The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab

The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab Akihiro Yoshimura, Akira Nagahara, Yu Ishizuya, Yoshiyuki Yamamoto, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3829689/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Although immune checkpoint inhibitors (ICIs) have gained approval for metastatic renal cell carcinoma (mRCC), the response rate is still limited. Therefore, it is urgent to explore novel and concise markers of responses to ICIs that can help assess clinical benefits. Recently, it has been noted that peripheral blood eosinophil counts is an independent factor correlated with clinical outcome of ICIs in some types of cancer. Methods We investigated peripheral blood absolute eosinophil counts (AECs) at baseline and 4 weeks after the initiation of nivolumab for mRCC patients between February 2016 to May 2022. In addition, we examined clinicopathological features including irAEs and analyzed the correlation between AECs and clinical efficacy of nivolumab. Results Of all patients, 22 patients (27.0%) developed irAEs. The median AECs in patients with irAEs was significantly higher at baseline and 4 weeks after the treatment compared to those without irAEs (p < 0.001 and p = 0.001, respectively). With the cutoff value of AECs of 329 cells/µL at 4 weeks after the treatment for prediction of irAEs, high-AECs groups had significantly higher number of responders compared with that in low-AECs group (p < 0.001). Accordingly, the progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high-AECs group than those in low-AECs group (p = 0.03 and p = 0.009, respectively). Conclusion High AECs at 4 weeks after the treatment serve as the prominent surrogate marker associated with the incidence of irAEs and better clinical outcome in mRCC patients receiving nivolumab. renal cell carcinoma immune checkpoint inhibitor eosinophil immune- related adverse event Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Renal cell carcinoma (RCC) accounts for about 2–4% of all types of cancer worldwide [ 1 ]. The 5-year specific survival of early stage is reported to be 90%, but once metastasized, the 5-year survival plummets to 14%, although 17% of RCC patients present with the evidence of distant metastasis at initial diagnosis [ 2 , 3 ]. In addition, 20% of RCC patients who undergo surgical resection of localized RCC eventually develop distant metastases, necessitating subsequent therapeutic interventions including immune checkpoint inhibitors (ICIs)-based treatments [ 4 ]. ICIs have been widely used in the treatment of many types of cancer and have remarkably improved the prognosis of cancer patients. However, the majority of patients may not benefit from the therapy with ICIs and sometimes experience severe immune-related adverse events (irAE). To date, numerous biomarkers, including PD-L1 expression, tumor mutation burden, and tumor-infiltrating lymphocytes in cancer tissues, have been suggested to play a crucial role in influencing the therapeutic response to ICIs [ 5 ]. However, these markers mainly focus on the tumor state at the time of diagnosis and sometimes produce contradictory outcomes. Therefore, there is an urgent need for non-invasive biomarkers that can predict the efficacy of ICIs, aiming to prevent unnecessary treatments. Various factors have been investigated to predict response, and an association between neutrophil lymphocyte ratio (NLR) and therapeutic response has been reported as a typical marker in peripheral blood in several cancer types including RCC [ 6 , 7 , 8 ]. Recently, several studies reported that peripheral eosinophil counts may predict the incidence of irAE and are associated with the response to ICIs in several types of cancer [ 9 – 16 ]. However, there have been not fully understood the utility of eosinophil counts in RCC, especially with ICIs treatment. In the present study, we demonstrated that metastatic RCC (mRCC) patients who experienced severe irAE had consistently higher eosinophil counts before and at any time point after the nivolumab when compared to those without. Furthermore, the high absolute eosinophil counts (AECs) at an early time point were significantly associated with a better clinical outcome in mRCC patients. Collectively, these markers may concisely and practically predict clinical response in mRCC patients with anti-PD-1 inhibitor. Materials and Methods Patients We retrospectively investigated data from 83 mRCC patients treated by nivolumab at 2 institutions (Osaka International Cancer Institute and Osaka University Medical Hospital) from February 2016 to May 2022. For each patient, we collected baseline demographic and clinical data including age, gender, with or without nephrectomy, histological type, Karnofsky Performance Status (KPS), International Metastatic RCC Database Consortium (IMDC) risk classification, metastatic site and treatment line of nivolumab. Peripheral-blood AECs were measured at baseline, 2 weeks, 4 weeks and 6 weeks after initiation of nivolumab. Tumor response was evaluated every 8–12 weeks, according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST ver1.1), using computed tomography. Adverse events were evaluated by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE ver5.0). For each patient, the best response during treatment including complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), was measured. Progression-free survival (PFS) was defined as the time from the initiation of nivolumab to documented progression or death of any cause. Overall survival (OS) was defined as the time from the start of nivolumab to documented death of any cause or last contact. The study was approved by the Institutional Review Board of each institution (approval number 018–0003 in Osaka University Hospital and 18042 in Osaka International Cancer Institute) and was conducted in accordance with the Declaration of Helsinki. Treatment The patients received 240 mg/body of nivolumab every two weeks or 480 mg/body every four weeks until disease progression, clinical deterioration, unacceptable toxicity, or patient’s refusal. Statistical analysis We divide the patients into two groups according to the best response and irAE grades. The AECs of two groups were compared using the t-test. PFS and OS were estimated by the Kaplan–Meier method and compared with the log-rank test. The prognostic significance of certain parameters was assessed by the Cox proportional hazards regression model. Differences were considered significant at p value < 0.05. All statistical analyses were conducted in JMP-software ver. 17.0 (SAS Institute, Cary, NC, USA). Results Patients’ characteristics The clinical characteristics of all patients are shown in Table 1 . The median age at treatment was 64 years (range, 27–83). Nephrectomy had been performed in 74 patients (89%). The most predominant histological type was clear cell RCC (82.0%). With respect to the IMDC risk classification, 7%, 67%, and 25% were classified as favorable-, intermediate-, and