Combination of squamous cell carcinoma antigen immunocomplex and alpha-fetoprotein in mid- and long-term prediction of hepatocellular carcinoma among cirrhotic patients

World Journal of Gastroenterology ISSN 1007-9327 (print) ISSN 2219-2840 (online) World J Gastroenterol 2021 December 28; 27(48): 8201-8377 Published by Baishideng Publishing Group Inc WJG https://www.wjgnet.com IDecember 28, 2021 Volume 27 Issue 48 World Journal of Gastroenterology W J G Contents Weekly Volume 27 Number 48 December 28, 2021 FRONTIER Palmitoylation in Crohn’s disease: Current status and future directions 8201 Cheng WX, Ren Y, Lu MM, Xu LL, Gao JG, Chen D, Kalyani FS, Lv ZY, Chen CX, Ji F, Lin HN, Jin X New era of electrochemotherapy in treatment of liver tumors in conjunction with immunotherapies 8216 Trotovšek B, Djokić M, Čemažar M, Serša G Magnetic challenge against gastroesophageal reflux 8227 Bortolotti M REVIEW Emerging therapeutic options in inflammatory bowel disease 8242 Yamamoto-Furusho JK, Parra-Holguín NN Issues of origin, morphology and clinical significance of tumor microvessels in gastric cancer 8262 Senchukova MA Reciprocal interactions between gut microbiota and autophagy 8283 Lapaquette P, Bizeau JB, Acar N, Bringer MA ORIGINAL ARTICLE Basic Study Hepatitis B core antigen modulates exosomal miR-135a to target vesicle-associated membrane protein 2 promoting chemoresistance in hepatocellular carcinoma 8302 Wei XC, Xia YR, Zhou P, Xue X, Ding S, Liu LJ, Zhu F Dual therapy with zinc acetate and rifaximin prevents from ethanol-induced liver fibrosis by maintaining intestinal barrier integrity 8323 Fujimoto Y, Kaji K, Nishimura N, Enomoto M, Murata K, Takeda S, Takaya H, Kawaratani H, Moriya K, Namisaki T, Akahane T, Yoshiji H Case Control Study Combination of squamous cell carcinoma antigen immunocomplex and alpha-fetoprotein in mid- and long-term prediction of hepatocellular carcinoma among cirrhotic patients 8343 Gil-Gómez A, Rojas Á, Liu CH, Gallego-Duran R, Muñoz-Hernandez R, Fassina G, Pontisso P, Ampuero J, Romero-Gómez M Retrospective Study New prognostic model for patients with advanced gastric cancer: Fluoropyrimidine/platinum doublet for first-line chemotherapy 8357 Koo DH, Ryu MH, Lee MY, Moon MS, Kang YK WJG https://www.wjgnet.com II December 28, 2021 Volume 27 Issue 48 World Journal of Gastroenterology Contents Weekly Volume 27 Number 48 December 28, 2021 LETTER TO THE EDITOR Strategy for the control of drug-induced liver injury due to investigational treatments/drugs for COVID- 19 8370 Sato K, Yamazaki Y, Uraoka T Use of oral contraceptives and risk of pancreatic cancer in women: A recalculated meta-analysis of prospective cohort studies 8374 Bae JM WJG https://www.wjgnet.com III December 28, 2021 Volume 27 Issue 48 World Journal of Gastroenterology Contents Weekly Volume 27 Number 48 December 28, 2021 ABOUT COVER Editorial Board Member of World Journal of Gastroenterology, Jakob Robert Izbicki, MD, Professor, Chairman, Department of General, Visceral and Thoracic Surgery, University of Hamburg, Martinistr. 52, Hamburg D-20246, Germany. 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All rights reserved. 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA E-mail: [email protected] https://www.wjgnet.com WJG https://www.wjgnet.com 8343 December 28, 2021 Volume 27 Issue 48 World Journal of Gastroenterology W J G Submit a Manuscript: https://www.f6publishing.com World J Gastroenterol 2021 December 28; 27(48): 8343-8356 DOI: 10.3748/wjg.v27.i48.8343 ISSN 1007-9327 (print) ISSN 2219-2840 (online) ORIGINAL ARTICLE Case Control Study Combination of squamous cell carcinoma antigen immunocomplex and alpha-fetoprotein in mid- and long-term prediction of hepatocellular carcinoma among cirrhotic patients Antonio Gil-Gómez, Ángela Rojas, Chang-Hai Liu, Rocio Gallego-Duran, Rocio Muñoz-Hernandez, Giorgio Fassina, Patrizia Pontisso, Javier Ampuero, Manuel Romero-Gómez ORCID number: Antonio Gil-Gómez 0000-0001-9622-1761; Ángela Rojas 0000-0002-6853-627X; Chang-Hai