The prognostic nutritional index and postoperative complications after curative lung cancer resection: A retrospective cohort study

Journal Pre-proof The prognostic nutritional index and postoperative complications after curative lung cancer resection: A retrospective cohort study Sukhee Park, M.D., Hyun Joo Ahn, M.D., Ph.D., Mikyung Yang, M.D., Ph.D., Jie Ae Kim, M.D., Ph.D., Jin Kyoung Kim, M.D., Ph.D., Soo Jung Park, M.D. PII:

S0022-5223(19)32490-0

DOI:

https://doi.org/10.1016/j.jtcvs.2019.10.105

Reference:

YMTC 15274

To appear in:

The Journal of Thoracic and Cardiovascular Surgery

Received Date: 28 March 2019 Revised Date:

9 September 2019

Accepted Date: 1 October 2019

Please cite this article as: Park S, Ahn HJ, Yang M, Kim JA, Kim JK, Park SJ, The prognostic nutritional index and postoperative complications after curative lung cancer resection: A retrospective cohort study, The Journal of Thoracic and Cardiovascular Surgery (2019), doi: https://doi.org/10.1016/ j.jtcvs.2019.10.105. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery

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The prognostic nutritional index and postoperative complications after curative lung

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cancer resection: A retrospective cohort study

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Abbreviated title: PNI for lung cancer surgery

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Sukhee Park, M.D., 2Hyun Joo Ahn, M.D., Ph.D.*, 2Mikyung Yang, M.D., Ph.D., 2Jie Ae

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Kim, M.D., Ph.D., 2Jin Kyoung Kim, M.D., Ph.D., 2Soo Jung Park, M.D.

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Department of Anesthesiology and Pain Medicine, International St. Mary’s Hospital,

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Catholic Kwandong University School of Medicine, Incheon, Korea

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2

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University School of Medicine, Seoul, Korea.

Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan

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*Corresponding author:

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Hyun Joo Ahn, MD, PhD, Department of Anesthesiology and Pain Medicine, Samsung

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Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu,

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Seoul 06351, Korea.

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Tel.: +82-2-3410-0784; Fax: +82-2-3410-0361; E-mail: [email protected]

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Reprints will not be available from the corresponding author

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Declarations Acknowledgements: We greatly appreciate Dr. Insuk Sohn (Statistics and Data center of Samsung medical center, [email protected]) for statistical assistance. Funding: We did not receive any financial or institutional support. 1

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Competing interest: The authors declare no conflict of interest in the content of this study.

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Availability of data and materials: All data in this study are available from corresponding

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author on reasonable request.

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Consent for publication: Not applicable

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Prior presentations: Not applicable

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IRB information

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The date of IRB approval: Jan 14, 2019

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The number of IRB approval: Samsung Medical Center Institutional Review Board SMC

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2018-11-078-003, Chairperson Prof. Suk-Koo Lee, Seoul, Korea

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Word and element count

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Word counts; Abstract 215, Introduction 254, Discussion 804, Total 2552

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Number of Figures: 3

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Number of Tables: 4

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Number of Supplemental tables: 3

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English editing: The English in this document has been checked by at least two professional

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editors, both native speakers of English. For a certificate, please see:

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http://www.textcheck.com/certificate/MaYGU2

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Author/www.textcheck

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• Sukhee Park, M.D.: Assistant Professor, Department of Anesthesiology and Pain

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Medicine, International St. Mary’s Hospital, Catholic Kwandong University School of 2

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Medicine, Incheon, South Korea, [email protected]

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• Hyun Joo Ahn, M.D., Ph.D.: Associate professor, Department of Anesthesiology and Pain

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Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,

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Seoul, South Korea, [email protected]

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• Mikyung Yang, M.D., Ph.D.: Professor, Department of Anesthesiology and Pain

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Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,

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Seoul, South Korea, [email protected]

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• Jie Ae Kim, M.D., Ph.D.: Professor, Department of Anesthesiology and Pain Medicine,

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Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South

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Korea, [email protected]

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• Jin Kyoung Kim, M.D., Ph.D., Professor, Department of Anesthesiology and Pain

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Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine in

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Seoul, Korea. E mail: [email protected]

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• Soo Jung Park, M.D., Resident, Department of Anesthesiology and Pain Medicine,

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Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Korea.

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E mail: [email protected]

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Authors contributions • Sukhee Park: this author helped Study design/planning/Study conduct/Data analysis/ Revising paper/Drafting paper. • Hyun Joo Ahn: this author helped Study design/planning/Study conduct/Data analysis/ Revising paper/Drafting paper. • Mikyung Yang: this author helped Study conduct/Data analysis/ Revising paper/Drafting paper. 3

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• Jie Ae Kim: this author helped Study design /Data analysis/ Revising paper.

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• Jin Kyoung Kim: this author helped Study design/Study conduct/ Revising paper.

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• Soo Jung Park: this author helped Study conduct/ Revising paper.

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ABSTRACT

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Objective: The prognostic nutritional index is a score that represents a patient’s immune-

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nutritional status based on the lymphocyte count and serum albumin concentration. We

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hypothesized that preoperative prognostic nutritional index is associated with postoperative

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complications and long-term outcomes after curative resection of lung cancer.