poor-risk, respectively. The treatment line of nivolumab was 2nd, 3rd and 4th or later in 35, 28 and 20 patients, respectively. Table 1 Baseline characteristics of metastatic renal cell carcinoma patients treated with nivolumab. n = 83 Age(years) at treatment, median (range) 64 (27–83) Gender Male Female 56 (67%) 27 (33%) Prior nephrectomy Yes No 74 (89%) 9 (11%) Histological type Clear cell Papillary Chromophobe Other Unknown 68 (82%) 5 (6%) 2 (2%) 3 (4%) 5 (6%) KPS 100 90 80 70 50 41 (49%) 29 (35%) 4 (5%) 4 (5%) 5 (6%) IMDC risk classification Favorable Intermediate Poor 6 (7%) 56 (68%) 21 (25%) Metastatic site Lung Lymph Node Bone Pancreas Adrenal gland Liver Brain 48 (58%) 24 (29%) 26 (31%) 10 (12%) 9 (11%) 9 (11%) 2 (2%) Treatment line of nivolumab 2nd 3rd 4th or later 35 (42%) 28 (34%) 20 (24%) Duration of nivolumab treatment (months), median (range) 5.6 (0.7–35.7) Follow up period (month), median (range) 19.6 (0.8–59.1) Objective response CR PR SD PD 7 (8%) 17 (21%) 30 (36%) 29 (35%) Time to irAE (day), median (range) 90 (21–595) Clinical outcomes of patients with nivolumab The median duration of nivolumab treatment was 5.6 month (range, 0.7–35.7), and the median follow-up period was 19.6 month (range, 0.8–59.1). During the observational period, 39 patients died from cancer. Overall, the median OS was 25.5 months, and the median PFS was 5.7 months (Supplementary Fig. 1). Among 83 patients, CR and PR were achieved in 24 patients and SD was observed in 30 patients, resulting in objective response rate (ORR) of 28.9% and disease control rate (DCR) of 65.0%. In the present study, we defined responders as patients with CR, PR. Safety analysis In the present study, 22 patients (27%) experienced a total of 11 different irAE categories (Table 2 ). Among them, grade 3 irAE occurred in 13 patients (16%). There were no patients with grade 4 or higher. Of the grade 3 cases, 2 cases improved with nivolumab discontinuation and steroid treatment, whereas 1 case with G3 diabetes mellitus required continuous insulin administration. Table 2 Summary of irAEs in metastatic renal cell carcinoma patients with nivolumab. Grade 1 Grade 2 Grade 3 Grade 4 or 5 Interstitial pneumonia 1 3 1 Rash 1 2 1 Colitis 4 Adrenal failure 3 Peripheral neuropathy 1 1 Renal failure 1 1 Hypothyroidism 1 Fever 1 Diabetes Mellitus 1 Hepatitis 1 Pancreatitis 1 Total 4 (5%) 8 (10%) 13 (16%) 0 Correlation between the absolute eosinophil counts value and irAE Next, we examined the whether the AECs value affected the grade of irAE. The median AECs value of the patients with irAE at baseline and 4weeks after the initiation of treatment was significantly higher than those without irAE (217 cells/uL versus 170 cells/uL, p < 0.001 and 357 cells/uL versus 211 cells/uL, p = 0.001, Fig. 1 A). The optimal cutoff value of AECs to differentiate the occurrence of irAE was 329 cells/µL at 4 weeks after the treatment, as determined by ROC curve (Fig. 1 B). When we divided the patients with the cutoff value (329 cells/µL) of AECs, we observed that the incidence of irAEs was significantly higher in high-AECs group (n = 12, 52%) compared with that in low-AECs group (n = 10, 17%) (p < 0.001, Fig. 1 C). Moreover, when we examined the contribution of the irAE to improve the prognosis in mRCC patients, PFS and OS were significantly longer for patients who developed irAE than those who did not (p = 0.021 and p = 0.007, respectively, Fig. 2 A and 2 B). Correlation between the absolute eosinophil counts value and clinical efficacy in patients with nivolumab We further investigated whether the AECs value affects the clinical efficacy of mRCC patients with nivolumab. As a result, responders exhibited a significantly higher AECs value than those of non-responders at 4 weeks after the treatment (332 cells/uL versus 216 cells/uL, p = 0.008, Fig. 3 A). Importantly, when we divided the patients with the cutoff value (329 cells/µL), the percentage of responder was significantly higher in high-AECs group compared with that in low-AECs group (p < 0.001, Fig. 3 B). The PFS and OS were significantly longer in patients with high AECs value than those with low AECs value (p = 0.03 and p = 0.009, respectively, Fig. 4 ). Furthermore, the impacts of several clinicopathologic factors on PFS and OS in these 83 patients were evaluated (Table 3 , 4 ). Univariate analysis identified AECs value, IMDC classification, the number of metastatic site and irAE were significantly associated with OS. Interestingly, in the multivariate analysis, higher AECs value was significantly associated with a better OS in patients (HR 0.401, 95% CI 0.176–0.909, p = 0.028). Table 3. Univariate and multivariate logistic regression analysis for the prognostic factors of progression-free survival (n=83). Valuables Univariate Analysis Multivariate Analysis HR(95%CI) P value HR(95%CI) P value Age <65 Reference ≥65 1.028 (0.655-1.613) 0.90 - - Gender Male Reference Female 1.487 (0.912-2.423) 0.11 - - IMDC ≤Intermediate Reference poor 1.945 (1.141-3.315) 0.014 1.709 (0.892-3.271) 0.04 Histological type Clear Reference non-clear 1.381 (0.781-2.444) 0.27 - - Metastatic site Single Reference Multiple 1.575 (0.985-2.519) 0.058 - - No. of treatment line ≥ 3rd Reference 2nd 0.684 (0.429-1.091) 0.11 - - irAE No Reference Yes 0.549 (0.322-0.921) 0.023 0.552 (0.246-1.239) 0.15 4 week absolute eosinophil counts <329 cells/µL Reference ≥329 cells/µL 0.579 (0.348-0.965) 0.036 0.404 (0.188-0.865) 0.15 Table 4. Univariate and multivariate logistic regression analysis for the prognostic factors of overall survival (n=83). Valuables Univariate Analysis Multivariate Analysis HR(95%CI) P value HR(95%CI) P value Age <65 Reference ≥65 0.822 (0.462-1.463) 0.51 - - Gender Male Reference 0.319 Female 1.498 (0.825-2.719) 0.18 - - IMDC ≤Intermediate Reference poor 1.977 (1.055-3.704) 0.033 1.554 (0.813-2.970) 0.18 Histological type Clear Reference non-clear 1.685 (0.873-3.252) 0.12 - - Metastatic site Single Reference Multiple 2.103 (1.176-3.759) 0.012 2.072 (1.121-3.829) 0.020 No. of treatment line ≥ 3rd Reference 2nd 0.892 (0.4595-1.607) 0.70 - - irAE No Reference Yes 0.365 (0.170-0.783) 0.010 0.567 (0.251-1.280) 0.17 4 week absolute eosinophil counts <329 cells/µL Reference ≥329 cells/µL 0.376 (0.174-0.808) 0.012 0.400 (0.176-0.909) 0.029 Discussion The landscape of oncology has been drastically revolutionized by the emergence of ICIs, significantly enhancing the prognosis of previously incurable cancers [ 17 ]. However, the response rate to ICIs for mRCC is still limited [ 18 – 22 ], and treatment-related irAE often causes discontinuation of ICIs. Therefore, it is critical to identify biomarkers to predict the response of patients to ICIs to enable a precision medicine approach. Although the association between peripheral eosinophil counts and the response to ICIs has been observed in several types of cancer, the evidence is still limited due to the variety of evaluation methods of eosinophils. Hence, in this study, we performed the data analysis of mRCC patients treated with nivolumab and clarified some evidences