Liu 0000-0003-3901-3039; Rocio Gallego-Duran 0000-0002-9452- 1661; Rocio Muñoz-Hernandez 0000- 0003-3765-6276; Giorgio Fassina 0000-0003-1845-2657; Patrizia Pontisso 0000-0003-2077-9202; Javier Ampuero 0000-0002-8332-2122; Manuel Romero-Gómez 0000-0001- 8494-8947. Author contributions: Gil-Gómez A led the formal analysis and writing-original draft; Rojas A equally contributed to the data curation and supported the formal analysis; Liu CH supported formal analysis and writing-original draft; Gallego-Duran R equally contributed to data curation, and led the resources; Muñoz- Hernandez R supported the data curation and validation; Fassina G and Pontisso P equally contributed to the validation; Ampuero J supported the conceptualization, led the supervision, and equally contributed to the writing-review and editing; Romero-Gómez M led the conceptualization, and equally contributed to the writing-review and editing. Institutional review board Antonio Gil-Gómez, Ángela Rojas, Rocio Gallego-Duran, Rocio Muñoz-Hernandez, Javier Ampuero, Manuel Romero-Gómez, SeLiver Group, Institute of Biomedicine of Seville, Seville 41013, Spain Antonio Gil-Gómez, Ángela Rojas, Rocio Gallego-Duran, Rocio Muñoz-Hernandez, Javier Ampuero, Manuel Romero-Gómez, CIBERehd, Instituto de Salud Carlos III, Madrid 28029, Spain Antonio Gil-Gómez, Mucosal Immunity Lab, IRCCS Humanitas Research Hospital, Milan 20089, Italy Chang-Hai Liu, Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610017, Sichuan Province, China Chang-Hai Liu, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Chengdu 610017, Sichuan Province, China Giorgio Fassina, Life Biotechnology, Padua University, Venice 30175, Italy Patrizia Pontisso, Department of Clinical and Experimental Medicine, University of Padova, Padova 35123, Italy Javier Ampuero, Manuel Romero-Gómez, UCM Digestive Diseases, Virgen del Rocío University Hospital, Seville 41014, Spain Corresponding author: Manuel Romero-Gómez, MD, Full Professor, SeLiver Group, Institute of Biomedicine of Seville, Avda. Manuel Siurot sn, Seville 41013, Spain. [email protected] Abstract BACKGROUND The combination of alpha-fetoprotein (AFP) and squamous cell carcinoma antigen immunocomplex (SCCA-IgM) have been proposed for its use in the screening of hepatocellular carcinoma (HCC). Current screening programs for all cirrhotic patients are controversial and a personalized screening is an unmet need in the Gil-Gómez A et al. Predictive model of HCC in cirrhosis WJG https://www.wjgnet.com 8344 December 28, 2021 Volume 27 Issue 48 statement: Human samples were collected after obtaining a signed informed consent as approved by the Ethical Committee both hospitals (C330020). Informed consent statement: Human samples were collected after obtaining a signed informed consent. Conflict-of-interest statement: The authors declare no conflict of interest. Data sharing statement: The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy reasons. Supported by Sara Borrell postdoctoral fellowships from Instituto de Salud Carlos III to support Ángela Rojas postdoctoral contract; Consejería de Salud y Familias, Junta de Andalucía supporting Antonio Gil-Gómez contract; PI19/01404 Grant from Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III; PI19/00589/Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III; and the Xeptagen, Italy, provided the ELISA kits for the measurements of SCCA-IgM. None of the founders had a role in the design, writing or interpretation of the study. Country/Territory of origin: Spain Specialty type: Gastroenterology and Hepatology Provenance and peer review: Invited article; Externally peer reviewed. Peer-review model: Single blind Peer-review report’s scientific quality classification Grade A (Excellent): 0 Grade B (Very good): B Grade C (Good): 0 Grade D (Fair): 0 Grade E (Poor): 0 Open-Access: This article is an precision medicine era. AIM To determine the role of the combination of SCCA-IgM and AFP in predicting mid- and long-term appearance of