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Methodological considerations regarding a gene signature to predict microvascular invasion in hepatocellular carcinoma

  • Ke-Chun Wang
    Affiliations
    Department of HBP Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China

    College of Basic Medicine, Naval Medical University, Shanghai, China

    Department of Hepatic Surgery, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
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  • Li-Yang Sun
    Affiliations
    Department of HBP Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China

    Graduate School, Bengbu Medical College, Bengbu, China
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  • Ming-Da Wang
    Correspondence
    Corresponding author. Address: Department of Hepatic Surgery, the Third Affiliated Hospital of Naval Medical University, Shanghai, China; Department of HBP Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China.
    Affiliations
    Department of HBP Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China

    Department of Hepatic Surgery, The Third Affiliated Hospital of Naval Medical University, Shanghai, China
    Search for articles by this author

      Linked Article

      To the Editor:
      We read with great enthusiasm the recent article in Journal of Hepatology by Beaufrère et al.
      • Beaufrère A.
      • Caruso S.
      • Calderaro J.
      • Poté N.
      • Bijot J.C.
      • Couchy G.
      • et al.
      Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.
      The authors proposed a 6-gene transcriptomic signatures by using preoperative liver biopsies, which was revealed to be independently associated with the presence of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) by univariate and multivariate logistic regression analyses. Then, the authors demonstrated that this 6-gene signature, as a surrogate maker of MVI, was independently associated with overall survival (OS) after curative resection of HCC by univariate and multivariate Cox-regression analysis. Although interesting, we would like to express the following concerns regarding the statistical analysis in this study:
      First, there were many overlapping variables in the multivariate analyses used to predict MVI and OS, as shown in Table 2 and Table S3 in this study.
      • Beaufrère A.
      • Caruso S.
      • Calderaro J.
      • Poté N.
      • Bijot J.C.
      • Couchy G.
      • et al.
      Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.
      We noticed that the following variables were enrolled into their multivariate analyses, including α-fetoprotein (AFP) score (>2 vs. ≤2), Barcelona Clinic Liver Cancer (BCLC) stage (B-C vs. 0-A), tumor size (>3 cm vs. ≤3 cm), and tumor number (≥2 nodules vs. 1 nodule). As we know, the assessment of AFP score requires not only preoperative AFP values but also tumor size and tumor number,
      • Duvoux C.
      • Roudot-Thoraval F.
      • Decaens T.
      • Pessione F.
      • Badran H.
      • Piardi T.
      • et al.
      Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.
      while the identification of BCLC stage also requires tumor size and tumor number.
      • Reig M.
      • Forner A.
      • Rimola J.
      • Ferrer-Fàbrega J.
      • Burrel M.
      • Garcia-Criado Á.
      • et al.
      BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.
      That’s to say, the variables of tumor size and tumor number were put into the multivariate analyses in the form of 3 overlaps, which inevitably led to fatal errors from the statistical perspective.
      Second, recurrence or recurrence-free survival (RFS), but not OS, may be a more appropriate endpoint in this study. It’s known that the presence of MVI is closely related to more aggressiveness of HCC, resulting in increased probability of postoperative recurrence following HCC resection.
      • Erstad D.J.
      • Tanabe K.K.
      Prognostic and therapeutic implications of microvascular invasion in hepatocellular carcinoma.
      ,
      • Zhang X.
      • Li J.
      • Shen F.
      • Lau W.Y.
      Significance of presence of microvascular invasion in specimens obtained after surgical treatment of hepatocellular carcinoma.
      Herein, we do not deny the independent association between MVI (or this 6-gene signature as a surrogate marker of MVI) and OS demonstrated by Beaufrère et al., which can be understood as the high mortality due to the high recurrence rate. However, we believe that all readers, like us, are more interested in the results of the correlation between MVI (or the MVI surrogate marker) and recurrence (or RFS). We gratefully appreciate that the authors can present the relevant results for the readers.
      Third, the variables related to liver function status were missing in the univariate and multivariate analysis for predicting OS in this study. Numerous studies have shown that variables reflecting preoperative liver function are associated with long-term OS after curative resection for patients with HCC, such as the Child-Pugh grade or the ALBI (albumin-bilirubin) score, etc.
      • Johnson P.J.
      • Berhane S.
      • Kagebayashi C.
      • Satomura S.
      • Teng M.
      • Reeves H.L.
      • et al.
      Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade.
      • Hanazaki K.
      • Kajikawa S.
      • Shimozawa N.
      • Mihara M.
      • Shimada K.
      • Hiraguri M.
      • et al.
      Survival and recurrence after hepatic resection of 386 consecutive patients with hepatocellular carcinoma.
      • Berardi G.
      • Morise Z.
      • Sposito C.
      • Igarashi K.
      • Panetta V.
      • Simonelli I.
      • et al.
      Development of a nomogram to predict outcome after liver resection for hepatocellular carcinoma in Child-Pugh B cirrhosis.
      We noticed that Child-Pugh grade appeared in the description of patients’ baseline characteristics (Table 1 in this study
      • Beaufrère A.
      • Caruso S.
      • Calderaro J.
      • Poté N.
      • Bijot J.C.
      • Couchy G.
      • et al.
      Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.
      ), but why was this variable not put into the univariate and multivariate analyses of OS (Table S3 in this study
      • Beaufrère A.
      • Caruso S.
      • Calderaro J.
      • Poté N.
      • Bijot J.C.
      • Couchy G.
      • et al.
      Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.
      )?

      Financial support

      Supported by Adjunct Talent Fund of Zhejiang Provincial People's Hospital (No: 2021-YT).

      Authors’ contributions

      K-C. W and L-Y. S contributed equally to this letter. K-C. W designed the letter; K-C. W and L-Y. S wrote the letter; M-D. W revised the letter. All the authors reviewed the paper and approved the final version.

      Conflict of interest

      All authors have declared no conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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        • Poté N.
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        • Couchy G.
        • et al.
        Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies.
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        • Roudot-Thoraval F.
        • Decaens T.
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        Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.
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        BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.
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