about AECs affecting adverse events and clinical outcomes. First, we found mRCC patients with irAE had higher AECs value compared to those without irAE at baseline and 4 weeks after treatment (Fig. 1 A). Our findings partially align with the data published by Ma et al. reported that irAE was more likely to occur in patients with higher AECs at the start of treatment in multiple cancer types treated with PD-1 or PD-L1 inhibitors [ 15 ]. Giommoni et al. also reported that high AECs at the start of treatment was a significant risk factor for the occurrence of irAE in 168 cancer patients including 43 RCC patients [ 16 ]. In the present study, we first confirmed continuous activation of eosinophils in patients with irAE throughout nivolumab treatment, suggesting that it may be useful to prepare for the occurrence of irAE by regularly monitoring AECs. Secondly, our results demonstrated superior efficacy outcomes in patients with high AECs value at 4 weeks after treatment, as evidenced by improved PFS and OS in this group (Fig. 3 , 4 ). In this decade, several studies reported the relationship between eosinophils and the efficacy of ICI treatment in several types of cancer with a focus on the ratio of pre- and post-treatment eosinophils [ 9 – 13 ]. In our study, we first propose that absolute value of eosinophils counts at 4 weeks after the treatment clearly allow identifying early surrogate biomarkers in the peripheral blood for predicting clinical responses to anti-PD-1 therapy. Eosinophils infiltrate multiple tumors and regulate tumor progression either directly by interacting with tumor cells or indirectly by shaping the tumor microenvironment [ 23 ]. Carretero et al. reported that eosinophils evoke further immune response with CD8 + T cells in tumor microenvironment by producing C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 (CXCL9), and CXCL10 [ 24 ]. These results may support the potential mechanism of anti-cancer immune response of peripheral eosinophils in cancer patients. There are several limitations to this study. First, our small sample size may limit the generalization for our findings to other types of cancer. Second, we only enrolled mRCC patients with anti-PD-1 therapy. Given that ICI combination therapies have become standard first-line treatments in mRCC field, further prospective studies are required to consolidate our results. Conclusion We found that the high absolute eosinophil counts at 4 weeks after the start of nivolumab was a prominent prognostic marker associated with clinical outcome in mRCC patients. Declarations Retrospectively registered on May 1, 2022: Number 018–0003 in Osaka University Hospital and 18042 in Osaka International Cancer Institute Conflict of interest statement None. References Siegel RL, Miller KD, Fuchs HE, Jemal A: Cancer Statistics, 2021. CA Cancer J Clin 2021, 71(1):7-33. Cancer facts and figures. 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Kaplan–Meier survival curves show (A) progression-free survival and (B) overall survival of all patients. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3829689","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":265056993,"identity":"a377970a-5bc1-41f9-a4d9-4750d9a5d567","order_by":0,"name":"Akihiro Yoshimura","email":"","orcid":"","institution":"Osaka University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Akihiro","middleName":"","lastName":"Yoshimura","suffix":""},{"id":265056994,"identity":"cacf213e-9411-4c3c-9d7d-627b7310e665","order_by":1,"name":"Akira Nagahara","email":"","orcid":"","institution":"Osaka International Cancer 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Kato","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIiWNgGAWjYBACCRDxAZkjAZNibMClhZmBcQbJWph5sGrBBSTbzx98bNt2T45B7PDBGwwVdfKS7QfYJBhq7BiYZ2O3Rponmdk4t63YmEE6LdmC4cxhw9k8CUAtx5IZGOccwKpFjiGZTTq3LSGxQTrHTIKx7QDjPIb8bxIMbAeAXkzAroX/MZu0JVgLUCVjW539PP4HQFv+4dYiLQG0hRFiCxtQC3PibIkEEAO3FskZj40Ne84lGLNJpxlbJJw5nDxzxgNmi8S+ZB5cfpE4n/jwwY+yBDl+6eSHNz5U1NnOOJ/AeOPDNzs5QxwhBgdsIALuEiCDx3AGLrU4gTzBSB0Fo2AUjIIRAgDIBFBS4VuAogAAAABJRU5ErkJggg==","orcid":"","institution":"Osaka University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Taigo","middleName":"","lastName":"Kato","suffix":""}],"badges":[],"createdAt":"2024-01-02 14:14:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3829689/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3829689/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49238003,"identity":"b1deb57f-eeea-4be2-8ab6-2da045eefdcf","added_by":"auto","created_at":"2024-01-05 18:10:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":251146,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of absolute eosinophil counts between irAE group and non- irAE group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) \u0026nbsp;The median absolute eosinophil counts (AECs) of patients with irAE at baseline and 4weeks after the initiation of treatment were significantly higher than those without irAE (217 cells/uL \u003cem\u003eversus\u003c/em\u003e 170 cells/uL, p \u0026lt; 0.001 and 357 cells/uL \u003cem\u003eversus\u003c/em\u003e 211 cells/uL, p = 0.001). The median value is represented by the middle horizontal line in each box. The bottom and top of each box indicate the 25th and 75th percentiles, respectively. The ends of the whiskers indicate the minimum and maximum of all data.\u003c/p\u003e\n\u003cp\u003e(B) \u0026nbsp;Receiver operating characteristics curve analysis at 4 weeks after the treatment: area under curve = 0.686, sensitivity = 82.0 %, specificity = 59.1 %, cutoff value = 329 cells/µL.\u003c/p\u003e\n\u003cp\u003e(C) \u0026nbsp;When we divided the patients with the cutoff value (329 cells/µL) of counts, we observed that the incidence of irAE was significantly higher in high-AECs group (n=12, 52%) compared with that in low-AECs group (n = 10, 17%) (p \u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3829689/v1/6f8e89d4daa5af8e77f1d8c0.png"},{"id":49237706,"identity":"1b5513ef-5a7c-4acc-a842-c823adb3af0b","added_by":"auto","created_at":"2024-01-05 18:02:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":204978,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between the presence of irAEs and clinical outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier survival curves show (A) progression-free survival (PFS) and (B) overall survival (OS) between irAE group and non-irAE group. Patients with irAE had significantly better PFS (median 10.9 months \u003cem\u003eversus\u003c/em\u003e 3.7 months, p = 0.02) and OS (median NR \u003cem\u003eversus\u003c/em\u003e 16.0 months, p = 0.007) than those without irAE.