HCC. METHODS Two-hundred and three cirrhotic patients (Child A 74.9%, B 21.2%, C 3.9%) were followed-up prospectively every six months to screen HCC by ultrasound and AFP according to European Association for the Study of the Liver guidelines. The estimation cohort was recruited in Italy (30.5%; 62/203) and validation cohort from Spain (69.5%; 141/203). Patients underwent to evaluate SCCA-IgM by enzyme-linked immunosorbent assay (Hepa-IC, Xeptagen, Italy) and AFP levels at baseline. Patients were followed-up for 60 mo, being censored at the time of the appearance of HCC. RESULTS There were 10.8% and 23.1% of HCC development at two- and five-years followup. Patients with HCC showed higher levels of SCCA-IgM than those without it (425.72 ± 568.33 AU/mL vs 195.93 ± 188.40 AU/mL, P = 0.009) during the fiveyear follow-up. In multivariate analysis, after adjusting by age, sex, aspartate transaminase and Child-Pugh, the following factors were independently associated with HCC: SCCA-IgM [Hazard ratio (HR) = 1.001, 95%CI: 1.000-1.002; P = 0.003], AFP (HR = 1.028, 95%CI: 1.009-1.046; P = 0.003) and creatinine (HR = 1.564 95%CI: 1.151-2.124; P = 0.004). The log-rank test of the combination resulted in 7.488 (P = 0.024) in estimation cohort and 11.061 (P = 0.004) in the validation cohort, and a 100% of correctly classified rate identifying a low-risk group in both cohorts in the two-year follow-up. CONCLUSION We have constructed a predictive model based on the combination of SCCA-IgM and AFP that provides a new HCC screening method, which could be followed by tailored HCC surveillance for individual patients, especially for those cirrhotic patients belonging to the subgroup identified as low-risk of HCC development. Key Words: Squamous cell carcinoma antigen; Hepatocellular carcinoma prediction; Precision medicine; Stratification of cirrhotic patient ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved. Core Tip: Current screening programs of hepatocellular carcinoma (HCC) for all cirrhotic patients are controversial and a personalized strategy is an unmet need in the precision medicine era. By studying circulating biomarkers in two-hundred and three cirrhotic patients followed-up for 60 mo, we found that the combination of circulating alpha-fetoprotein and squamous cell carcinoma antigen immunocomplex resulted in a 100% of correctly classified rate identifying a low-risk group of HCC at two years of follow-up in two different cohorts. This predictive model provides a new screening method, which could be followed by tailored HCC surveillance for individual patients. Citation: Gil-Gómez A, Rojas Á, Liu CH, Gallego-Duran R, Muñoz-Hernandez R, Fassina G, Pontisso P, Ampuero J, Romero-Gómez M. Combination of squamous cell carcinoma antigen immunocomplex and alpha-fetoprotein in mid- and long-term prediction of hepatocellular carcinoma among cirrhotic patients. World J Gastroenterol 2021; 27(48): 8343-8356 URL: https://www.wjgnet.com/1007-9327/full/v27/i48/8343.htm DOI: https://dx.doi.org/10.3748/wjg.v27.i48.8343 Gil-Gómez A et al. Predictive model of HCC in cirrhosis WJG https://www.wjgnet.com 8345 December 28, 2021 Volume 27 Issue 48 open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: htt ps://creativecommons.org/Licens es/by-nc/4.0/ Received: April 22, 2021 Peer-review started: April 22, 2021 First decision: June 13, 2021 Revised: June 27, 2021 Accepted: December 8, 2021 Article in press: December 8, 2021 Published online: December 28, 2021 P-Reviewer: Shousha HI S-Editor: Wang JL L-Editor: A P-Editor: Wang JL INTRODUCTION Hepatocellular carcinoma (HCC) is the most common malignant primary liver tumor and the second leading cause of cancer-related death in the world, according to the World Health Organization[1]. Up to 90% of HCCs in the Western world seem to occur in patients with cirrhosis, with an annual incidence ranging from 2% to 4% with differences in age, gender, etiology and duration of the cirrhosis[2,3]. According to the Barcelona Clinic Liver Cancer