Review for 10.1186/s12876-025-04208-z (2025)

Title: Efficacy and Safety of Reduced Thromboprophylaxis with Low Molecular Weight
Heparin for Hepatocellular Carcinoma after conversion therapy
Version: 0 Date: 26 May 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
1. Study Design and Cohort Definition
-The retrospective design inherently limits causality and introduces selection and reporting bias.
While acknowledged in the discussion, the manuscript lacks a robust strategy to mitigate this
(e.g., propensity score matching or sensitivity analyses).
-Definition of “Reduced Thromboprophylaxis”: The cutoff used (#100 IU/kg and <5 days)
appears arbitrary and is not justified with evidence or precedent in the literature. There is also
no rationale given for why this threshold was chosen over other definitions.
-No Control Group without LMWH: The comparison is not between reduced LMWH and full-
dose LMWH, but rather reduced versus “those not” (unclear if this means standard dose or no
LMWH at all). This ambiguity weakens the conclusions.
2. Methodological Limitations
-Lack of Sample Size Calculation: No justification of power analysis is provided, leaving the
adequacy of the sample size in question. The P-values and effect estimates (e.g., OS HR 0.63,
P = 0.285) suggest the study is underpowered to detect meaningful differences.
-Heterogeneous Surgical Procedures: Including various types of hepatectomies (major, minor,
anatomical, non-anatomical) introduces heterogeneity, which could significantly impact
outcomes. The impact of surgery type on bleeding and VTE is not adequately stratified or
adjusted for.
-Confounding Variables Not Controlled: Many confounders such as cirrhosis severity, liver
function, tumor burden, cardiovascular risk, and Lenvatinib treatment duration are not
adequately adjusted for. Multivariable analyses are lacking or insufficiently described.
3. Data Analysis Concerns
-Univariate Analyses Only: Although univariate logistic regression is performed, there is
no clear multivariate analysis to control for confounding. The lack of multivariate models
significantly undermines the reliability of findings.
-Imprecise Effect Estimates: Some reported results (e.g., HR 0.63, CI 0.27–1.47) are very
imprecise with wide confidence intervals, reflecting limited statistical power and undermining
interpretability.
-Missing Data Handling: There is no mention of how missing data were handled, if any. This is
essential in retrospective studies where EMR-derived data are often incomplete.
4. Interpretation and Scientific Rigor
-Overinterpretation of Trends: The manuscript draws suggestive conclusions from non-
significant trends (e.g., better OS with reduced LMWH, lower VTE despite no significance).
These interpretations are speculative and should be stated more cautiously.
-Circular Justifications: The authors suggest that reduced LMWH “might reduce” VTE despite
no statistical support and cite studies with conflicting or irrelevant findings without clearly
contextualizing them.
-Lenvatinib Duration Interpretation: The observation that longer Lenvatinib use worsens
survival is mentioned but dismissed as possibly biased, without a thorough attempt to analyze
or adjust for this.
5. Writing and Presentation
-Language and Grammar Issues: The manuscript contains multiple grammatical errors, awkward
phrasings, and formatting inconsistencies. Examples include:
“targeted cancer therapy would increase the risk for adverse cardiovascular events”
“Despite of absence” # should be “despite the absence”
“conversion therapy.Introduction” – formatting issue
-Inadequate Citation of Key Studies: Key points, especially about anticoagulation in HCC or
after Lenvatinib, are made without sufficient literature support or citation of landmark trials or
guidelines.
6. Ethical and Clinical Implications
-Ethical Oversight Adequately Described, but the waiver of informed consent might warrant
more detail regarding patient risk minimization.
-Clinical Relevance Needs Emphasis: The study's potential to change clinical practice is not well
articulated. What are the real-world implications for surgical teams or oncologists?