Copyright
©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jan 15, 2022; 14(1): 295-318
Published online Jan 15, 2022. doi: 10.4251/wjgo.v14.i1.295
Intertwined leukocyte balances in tumours and peripheral blood as robust predictors of right and left colorectal cancer survival
Ramón Cantero-Cid, Karla Marina Montalbán-Hernández, Jenny Guevara, Alejandro Pascual-Iglesias, Elisa Pulido, José Carlos Casalvilla, Cristóbal Marcano, Cristina Barragán Serrano, Jaime Valentín, Gloria Cristina Bonel-Pérez, José Avendaño-Ortiz, Verónica Terrón, Roberto Lozano-Rodríguez, Alejandro Martín-Quirós, Elvira Marín, Eva Pena, Laura Guerra-Pastrián, Eduardo López-Collazo, Luis Augusto Aguirre
Ramón Cantero-Cid, Karla Marina Montalbán-Hernández, Alejandro Pascual-Iglesias, Elisa Pulido, José Carlos Casalvilla, Jaime Valentín, Gloria Cristina Bonel-Pérez, José Avendaño-Ortiz, Verónica Terrón, Roberto Lozano-Rodríguez, Elvira Marín, Eduardo López-Collazo, Luis Augusto Aguirre, Tumor Immunology Laboratory, The Innate Immune Response Group, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid 28046, Spain
Jenny Guevara, Cristóbal Marcano, Cristina Barragán Serrano, Digestive Surgery Service, La Paz University Hospital, Madrid 28046, Spain
Alejandro Martín-Quirós, Emergency Department and Emergent Pathology Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid 28046, Spain
Eva Pena, Laura Guerra-Pastrián, Pathologic Anatomy Service, Hospital La Paz, Madrid 28046, Spain
Author contributions: Cantero-Cid R and Montalbán-Hernández KM contributed equally to the manuscript; Cantero-Cid R participated in the design of the study and performed patient recruitment, surgery, and sample collection; Montalbán-Hernández KM performed sample collection, assisted with sample analysis, and performed image analysis; Pulido E performed sample analysis and assisted with image analysis; Pascual-Iglesias A performed statistical analysis; Casalvilla JC assisted with sample analysis and with image analysis; Valentín J assisted with sample analysis and with image analysis; Bonel-Pérez GC assisted with sample analysis and with image analysis; Avendaño-Ortiz J assisted with sample analysis; Terrón V assisted with sample analysis; Lozano-Rodríguez R assisted with sample analysis; Martín-Quirós A participated in patient recruitment; Marín E performed sample analysis; Guevara J participated in patient recruitment, surgery, sample collection, and assisted with data analysis; Marcano C participated in patient recruitment, surgery, sample collection, and assisted with data analysis; Barragán C participated in patient recruitment, surgery, and sample collection; Pena E was involved with sample collection and assisted with anatomo-pathological analyses; Guerra-Pastrián L was involved with sample collection and performed anatomo-pathological analyses; López-Collazo E participated in the design and oversight of the study and drafted the manuscript; Aguirre LA designed and supervised the study, assisted with data analysis, and drafted the manuscript; all authors read and approved the final manuscript.
Supported by the Foundation for the Hospital La Paz Institute for Health Research, No. PI698; Fundación Familia Alonso; Fundación Antolín Garcíarena and the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowaska-Curie-’laCaixa’, No. 713673.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee for Clinical Research of the La Paz University Hospital (Madrid, Spain). Access number: PI-1958.
Informed consent statement: All study participants, or their legal guardian, provided written consent prior to study enrolment.
Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.
Data sharing statement: There is no additional data available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Luis Augusto Aguirre, PhD, Senior Researcher, Tumor Immunology Laboratory, The Innate Immune Response Group, Hospital La Paz Institute for Health Research (IdiPAZ), Paseo de la Castellana, 261, Madrid 28046, Spain. luis.augusto.aguirre@idipaz.es
Received: May 16, 2021
Peer-review started: May 16, 2021
First decision: June 16, 2021
Revised: August 7, 2021
Accepted: November 30, 2021
Article in press: November 30, 2021
Published online: January 15, 2022
BACKGROUND
Colorectal cancer (CRC) accounts for 9.4% of overall cancer deaths, ranking second after lung cancer. Despite the large number of factors tested to predict their outcome, most patients with similar variables show big differences in survival. Moreover, right-sided CRC (RCRC) and left-sided CRC (LCRC) patients exhibit large differences in outcome after surgical intervention as assessed by preoperative blood leukocyte status. We hypothesised that stronger indexes than circulating (blood) leukocyte ratios to predict RCRC and LCRC patient outcomes will result from combining both circulating and infiltrated (tumour/peritumour fixed tissues) concentrations of leukocytes.