stratification, patients diagnosed on stage 0 and A of HCC have a tremendously better five-year HCC-free rate (93%) than those patients diagnosed on the advanced stage (5%) due to the availability of curative therapies such as surgical resection or liver transplantation[4]. However, the vast majority of HCC patients are diagnosed at advanced stages[5] and only a small proportion of new HCC patients are diagnosed through the surveillance[6]. Tumor stage at diagnosis can be impacted by several factors in clinical practice, including low surveillance rates and compliance and delays in follow-up of abnormal screening tests[4]. Therefore, in order to diagnose HCC at the early stage, besides having an accurate diagnostic tool, an appropriate strategy of HCC surveillance specifically focusing on well-defined high-risk population is essential and indispensable. Current guidelines[7,8] recommend HCC screening by abdominal ultrasound at 6- month intervals in cirrhotic patients. However, the practice guideline-recommended “one-size-fits-all” HCC screening program for early tumor detection is performed in less than 20% of the target population and its implementation in clinical practice is far from satisfactory due to multiple patient- and provider-related factors[9]. More importantly, the risk of developing HCC is likely not uniform across all cirrhotic patients[10,11]. Therefore, an individual HCC risk prediction followed by tailoring the personalized surveillance strategy is expected to overcome the challenge in the era of precision medicine[9,12]. SERPINB3 and SERPINB4, formerly known as squamous cell carcinoma antigen 1-2 (SCCA1/2), are two isoforms of Clade B Serine Protease Inhibitors that are found physiologically in the spinous and granular layers of normal squamous epithelium such as tongue, esophagus, lung and uterus among others, while become highly expressed in squamous cell carcinomas of these organs[13,14]. Recent evidences found the plasma levels of both SCCA[15] and immunoglobulin M complex (SCCA-IgM)[16] associated with liver tumor development, suggesting that monitoring of SCCA and SCCA-IgM levels might be useful for identifying cirrhotic patients at higher risk of developing HCC[15]. A large number of studies further supported the usefulness of SCCA-IgM for the diagnosis[17] and monitoring of chronic liver disease[18-20] including the histological response after antiviral treatments. A recent meta-analysis concluded that both SCCA and SCCA-IgM had a similar moderate diagnostic accuracy (0.7-0.9) for HCC screening; however, a combination of SCCA and SCCA-IgM was the best diagnostic option[17]. Pozzan et al[21] proved that SCCA-IgM alone was able to predict HCC-free and progression-free survival for intermediate-stage patients treated by transcatheter arterial chemoembolization. Lately, Biasiolo et al[22] showed that SCCA-IgM alone but not AFP was significant to predict the HCC-free survival in a prospective cohort. However, the previous study did not assess the combination of SCCA-IgM and AFP, and there was no external validation study that further confirmed those results. More importantly, the majority of previous studies were performed only in Italian cohorts with a dominant hepatitis C etiology by a uni-center design. The present study aims to evaluate the potential role of the combination of SCCA-IgM and AFP as a biomarker in the mid-term and long-term prediction of HCC among patients with cirrhosis by using a multi-center and internal-external-validation study design. MATERIALS AND METHODS Patients From January 2007 to March 2016, 62 cirrhotic patients (30.5%; 62/203) were enrolled from the outpatient clinics of the Azienda Ospedaliera di Padova (Padova, Italy) as estimation cohort and 155 cirrhotic patients (69.5%; 141/203) were included at Valme University Hospital (Seville, Spain) as validation cohort. The study was retrospectively performed on prospectively collected sera. Patients were followed-up every six months for HCC screening