Preoperative prediction score of hepatocellular carcinoma recurrence in living donor liver transplantation: Validation of SNAPP score developed at Asan Medical Center

The previously proposed scoring systems are not readily available because of the lack simplicity for predicting hepatocellular carcinoma (HCC) recurrence. We aimed to develop and validate new score system, which can predict HCC recurrence after living donor liver transplantation (LDLT) by using morphologic biologic data. Predictors LDLT were developed (n = 627) validated 806) in 1433 patients whom we could collect information date between 2007 2016 at Asan Medical center (AMC) create SNAPP (tumor Size Number, alpha-fetoprotein [AFP], vitamin K absence-II [PIVKA-II], positron emission tomography [PET]). On logistic regression based on 3-year recurrence-free survival, factors independently associated with was highly predictive (C statistic, 0.920), 5-year post-LT rates significantly different low, intermediate, high groups. performance (C-index [95% confidence interval], 0.840 [0.801-0.876]) tumor better than that New York/California, Risk Estimation Tumor Recurrence After Transplant (RETREAT), Model Liver (MoRAL) score. provides excellent prognostication patients. Hence, help voluntary patients’ decisions about whether undergo or not. In Asia, including South Korea, Japan, Taiwan, Hong Kong, India, Turkey, has already been established treatment satisfying Milan criteria (MC, 1 lesion ≤5 cm, 2-3 lesions ≤3 cm) under shortage deceased whole donation.1Lee S-G Hwang S Moon D-B et al.Expanded indication one large-volume center.Liver Transpl. 2008; 14: 935-945Crossref PubMed Scopus (0) Google Scholar, 2Park GC Song GW DB Lee SG. A review current status transplantation.Hepatobiliary Surg Nutr. 2016; 5: 107-117PubMed 3Yoon YI Living carcinoma: an Asian perspective.Dig Dis Sci. 2019; 64: 993-1000Crossref (16) 4Yoon Y-I G-W al.Outcome ABO-incompatible adult living-donor carcinoma.J Hepatol. 2018; 68: 1153-1162Abstract Full Text PDF (23) Scholar However, MC drawbacks too conservative, particularly LDLT, may exclude some having favorable biology among beyond MC.5Halazun KJ Tabrizian P Najjar M al.Is it time abandon criteria? Results a bicoastal US collaboration redefine selection policies.Ann Surg. 268: 690-699Crossref As result, many groups offer other complement MC. Until now, there reliable model LDLT.6Lee J-H Cho Y Kim HY al.Serum markers provide refined selecting candidate criteria.Ann 263: 842-850Crossref (64) 7Sudan D Chapman WC Cameron JL Agopian V. novel prognostic nomogram accurately predicts transplantation: analysis 865 consecutive transplant recipients discussion.J Am Coll 2015; 220: 427-429PubMed 8Mehta N Heimbach J Harnois DM al.Validation risk estimation (RETREAT) transplant.JAMA Oncol. 2017; 3: 493-500Crossref (171) 9Bonadio I Colle Geerts al.Liver comparing Milan, UCSF, criteria: long-term follow-up Western single institutional experience.Clin Transplant. 29: 425-433Crossref (19) To system surpasses ability pathologic outcome, microvascular invasion, should be included as critical factors.10Mazzaferro V Llovet JM Miceli R al.Predicting survival retrospective, exploratory analysis.Lancet 2009; 10: 35-43Abstract (1398) Scholar,11Kirchner VA Mongin al.East vs west: predictors oncologic outcomes following DD LD HCC.Transplantation. 102: S253-S254Crossref problem is how identify invasion presents before operation. Recently, study have reported (AFP), protein induced absence antagonist-II (PIVKA-II) tomography/computed 18F-fluorodeoxyglucose (FDG PET/CT).12Yaprak O Acar Ertugrul G al.Role pre-transplant 18F-FDG PET/CT transplantation.World Gastrointest 336-343Crossref Scholar,13Hong Suh KS SW al.Alpha-fetoprotein F-18-FDG transplantation.J 852-859Abstract Because they correlate well explant pathology, therefore, derive closest outcome pathology elevated level positive results FDG altogether. concurrent application those 3 parameters their significance factor