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. 2025 Mar;32(3):1963-1972.
doi: 10.1245/s10434-024-16533-w. Epub 2024 Dec 7.

Survival Impacts of Mitochondrial Status in Esophageal Squamous Cell Carcinoma Patients

Kotaro Sugawara  1   2   3 , Shingo Sakashita  4 , Takashi Fukuda  2 , Chiaki Murakami  1   5 , Daiji Oka  2 , Gulanbar Amori  1 , Kumiko Ishibashi  1 , Yasuhito Kobayashi  1 , Hiroaki Kanda  1 , Noriko Motoi  6   7
Affiliations

Survival Impacts of Mitochondrial Status in Esophageal Squamous Cell Carcinoma Patients

Kotaro Sugawara et al. Ann Surg Oncol. 2025 Mar.

Abstract

Background: Little is known about the survival impacts of mitochondrial status in esophageal squamous cell carcinoma (ESCC) patients who undergo neoadjuvant chemotherapy (NAC) followed by surgery.

Methods: In total, 260 pre-NAC samples from ESCC patients were analyzed. Mitochondrial status was estimated employing an objective, immunohistochemistry-based system (Mito-score). Mito-scores were dichotomized according to the median value of our cohort. We also evaluated the immune microenvironment (CD4, CD8, Foxp3, HLA class-1, Ki-67 and programmed death ligand-1) on pre-NAC specimens. Multivariate Cox hazards models were applied to determine independent predictors of poor overall survival (OS).

Results: Patients with cT3-4 tumors had higher Mito-scores than those with cT1-2 tumors (p = 0.06), and good responders to NAC had significantly higher Mito-scores than poor responders to NAC (p = 0.04). CD8 cells and Ki-67 expression were significantly higher in Mito-high than Mito-low tumors (p = 0.017 and p < 0.001, respectively). Patients with low Mito-scores had significantly poorer OS than those with high Mito-scores (3-year OS: 57.6% vs. 68.2%; p = 0.03). A survival difference by Mito-score was evident in cStage III-IV patients (3-year OS: low 50.6% vs. high 66.1%; p = 0.006). Multivariable analysis revealed that a low Mito-score (hazard ratio 1.59, 95% confidence interval 1.12-2.24; p = 0.009) as well as pT3-4 disease (p < 0.001) and pN2-3 disease (p < 0.001) were independently associated with poor OS outcomes.

Conclusions: A low Mito-score before NAC had a significant survival impact in ESCC patients, especially in those with advanced disease. Mitochondrial status might be associated with tumor aggressiveness and responsiveness to NAC, thereby possibly affecting the survival outcomes of ESCC patients.

Keywords: Esophageal squamous cell carcinoma; Mitochondria; Neoadjuvant chemotherapy; Tumor microenvironment.

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Conflict of interest statement

Disclosure: Kotaro Sugawara, Shingo Sakashita, Takashi Fukuda, Chiaki Murakami, Daiji Oka, Gulanbar Amori, Kumiko Ishibashi, Yasuhito Kobayashi, Hiroaki Kanda, and Noriko Motoi have no conflicts of interest to declare that may be relevant to the contents of this study. Human and Animal Rights: All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed Consent: Informed consent was obtained from all individual participants in the form of opt-out on the website. Those who rejected participation, were excluded.

Figures

Fig. 1
Fig. 1
Survival outcomes according to Mito-score. (a) Patients with low Mito-scores had significantly poorer overall survival than those with high Mito-scores (p = 0.03). (b) No significant survival difference was found in cStage II patients (p = 0.80), while the (c) survival difference was evident in cStage III–IV patients (p = 0.006).
Fig. 2
Fig. 2
Immune cells according to Mito-scores. The densities of (a) CD4 cells (/mm2), CD8 cells (/mm2) and Foxp3 cells (/mm2), (b) PD-L1 expression (CPS), and (c) MIB-1 cells (%) and HLA-1 cells (%) were determined and were compared according to Mito-scores. The results are presented as the mean ± SEM. A two-tailed Student’s t test or the Mann–Whitney nonparametric test was used to determine statistical significance (* p < 0.05, ** p < 0.01, *** p < 0.001). PD-L1 programmed death-ligand 1, CPS combined positive score, SEM standard error of the mean, ns non-significant
Fig. 3
Fig. 3
Representative pathological images of high/low Mito-score tumors. Bar represents 100 μm.
See this image and copyright information in PMC

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