The Dynamic Change in the Neutrophil–Lymphocyte Ratio and Systemic Inflammatory Response Index After Undergoing an Intensive Resistance-Based Exercise Program

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article titled “The Dynamic Change in the Neutrophil-Lymphocyte Ratio and Systemic Inflammatory Response Index After Undergoing an Intensive Resistance-Based Exercise Program” presents an interesting and clinically relevant exploration of how resistance exercise affects systemic inflammatory markers in women with breast cancer. The topic is timely and potentially impactful, as it connects oncological outcomes with lifestyle interventions. The authors correctly identify an evidence gap concerning how resistance-based exercise might modulate inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) and the systemic inflammatory response index (SIRI). The study’s strengths include its translational relevance and the clinical importance of the biomarkers examined. However, despite its conceptual value, the article suffers from considerable methodological and statistical weaknesses. These include the very small and highly selective sample, retrospective analysis design, lack of a control group, and limited statistical rigor in data handling and interpretation. The authors’ conclusions are generally consistent with their findings, but the internal validity of the study is weak, and the generalizability of results is minimal. The paper would require substantial revisions in design, analytical transparency, and methodological justification to meet the standards of a strong scientific report.

Abstract

The abstract is well written, providing a concise overview of the rationale, methods, and key results. The background effectively sets the clinical context, highlighting the prognostic importance of NLR and SIRI in cancer. However, the methodological details are too sparse and somewhat misleading. The design is described as an evaluation of “two prospective clinical trials,” yet the analysis itself is retrospective and observational. This distinction should be made explicit in the abstract to maintain scientific transparency. The authors mention the exclusion of participants based on various clinical factors, but they do not specify the resulting small sample size in the abstract, which misrepresents the study’s statistical limitations. The statistical approach is presented briefly but without mention of effect sizes, confidence intervals, or whether normality assumptions were verified before applying nonparametric tests. The results are clearly presented, but the clinical relevance of the reported p-values is overstated. The conclusion would benefit from acknowledging the exploratory nature of the study and its limited power.

Introduction

The introduction is well constructed and logically organized. The authors effectively explain the relevance of systemic inflammation to cancer progression and survival, referencing appropriate literature on NLR and SIRI as prognostic indicators. The connection between exercise and modulation of inflammatory markers is well established in general populations, and the gap identified—its effect in women with breast cancer—is justified. Nevertheless, the introduction would benefit from a clearer articulation of the study’s hypothesis. The authors state their intention “to assess whether NLR and SIRI improved after the intervention,” but they do not define what constitutes “improvement” or how clinical significance would be evaluated. Moreover, the rationale for focusing exclusively on resistance training rather than a combined exercise model (aerobic and resistance) is not sufficiently justified. The authors should also acknowledge potential confounding factors inherent to exercise interventions, such as concurrent medication use, diet, or time since cancer treatment, which could influence inflammatory markers independently of exercise. Overall, the introduction provides a strong clinical foundation but lacks precision in hypothesis formulation and variable control.

Materials and Methods

This section is presented clearly but reveals significant methodological and statistical limitations. The study is a retrospective secondary analysis of two independent, prospective exercise trials (EXERT-BC and EXERT-BCN). Although both original protocols were well defined, this subsequent analysis introduces selection bias, as only participants with available pre- and post-intervention blood tests were included. Out of 84 total participants, only 21 met inclusion criteria, which severely limits statistical power and external validity. Moreover, there was no control group, randomization, or blinding, making it impossible to attribute observed changes in NLR and SIRI solely to the exercise intervention. The inclusion and exclusion criteria are described comprehensively, but there is no discussion of potential selection effects—specifically, whether the included participants differed systematically from those excluded.

The exercise protocol is described adequately, but no data are provided on adherence, session compliance, or training intensity quantification (e.g., load progression, RPE, or training volume), which are crucial for interpreting physiological adaptations. The timing of blood draws—up to four months before or after the intervention—is highly problematic, as inflammatory markers fluctuate with numerous clinical and lifestyle factors. Such temporal variability introduces uncontrolled measurement error.