according to European Association for the Study of the Liver guidelines[7]. The study was performed by following the ethical guidelines Gil-Gómez A et al. Predictive model of HCC in cirrhosis WJG https://www.wjgnet.com 8346 December 28, 2021 Volume 27 Issue 48 expressed in the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. Human samples were collected after obtaining a signed informed consent as approved by the Ethical Committee of both hospitals. Cirrhosis was diagnosed by documenting at least one of the following: clinical (esophageal varices, liver dysfunction, or previous ascites or variceal bleeding), pathological (liver biopsy) or radiological (coarse/nodular/lobar redistribution on ultrasound) markers of cirrhosis. Demographic, clinical and laboratory parameters were recorded at the first visit including age, sex, etiology of cirrhosis, aspartate transaminase (AST), alanine aminotransferase, bilirubin, albumin, creatinine and platelet levels. Patients with both chronic viral hepatitis and a history of alcohol intake were categorized as having viral hepatitis. Similarly, patients with steatohepatitis were included as alcoholic cirrhosis if alcohol was determined as the cause of liver disease in the clinical record. Non-alcoholic steatohepatitis, as well as autoimmune liver diseases such as autoimmune hepatitis, primary biliary cirrhosis or primary sclerosing cholangitis, were categorized as “Others”. Follow-up time was censored at the last clinic visit, death, liver transplantation or diagnosis of HCC within the term of 60 mo. HCC was diagnosed without biopsy in the majority of the cases because of current clinical diagnostic approaches, including ultrasonography, computed tomography, magnetic resonance imaging were sufficient to diagnose HCC[7,8]. Sample storage and assays Peripheral blood sample was collected from each patient at the time of the first clinic visit. Plasma and serum aliquots were stored in cryovials at -80ºC after centrifugation for 10 min at 1500 ×g at 4ºC. Serum AFP and SCCA-IgM were measured for each patient by an experienced technician who was blind to the clinical information. AFP levels were determined by an electrochemiluminescence immunoassay using an automatized analyzer Elecsys (Roche, Switzerland) and SCCA-IgM was measured in duplicate using commercially available enzyme-linked immunosorbent assay kits according to the manufacturer’s instructions (Hepa-IC, Xeptagen, Venice, Italy). The amount of SCCA-IgM immune complexes was expressed in arbitrary units (AU)/mL by interpolation of samples absorbance on the calibration curves plotted with SCCA- IgM calibrators. Statistical analysis Cox proportional hazards regression was used to estimate the hazard ratio (HR) and CI. Comparisons between categorical variables were made by the Chi-square or Fisher test. Results are presented as frequencies and percentages for categorical variables, means ± SDs for normal continuous variables and median, quartile 1 and 3 for not normal continuous variables. Missing data was listwise deleted (complete-case analysis). Those factors showing statistical (P < 0.05) association to HCC in univariate analyses were combined in a backwards stepwise multivariable model. Factors not significant but of potential clinical relevance such as age and sex were also included in order to avoid confounding. In the estimation cohort, we used two-year follow-up data to perform the univariate and multivariate analysis to assess the factors independently associated with HCC-free survival because cirrhotic patients need to be screened at least every two years. Akaike’s information criterion (AIC) was additionally computed to select the most robust predictors. The predictive cut-off of SCCA-IgM was established by means of receiver operating characteristic (ROC) curve method at a value that maximized specificity and sensitivity according to Youden index. The same AFP cut-off value derived from estimation cohort (5 ng/mL) was used in validation cohort. Categorical