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Methods: We retrospectively analyzed 1,011 patients with pathological stage I–III

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adenocarcinoma and squamous cell carcinoma who underwent open thoracotomy for curative

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resection of lung cancer. The preoperative prognostic nutritional index was calculated as

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follows based on preoperative laboratory data: 10×serum albumin(g/dL)+5×total lymphocyte

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count(/nL). The cutoff value of prognostic nutritional index (cutoff value: 50) was obtained

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by receiver operating characteristics curve and patients were classified as high and low group.

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Outcomes were compared with the use of propensity scores and inverse probability weighting

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adjustment to reduce treatment selection bias.

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Results: The low group exhibited more postoperative complications [34% (96/285) vs. 24%

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(174/726); P=0.002] especially pneumonia [13% (36/285) vs. 6% (41/756); P<0.001] and

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delirium [10% (29/285) vs. 5% (36/726); P=0.002], and higher in-hospital mortality [4%

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(11/285) vs. 1% (9/726); P=0.007] than the high group. A low prognostic nutritional index

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was associated with higher postoperative pulmonary complications [odds ratio 1.7; 95%

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confidence interval 1.3-2.3], lower recurrence-free survival (hazard ratio 1.3; 95% confidence

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interval 1.1-1.5) and overall survival (hazard ratio 1.5; 95% confidence interval 1.2-1.8) after

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balancing the co-variables.

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Conclusions: The preoperative prognostic nutritional index was associated with

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postoperative pulmonary complications and long-term outcomes after curative resection of 5

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non-small cell lung cancer.

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Keywords: Prognostic

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Recurrence, Thoracic surgery

nutritional

index, Pneumonia,

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Postoperative complications,

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Perspective statement

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The prognostic nutritional index, calculated from the serum albumin and lymphocyte count,

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is a marker of immune-nutritional status. Our findings indicated that low prognostic

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nutritional index is associated with increased post-operative complications and reduced

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recurrence-free and overall survival following curative resection of lung cancer.

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Central message

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The preoperative prognostic nutritional index was associated with postoperative

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complications and long-term outcomes after curative resection of non-small cell lung cancer.

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Central figure

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Prognostic nutritional index is associated with post-thoracotomy outcomes.

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Abbreviation and acronyms

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ASA=American Society of Anesthesiologists physical status

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CAR=C-reactive protein-albumin ratio

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DLCO=Diffusing capacity for carbon monoxide

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FEV1=Forced expiratory volume in 1 second

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NK=Natural killer

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NLR=Neutrophil-lymphocyte ratio

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NSCLC=Non-small cell lung cancer

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OS=Overall survival

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PLR=Platelet-lymphocyte ratio

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PNI= prognostic nutritional index 7

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RFS=Recurrence-free survival

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TNM=tumor, node, and metastasis

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Lung cancer is the most common cause of cancer-related death worldwide.1 Surgical

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resection continues to play an important role in the treatment of non-small cell lung cancer

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(NSCLC). However, postoperative complications are common2 and recurrence after curative

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resection is still high in NSCLC patients.3

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Many risk factors have been examined for poor outcomes after curative resection of lung

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cancer, but the immune-nutritional status of patients has not attracted much research attention.

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Only recently, the Enhanced Recovery After Surgery (ERAS) protocol has emphasized the

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immune-nutritional status as an important aspect for early recovery in thoracic surgery.4

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However, the immune-nutritional status may serve not only as a recommendation of ERAS

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protocol but also as a potential predictor of postoperative complications and cancer

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progression.5-7

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The prognostic nutritional index (PNI), was first introduced as a multiparameter index of

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nutritional status in non-emergency general surgical patients, relating the risk of

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postoperative complications to baseline nutritional status.8 Then, this index was simplified as

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a calculation of two parameters, the peripheral blood lymphocyte count and serum albumin

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concentration, to assess the immune-nutritional status of patients.9 When applied

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prospectively to gastrointestinal surgical patients, PNI provided an accurate, quantitative

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estimate of operative risk, permitting rational selection of patients to receive preoperative

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nutritional support.8 Recently, the PNI has been shown to be a useful predictor of survival in

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patients with digestive system carcinomas.10

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In the present study, we investigated whether the preoperative PNI is associated with

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postoperative complications after curative resection of NSCLC patients. In addition, we

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analyzed the relationship between PNI and cancer recurrence/overall survival (OS). Our

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hypothesis was low PNI is associated with higher postoperative complications and cancer 9

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recurrence and lower OS than high PNI.

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10

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METHODS

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The Institutional Review Board of Samsung Medical Center approved this study (SMC

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2018-11-078-001). This research used patient data with written consent from the patient to

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use his or her medical records for comprehensive research purposes. This manuscript adheres

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to the STROBE guidelines.

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Patients

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Electronic records were obtained for all patients who underwent open thoracotomy for

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primary NSCLC between 2009 and 2013 at a tertiary care university hospital (n = 1,529). The

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inclusion criteria were open thoracotomy for pathological stage I–III adenocarcinoma and

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squamous cell carcinoma. The exclusion criteria were simple wedge resection, distant

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metastasis at diagnosis, histological diagnoses other than adenocarcinoma and squamous cell

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carcinoma and treatment with neo-adjuvant therapy.

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The PNI is 10 × serum albumin (g/dL) + 5 × total lymphocyte count (/nL). The latest

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laboratory data within 1 month before operation were used for the PNI calculation. Receiver

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operating characteristics (ROC) analysis was performed to obtain cutoff values using our data.