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-3829689/v1/4aa58093bd15cf81ceb3ed4b.png"},{"id":49237707,"identity":"e97ba279-865c-4028-b7c5-e81f569fc262","added_by":"auto","created_at":"2024-01-05 18:02:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":240531,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparison of absolute eosinophil counts between responders and non-responders\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) \u0026nbsp;Responders had significantly higher absolute eosinophil counts (AECs) at 4 weeks after the initiation of nivolumab compared to that in non-responders (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e(B) \u0026nbsp;When we divided the patients with the cutoff value (329 cells/µL) of AECs at 4 weeks after the initiation of nivolumab, the percentage of responder was significantly higher in high-AECs group (n = 11, 48%) compared with that in low-AECs group (n = 13, 22%) (p\u0026lt;0.001).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-3829689/v1/479e030eca08deff113cc1a6.png"},{"id":49238004,"identity":"05d02c76-eed6-49a4-975a-642b76a2b9a0","added_by":"auto","created_at":"2024-01-05 18:10:18","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":215252,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between absolute eosinophil counts at 4 weeks after the initiation of nivolumab and clinical outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier survival curves show (A) progression-free survival (PFS) and (B) overall survival (OS) between high-absolute eosinophil counts (AECs) group and low-AECs group. Patients with high-AECs had significantly better PFS (median 12.2 months \u003cem\u003eversus\u003c/em\u003e 4.3 months, p = 0.03) and OS (median NR \u003cem\u003eversus\u003c/em\u003e 16.4 months, p = 0.009) than those with low-AECs.\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-3829689/v1/f7c1bc78cd6811efa00d7994.png"},{"id":54281063,"identity":"60e07e1c-45e3-4a86-a364-f0883eb7760d","added_by":"auto","created_at":"2024-04-08 09:02:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1231492,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3829689/v1/bb8ac776-2350-42ca-8647-c101c62d01a4.pdf"},{"id":49237711,"identity":"bd9deee7-01b9-4dd0-b7a9-4f4e155e752c","added_by":"auto","created_at":"2024-01-05 18:02:19","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":148188,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig. 1. \u003c/strong\u003eKaplan–Meier survival curves show (A) progression-free survival and (B) overall survival of all patients.\u003c/p\u003e","description":"","filename":"SupplemantaryFig1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3829689/v1/1101e5ad5dd68203d389ae68.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRenal cell carcinoma (RCC) accounts for about 2\u0026ndash;4% of all types of cancer worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The 5-year specific survival of early stage is reported to be 90%, but once metastasized, the 5-year survival plummets to 14%, although 17% of RCC patients present with the evidence of distant metastasis at initial diagnosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In addition, 20% of RCC patients who undergo surgical resection of localized RCC eventually develop distant metastases, necessitating subsequent therapeutic interventions including immune checkpoint inhibitors (ICIs)-based treatments [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eICIs have been widely used in the treatment of many types of cancer and have remarkably improved the prognosis of cancer patients. However, the majority of patients may not benefit from the therapy with ICIs and sometimes experience severe immune-related adverse events (irAE). To date, numerous biomarkers, including PD-L1 expression, tumor mutation burden, and tumor-infiltrating lymphocytes in cancer tissues, have been suggested to play a crucial role in influencing the therapeutic response to ICIs [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, these markers mainly focus on the tumor state at the time of diagnosis and sometimes produce contradictory outcomes. Therefore, there is an urgent need for non-invasive biomarkers that can predict the efficacy of ICIs, aiming to prevent unnecessary treatments.\u003c/p\u003e \u003cp\u003eVarious factors have been investigated to predict response, and an association between neutrophil lymphocyte ratio (NLR) and therapeutic response has been reported as a typical marker in peripheral blood in several cancer types including RCC [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Recently, several studies reported that peripheral eosinophil counts may predict the incidence of irAE and are associated with the response to ICIs in several types of cancer [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, there have been not fully understood the utility of eosinophil counts in RCC, especially with ICIs treatment.\u003c/p\u003e \u003cp\u003eIn the present study, we demonstrated that metastatic RCC (mRCC) patients who experienced severe irAE had consistently higher eosinophil counts before and at any time point after the nivolumab when compared to those without. Furthermore, the high absolute eosinophil counts (AECs) at an early time point were significantly associated with a better clinical outcome in mRCC patients. Collectively, these markers may concisely and practically predict clinical response in mRCC patients with anti-PD-1 inhibitor.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eWe retrospectively investigated data from 83 mRCC patients treated by nivolumab at 2 institutions (Osaka International Cancer Institute and Osaka University Medical Hospital) from February 2016 to May 2022. For each patient, we collected baseline demographic and clinical data including age, gender, with or without nephrectomy, histological type, Karnofsky Performance Status (KPS), International Metastatic RCC Database Consortium (IMDC) risk classification, metastatic site and treatment line of nivolumab. Peripheral-blood AECs were measured at baseline, 2 weeks, 4 weeks and 6 weeks after initiation of nivolumab.\u003c/p\u003e \u003cp\u003eTumor response was evaluated every 8\u0026ndash;12 weeks, according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST ver1.1), using computed tomography. Adverse events were evaluated by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE ver5.0). For each patient, the best response during treatment including complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), was measured. Progression-free survival (PFS) was defined as the time from the initiation of nivolumab to documented progression or death of any cause. Overall survival (OS) was defined as the time from the start of nivolumab to documented death of any cause or last contact.\u003c/p\u003e \u003cp\u003e The study was approved by the Institutional Review Board of each institution (approval number 018\u0026ndash;0003 in Osaka University Hospital and 18042 in Osaka International Cancer Institute) and was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003eThe patients received 240 mg/body of nivolumab every two weeks or 480 mg/body every four weeks until disease progression, clinical deterioration, unacceptable toxicity, or patient\u0026rsquo;s refusal.