variables were compared by means of the Kaplan-Meier method, with curves compared using the log-rank test. The Harrell’s concordance index (C-index) was used to assess the score’s discrimination ability. C- index values and the corresponding 95%CIs were estimated for each main study time point. The sensitivity, specificity, positive predictive value and negative predictive value were calculated to demonstrate the predictive ability. SPSS (version 25.0; SPSS Inc., IL, the United States) and Stata 11 (StataCorp, College Station, TX) statistical packages were used. Gil-Gómez A et al. Predictive model of HCC in cirrhosis WJG https://www.wjgnet.com 8347 December 28, 2021 Volume 27 Issue 48 RESULTS Identification of the study cohort and baseline characteristics The baseline characteristics and biochemical parameters of the overall cohort, as well as estimation and validation cohorts, are shown in Table 1. Briefly, a total of 203 patients with liver cirrhosis were included in the study, with 74.9% Child-Pugh A, 21.2%B, and 3.9% Child-Pugh C. The most common etiology of cirrhosis was alcohol (54.2%), followed by HCV (27.1%) and HBV (8.4%). HCC development was observed in 22 patients (10.8%) during the two-year follow-up (22.1 ± 5.11) and 47 patients (23.2%) during the five-year follow-up (41.9 ± 16.0 mo). The baseline values of serum SCCA-IgM were significantly higher in patients who developed HCC than in those who did not (514.17 ± 714.43 AU/mL vs 216.92 ± 233.51 AU/mL, P < 0.001) during the two-year follow-up, as well as AFP (23.91 ± 41.37 ng/mL vs 6.16 ±10.49 ng/mL, P < 0.001). Identification of risk factors for HCC development Univariate analysis showed that the levels of SCCA-IgM (P = 0.004), AFP (P < 0.001), AST (P = 0.021) and creatinine (P = 0.018) were associated with two-year HCC-free survival in the estimation cohort (Table 2). Nevertheless, Child-Pugh classification, platelets count and other biochemical parameters were similar between both groups of patients. By using a multivariate Cox regression, after adjusting for age, gender, AST and Child-Pugh, SCCA-IgM (HR = 1.001, 95%CI: 1.000-1.002; P = 0.003), AFP (HR = 1.028, 95%CI: 1.009-1.046; P = 0.003) and creatinine (HR = 1.564, 95%CI: 1.151-2.124; P = 0.004) were independently associated with increased two-year risk of HCC. Internal estimation of the combination of SCCA-IgM and AFP After multivariate analysis, the model including SCCA-IgM, AFP and creatinine was the most robust for the prediction of HCC development (AIC: 44.83); however, no statistical significance was observed in ROC curve analysis (P = 0.234) so the second model consisting of the combination of SCCA-IgM and AFP was chosen (AIC: 55.54). Therefore, we performed ROC curve to explore the ability of SCCA-IgM and AFP in predicting the patients with cirrhosis to develop HCC during the two-year follow-up. By establishing a cut-off of 124 AU/mL for SCCA-IgM (sensitivity of 75% and specificity of 76%) and using a cut-off of 5 ng/mL for AFP (sensitivity of 75% and specificity of 48%), we obtained AUROCs of 0.74 (95%CI: 0.55-0.93; P = 0.029) and 0.73 (95%CI: 0.52-0.95; P = 0.034), respectively. However, although the predictive ability of the combination of SCCA-IgM and AFP was also significant [AUROC 0.77 (95%CI: 0.63-0.92; P = 0.013)], we observed no statistical significance when comparing the combinatory model to SCCA-IgM (P = 0.669) or AFP (P = 0.715) alone (Figure 1). This combination allowed us to stratify the cohort into low-risk group (AFP < 5 ng/mL and SCCA-IgM < 124 AU/mL), intermediate-risk group (AFP > 5 ng/mL or SCCA-IgM > 124 AU/mL) and high-risk group (AF P> 5 ng/mL and SCCA-IgM > 124 AU/mL). The predicted mean survival curves were compared by Kaplan-Meier at two- and five-years follow-up in the estimation cohort (Figure 2). Notably, we found that the low-risk group that was stratified by the combination of SCCA-IgM and AFP correctly identified a 100% of HCC-free survival rate in two-year followed-up which was further confirmed in the