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The cutoff value of PNI was 50 for postoperative complication, was 51 for overall survival,

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was 50 for recurrence free survival. We chose 50 as a common cutoff. Patients were placed in

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either the low or high PNI group, with PNI values of < 50 and ≥ 50, respectively. Other

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inflammation-based prognostic scores [The preoperative neutrophil-lymphocyte ratio

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(NLR),11 the platelet-lymphocyte ratio (PLR),12 and C-reactive protein-albumin ratio (CAR)13]

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were also obtained. The definitions and cutoff values for NLR, PLR, and CAR were based on

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a previous report.14-16

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11

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Data collection

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Data were obtained from computerized medical records and the tumor registry of the

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Department of Thoracic Surgery. The clinical tumor, node, and metastasis (TNM) stage of

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each patient were reclassified after surgery based on the pathology results and the recently

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revised Eighth Edition Lung Cancer Stage Classification.17

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The postoperative complications included pulmonary complications, postoperative

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delirium, newly developed atrial fibrillation, renal complication, myocardial infarction, stroke,

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and wound infection before discharge. Acute respiratory distress syndrome was defined in

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accordance with the 2012 Berlin definition.18 Pneumonia was diagnosed by the attending

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physician based on chest X-ray and/or computed tomography (CT), blood tests,

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and culture of the sputum. Delirium was defined by the confusion assessment method. Renal

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complication was defined using the Acute Kidney Injury Network classification ≥ 2.

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The recurrence of NSCLC was defined based on radiological evidence; patients were

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monitored for recurrence by chest radiography and computerized tomography every 3–6

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months. Recurrence-free survival (RFS) was calculated from the date of surgery to the date of

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recurrence, or to the last date the patient was seen without recurrence according to the

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patient’s medical records. OS was calculated from the date of surgery to the date of death or

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to the last date that the patient was seen alive according to medical records. Perioperative

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death was included in the overall survival

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Statistical analysis

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Our hypothesis was PNI < 50 is associated with higher postoperative complications and

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cancer recurrence and lower OS than ≥ PNI 50. The primary endpoints were postoperative

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pulmonary complications, RFS, and OS between the high PNI group and low PNI group. 12

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Continuous variables are expressed as the median (interquartile range) or mean ± standard

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deviation, and categorical variables are presented as the frequency (percentage). The high and

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low PNI groups were compared by the chi-square test or Fisher’s exact test for categorical

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variables, and by the t-test or the Wilcoxon rank-sum test for continuous variables.

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A multivariable logistic regression analysis was used to analyze the risk factors for

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pulmonary complications. Cox proportional hazards models were used to assess the effects of

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the preoperative PNI on RFS and OS, with adjustment for possible confounders. Variables

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which are clinically relevant and without collinearity were analyzed by multivariable analysis

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(method: enter, enter variable if P < 0.05, remove variable if P > 0.1). FEV1 and DLCO had

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high collinearity (r = 0.614). Therefore, FEV1 which was performed for the most patients

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were included for multivariable analysis. RFS and OS were also analyzed using the Kaplan-

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Meier method and the log-rank test.

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To minimize bias resulting from imbalance in covariate distributions between the high and

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low PNI group, we also applied the inverse probability of treatment weighting (IPTW)

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method.19 Exposure was low PNI. Matched pairs were age, gender, ASA classification,

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hypertension, diabetes mellitus, smoking, underlying lung disease, FEV1, underlying heart

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disease, surgical extent, and clinical TNM stage. We considered the covariate distribution to

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be balanced if the standardized mean difference was < 0.1. The multivariable logistic

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regression analysis was performed for pulmonary complications and Cox proportional

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hazards models was performed for RFS and OS in the IPTW-adjusted data. Survival curves

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were estimated with the use of the inverse-probability-weighting approach of Cole and

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Hernan.20

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All reported P values were two-sided, and P < 0.05 was considered statistically significant.

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Analyses were performed using SPSS statistical software for Windows, version 25.0 (IBM, 13

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Chicago, IL, USA), SAS version 9.4 (SAS Institute Inc, Cary, NC, USA) or R 3.4.3 (R

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Development Core Team, Vienna, Austria; http://www.R-project.org/).

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RESULTS

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From an initial group of 1,529 patients who underwent open thoracotomy for curative

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resection of lung cancer between 2009 and 2013, we excluded 24 patients with distant

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metastases at diagnosis, 101 patients with histological diagnoses other than adenocarcinoma

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and squamous cell carcinoma, 386 patients who had received neo-adjuvant therapy, and 7

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patients with incomplete data. The remaining 1,011 patients were included in the analysis. No

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patient was lost to follow-up (Fig. 1).

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Patient characteristics according to the preoperative PNI Of the 1,011 patients, 726 presented with high PNIs (72%), and 285 presented with low PNIs (28%). The median preoperative PNI was 53 (interquartile, 49 to 57).

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The baseline characteristics of the high and low PNI groups are listed in Table 1. Age,

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male sex, ASA class ≥ 3 were higher while body mass index (BMI) and hemoglobin were

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lower in the low PNI group (Table 1). Other inflammation-based prognostic scores, NLR,

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PLR, and CAR were higher in the low PNI group than in the high PNI group (Table 1).