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eWe divide the patients into two groups according to the best response and irAE grades. The AECs of two groups were compared using the t-test. PFS and OS were estimated by the Kaplan\u0026ndash;Meier method and compared with the log-rank test. The prognostic significance of certain parameters was assessed by the Cox proportional hazards regression model. Differences were considered significant at p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were conducted in JMP-software ver. 17.0 (SAS Institute, Cary, NC, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eThe clinical characteristics of all patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age at treatment was 64 years (range, 27\u0026ndash;83). Nephrectomy had been performed in 74 patients (89%). The most predominant histological type was clear cell RCC (82.0%). With respect to the IMDC risk classification, 7%, 67%, and 25% were classified as favorable-, intermediate-, and poor-risk, respectively. The treatment line of nivolumab was 2nd, 3rd and 4th or later in 35, 28 and 20 patients, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of metastatic renal cell carcinoma patients treated with nivolumab.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;83\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge(years) at treatment, median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64 (27\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (67%)\u003c/p\u003e \u003cp\u003e27 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior nephrectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (89%)\u003c/p\u003e \u003cp\u003e9 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistological type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClear cell\u003c/p\u003e \u003cp\u003ePapillary\u003c/p\u003e \u003cp\u003eChromophobe\u003c/p\u003e \u003cp\u003eOther\u003c/p\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68 (82%)\u003c/p\u003e \u003cp\u003e5 (6%)\u003c/p\u003e \u003cp\u003e2 (2%)\u003c/p\u003e \u003cp\u003e3 (4%)\u003c/p\u003e \u003cp\u003e5 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003cp\u003e90\u003c/p\u003e \u003cp\u003e80\u003c/p\u003e \u003cp\u003e70\u003c/p\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (49%)\u003c/p\u003e \u003cp\u003e29 (35%)\u003c/p\u003e \u003cp\u003e4 (5%)\u003c/p\u003e \u003cp\u003e4 (5%)\u003c/p\u003e \u003cp\u003e5 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIMDC risk classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFavorable\u003c/p\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003cp\u003ePoor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (7%)\u003c/p\u003e \u003cp\u003e56 (68%)\u003c/p\u003e \u003cp\u003e21 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic site\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003cp\u003eLymph Node\u003c/p\u003e \u003cp\u003eBone\u003c/p\u003e \u003cp\u003ePancreas\u003c/p\u003e \u003cp\u003eAdrenal gland\u003c/p\u003e \u003cp\u003eLiver\u003c/p\u003e \u003cp\u003eBrain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (58%)\u003c/p\u003e \u003cp\u003e24 (29%)\u003c/p\u003e \u003cp\u003e26 (31%)\u003c/p\u003e \u003cp\u003e10 (12%)\u003c/p\u003e \u003cp\u003e9 (11%)\u003c/p\u003e \u003cp\u003e9 (11%)\u003c/p\u003e \u003cp\u003e2 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment line of nivolumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2nd\u003c/p\u003e \u003cp\u003e3rd\u003c/p\u003e \u003cp\u003e4th or later\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (42%)\u003c/p\u003e \u003cp\u003e28 (34%)\u003c/p\u003e \u003cp\u003e20 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDuration of nivolumab treatment (months), median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.6 (0.7\u0026ndash;35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eFollow up period (month), median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.6 (0.8\u0026ndash;59.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObjective response\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003cp\u003ePR\u003c/p\u003e \u003cp\u003eSD\u003c/p\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (8%)\u003c/p\u003e \u003cp\u003e17 (21%)\u003c/p\u003e \u003cp\u003e30 (36%)\u003c/p\u003e \u003cp\u003e29 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c4\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eTime to irAE (day), median (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90 (21\u0026ndash;595)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eClinical outcomes of patients with nivolumab\u003c/h2\u003e \u003cp\u003eThe median duration of nivolumab treatment was 5.6 month (range, 0.7\u0026ndash;35.7), and the median follow-up period was 19.6 month (range, 0.8\u0026ndash;59.1). During the observational period, 39 patients died from cancer. Overall, the median OS was 25.5 months, and the median PFS was 5.7 months (Supplementary Fig.\u0026nbsp;1). Among 83 patients, CR and PR were achieved in 24 patients and SD was observed in 30 patients, resulting in objective response rate (ORR) of 28.9% and disease control rate (DCR) of 65.0%. In the present study, we defined responders as patients with CR, PR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eSafety analysis\u003c/h2\u003e \u003cp\u003eIn the present study, 22 patients (27%) experienced a total of 11 different irAE categories (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among them, grade 3 irAE occurred in 13 patients (16%). There were no patients with grade 4 or higher. Of the grade 3 cases, 2 cases improved with nivolumab discontinuation and steroid treatment, whereas 1 case with G3 diabetes mellitus required continuous insulin administration.\u003c/p\u003e \u003ctable id=\"Tab2\" border=\"1\" \u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSummary of irAEs in metastatic renal cell carcinoma patients with nivolumab.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" style=\"width: 33.5887%;\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003eGrade 1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003eGrade 2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003eGrade 3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" style=\"width: 20.8482%;\"\u003e\n \u003cp\u003eGrade 4 or 5\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eInterstitial pneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eColitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eAdrenal failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003ePeripheral neuropathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eRenal failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eDiabetes Mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eHepatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\" style=\"width: 47.2559%;\"\u003e\n \u003cp\u003ePancreatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" style=\"width: 33.5887%;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e4 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 13.6671%;\"\u003e\n \u003cp\u003e8 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 14.5937%;\"\u003e\n \u003cp\u003e13 