Statistical analysis is rudimentary. The authors used Mann–Whitney and Wilcoxon signed-rank tests for comparisons but provided no rationale for test selection or any assessment of normality. There is no correction for multiple comparisons, despite analyzing several outcomes (baseline, post, and delta NLR/SIRI values). No effect sizes, confidence intervals, or measures of variability beyond interquartile ranges are reported, which prevents evaluation of clinical significance. The authors should have reported standardized effect sizes (e.g., r or Cohen’s d) and provided justification for their significance threshold (p < 0.05). The absence of a priori power analysis further undermines the credibility of statistical inference.

Results

The results are presented in a straightforward and readable manner, with accompanying tables and figures. The flow diagram clarifies participant inclusion and exclusion, and descriptive statistics are reported appropriately. The finding of significant decreases in NLR and SIRI following the exercise intervention (p = 0.016 and p = 0.018, respectively) is clearly stated. However, given the small sample size and high within-subject variability, these differences may not reflect a robust biological effect. The authors do not report the magnitude of change or its confidence interval, nor do they address whether the changes observed are clinically meaningful rather than simply statistically significant.

Additionally, subgroup comparisons (e.g., participants with increased vs. decreased SIRI) are underpowered and add little interpretative value. No sensitivity analyses or robustness checks were performed to test whether the results persist under different analytical assumptions. The graphical representation of data lacks statistical overlays (e.g., boxplots with medians and outliers) that would enhance interpretability. Without a control group, it is impossible to distinguish the intervention’s effects from regression to the mean or natural fluctuations in inflammatory markers.

Discussion

The discussion section is coherent and well written, integrating the findings within a broader context of exercise oncology literature. The authors provide plausible biological explanations for the observed reduction in inflammation, citing the anti-inflammatory effects of chronic exercise and its potential implications for cancer survivorship. However, the discussion is overly optimistic relative to the study’s methodological constraints. The small sample size, lack of a control group, and retrospective design substantially limit the ability to infer causality, yet these limitations are acknowledged only briefly at the end. The authors suggest that reductions in NLR and SIRI may represent mechanisms by which exercise reduces cancer mortality, but this claim extends beyond the evidence presented. Furthermore, potential confounding variables such as diet, medication (especially endocrine therapy), and psychosocial stress are not discussed, despite their well-known influence on immune and inflammatory parameters.

The authors appropriately reference the quintile distribution of NLR in the literature and attempt to relate their results to clinically relevant thresholds. However, this analysis is speculative and should be presented as exploratory. The absence of data on adherence and individual variability further weakens the strength of interpretation. The discussion would benefit from a more critical tone and a stronger emphasis on the preliminary nature of these findings.

Practical Applications

The authors correctly highlight that structured resistance training may have anti-inflammatory benefits for women recovering from breast cancer treatment. However, the practical implications are overstated given the study’s limitations. Recommendations such as integrating exercise into survivorship care plans should be supported by larger, randomized evidence. The paper would be improved by specifying the nature and intensity of training that appeared most beneficial, rather than making general claims. Moreover, the authors should caution clinicians that the findings are preliminary and that inflammatory markers are influenced by multiple physiological and environmental factors beyond exercise.

Conclusions

The conclusion succinctly summarizes the main finding that a 12-week resistance training program was associated with improved inflammatory profiles (reduced NLR and SIRI). However, the claim that exercise “might promote lower levels of inflammation” should be tempered with explicit acknowledgment of the study’s exploratory and uncontrolled design. The authors should also emphasize the need for randomized controlled trials with larger samples and standardized biomarker collection to validate these preliminary results.