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Postoperative complications and the hospital course

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Postoperative complications occurred in 270/1011 patients (27%) and were more likely in

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the low PNI group [174/726 (24%) vs. 96/285 (34%)]. Pulmonary complications occurred in

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111/1011 patients (11%) and were more likely in the low PNI group [68/726 (9%) vs. 43/285

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(15%)]. For an individual complication, pneumonia and delirium occurred more frequently in

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the low PNI group (Table 2). In-hospital mortality was higher and length of ICU and hospital

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stay was longer in the low PNI group than the high PNI group (Table 2).

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Multivariable analysis revealed that a low preoperative PNI [OR = 1.5 (95% confidence 15

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interval (CI): 1.0–2.7), P = 0.089] was associated with postoperative pulmonary

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complications. Other associated variables were age, current smoking status, and FEV1 (Table

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3). Extent of surgery (P = 0.219) did not improve the model estimate (AUCROC before and

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after addition of the data: 0.727 vs. 0.732), thus, was not included in the model.

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RFS The mean RFS were 4.2 [95% CI: 4.0 to 4.4)] years and 3.8 (95% CI: 3.5 to 4.1) years in the high and low PNI groups (log-rank P = 0.004; Fig. 2A).

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Cox proportional hazard analysis indicated that a low preoperative PNI was associated

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with poor RFS [HR = 1.3 (95% CI: 1.0 to 1.7), P = 0.047]. Regarding other risk factors, age,

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surgical extent, the pathological TNM stage, cell types, and lymphovascular invasion were

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associated with the RFS (Table 3).

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OS The mean OS was 4.8 (95% CI: 4.7 to 5.0) years and 4.5 (95% CI: 4.3 to 4.8) years in the high and in the low PNI group (log-rank P = 0.001; Fig. 2B).

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Cox proportional hazard analysis indicated that a low preoperative PNI was associated

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with poor OS [HR = 1.5 (95% CI: 1.1 to 2.1), P = 0.026]. For other risk factors, age,

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underlying lung disease, surgical extent, pathological TNM stage, and lymphovascular

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invasion were associated with a worse OS (Table 3).

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Inverse probability of treatment weighting (IPTW) for balancing co-variables between the high and low PNI groups IPTW was performed between the high and low PNI groups to balance the co-variables. 16

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The high and low PNI groups were well balanced within 10% of standardized difference

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(Supplemental Table 1). A low PNI was associated with postoperative pulmonary

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complications [OR = 1.7 (95% CI: 1.3 to 2.3), P < 0.001]. Other associated variables were

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current smoking status, FEV1, underlying lung disease, and surgical extent (Table 4).

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A low PNI was also associated with RFS and OS after IPTW [HR = 1.3 (95% CI: 1.1 to

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1.6), P = 0.002; HR = 1.5 (95% CI: 1.2 to 1.9), P = 0.001; Table 4). RFS and OS were lower

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in the low PNI group [4.1 (95% CI: 3.9 to 4.2) years vs. 3.8 (95% CI: 3.7 to 4.0) years, log-

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rank P = 0.003; 4.7 (95% CI: 4.6 to 4.9) years vs. 4.6 (95% CI: 4.5 to 4.7) years, log-rank P =

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0.004; Fig. 3). Figure 4 is a graphical summary which shows PNI is associated with post-

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thoracotomy outcomes.

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Characteristics of tumor pathology according to the preoperative PNI

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Cancer with poor differentiation was more prevalent in the low PNI group than in the high

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PNI group (Supplement Table 2). There were significant differences in the tumor size, T2

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component, and T3 component between the high and low PNI groups (Supplement Table 3).

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DISCUSSION

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This study demonstrated that the preoperative PNI was associated with increased in-hospital

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mortality and postoperative complications, especially for pneumonia and delirium in patients

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who have undergone open thoracotomy for NSCLC. Low PNI was also associated with poor

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RFS and OS. Poor prognosis in the low PNI group persisted after balancing other variables

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using IPTW.

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The PNI was first proposed in 1980s,8 and further simplified by the use of the serum

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albumin level and peripheral lymphocyte count.9 Low PNI was associated with poor overall

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survival especially in digestive system carcinomas.10,14 Since the application of the PNI to

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predict cancer recurrence following colorectal surgery,14 higher recurrence rates have been

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reported in patients with low PNIs in renal cell carcinoma,16 hepatocellular carcinoma,15,21

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and lung cancer.11,22 However, there have been few studies regarding whether PNI affects

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postoperative complications especially in lung cancer. We found that the preoperative PNI

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was associated not only with cancer recurrence and OS in NSCLC patients but also to

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postoperative complications and in-hospital mortality. Among postoperative complications,

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pneumonia and delirium were higher in the low PNI group than the high PNI group. In-

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hospital mortality was more than 3-fold higher in the low PNI group than the high PNI group.

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Hypoalbuminemia is the most common cause of deficient immunity, especially cell-

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mediated immunity,23,24 and has unfavorable effects on the immune response.25 Postoperative

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infections are known to increase in patients with hypoalbuminemia.5,26 The PNI, which is

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based on albumin levels and lymphocyte count, may therefore predict the development of

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infectious pulmonary complications such as pneumonia.

