrhage treated with gastroduodenal artery angioembolization (n = 1), and colonic perforation treated with hemicolectomy (n = 1). Figure 3: Contrast-enhanced CT axial scan during the venous phase of a 67-year-old female mRCC patient, showing 2 cystic hepatic metastases (**a**). The lesions showed SD at follow-up with dimensional stability after ICI treatment (**b**). An organ-specific response of 10% for hepatic metastasis, 19% for lung metastasis, 20% for brain metastasis, 35% for lymph node metastasis, and 25% for both for adrenal and intraperitoneal metastases was detected. Moreover, 13 patients experienced differential responses to ICIs, with 6 patients experiencing differential intra-organ responses. In 21 patients, a variation in tumor burden from \(-64\) to +185% (median: \(-12\%\)) was found at the time point of best overall response. Discordance of best overall response was found in four patients (14%) who showed iSD according to iRECIST 1.1 and PD according to RECIST 1.1. The remaining three patients had iUPD as defined by iRECIST but were confirmed progress by RECIST 1.1. The development of new lesions was found during therapy in eight patients (38%). Sites of development of target lesions included the liver (n = 3), lymph nodes and brain (n = 2), adrenal gland (n = 1), and lung and peritoneal metastases (n = 1). According to the iRECIST criteria, these patients were classified as iSD (n = 3), iPD (n = 4), and iUPD (n = 1). Nineteen patients (90.4%) showed more than one lesion in the same organ. A different response was found between organ categories (Kruskal-Wallis \(p\) = 0.003), with the best shrinkage for the adrenal glands and lymph nodes, followed by the lungs, while liver and miscellaneous lesions had the least shrinkage. The response rates also differed significantly among the lesion groups according to the location (Fisher \(p\) = 0.02) [26]. This study provides important data regarding the response to nivolumab related to sites of metastasis and differences in staging between the iRECIST and RECIST1.1 criteria. This knowledge might be helpful in predicting responses to nivolumab treatment in mRCC patients according to the site of metastasis. The iRECIST criteria should be used for the staging of mRCC patients treated with ICIs [26]. [PERSON] et al. [28] compared the iRECIST and RECIST 1.1 criteria for radiological tumor response in metastatic clear-cell renal cell carcinoma (mccRCC) patients treated with programmed cell death-1 inhibitor therapy [28].