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Introduction: The main cause of anastomotic leakage (AL) is tissue hypoxia, which results from impaired perfusion of the pedicle stomach graft after esophageal reconstruction. Clinical judgment is unreliable in determining graft perfusion. Therefore, an objective, validated, and reproducible method is urgently needed. Near infrared fluorescence perfusion imaging using indocyanine green (ICG) is an emerging and promising modality. This study's objectives are to evaluate the feasibility of quantification of ICG angiography (ICGA) to assess graft perfusion and to validate ICGA by comparison with hemodynamic parameters, blood and tissue expression of hypoxia-induced markers, and tissue mitochondrial respiration rates. And, second, to evaluate its ability to predict AL in patients after minimally invasive esophagectomy (MIE). Methods: Patients (N = 70) with resectable esophageal cancer will be recruited for standard MIE. ICGA will be performed after graft creation and thoracic pull-up. Dynamic digital images will be obtained starting after intravenous bolus administration of ICG. The resulting images will be subjected to curve analysis and to compartmental analysis based on the adiabatic approximation to tissue homogeneity kinetic model. The calculated perfusion parameters will be compared to intraoperative hemodynamic data to evaluate the effects of patient hemodynamics. To verify whether graft perfusion represents tissue oxygenation, ICGA perfusion parameters will be compared with systemic and serosa lactate from the stomach graft. In addition, perfusion parameters will be compared to tissue expression of hypoxia-related markers and mitochondrial chain respiratory rate. Finally, the ability of functional, histological, and cellular perfusion and oxygenation parameters to predict AL and postoperative morbidity in general will be evaluated using the appropriate univariate and multivariate statistical analyses. Discussion: The results of this project may lead to a novel, reproducible, and minimally invasive method to objectively assess perioperative anastomotic perfusion during MIE, potentially reducing the incidence of AL and its associated severe morbidity and mortality. Trial registration: Clinicaltrials.gov registration number is NCT03587532. The study was approved by the ethical committee of the Ghent University, Belgium (B670201836427).