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" style=\"width: 20.8482%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between the absolute eosinophil counts value and irAE\u003c/h2\u003e \u003cp\u003eNext, we examined the whether the AECs value affected the grade of irAE. The median AECs value of the patients with irAE at baseline and 4weeks after the initiation of treatment was significantly higher than those without irAE (217 cells/uL \u003cem\u003eversus\u003c/em\u003e 170 cells/uL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and 357 cells/uL \u003cem\u003eversus\u003c/em\u003e 211 cells/uL, p\u0026thinsp;=\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The optimal cutoff value of AECs to differentiate the occurrence of irAE was 329 cells/\u0026micro;L at 4 weeks after the treatment, as determined by ROC curve (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). When we divided the patients with the cutoff value (329 cells/\u0026micro;L) of AECs, we observed that the incidence of irAEs was significantly higher in high-AECs group (n\u0026thinsp;=\u0026thinsp;12, 52%) compared with that in low-AECs group (n\u0026thinsp;=\u0026thinsp;10, 17%) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Moreover, when we examined the contribution of the irAE to improve the prognosis in mRCC patients, PFS and OS were significantly longer for patients who developed irAE than those who did not (p\u0026thinsp;=\u0026thinsp;0.021 and p\u0026thinsp;=\u0026thinsp;0.007, respectively, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation between the absolute eosinophil counts value and clinical efficacy in patients with nivolumab\u003c/h2\u003e \u003cp\u003eWe further investigated whether the AECs value affects the clinical efficacy of mRCC patients with nivolumab. As a result, responders exhibited a significantly higher AECs value than those of non-responders at 4 weeks after the treatment (332 cells/uL \u003cem\u003eversus\u003c/em\u003e 216 cells/uL, p\u0026thinsp;=\u0026thinsp;0.008, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Importantly, when we divided the patients with the cutoff value (329 cells/\u0026micro;L), the percentage of responder was significantly higher in high-AECs group compared with that in low-AECs group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The PFS and OS were significantly longer in patients with high AECs value than those with low AECs value (p\u0026thinsp;=\u0026thinsp;0.03 and p\u0026thinsp;=\u0026thinsp;0.009, respectively, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFurthermore, the impacts of several clinicopathologic factors on PFS and OS in these 83 patients were evaluated (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Univariate analysis identified AECs value, IMDC classification, the number of metastatic site and irAE were significantly associated with OS. Interestingly, in the multivariate analysis, higher AECs value was significantly associated with a better OS in patients (HR 0.401, 95% CI 0.176\u0026ndash;0.909, p\u0026thinsp;=\u0026thinsp;0.028).\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 3. \u0026nbsp;\u003c/strong\u003eUnivariate and multivariate logistic regression analysis for the prognostic factors of progression-free survival (n=83).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.15313935681470137%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.05053598774885%\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eValuables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.546707503828483%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.249617151607964%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariate Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2506265664160401%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.59398496240601%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.035087719298245%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.83709273182957%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.283208020050125%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;65\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.028 (0.655-1.613)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eGender\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.487 (0.912-2.423)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eIMDC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026le;Intermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003epoor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.945 (1.141-3.315)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e1.709 (0.892-3.271)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eHistological type\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eClear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003enon-clear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.381 (0.781-2.444)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMetastatic site\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eSingle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.575 (0.985-2.519)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNo. of treatment line\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge; 3rd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003e2nd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e0.684 (0.429-1.091)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.700305810397552%\" colspan=\"2\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eirAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.240480961923847%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.060120240480963%\" valign=\"top\"\u003e\n \u003cp\u003e0.549 (0.322-0.921)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.22244488977956%\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.85571142284569%\" valign=\"top\"\u003e\n \u003cp\u003e0.552 (0.246-1.239)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.62124248496994%\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e4 week absolute eosinophil counts\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;329 cells/\u0026micro;L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;329 cells/\u0026micro;L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e0.579 (0.348-0.965)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e0.404 (0.188-0.865)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4. \u0026nbsp;\u003c/strong\u003eUnivariate and multivariate logistic regression analysis for the prognostic factors of overall survival (n=83).