investigated prediction HCC. this study, tried find out most effective method PET-CT together. Subsequently, undergoing precise straightforward designed Center, preoperative imaging (CT/magnetic resonance [MRI] PET/CT) LDLT. boards approved Center (AMC; 2014-0831). (age ≥ 18 years) from January December 2016. Patients intrahepatic cholangiocarcinoma mixed HCC–cholangiocarcinoma explants excluded. During period, total 1581 received carcinoma, 1451 had all examination required study. Eighteen lost follow-up. development validation group consisted 627 (2007-2011) 806 (2012-2016) patients, respectively, who underwent AMC. variables age, sex, size, number HCC, (AFP PIVKA-II) operation, cause disease, End-Stage-Liver Disease (MELD) reviewed evaluate staging also know presence microscopic vascular invasion. Pathologic explanted size tumors viability. categories stages evaluated: within University California San Francisco (UCSF) AMC criteria. Maintenance immunosuppression mainly triple regimen tacrolimus, mycophenolate mofetil, prednisone. All contrast-enhanced CT MRI month uptake, plot circular regions interest (ROIs) normal measured standardized uptake value (SUV) each ROI. maximum SUV (SUVmax) For identifying positivity, used SUV-max normal-liver SUVmax (TSUVmax/LSUVmax) values. From previous TSUVmax/LSUVmax 1.15 PET recurrence.14Lee JW Paeng JC Kang KW al.Prediction Nucl Med. 50: 682-687Crossref (132) grouped several ways, existing criteria, then analyzed receiver operating characteristics (ROC) curve. Among groups, choose precisely. our defined optimal cutoff point showing highest C-index values specificity 0.85. calculated formula: C – index (sensitivity + specificity)/2. necessary avoid excluding large would multivariate Cox analyses revealed combination significant recurrences.15Kim SH WJ al.Preoperative (AFP) 461-469Crossref probabilities rate estimated Kaplan-Meier compared log-rank test. Univariate multivariable hazard ratios (HRs) determined (RFS) 95% intervals (CIs).16Sullivan LM Massaro D’Agostmo RB. Presentation data clinical use: Framingham Study functions.Stat 2004; 23: 1631-1660Crossref (1087) univariate < .05 analysis, final selected backward stepwise elimination (P > removal). [PET]) created simple integer HRs independent Each produced simplified scale reflecting relative impact covariables. component summed calculate stratified according possibility score, where low-risk 0-2, acceptable 3-4, high-risk >5 (Table 1).TABLE 1Recurrence stratification scoreSNAPP scoreRisk recurrenceRecurrence free survival1 y3 y5 yDevelopmentValidationDevelopmentValidationDevelopmentValidation0-2Low98%96%97%94%97%94%3-4Acceptable82%89%71%80%71%77%5 moreHigh46%55%35%45%31%25%Abbreviations: PET, tomography; SNAPP, (PIVKA-II). Open table tab Abbreviations: summarized Table 2. mean HCCs detected scan 2.84 cm (SD, 1.33) 1.96 nodules 1.08) group, respectively. Hepatitis B main disease (90.0% [n 564] 83.0% 669]). Compared developmental no maximal tumors, median markers, positivity group. difference stage criterion (UCSF [15.9% 18.7%], [8.6% 9.3%]) (7.8% 49] 10.4% 84]).TABLE 2Clinical studyClinical characteristicsGroupsP (SMD)Development 627)Validation 806)Age, (SD), y53.02 (6.80)53.15 (6.28).718 (0.02)Male, sex (%)534 (85.2%)709 (88.0%).121 (0.08)DiagnosisHepatitis (HCV)30 (4.8%)55 (6.8%)Hepatitis (HBV)564 (90.0%)669 (83.0%)HBV HCV19 (3.0%)75 (9.3%)Cryptogenic14 (2.2%)7 (0.9%)MELD (SD)12.60 (5.29)11.00 (4.11)Maximal (radiologic)≤3 cm423 (67.5%)636 (78.9%)<.001 (0.23)3-6 cm184 (29.3%)163 (20.2%)>6 cm20 (3.2%)7 (0.9%)Number (radiologic)1293 (46.4%)372 (46.2%).467 (0.04)2-3253 (40.4%)324 (40.2%)≥481 (12.9%)109 (13.6%)AFP, ng/mL14.5 (0.78-15 400)11.9 (0.72-42 200)PIVKA-II, mAU/mL29.0 (5.0-6970)25.0 (11.0-19 400)PET-CTIsometabolic476 (75.9%)608 (75.4%).833 (0.01)Hypermetabolic151 (24.1%)198 (24.6%)Milan (radiologic)Within462 (73.7%)615 (76.3%).255 (0.06)Beyond165 (26.3%)191 (23.7%)UCSF (pathologic)Within527 (84.1%)655 (81.3%).169 (0.07)Beyond100 (15.9%)151 (18.7%)Asan (pathologic)Within573 (91.4%)722 (89.6%).649 (0.02)Beyond49 (8.6%)75 (9.3%)Follow-up, mo79 (1-109)43 (5-64)Microvascular (pathologic)No578 (92.2%)722 (89.6%).092 (0.09)Yes49 (7.8%)84 (10.4%)Abbreviations: MELD, Disease; PET-CT, tomography-computed (PIVKA-II); SMD, difference; Francisco. Areas curve (AUCs) (max 5 6 0.728 0.741 .000). Also, AUCs numbers 0.649 0.730 .000), respectively (Figure 1). 