Final Assessment

This article addresses an important and novel research question at the intersection of oncology, exercise physiology, and immunology. Its translational potential is significant, but its scientific rigor is limited by design and execution. The study lacks adequate methodological control, statistical robustness, and analytical depth to support strong conclusions. To improve the manuscript, the authors should (1) clarify the retrospective nature of the analysis, (2) conduct or report effect sizes and confidence intervals, (3) control or at least discuss potential confounding variables, (4) justify the use of nonparametric tests, and (5) moderate the interpretative claims regarding causality. After addressing these issues, the paper could serve as a meaningful pilot study supporting future randomized trials. 

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The Dynamic Change in the Neutrophil-Lymphocyte Ratio and Systemic Inflammatory Response Index After Undergoing an Intensive Resistance-Based Exercise Program

The authors offer a timely, fitting investigation concerning a 12-week intense resistance exercise program and its impact on systemic inflammatory markers (NLR and SIRI) for women facing breast cancer. That's really the scope for JFMK and makes the perfect cross linking of exercise physiology, oncology, and practice within the clinic. Because the study's rationale is really good considering the biomarkers' prognostic value plus growing interests into exercise oncology. The manuscript boasts strengths with its novel focus on only a resistance-based intervention and it uses clinically relevant inflammatory indices. Yet, several very critical issues need to addressed prior to its publication consideration. Primarily, methodological clearness, statistical reporting is a must, the framing of the conclusions overall too.

Major comments:

Abstract:

Comment: The abstract needs even better specificity tho'.

Suggestion: Methods should show that this was really a retrospective analysis and uses two trial projections. The sentence "Laboratory values taken before and after." requires another, more clear writing style, so it will read something like, "Laboratory values of complete blood counts extracted both before and after taking part.".

Results: The phrase "statistical difference" really ought to be replaced with more precision like a "statistically significant reduction" for clearness.

Report those median values and IQRs for pre and post SIRI/NLR for, ya know, giving readers a feel for effect size.

Conclusions, the conclusion there is a bit overreaching. It needs softening, reflecting the preliminary and sorta associative nature of the findings. Like, "A 12-week intensive resistance exercise was seen to have an impact that was statistically significant on NLR and SIRI. This well, suggest, a benefit on inflammation."

Introduction:

Comment: The introduction quite well sets up how important NLR and SIRI are for forecasting. Although the argument about just looking at resistance training is a bit too short.

Suggestion is: go on and give more rationale. Like, say that even though we studied mixed exercises, what happens to resistance training when it’s all alone with these biomarkers isn't all that well-understood even with the help from its gains in strength and muscle. Cite a review on how resistance training works.

Methods (Exercise Protocol): This description about how exercises work just won't let them be reproduced, which is key, you know? References are alright, but a wee sum of the most important pieces is needed like some exercises intensity and a plan for sessions, too.

Alright, here's the refined output:

Suggestion: How about adding a quick summary about the exercise plan? For example, something like: "This 12-week program involved three weekly sessions under supervision, about 45 minutes each. The focus was on compound moves think squats deadlifts and presses. The intensity gradually increased to match everyone's abilities, targeting, say, 70-85% of their one-rep max."

Comment (Statistics): The statistical work looks fine for this non-parametric data. Some tweaks in the reporting will do good.

Suggestion: For the Wilcoxon signed-rank test report the test stats, W or V plus the p-value it's just good practice. The tables have medians and IQRs which is fab but please make the main text share 'em too maybe something like: "SIRI's median fell from X [IQR] to Y [IQR] p=0.018."

Results:

Comment: The result part is mainly clear as crystal. Though, Figure 3 is mentioned but missing which, quite frankly is, super important.

Suggestion: Figure 3 displaying before and after values HAS to be in the final submission. And Figure 2's caption needs to really make it clear that the dash is for that 25% drop zone.

Discussion:

Comment: Discussion works it shows what the findings means but you could boost it by really contextualizing and owning up to all the limits!

Suggestion: Given "This study is the first of its kind" stated, a brief comparison of your findings with current exercise literature on NLR in different groups (e.g., studies on teens and burn victims) would be helpful to speculate on why resistance training might yield akin or differing results, it would add value.