AIM
To seek variables involving leukocyte balances in peripheral blood and tumour tissues and to predict the outcome of CRC patients.
METHODS
Sixty-five patients diagnosed with colon adenocarcinoma by the Digestive Surgery Service of the La Paz University Hospital (Madrid, Spain) were enrolled in this study: 43 with RCRC and 22 with LCRC. Patients were followed-up from January 2017 to March 2021 to record overall survival (OS) and recurrence-free survival (RFS) after surgical interventions. Leukocyte concentrations in peripheral blood were determined by routine laboratory protocols. Paraffin-fixed samples of tumour and peritumoural tissues were assessed for leukocyte concentrations by immunohistochemical detection of CD4, CD8, and CD14 marker expression. Ratios of leukocyte concentration in blood and tissues were calculated and evaluated for their predictor values for OS and RFS with Spearman correlations and Cox univariate and multivariate proportional hazards regression, followed by the calculation of the receiver-operating characteristic and area under the curve (AUC) and the determination of Youden’s optimal cutoff values for those variables that significantly correlated with either RCRC or LCRC patient outcomes. RCRC patients from the cohort were randomly assigned to modelling and validation sets, and clinician-friendly nomograms were developed to predict OS and RFS from the respective significant indexes. The accuracy of the model was evaluated using calibration and validation plots.
RESULTS
The relationship of leukocyte ratios in blood and peritumour resulted in six robust predictors of worse OS in RCRC: CD8+ lymphocyte content in peritumour (CD8pt, AUC = 0.585, cutoff < 8.250, P = 0.0077); total lymphocyte content in peritumour (CD4CD8pt, AUC = 0.550, cutoff < 10.160, P = 0.0188); lymphocyte-to-monocyte ratio in peritumour (LMRpt, AUC = 0.807, cutoff < 3.185, P = 0.0028); CD8+ LMR in peritumour (CD8MRpt, AUC = 0.757, cutoff < 1.650, P = 0.0007); the ratio of blood LMR to LMR in peritumour (LMRb/LMRpt, AUC = 0.672, cutoff > 0.985, P = 0.0244); and the ratio of blood LMR to CD8+ LMR in peritumour (LMRb/CD8MRpt, AUC = 0.601, cutoff > 1.485, P = 0.0101). In addition, three robust predictors of worse RFS in RCRC were found: LMRpt (AUC = 0.737, cutoff < 3.185, P = 0.0046); LMRb/LMRpt (AUC = 0.678, cutoff > 0.985, P = 0.0155) and LMRb/CD8MRpt (AUC = 0.615, cutoff > 1.485, P = 0.0141). Furthermore, the ratio of blood LMR to CD4+ LMR in peritumour (LMRb/CD4MRpt, AUC = 0.786, cutoff > 10.570, P = 0.0416) was found to robustly predict poorer OS in LCRC patients. The nomograms showed moderate accuracy in predicting OS and RFS in RCRC patients, with concordance index of 0.600 and 0.605, respectively.
CONCLUSION
Easily obtainable variables at preoperative consultation, defining the status of leukocyte balances between peripheral blood and peritumoural tissues, are robust predictors for OS and RFS of both RCRC and LCRC patients.
Core Tip: This was a prospective study involving 65 patients with colorectal cancer, seeking to find robust predictors of survival after surgical intervention amongst the leukocyte balances in peripheral blood, tumour, and peritumoural tissues. A number of these variables are shown to predict overall survival and recurrence-free survival in both right-sided colorectal cancer and left-sided colorectal cancer patients, thus allowing the improvement of pre- and postoperative patient treatments.