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Notably, the PNI was also associated with postoperative delirium in our study. Increased

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inflammatory reaction is one of the strongest risk factors for postoperative delirium.27,28 18

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The low PNI group showed higher levels of NLR,29 PLR30, and CAR, which are markers

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of systemic inflammation, than the high PNI group. The increased inflammatory reaction

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in addition to poor nutritional condition, which are reflected by a low PNI, may

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contribute to the development of postoperative delirium. In previous study on the elderly

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patients undergoing colorectal surgery, the PNI was found to be an independent risk factor

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for postoperative delirium.31

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A low PNI was associated with poor RFS and OS in the current study. There is substantial

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evidence that cancer-cell proliferation, invasion, and migration depend on interactions

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between tumor cells and the immunological response of the host.23,24,32-34 Lymphocytes

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include natural killer (NK) cells and T cells, which play fundamental roles in host defense via

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cell-mediated immunity. NK cells are crucial for surveillance and destruction of circulating

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tumor cells, and T cells release cytokines and growth factors to regulate immune cell

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function.35,36 In addition, T cells infiltrate cancer nests to destroy cancer cells.7,37,38 Low

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lymphocyte counts in the low-PNI group may represent a poor immunological response of

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the host at the critical moment of the metastatic cascade.

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The PNI is a simple and easily measured parameter before surgery, thus could be

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incorporated into preoperative evaluations. The PNI can guide perioperative resource

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allocation to prevent pneumonia and delirium. Also, additional treatments such as close

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monitoring and frequent follow-up could be considered for patients with low PNIs.

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However, it is not yet known whether the correction of hypoalbuminemia can reduce

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postoperative complications or cancer recurrence. Further studies are required to determine

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whether preoperative nutritional support, correction of hypoalbuminemia, and subsequent

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increase of PNI can effectively reduce postoperative complications, cancer recurrence, and

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improve the patient survival. 19

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Our study had several limitations. First, the uncontrolled and unrecorded data inherent in

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the retrospective design might have influenced the results. Second, it is unclear whether a low

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preoperative PNI directly caused postoperative complications and recurrence or whether it

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was just an epiphenomenon. Third, we did not consider perioperative changes in the PNI.

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Many hemodynamic and physiological changes can occur during surgery and in the early

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postoperative period, due to blood loss, transfusion, inflammation, loss of appetite, and

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nutritional malabsorption.39,40 Considerable changes in the PNI are therefore possible after

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surgery. Additional research is needed to determine the effects of short- and long-term PNI

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changes on postoperative complications and cancer recurrence.

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In conclusion, the risk of postoperative complications and mortality were significantly

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higher in patients with a low preoperative PNI. Our findings suggest that the preoperative

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PNI provides important information on perioperative patient care and prognosis, and can be

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incorporated into preoperative evaluations of NSCLC patients.

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20

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Reduce Cancer Recurrence, but Is Related to Higher Overall Survival in Lung Cancer

459

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460 461

25

462

FIGURE LEGENDS

463 464

Fig 1. Flow diagram. PNI = the prognostic nutritional index.

465 466

Fig 2. Recurrence-free survival (A) and Overall survival (B) between the high and low PNI

467

groups. The log-rank P = 0.004 for recurrence free survival. The log-rank P = 0.001 for

468

overall survival. PNI = the prognostic nutritional index.

469 470

Fig 3. Recurrence-free survival (A) and Overall survival (B) between the high and low PNI

471

groups after balancing co-variables. The log-rank P = 0.003 for recurrence free survival. The

472

log-rank P = 0.004 for overall survival. PNI = the prognostic nutritional index.

473 474

Fig. 4. Prognostic nutritional index is associated with post-thoracotomy outcomes.

475 476

Graphical Abstract. Prognostic nutritional index is associated with post-thoracotomy

477

outcomes.

478 479

Central picture: Prognostic nutritional index is associated with post-thoracotomy outcomes.

480 481

Video legend: The prognostic nutritional index (PNI) may serve as an important prognostic

482

marker in curative resection of lung cancer.

483

26

484

Table 1 Baseline characteristics of the patients PNI ≥ 50 (N=726)

PNI < 50 (N=285)

P

65 (59, 70)

69 (64, 73)

<0.001

Patient factors Age (years) Male

636 (81)

287 (89)

0.001

2

24 (22, 26)

22 (20, 24)

<0.001

ASA classification ≥ 3

50 (7)

32 (11)

0.023

290 (40)

116 (41)

0.88

125 (17)

56 (20)

0.41

187 (27)

66 (25)

0.59

94 (13)

42 (15)

0.52

87 ± 19

86 ± 20

0.34

93 ± 20 45 (6)

88 ± 22 21 (7)

0.001

13.8 (12.8, 14.6)

12.5 (11.3, 13.4)

<0.001

Absolute neutrophil count (/nL)

4.0 (3.1, 5.2)

4.5 (3.0, 6.3)

0.010

Absolute lymphocyte count (/nL)

2.3 (1.9, 2.7)

1.5 (1.3, 1.8)

<0.001

Albumin (g/dL)

4.4 (4.2, 4.6)

3.9 (3.6, 4.1)

<0.001

234 (199, 281)

236 (184, 319)

0.41

0.2 (0.1, 0.9)

0.7 (0.1, 3.8)

<0.001

PNI

55 (52, 58)

47 (45, 49)

<0.001

NLR

1.8 (1.3, 2.4)

2.9 (2.1, 4.3)

<0.001

PLR

104 (83, 136)

159 (117, 219)

<0.001

CAR

0.0 (0.0, 0.2)

0.2 (0.0, 1.1)