five-year follow-up (100%) (Figure 2C). External validation The same cut-off values were used for the validation cohort to confirm the results of the predictive ability of HCC-free survival. Again, the low-risk group showed a 100% of two-year and 96.2% of five-year follow-up of HCC-free survival rate (Figure 3C). However, there were no differences between the combination and SCCA-IgM or AFP alone in the comparative C-index estimates for the validation data cohort (Table 3), as are the results of the conrmatory analysis of the predictive ability of both the two- and five-year HCC-free survival. For practical applications, we calculated sensitivity, specicity, positive predictive value (PPV), negative predictive value and likelihood ratio (LR) of the combination of SCCA-IgM and AFP to demonstrate the predictive ability (Table 4). An LR- of 0 were obtained in both estimation and validation cohort in two-year follow-up, so the lowrisk group of patients who did not develop HCC could be accurately ruled-out. The correctly classified rate increased from 75.3% (estimation cohort) to 78.8% (validation cohort) in two-year follow-up and from 61.1% (estimation cohort) to 68.5% (validation cohort) in five-year follow-up. Gil-Gómez A et al. Predictive model of HCC in cirrhosis WJG https://www.wjgnet.com 8354 December 28, 2021 Volume 27 Issue 48 ARTICLE HIGHLIGHTS Research background Early diagnosis or prediction of hepatocellular carcinoma (HCC) development would have a major impact on the prognosis of patients under surveillance. Research motivation Current screening programs for HCC are far from being satisfactory due to patient- and provider-related factors. Individualizing the program according to the risk of HCC development could be a strategy to overcome these challenges in the era of precision medicine. Research objectives This study aimed to evaluate non-invasive biomarkers in the prediction of HCC among patients with cirrhosis. Research methods Retrospective cohort study analyzing the association of baseline serum biomarkers with the development of HCC in the mid- and long-term in cirrhotic patients of different etiologies. Research results Squamous cell carcinoma antigen immunocomplex (SCCA-IgM) serum levels are associated to the development of HCC at midlong-term, independently of previously known predictors. Research conclusions A predictive model based on the combination of alpha-fetoprotein and SCCA-IgM levels could provide a new HCC screening method, optimizing surveillance for individual patients, especially for cirrhotic patients allocated in the low-risk group. Research perspectives Tailored HCC surveillance assessed by non-invasive biomarkers in individual patients would help to better allocate the resources to those patients at higher risk of developing HCC. REFERENCES Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology 2019; 156: 477-491.e1 [PMID: 30367835 DOI: 10.1053/j.gastro.2018.08.065] 1 Bruix J, Reig M, Sherman M. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma. 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Predictive model of HCC in cirrhosis WJG https://www.wjgnet.com 8356 December 28, 2021 Volume 27 Issue 48 Goossens N, Singal AG, King LY, Andersson KL, Fuchs BC, Besa C, Taouli B, Chung RT, Hoshida Y. Cost-Effectiveness of Risk Score-Stratified Hepatocellular Carcinoma Screening in Patients with Cirrhosis. Clin Transl Gastroenterol 2017; 8: e101 [PMID: 28640287 DOI: 10.1038/ctg.2017.26] 31 Di Tommaso L, Spadaccini M, Donadon M, Personeni N, Elamin A, Aghemo A, Lleo A. Role of liver biopsy in hepatocellular carcinoma. 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Liver Cancer 2020; 9: 682-720 [PMID: 33442540 DOI: 10.1159/000509424] 33 Published by Baishideng Publishing Group Inc 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA Telephone: +1-925-3991568 E-mail: [email protected] Help Desk: https://www.f6publishing.com/helpdesk https://www.wjgnet.com © 2021 Baishideng Publishing Group Inc. All rights reserved.