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"652\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.15313935681470137%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.05053598774885%\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eValuables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.546707503828483%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariate Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.249617151607964%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariate Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2506265664160401%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.59398496240601%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.035087719298245%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.83709273182957%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR(95%CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.283208020050125%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;65\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e0.822 (0.462-1.463)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eGender\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\n \u003cp\u003e0.319\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.498 (0.825-2.719)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eIMDC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026le;Intermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003epoor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.977 (1.055-3.704)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e1.554 (0.813-2.970)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eHistological type\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eClear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003enon-clear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e1.685 (0.873-3.252)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMetastatic site\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eSingle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003eMultiple\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e2.103 (1.176-3.759)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e2.072 (1.121-3.829)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eNo. of treatment line\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge; 3rd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003e2nd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e0.892 (0.4595-1.607)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.700305810397552%\" colspan=\"2\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eirAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.240480961923847%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.060120240480963%\" valign=\"top\"\u003e\n \u003cp\u003e0.365 (0.170-0.783)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.22244488977956%\"\u003e\n \u003cp\u003e0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.85571142284569%\" valign=\"top\"\u003e\n \u003cp\u003e0.567 (0.251-1.280)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.62124248496994%\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.1529051987767584%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.547400611620795%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e4 week absolute eosinophil counts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.4434250764526%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;329 cells/\u0026micro;L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.93577981651376%\" valign=\"top\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.562691131498472%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"21.25382262996942%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.103975535168196%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"0.2%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.2%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026ge;329 cells/\u0026micro;L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30%\" valign=\"top\"\u003e\n \u003cp\u003e0.376 (0.174-0.808)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.2%\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.8%\" valign=\"top\"\u003e\n \u003cp\u003e0.400 (0.176-0.909)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.6%\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe landscape of oncology has been drastically revolutionized by the emergence of ICIs, significantly enhancing the prognosis of previously incurable cancers [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, the response rate to ICIs for mRCC is still limited [\u003cspan additionalcitationids=\"CR19 CR20 CR21\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and treatment-related irAE often causes discontinuation of ICIs. Therefore, it is critical to identify biomarkers to predict the response of patients to ICIs to enable a precision medicine approach. Although the association between peripheral eosinophil counts and the response to ICIs has been observed in several types of cancer, the evidence is still limited due to the variety of evaluation methods of eosinophils. Hence, in this study, we performed the data analysis of mRCC patients treated with nivolumab and clarified some evidences about AECs affecting adverse events and clinical outcomes.\u003c/p\u003e \u003cp\u003eFirst, we found mRCC patients with irAE had higher AECs value compared to those without irAE at baseline and 4 weeks after treatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Our findings partially align with the data published by Ma et al. reported that irAE was more likely to occur in patients with higher AECs at the start of treatment in multiple cancer types treated with PD-1 or PD-L1 inhibitors [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Giommoni et al. also reported that high AECs at the start of treatment was a significant risk factor for the occurrence of irAE in 168 cancer patients including 43 RCC patients [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In the present study, we first confirmed continuous activation of eosinophils in patients with irAE throughout nivolumab treatment, suggesting that it may be useful to prepare for the occurrence of irAE by regularly monitoring AECs.\u003c/p\u003e \u003cp\u003eSecondly, our results demonstrated superior efficacy outcomes in patients with high AECs value at 4 weeks after treatment, as evidenced by improved PFS and OS in this group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). In this decade, several studies reported the relationship between eosinophils and the efficacy of ICI treatment in several types of cancer with a focus on the ratio of pre- and post-treatment eosinophils [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In our study, we first propose that absolute value of eosinophils counts at 4 weeks after the treatment clearly allow identifying early surrogate biomarkers in the peripheral blood for predicting clinical responses to anti-PD-1 therapy. Eosinophils infiltrate multiple tumors and regulate tumor progression either directly by interacting with tumor cells or indirectly by shaping the tumor microenvironment [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Carretero et al. reported that eosinophils evoke further immune response with CD8\u0026thinsp;+\u0026thinsp;T cells in tumor microenvironment by producing C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 (CXCL9), and CXCL10 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. These results may support the potential mechanism of anti-cancer immune response of peripheral eosinophils in cancer patients.