<0.001

BMI (kg/m ) Hypertension Diabetes mellitus Current smoker

a

Underlying lung disease

b

FEV1 (n=1,005) DLCO (n=957) c

Underlying heart disease Hemoglobin (mg/L)

Platelet count (/nL) CRP (mg/L)

0.59

Inflammation-based prognostic scores

Operation extent

0.45

Segmentectomy

57 (8)

16 (6)

Lobectomy

591 (81)

236 (82)

Pneumonectomy

78 (11)

33 (12)

TNM stage, pathological

0.42

I

243 (33)

87 (30)

II

268 (37)

102 (36)

III

215 (30)

96 (34)

TNM stage, clinical

485

0.20

I

302 (42)

101 (35)

II

301(41)

130 (46)

III

123 (17)

54 (19)

Data are presented as the mean ± standard deviation, the median (interquartile) or frequency (percent). 27

486

a

Current smoker, current smoking or quitting it within 1 month; bUnderlying lung disease included

487

chronic obstructive pulmonary disease, bronchiectasis, asthma, and interstitial lung disease;

488

c

489

nutritional index; BMI, body mass index; ASA, American Society of Anesthesiologists; FEV1, forced

490

expiratory volume in one second; DLCO, diffusing capacity of the lung for carbon monoxide; CRP, C-

491

reactive protein; NLR, neutrophil-lymphocyte ratio; PLR, platelet-lymphocyte ratio; CAR, C-reactive

492

protein-albumin ratio; TNM, tumor node metastasis..

Underlying heart disease included coronary artery disease and heart failure; PNI, prognostic

493

28

494

Table 2 Postoperative complications and hospital course following open thoracotomy for NSCLC PNI ≥50 (N=726)

PNI < 50 (N=285)

Unadjusted OR (95% CI)

P

174 (24)

96 (34)

1.6 (1.2, 2.2)

0.002

68 (9)

43 (15)

1.7 (1.1, 2.6)

0.009

Pneumonia

41 (6)

36 (13)

2.4 (1.5, 3.9)

<0.001

ARDS

37 (5)

21 (7)

1.5 (0.9, 2.6)

0.16

140 (19)

75 (26)

1.5 (1.1, 2.1)

0.013

36 (5)

29 (10)

2.2 (1.3, 3.6)

0.002

Atrial fibrillation

100 (14)

53 (19)

1.4 (1.0, 2.1)

0.051

Myocardial infarct

0 (0)

1 (0.4)

Stroke

1 (0)

3 (1)

7.7 (0.8, 74.5)

0.07

Renal complication

18 (3)

7 (3)

1.0 (0.4, 2.4)

0.98

Wound infection

16 (2)

8 (3)

1.3 (0.5, 3.0)

0.57

Length of general ward stay (days)

8 (7,11)

9 (7,13)

0.001

Length of ICU stay (days)

1 (1,2)

1 (1,3)

<0.001

9 (1)

11 (4)

Postoperative complications, total Pulmonary complications

Extra-pulmonary complications Delirium

In-hospital death

0.22

3.2 (1.3, 7.8)

0.007

495

Data are presented as the median (interquartile) or frequency (percent). NSCLC; non-small cell lung

496

cancer; PNI, prognostic nutritional index; ARDS, acute respiratory distress syndrome; ICU, intensive

497

care unit; OR, odds ratio; CI, confidence interval.

29

498

Table 3 Univariable and multivariable analysis for pulmonary complications, recurrence free survival and overall survival in un-adjusted and un-weighted data Postoperative pulmonary complications

PNI < 50 Patient factors Age Female ASA classification≥ 3 Hypertension Diabetes mellitus Current smokera Underlying lung diseaseb FEV1 Underlying heart diseasec Operation extent Lobectomy Segmentectomy Pneumonectomy TNM stage I II III Cell types Squamous cell carcinoma Adenocarcinoma Poor tumor differentiation Lymphovascular invasion Perineural invasion

Recurrent free survival

Overall survival

Univariable OR P

Multivariable OR (95% CI)

Univariable HR P

Multivariable HR (95% CI)

Univariable HR P

Multivariable HR (95% CI)

1.7

0.009

1.5 (1.0, 2.7)

1.5

0.004

1.3 (1.0, 1.7)

1.7

0.001

1.5 (1.1, 2.1)

1.03 0.2 1.6 1.1 1.1 2.0 1.9 0.97 0.5

0.011 0.001 0.144 0.770 0.767 0.001 0.012 <0.001 0.115

1.03 (1.00, 1.07) 0.4 (0.2, 1.0) 1.2 (0.6, 2.5) 1.0 (0.6, 1.5) 1.0 (0.6, 1.7) 1.9 (1.2, 3.0) 1.6 (0.9, 2.6) 0.98 (0.97,0.99) 0.4 (0.1, 1.3)

1.02 0.9 1.1 0.9 1.3 0.9 1.0

0.029 0.595 0.775 0.307 0.095 0.396 0.822

1.02 (1.01, 1.04) 0.94 (0.7, 1.4) 1.1 (0.7, 1.8) 0.8 (0.6, 1.1) 1.3 (0.9, 1.8) 0.8 (0.6, 1.2) 1.3 (0.9, 1.9)

0.9

0.649

0.8 (0.4, 1.3)

