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      Impact of lymphadenectomy extent on immunotherapy efficacy in postresectional recurred non-small cell lung cancer: a multi-institutional retrospective cohort study

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          Abstract

          Background:

          Lymph node (LN) dissection is a common procedure for non-small cell lung cancer (NSCLC) to ascertain disease severity and treatment options. However, murine studies have indicated that excising tumor-draining LNs diminished immunotherapy effectiveness, though its applicability to clinical patients remains uncertain. Hence, the authors aim to illustrate the immunological implications of LN dissection by analyzing the impact of dissected LN (DLN) count on immunotherapy efficacy, and to propose a novel ‘immunotherapy-driven’ LN dissection strategy.

          Materials and methods:

          The authors conducted a retrospective analysis of NSCLC patients underwent anti-PD-1 immunotherapy for recurrence between 2018 and 2020, assessing outcomes based on DLN count stratification.

          Results:

          A total of 144 patients were included, of whom 59 had a DLN count less than or equal to 16 (median, IQR: 11, 7–13); 66 had a DLN count greater than 16 (median, IQR: 23, 19–29). With a median follow-up time of 14.3 months (95% CI: 11.0–17.6), the overall median progression-free survival (PFS) was 7.9 (95% CI: 4.1–11.7) months, 11.7 (95% CI: 7.9–15.6) months in the combination therapy subgroup, and 4.8 (95% CI: 3.1–6.4) months in the immunotherapy alone subgroup, respectively. In multivariable Cox analysis, DLN count less than or equal to 16 is associated with an improved PFS in all cohorts [primary cohort: HR=0.26 (95% CI: 0.07–0.89), P=0.03]; [validation cohort: HR=0.46 (95% CI: 0.22–0.96), P=0.04]; [entire cohort: HR=0.53 (95% CI: 0.32–0.89), P=0.02]. The prognostic benefit of DLN count less than or equal to 16 was more significant in immunotherapy alone, no adjuvant treatment, pN1, female, and squamous carcinoma subgroups. A higher level of CD8+ central memory T cell (Tcm) within LNs was associated with improved PFS (HR: 0.235, 95% CI: 0.065–0.845, P=0.027).

          Conclusions:

          An elevated DLN count (cutoff: 16) was associated with poorer immunotherapy efficacy in recurrent NSCLC, especially pronounced in the immunotherapy alone subgroup. CD8+Tcm proportions in LNs may also impact immunotherapy efficacy. Therefore, for patients planned for adjuvant immunotherapy, a precise rather than expanded lymphadenectomy strategy to preserve immune-depending LNs is recommended.

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          Most cited references58

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          Robust enumeration of cell subsets from tissue expression profiles

          We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles. When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen, and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content, and closely related cell types. CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersort.stanford.edu).
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            Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer

            Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).
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              TIMER2.0 for analysis of tumor-infiltrating immune cells

              Abstract Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the limitations of direct measurement methods, computational algorithms are often used to infer immune cell composition from bulk tumor transcriptome profiles. These estimated tumor immune infiltrate populations have been associated with genomic and transcriptomic changes in the tumors, providing insight into tumor–immune interactions. However, such investigations on large-scale public data remain challenging. To lower the barriers for the analysis of complex tumor–immune interactions, we significantly improved our previous web platform TIMER. Instead of just using one algorithm, TIMER2.0 (http://timer.cistrome.org/) provides more robust estimation of immune infiltration levels for The Cancer Genome Atlas (TCGA) or user-provided tumor profiles using six state-of-the-art algorithms. TIMER2.0 provides four modules for investigating the associations between immune infiltrates and genetic or clinical features, and four modules for exploring cancer-related associations in the TCGA cohorts. Each module can generate a functional heatmap table, enabling the user to easily identify significant associations in multiple cancer types simultaneously. Overall, the TIMER2.0 web server provides comprehensive analysis and visualization functions of tumor infiltrating immune cells.
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                Author and article information

                Contributors
                Journal
                Int J Surg
                Int J Surg
                JS9
                International Journal of Surgery (London, England)
                Lippincott Williams & Wilkins (Hagerstown, MD )
                1743-9191
                1743-9159
                January 2024
                26 September 2023
                : 110
                : 1
                : 238-252
                Affiliations
                [a ]Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
                [b ]Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
                [c ]Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
                [d ]Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
                [e ]Institute of Cancer, Xinqiao Hospital, The Army Medical University, Chongqing, China
                [f ]Department of Cardiothoracic Surgery, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
                [g ]Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
                [h ]Department of Thoracic Surgery, St. James's University Hospital, Leeds, UK
                [i ]Department of Surgery, Division of Cardiothoracic Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
                [j ]Department of Surgery, Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina, USA
                Author notes
                [* ]Corresponding author. Address: Department of Thoracic Oncology and Surgery, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory Disease, Guangzhou, People’s Republic of China. Tel.: +86 20 83337792; fax: +86 20 83350363. E-mail: liangwh1987@ 123456163.com (W. Liang); Tel.: +86 20 83337792; fax: +86 20 83350363. E-mail: drjianxing.he@ 123456gmail.com (J. He); Department of Medical Oncology, Shanghai Pulmonary Hospital and Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, People's Republic of China. E-mail: susu_mail@ 123456126.com (C. Su) .
                Article
                IJS-D-23-01235 00026
                10.1097/JS9.0000000000000774
                10793742
                37755384
                1099da89-7dd7-4a30-85cd-d95d0bce4e65
                Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0/

                History
                : 19 June 2023
                : 10 September 2023
                Categories
                Original Research
                Custom metadata
                TRUE
                T

                Surgery
                immunotherapy,lymph node dissection,non-small cell lung cancer,pd-1 blockade,postresectional recurrence

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