03548195

March 23, 2026, 06:38

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Sheriefet al. [1]demonstrated dual parametric evaluation to assess diagnostic performance for Hepatocellular carcinoma (HCC), discriminating from Hepatitis C-related liver Cirrhosis and Healthy control cohorts via plasma in a single centred Egyptian population.This study [1] revealed two leading biomarkers with exceptional accuracy (AUC >0.99); hsa-miR-21-5p (Sensitivity and Specificity of 98.6% and 96.7%, respectively) and Leukocyte-associated immunoglobulin-like receptor-1(LAIR-1) mean fluorescence intensity (MFI) (Sensitivity and Specificity of 100 % and 98.3%, respectively). Sherief et al. [1]aims to address one of the clinically challenging issues i.e. lack of sensitive, specific circulatory biomarker/s for early diagnosis of Hepatocellular Carcinoma (HCC).Commentary noted several strengths of the study by Sherief et al. [1],such as; looks technicallymoderatein study design, methodology and innovation level i.e. prospective study, minimally invasive sample collection, exploration of dual parameters: tumour derived circulatory micro-RNA and immune related marker. Additionally, study employed rigorous statistical analysis for diagnostic performance assessment including ROC curve analysis, comparative Sensitivity/Specificity,revealed promising findings that may pave for future research towards biomarkers validation and discovery. However,present commentary observed several concerns for the study by Sherief et al. [1]; (i) Lack of mechanistic cascade exploration including causal pathway/s.(ii) Median age of HCC cohort is significantly higher than Hepatitis C-related liver Cirrhosis and Healthy control, may be a biasing factor in expression pattern. (iii) Since study did not include follow up subjects that limits for probing of prognostic markers. (iv) Paucity of multi-centric involvement for diversified population, may limit the findings for generalized conception. (v) Validation of findings through blinded samples may demonstrate a better decision regarding applicability. (vi) Authors used word ‘noninvasive’, for plasma-based markers investigation(vii) Global Cancer statistics 2022,wasalready published in 2024[2], still authors used GLOBOCON 2020 [3] reference in epidemiological outline in the manuscript [1], latest reference can provide contemporary status. The article by Sherief et al. [1], demonstrated balanced and structured scientific contents along with logical explanations. However, addition of graphical abstract to present the study in nutshell may improve the visibility for readers. A large sample sized, multi-centered,longitudinal study, involving diversified geographical and ethnic population of HCC, Hepatitis C-related liver Cirrhosis, Healthy control cohorts, and mechanistically relevant subgroups, using common protocol, validation through blinded samples, may provide potential edge for HCCdiagnosticsto achieve common consensus and identification of prognostic biomarkers. Integrated nomogram ofhsa-miR-21-5p with LAIR-1 MFI, may be explored for possible better diagnosticsetup. Application of Artificial Intelligence (AI) may be explored for diagnostic performance as well as high throughput outcomes. References: 1. Sherief DE, Shehata HH, Nosair N, Othman AAA, Sadaka E, Elgamal R. Dual-parameter liquid biopsy using plasma miR-21-5p and T cell LAIR-1 mean fluorescence intensity for hepatocellular carcinoma diagnosis in a high-risk Egyptian cohort. World J Gastrointest Oncol 2026 March 15a; 18(3): 116567. 2. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for36 cancers in185 countries. CA Cancer J Clin. 2024; 74:229–263 3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021; 71: 209-249

Replied on March 25, 2026, 02:53

We sincerely thank the reader for the careful evaluation of our work and for the constructive and insightful comments. We are pleased that the overall design, methodological approach, and the dual-parameter strategy combining circulating miR-21-5p and T-cell LAIR-1 expression were recognized as strengths of the study. We particularly appreciate the acknowledgment of the high diagnostic performance and the potential clinical relevance of minimally invasive biomarkers in hepatocellular carcinoma. Regarding the points raised: - Mechanistic insights: We agree that exploring the underlying biological pathways linking miR-21-5p and LAIR-1 expression to hepatocarcinogenesis would add important depth. This was beyond the scope of the current diagnostic-focused study; however, it represents a key direction for our ongoing and future research. - Age differences between groups: We acknowledge that the higher median age in the HCC cohort may act as a potential confounder. Although our primary objective was diagnostic discrimination, future studies with matched cohorts or adjusted analyses would further strengthen the findings. - Lack of follow-up data: As correctly noted, our study was designed to evaluate diagnostic performance rather than prognostic outcomes. Longitudinal follow-up studies are planned to assess the prognostic value of these biomarkers. Single-center design: We agree that multi-center validation across broader populations is essential before clinical implementation. Our findings should be considered exploratory but promising. Blinded validation: We appreciate this important suggestion and will incorporate blinded validation strategies in future studies to enhance robustness. - Terminology (“noninvasive”): We acknowledge the nuance in terminology and agree that “minimally invasive” may be more precise for plasma-based assays. Epidemiological references: We appreciate the note regarding updated global cancer statistics and will ensure use of the most recent data in future work. Graphical abstract and advanced modeling: We thank the reader for these valuable suggestions. The development of integrative models, including nomograms and AI-based approaches, represents an exciting extension of our current findings and is under consideration in future research. Once again, we thank the reader for the thoughtful and constructive feedback, which we believe will help guide further refinement and expansion of this line of research.