1.04 0.4 1.2 0.8 1.5 1.3 1.9 1.00 1.6

<0.001 0.002 0.591 0.259 0.046 0.240 0.002 0.641 0.075

1.04 (1.02, 1.07) 0.5 (0.3, 1.1) 0.8 (0.4, 1.6) 0.7 (0.5, 1.0) 1.4 (0.9, 2.1) 1.1 (0.8, 1.6) 2.0 (1.3, 3.2) 1.00 (1.00, 1.01) 1.5 (0.8, 2.6)

0.309 0.305

Reference 0.4 (0.1, 1.3) 1.3 (0.7, 2.3)

0.203 <0.001

Reference 0.94 (0.5, 1.7) 1.5 (1.0, 2.2)

0.268 0.003

Reference 0.8 (0.3, 1.9) 1.5 (1.0, 2.4)

0.235 0.901

Reference 1.02 (0.6, 1.6) 1.1 (0.6, 2.0)

1.6 3.4

0.005 <0.001

Reference 1.5 (1.0, 2.1) 2.7 (1.9, 3.8)

1.5 2.3

0.094 <0.001

Reference 1.08 (0.7, 1.7) 1.7 (1.1, 2.7)

0.9 1.7 2.2 1.5

0.222 0.042 <0.001 0.014

Reference 0.7 (0.6, 1.0) 1.2 (0.93, 1.6) 1.7 (1.3, 2.2) 1.02 (0.7, 1.5)

1.4 1.5 2.4 1.2

0.039 0.040 <0.001 0.426

Reference 1.08 (0.7, 1.6) 1.1 (0.8, 1.7) 2.0 (1.4, 2.9) 0.9 (0.5, 1.4)

0.3 1.3

1.1 1.3

0.7 1.8

30

0.6 1.9

499

a

500

interstitial lung disease; cUnderlying heart disease included coronary artery disease and heart failure; d Clinical TNM for PPCs, Pathological TNM for RFS and OS; PNI,

501

prognostic nutritional index; ASA, American Society of Anesthesiologists; TNM, tumor node metastasis; CI, confidence interval; OR, odds ratio; HR, hazards ratio.

Current smoker, current smoking or quitting it within 1 month; bUnderlying lung disease included chronic obstructive pulmonary disease, bronchiectasis, asthma, and

502

31

503 504

Table 4 Univariable and multivariable analysis for pulmonary complications, recurrence free survival and overall survival in the patients adjusted with the use of inverse probability weighting. Exposure was PNI <50. Postoperative pulmonary complications

PNI < 50 Patient factors Age Female ASA classification≥ 3 Hypertension Diabetes mellitus Current smokera Underlying lung diseaseb FEV1 Underlying heart diseasec Operation extent Lobectomy Segmentectomy Pneumonectomy TNM stage I II III Cell types Squamous Adenocarcinoma Poor tumor differentiation Lymphovascular invasion Perineural invasion

Recurrent free survival

Overall survival

Univariable OR P

Multivariable OR (95% CI)

HR

Univariable P

Multivariable HR (95% CI)

HR

Univariable P

Multivariable HR (95% CI)

1.7

<0.001

1.7 (1.3,2.3)

1.3

0.003

1.3 (1.1, 1.6)

1.4

0.004

1.5 (1.2, 1.9)

0.99 0.5 1.3 1.1 1.2 2.1 1.9 0.98 0.4

0.277 0.003 0.319 0.446 0.192 <0.001 <0.001 <0.001 0.009

0.98 (0.97, 1.00) 0.8 (0.5,1.2) 1.1 (0.7,1.9) 1.1 (0.8,1.5) 1.1 (0.8, 1.6) 1.8 (1.3, 2.5) 1.6 (1.1, 2.3) 0.98 (0.97, 0.98) 0.4 (0.2, 1.1)

1.01 1.0 0.9 0.9 1.4 0.9 1.1

0.049 0.889 0.546 0.237 0.005 0.139 0.460

1.02 (1.01, 1.03) 1.01 (0.8, 1.3) 1.0 (0.7, 1.3) 0.9 (0.7, 1.1) 1.3 (1.1, 1.7) 0.8 (0.7, 1.0) 1.4 (1.1 1.9)

1.02

0.926

0.8 (0.6, 1.2)

1.02 0.4 0.9 0.8 1.4 1.4 1.9 0.99 1.3

<0.001 <0.001 0.754 0.097 0.011 0.009 <0.001 0.059 0.240

1.04 (1.02, 1.06) 0.5 (0.3, 0.9) 0.7 (0.5, 1.2) 0.8 (0.6, 1.0) 1.5 (1.1, 1.9) 1.2 (0.9, 1.6) 2.0 (1.5, 2.8) 1.00 (0.99, 1.01) 1.2 (0.8, 1.8)

0.2 1.0

0.916 0.006

0.3 (0.1, 0.6) 0.9 (0.6, 1.4)

0.7 1.6

Reference <0.001 0.7 (0.5, 1.1) <0.001 1.3 (1.0, 1.7)

0.7 1.8

<0.001 0.004

0.9 (0.5, 1.7) 1.4 (1.0, 1.7)

1.3 2.8

Reference <0.001 1.3 (1.0, 1.6) <0.001 2.3 (1.8, 2.9)

1.2 2.2

<0.001 <0.001

1.0 (0.7, 1.4) 1.7 (1.2, 2.3)