\u003c/p\u003e \u003cp\u003eThere are several limitations to this study. First, our small sample size may limit the generalization for our findings to other types of cancer. Second, we only enrolled mRCC patients with anti-PD-1 therapy. Given that ICI combination therapies have become standard first-line treatments in mRCC field, further prospective studies are required to consolidate our results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe found that the high absolute eosinophil counts at 4 weeks after the start of nivolumab was a prominent prognostic marker associated with clinical outcome in mRCC patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eRetrospectively registered on May 1, 2022: Number 018\u0026ndash;0003 in Osaka University Hospital and 18042 in Osaka International Cancer Institute\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConflict of interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Fuchs HE, Jemal A: Cancer Statistics, 2021. CA Cancer J Clin 2021, 71(1):7-33.\u003c/li\u003e\n\u003cli\u003eCancer facts and figures. 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Cancer Treat Rev 2021, 94:102157.\u003c/li\u003e\n\u003cli\u003eWu X, Han R, Zhong Y, Weng N, Zhang A: Post treatment NLR is a predictor of response to immune checkpoint inhibitor therapy in patients with esophageal squamous cell carcinoma. Cancer Cell Int 2021, 21(1):356.\u003c/li\u003e\n\u003cli\u003eRen F, Zhao T, Liu B, Pan L: Neutrophil-lymphocyte ratio (NLR) predicted prognosis for advanced non-small-cell lung cancer (NSCLC) patients who received immune checkpoint blockade (ICB). Onco Targets Ther 2019, 12:4235-4244.\u003c/li\u003e\n\u003cli\u003eChen X, Meng F, Jiang R: Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker for Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis. Front Oncol 2021, 11:746976.\u003c/li\u003e\n\u003cli\u003eDelyon J, Mateus C, Lefeuvre D, Lanoy E, Zitvogel L, Chaput N, Roy S, Eggermont AM, Routier E, Robert C: Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann Oncol 2013, 24(6):1697-1703.\u003c/li\u003e\n\u003cli\u003eMoreira A, Leisgang W, Schuler G, Heinzerling L: Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy. Immunotherapy 2017, 9(2):115-121.\u003c/li\u003e\n\u003cli\u003eNishikawa D, Suzuki H, Beppu S, Terada H, Sawabe M, Kadowaki S, Sone M, Hanai N: Eosinophil prognostic scores for patients with head and neck squamous cell carcinoma treated with nivolumab. Cancer Sci 2021, 112(1):339-346.\u003c/li\u003e\n\u003cli\u003eGhebeh H, Elshenawy MA, AlSayed AD, Al-Tweigeri T: Peripheral blood eosinophil count is associated with response to chemoimmunotherapy in metastatic triple-negative breast cancer. Immunotherapy 2022, 14(4):189-199.\u003c/li\u003e\n\u003cli\u003eChu X, Zhao J, Zhou J, Zhou F, Jiang T, Jiang S, Sun X, You X, Wu F, Ren S et al: Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. Lung Cancer 2020, 150:76-82.\u003c/li\u003e\n\u003cli\u003eHerrmann T, Ginzac A, Molnar I, Bailly S, Durando X, Mahammedi H: Eosinophil counts as a relevant prognostic marker for response to nivolumab in the management of renal cell carcinoma: a retrospective study. 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ESMO Open 2020, 5(6):e001079.\u003c/li\u003e\n\u003cli\u003ePowles T, Plimack ER, Soulieres D, Waddell T, Stus V, Gafanov R, Nosov D, Pouliot F, Melichar B, Vynnychenko I et al: Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020, 21(12):1563-1573.\u003c/li\u003e\n\u003cli\u003eMotzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grunwald V, Hutson TE, Kopyltsov E, Mendez-Vidal MJ et al: Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 2021, 384(14):1289-1300.\u003c/li\u003e\n\u003cli\u003eChoueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juarez VM, Hsieh JJ, Basso U, Shah AY et al: Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2021, 384(9):829-841.\u003c/li\u003e\n\u003cli\u003eGrisaru-Tal S, Itan M, Klion AD, Munitz A: A new dawn for eosinophils in the tumour microenvironment. Nat Rev Cancer 2020, 20(10):594-607.\u003c/li\u003e\n\u003cli\u003eCarretero R, Sektioglu IM, Garbi N, Salgado OC, Beckhove P, Hammerling GJ: Eosinophils orchestrate cancer rejection by normalizing tumor vessels and enhancing infiltration of CD8(+) T cells. Nat Immunol 2015, 16(6):609-617.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"renal cell carcinoma, immune checkpoint inhibitor, eosinophil, immune- related adverse event","lastPublishedDoi":"10.21203/rs.3.rs-3829689/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3829689/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAlthough immune checkpoint inhibitors (ICIs) have gained approval for metastatic renal cell carcinoma (mRCC), the response rate is still limited. Therefore, it is urgent to explore novel and concise markers of responses to ICIs that can help assess clinical benefits. Recently, it has been noted that peripheral blood eosinophil counts is an independent factor correlated with clinical outcome of ICIs in some types of cancer.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe investigated peripheral blood absolute eosinophil counts (AECs) at baseline and 4 weeks after the initiation of nivolumab for mRCC patients between February 2016 to May 2022. In addition, we examined clinicopathological features including irAEs and analyzed the correlation between AECs and clinical efficacy of nivolumab.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf all patients, 22 patients (27.0%) developed irAEs. The median AECs in patients with irAEs was significantly higher at baseline and 4 weeks after the treatment compared to those without irAEs (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;=\u0026thinsp;0.001, respectively). With the cutoff value of AECs of 329 cells/\u0026micro;L at 4 weeks after the treatment for prediction of irAEs, high-AECs groups had significantly higher number of responders compared with that in low-AECs group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Accordingly, the progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high-AECs group than those in low-AECs group (p\u0026thinsp;=\u0026thinsp;0.03 and p\u0026thinsp;=\u0026thinsp;0.009, respectively).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eHigh AECs at 4 weeks after the treatment serve as the prominent surrogate marker associated with the incidence of irAEs and better clinical outcome in mRCC patients receiving nivolumab.\u003c/p\u003e","manuscriptTitle":"The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-05 18:02:14","doi":"10.21203/rs.3.rs-3829689/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eeda1661-6e43-436c-af63-1aeea25adfc8","owner":[],"postedDate":"January 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-03T04:27:57+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-05 18:02:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3829689","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3829689","identity":"rs-3829689","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}