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      Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors

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          Abstract

          Background

          Selected patients with advanced non-small cell lung cancer (NSCLC) benefit from immunotherapy, especially immune checkpoint inhibitors such as PD-1 (programmed cell death protein 1) inhibitor. Peripheral blood biomarkers would be most convenient to predict treatment outcome and immune-related adverse events (irAEs) in candidate patients. This study explored associations between inflammation-related peripheral blood markers and onset of irAEs and outcome in patients with advanced NSCLC receiving PD-1 inhibitors.

          Methods

          A retrospective analysis was conducted of 102 patients with advanced NSCLC receiving PD-1 inhibitors from January 2017 to May 2019. Cox regression models were employed to assess the prognostic effect of low/high neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and prognostic nutrition index (PNI) on overall survival (OS) and progression-free survival (PFS). Logistic regression models were used to analyze the correlation between peripheral blood markers and the onset of irAEs.

          Result

          NLR < 5, LDH < 240 U/L, or PNI ≥ 45 was favorably associated with significantly better outcomes compared with higher, higher, or lower values, respectively. The multivariate analysis determined that these parameters were independently associated with both better PFS ( p = 0.049, 0.046, 0.014, respectively) and longer OS ( p = 0.007, 0.031, < 0.001, respectively). Patients with three favorable factors among NLR, LDH, and PNI had better PFS and OS than did those with two, one, or none. PNI and NLR were associated with the onset of irAEs.

          Conclusion

          In patients with advanced NSCLC treated with PD-1 inhibitors, pretreatment NLR, LDH, and PNI may be useful predictive markers of clinical outcome and irAEs.

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          Most cited references27

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            [Prognostic nutritional index in gastrointestinal surgery of malnourished cancer patients].

            Based on assessment of 200 malnourished cancer patients of digestive organs, a multiparameter index of nutritional status was defined to relating the risk of postoperative complications to base line nutritional status. The linear predictive model relating the risk of operative complication, mortality or both to nutritional status is given by the relation: prognostic nutritional index (PNI) = 10 Alb. + 0.005 Lymph. C., where Alb. is serum albumin level (g/100 ml) and Lymph. C. is total lymphocytes count/mm3 peripheral blood. When applied prospectively to 189 gastrointestinal surgical patients those who were malnourished and treated by TPN preoperatively, this index provided an accurate, quantitative estimate of operative risk. In general, resection and anastomosis of gastrointestinal tract can be safely practiced when the index is over 45. The same procedure may be dangerous between 45 and 40. In below 40, this kind of operation may be contraindicated. The prognostic nutritional index is useful also to know the prognosis of patients with terminal cancer. Despite practicing TPN to cancer patients with near terminal stages, if the PNI remains below 40 and total lymphocytes count remains below 1,000/mm3, the patients has high possibility to die within the next two months.
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              Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non–Small Cell Lung Cancer