0.8 1.5 1.9 1.6

Reference 0.036 <0.001 <0.001 0.001

1.4 1.4 2.2 1.6

0.004 0.004 <0.001 0.008

1.1 (0.8, 1.4) 1.1 (0.9, 1.4) 1.9 (1.5, 2.5) 1.0 (0.7, 1.4)

0.9 1.0

0.829 0.911

0.8 (0.6, 1.1) 0.8 (0.5, 1.2)

32

0.8 (0.6, 0.9) 1.2 (1.0, 1.5) 1.5 (1.2, 1.8) 1.1 (0.8, 1.4)

505

a

506

interstitial lung disease; cUnderlying heart disease included coronary artery disease and heart failure; d Clinical TNM for PPCs, Pathological TNM for RFS and OS; PNI,

507

prognostic nutritional index; ASA, American Society of Anesthesiologists; TNM, tumor node metastasis; CI, confidence interval; OR, odds ratio; HR, hazards ratio.

Current smoker, current smoking or quitting it within 1 month; bUnderlying lung disease included chronic obstructive pulmonary disease, bronchiectasis, asthma, and

33

Supplemental Table 1 Baseline characteristics of the patients adjusted with the use of inverse probability weighting PNI ≥ 50

PNI < 50

P

65 ± 9 83

65 ± 8 82

0.66

ASA classification ≥ 3, %

8

8

0.82

Hypertension, %

40

41

0.94

Diabetes mellitus, %

18

19

0.63

26

23

0.12

13

13

0.75

87 ± 19

87 ± 20

0.98

7

7

0.89

Patient factors Age (years) Male, %

a

Current smoker , % b

Underlying lung disease , % FEV1 (n=1,005) c

Underlying heart disease , % Surgical extent, %

0.61

0.60

Segmentectomy

54

46

Lobectomy

50

50

Pneumonectomy

50

50

TNM stage, clinical, %

0.85

I

51

49

II

50

50

III

50

50

Data are presented as the mean ± standard deviation, or percent. aCurrent smoker, current smoking or quitting it within 1 month; bUnderlying lung disease included chronic obstructive pulmonary disease, bronchiectasis, asthma, and interstitial lung disease; cUnderlying heart disease included coronary artery disease and heart failure; PNI, prognostic nutritional index; ASA, American Society of Anesthesiologists; FEV1, forced expiratory volume in one second; TNM, tumor, node, metastasis.

Supplemental Table 2 Clinicopathologic characteristics of the tumors according to the preoperative PNI

CEA (ng/mL)

PNI ≥ 50

PNI < 50

(N=726)

(N=285)

2.0 (1.3, 3.6)

2.2 (1.2, 3.5)

Cell types

0.84 0.052

Adenocarcinoma

323 (45)

107 (38)

Squamous cell carcinoma

403 (56)

178 (63)

147 (20)

76 (27)

Poor tumor differentiation

P

Pathologic stage

0.029 0.83

IA

173 (24)

59 (21)

IB

70 (10)

28 (10)

IIA

56 (8)

20 (7)

IIB

212 (29)

82 (29)

IIIA

177 (24)

79 (27)

IIIB

38 (5)

17 (6)

T stage

< 0.001

T1

245 (34)

76 (27)

T2a

145 (20)

47 (17)

T2b

114 (16)

38 (13)

T3

146 (20)

65 (23)

T4

76 (10)

59 (20)

N stage

0.14

N0

410 (56)

180 (63)

N1

208 (29)

72 (25)

N2

108 (15)

33 (12)

Multiple node invasion

144 (20)

50 (18)

0.52

Lymphovascular invasion

335 (46)

132 (46)

1.00

Perineural invasion

86 (20)

31 (11)

0.74

Data are presented as the median (25th percentile, 75th percentile) or frequency (percent). PNI, prognostic nutritional index; CEA, carcinoembryonic antigen

Supplemental Table 3 Characteristics of tumor components determining T stage according to the preoperative PNI PNI ≥ 50

PNI < 50

(N=726)

(N=285)

3.6 (2.5, 5.0)

4.2 (3.0, 6.0)

Tumor size ≤3 cm

263 (37)

80 (28)

Tumor size >3 to ≤4 cm

176 (24)

58 (20)

Tumor size >4 to ≤5 cm

140 (19)

55 (19)

Tumor size >5 to ≤7 cm

103 (14)

48 (18)

44 (6)

44 (15)

99 (14)

54 (19)

0.043

7 (1)

4 (1)

0.79

Visceral pleural invasion

97 (13)

52 (18)

0.06

Atelectasis or post obstructive pneumonitis

120 (17)

60 (21)

0.11

77 (11)

46 (16)

0.021

Chest wall invasion

48 (7)

30 (11)

0.049

Pericardium invasion

7 (1)

5 (2)

0.47

Satellite nodules in the same lobe

24 (3)

12 (4)

0.61

34 (5)

18 (6)

0.37

Mediastinum invasion

14 (2)

9 (3)

0.35

Diaphragm invasion

4 (1)

0 (0)

0.49

Heart, and great vessel invasion

7 (1)

3 (1)

1.00

Separate tumor in different lobe of ipsilateral lung

11 (2)

5 (2)

1.00

Tumor size (cm)

Tumor size >7 cm T2 component Main bronchus involvement

T3 component

T4 component

P <0.001

Data are presented as the median (25th percentile, 75th percentile) or frequency (percent). PNI, prognostic nutritional index.