Limitations: The blood draw timing limitation is well understood, and the authors ought to delve deeper into how a missing control group considerably restricts the work. Observed changes, despite their statistical significance, might have been influenced by the passage of time or unknown stuff and should be made explicit, plus conclusions adjusted accordingly.

Mechanisms: Suggesting lower inflammation connects exercise to less cancer deaths seems plausible. To bolster it, referencing exercise's anti-inflammatory affects might be smart.

Minor comments:

On Page 1 under author affiliation, the numbering seems off, as Author 4's spot has someone labeled Author 1, then it lists some people like this, "¹,³ Timothy P. Dougherty, M. D. , ² David J. Carpenter, M. D. , C. S. C. S. , ³ Chris Peluso, M. S. , C. S. C. S. , and ¹,³ Colin E. Champ, M. D. , C. S. C. S." The correspondence, therefore, must then refer to "1" or T. P. D.

Page 2: Methods: "EXRT-BC" probable needs a swap to "EXERT-BC" as it aligns with the abstract and clinicaltrials gov ID.

Page 3: Results: It appears "13 women" doesn't quite jive with the previous data. The text shows 3 got RT during the study while 13 before totaling 16 which, yep, equals 76% of 21. It's correct but better to rephrase "the remaining 13 women" to something like "the remaining 16 women 13 having completed radiation ahead of the first blood draw."

In my opinion, this paper is exploring a new and very interesting question for doctors and all that jazz. With the corrections needed, particularly in detailing the exercise bit, better stats reporting a more detailed limitations talk, plus general cleanup the paper becomes stronger, which would be good for the literature on function morphology and kinesiology.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The article addresses a very interesting topic, namely the effect of resistance training on the inflammatory process in cancer patients. In the form of a short report, the article presents interesting and promising results that may be useful for further research.

There are some minor issues the authors should consider before the publication:

Introduction

• The citation style is not the one indicated in the guidelines. Moreover the citation must be reported before the full stop.
• Lines 50-51: the sentence is extremely interesting and useful for the purpose of the study. However, this sentence need to be supported by the literature
• The aim of the study have to be stated clearer at the end of the introduction

Methods

• Lines 66-68: this sentence could be reworked to make clear that the authors used data collected in other two studies to conduct their word.
• Line 70: the periphrases “as previously described” could be misleading. Indeed it may refer to a previous description in your manuscript. My suggestion is to change with “is described elsewhere” or something similar. Moreover, a general description of the exercise could be helpful.
• Lines 70-72: Since inclusion criteria were clearly stated no exclusion criteria were cited. They are reported only later on in the text
• Lines 72-74: the sentence “Both regimens resulted in an increase in strength, balance, and mobility, and an improvement in muscle mass with a decrease in fat mass assessed on bioimpedance analysis and ultrasound.” appears to be out of context and placed in the wrong paragraph, since is more appropriate for the results section. Please move the sentence
• Lines 75-77: is this an inclusion criteria?
• Lines 77-82: are the exclusion criteria fully described? The text can be reworked in order to be clearer.
• In general, the methods section is robust, however it could be improved with a clear description of inclusion and exclusion criteria and with a general description of the training protocol, to increase the readability. Then, a small section should be added where the evaluation protocol is explained.

Results

• Lines 92-93: “two people were excluded due to active rash and diverticulitis” these are not reported as exclusion criteria
• Table 2: it is improbable (however possible) that the mean of the “Final NLR [IQR]” is 1.99 for all “Total Population”, “Those with an increase in the SIRI” and “Those with a decrease in the SIRI”. My suggestion is to verify these values

Discussion

• Lines 123-137: this paragraph appears to be more indicated for the introduction. Please move it there
• Given the nature of the article and the results considered by the authors, the brevity of the discussion seems appropriate. On the other hand, the authors could make a further effort to include some references in this section that could help discuss their findings. The context is clear, and the limitations are acknowledged.

Conclusion

• The conclusion is clear and concise and adequately summarizes the results of the study

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Everything is fine.

Reviewer 2 Report

Comments and Suggestions for Authors

No comments to add.