Review for 10.1186/s12876-025-04124-2 (2025)

Title: The Prognostic Value of Indoleamine 2,3-dioxygenase in Colorectal Cancer: A
Systematic Review and Meta-analysis
Version: 0 Date: 11 Apr 2025
Reviewer's report:
This manuscript addresses a clinically relevant topic by systematically evaluating the prognostic
significance of IDO expression in colorectal cancer. While the study is registered, follows
PRISMA guidelines, and applies standard meta-analytic techniques, the current version raises
several methodological and interpretational concerns that limit the strength and reliability of
the conclusions. These issues need to be thoroughly addressed before the manuscript can be
considered for publication. A major revision is required to improve clarity, methodological
transparency, and interpretation.
1. Overstatement of Prognostic Value Despite Non-significant OS Result
The meta-analysis found no statistically significant association between IDO expression and
overall survival (HR 0.75, 95% CI 0.49–1.15, P = 0.181). Nevertheless, the manuscript
repeatedly presents IDO as a promising prognostic biomarker. This interpretation overreaches
the available data and should be revised to accurately reflect the non-significant findings.
The discrepancy between DFS and OS should also be more thoroughly discussed, especially
considering the limited number of studies per outcome.
2. Substantial Heterogeneity Not Adequately Investigated
The heterogeneity for OS was high (I² = 83.1%), yet the current manuscript limits its analysis
to subgroup stratification, which is insufficient for a high-quality meta-analysis. No test for
subgroup interaction is provided, and meta-regression is not performed. The authors should
implement or at least justify the absence of more advanced techniques to explore heterogeneity.
Without this, the robustness of the pooled estimates remains questionable.
3. Unclear Definition and Use of Quality Assessment
The use of the Newcastle-Ottawa Scale is acceptable; however, the authors do not define the
threshold for study exclusion due to “low quality.” The criteria for exclusion should be clearly
specified, and the influence of study quality on outcomes should be more rigorously analyzed
(e.g., as a sensitivity or subgroup analysis).
4. Inadequate Detail on Data Extraction via Engauge Digitizer
The use of Engauge Digitizer introduces the risk of measurement error. The manuscript fails
to clarify whether this was performed independently by two reviewers or validated in any way.
This is a non-trivial issue that must be addressed, especially since some key HRs appear to be
derived from reconstructed data.
5. Exploratory Subgroup Analyses Without Pre-specification
Multiple subgroup analyses are presented based on geography, publication year, sample size,
and NOS score. The authors do not clarify whether these were pre-specified in the PROSPERO
protocol. If they were not, these findings must be framed as exploratory, and their interpretation
should be appropriately cautious to avoid data dredging.
6. Clarity of Endpoint Definitions
The terms OS, DFS, RFS, and PFS are mentioned in the inclusion criteria, but only OS and DFS
are primarily analyzed. It would be helpful to define each term at first mention and clarify why
RFS/PFS were excluded or unavailable in the final analysis.