              Question Are pretreatment derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level associated with resistance to immunotherapy in patients with advanced non–small cell lung cancer (NSCLC)? Findings In this cohort study evaluating 466 patients with advanced NSCLC, the Lung Immune Prognostic Index (LIPI), combining baseline dNLR and LDH, was associated with the outcomes of immunotherapy but not chemotherapy. Meaning Poor baseline LIPI, combining dNLR greater than 3 and LDH greater than upper limit of normal, was correlated with worse outcomes for immune checkpoint inhibitor treatment in patients with NSCLC, but not with chemotherapy. This cohort study investigates whether the pretreatment derived neutrophils/(leukocytes minus neutrophils) ratio and lactate dehydrogenase level are associated with resistance to immunotherapy in patients with advanced non–small cell lung cancer. Importance Derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitor (ICI) outcomes in patients with melanoma. Objective To determine whether pretreatment dNLR and LDH are associated with resistance to ICIs in patients with advanced non–small cell lung cancer (NSCLC). Design, Setting, and Participants Multicenter retrospective study with a test (n = 161) and a validation set (n = 305) treated with programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors in 8 European centers, and a control cohort (n = 162) treated with chemotherapy only. Complete blood cell counts, LDH, and albumin levels were measured before ICI treatment. A lung immune prognostic index (LIPI) based on dNLR greater than 3 and LDH greater than upper limit of normal (ULN) was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors). Main Outcomes and Measures The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS) and disease control rate (DCR). Results In the pooled ICI cohort (N = 466), 301 patients (65%) were male, 422 (90%) were current or former smokers, and 401 (87%) had performance status of 1 or less; median age at diagnosis was 62 (range, 29-86) years; 270 (58%) had adenocarcinoma and 159 (34%) had squamous histologic subtype. Among 129 patients with PD-L1 data, 96 (74%) had PD-L1 of at least 1% by immunohistochemical analysis, and 33 (26%) had negative results. In the test cohort, median PFS and OS were 3 (95% CI, 2-4) and 10 (95% CI, 8-13) months, respectively. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS (hazard ratio [HR] 2.22; 95% CI, 1.23-4.01 and HR, 2.51; 95% CI, 1.32-4.76, respectively). Median OS for poor, intermediate, and good LIPI was 3 months (95% CI, 1 month to not reached [NR]), 10 months (95% CI, 8 months to NR), and 34 months (95% CI, 17 months to NR), respectively, and median PFS was 2.0 (95% CI, 1.7-4.0), 3.7 (95% CI, 3.0-4.8), and 6.3 (95% CI, 5.0-8.0) months (both P  < .001). Disease control rate was also correlated with dNLR greater than 3 and LDH greater than ULN. Results were reproducible in the ICI validation cohort for OS, PFS, and DCR, but were nonsignificant in the chemotherapy cohort. Conclusions and Relevance Pretreatment LIPI, combining dNLR greater than 3 and LDH greater than ULN, was correlated with worse outcomes for ICI, but not for chemotherapy, suggesting that LIPI can serve as a potentially useful tool when selecting ICI treatment, raising the hypothesis that the LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI.
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                Author and article information

                Contributors
                liyongcsco@email.ncu.edu.cn
                Journal
                Cancer Immunol Immunother
                Cancer Immunol. Immunother
                Cancer Immunology, Immunotherapy
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0340-7004
                1432-0851
                29 April 2020
                29 April 2020
                2020
                : 69
                : 9
                : 1813-1822
                Affiliations
                [1 ]GRID grid.412604.5, ISNI 0000 0004 1758 4073, Department of Medical Oncology, , First Affiliated Hospital of Nanchang University, ; 17 Yongwai Zheng Road, Nanchang, 330000 China
                [2 ]GRID grid.260463.5, ISNI 0000 0001 2182 8825, Department of Medical Oncology, , Affiliated Ganzhou Hospital of Nanchang University (Ganzhou People’s Hospital), ; 18 Meiguan Road, Ganzhou, 341000 China
                [3 ]GRID grid.412604.5, ISNI 0000 0004 1758 4073, Critical Care Medicine, , First Affiliated Hospital of Nanchang University, ; 17 Yongwai Zheng Road, Nanchang, 330000 China
                Author information
                http://orcid.org/0000-0002-2342-088X
                Article
                2585
                10.1007/s00262-020-02585-w
                7413896
                32350592
                22a6ff4d-dc9d-4cce-a1ac-ca399a96c6e9
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 17 December 2019
                : 17 April 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: No.81560379
                Award ID: 81460292
                Award ID: 81660315
                Award Recipient :
                Funded by: Surface project of the Natural Science Foundation of Jiangxi Province
                Award ID: No.20181BAB205046
                Award Recipient :
                Funded by: Jiangxi Provincial Department of Science and Technology (CN)
                Award ID: No.2015BBG70236
                Award Recipient :
                Funded by: The Key Project of Education Department of Jiangxi Province
                Award ID: No.GJJ170012
                Award Recipient :
                Funded by: Guiding Science and Technology Project of Ganzhou
                Award ID: NO.GZ2018ZSF306
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                Oncology & Radiotherapy
                lung cancer,immunotherapy,immune-related adverse events,neutrophil-to-lymphocyte ratio,lactate dehydrogenase,prognostic nutrition index

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