100 maul/mol PIVKA-II [(C-index, sensitivity, specificity) (0.71, 0.55, 0.93)], 150 nag/mol AFP (0.68, 0.46, 0.90). Using shown powerful predictor expansion preexisting strict study.14Lee Mean 60.7 months (interquartile range [IQR], 25-91 months) patient employed 3-category protocol level: (5-year <20%) (theoretical 20%-80%; actual around 20%), >80%). Our usual within-Milan assessment blood (every 1-3 months), routine screening dynamic abdomen-pelvis (or ultrasonography case renal dysfunction), chest X-ray 3-6 additional 4-12 first years. principle, suggested repeating marker tests over 10 years years.17Hwang Ahn C-S al.Risk-based transplantation.Transplant Proc. 2013; 45: 3076-3084Crossref recurrence, bone scans performed (explant invasion). Overall 1, 3, 10.2%, 14.7%, 18.2% (95% CI, 7.1%-8.9%), 2). MELD analysis. (1) (2) number, (3) categorical variable cutoffs, (4) 3). derived RFS. An individual patient’s adding points 4 variables. statistical coefficients 3.TABLE 3Outcomes creation scorePredictorsUnivariate analysisMultivariate analysisSNAPP pointsBeta-coefficientPHazard ratio (CI)PHazard (CI)Maximum cm0-3NA(Reference)NA(Reference)0NA>3-6<.0015.99 (3.87-9.28).0012.89 (1.51-5.53)11.06>6<.00111.38 (4.46-29.09).0035.787 (1.509-22.183)21.86Total n1NA(Reference)NA(Reference)0NA2-3.091.56 (0.93-2.62).0033.06 (1.47-6.36)11.12≥4<.00122.95 (12.39-42.53)<.00137.84 (15.13-94.67)23.63Tumor groupAFP ≤ PIVKA 100NA(Reference)NA(Reference)0NAAFP 100<.0017.99 (4.12-15.52)<.00111.51 (4.80-27.58)12.44AFP 100<.00116.41 (9.28-29.02)<.00115.41 (7.40-32.05)22.73AFP 100<.00171.79 (28.61-180.14)<.00159.03 (18.50-188.39)34.08PET-CTIsometabolicNA(Reference)NA(Reference)0NAHypermetabolic<.0016.14 (4.02-9.40)<.0014.01 (2.12-7.58)11.39 Calculated scores ranged 0 7, common being (24.2% 152]) (25.4% 159]). No showed Predicted 1-, 3-, rose scored (Figures 4), higher (17.7% 111]) predicted 54.0%, 65%, 69%, statistic 0.920 0.675 0.56-0.79) statistics UCSF 0.632 0.510-0.754) 0.637 0.513-0.762).FIGURE 4Kaplan-Meier probability y [Color figure viewed wileyonlinelibrary.com]View Large Image Figure ViewerDownload Hi-res image Download (PPT) 40.1 (IQR, 31-54 months). Relatively lower 5-years observed 10.4%, 11.3%, 13.3% 1.3%-18.0%), but .407) 0.801-0.876). 4, CI], [0.801-0.945]) York/California (NYCA; 0.724 [0.682-0.866]) 0.684 [0.587-0.843]) similar c-index 0.836 [0.776-0.920]).TABLE 4Comparison recurrenceDevelopment groupValidation groupPrediction modelRecurrence (%)C-index CI)Recurrence CI)1 y1 ySNAPP scoreLow2.03.03.00.920 (0.901-0.945)4.06.06.00.840 (0.801-0.876)Moderate16.029.029.011.020.023.0High54.065.069.045.055.075.0New (NYCA) scoreLow4.05.07.00.745 (0.682-0.814)4.05.06.00.724 (0.682-0.866)Acceptable9.012.015.09.013.014.0High46.058.063.046.055.056.0Risk score00000.831 (0.781-0.918)0000.836 (0.776-0.920)12.03.06.000027.011.014.06.06.06.0312.020.034.016.022.023.0414.031.040.014.029.029.05 more34.050.067.034.045.056.0Model score≤314.88.012.015.00.63 (0.592-0.689)6.07.08.00.684 (0.587-0.843)>314.838.050.063.043.057.071.0 correlates pathology. Almost half (50.0%) 14.3% 35.7% Despite recent advances radiological masses, underestimating burden remains concern.18Sherman M. diagnosis carcinoma.Am Gastroenterol. 2010; 105: 610-612Crossref (38) Even accurate related biology.19Costentin CE Bababekov YJ Zhu AX Yeh H. Is reconsider milan deceased-donor transplantation?.Hepatology. 69: 1324-1336Crossref (25) during 10%-15%, even though low recurrence.20Yao FY Mehta Flemming al.Downstaging cancer transplant: criteria.Hepatology. 61: 1968-1977Crossref (270) Scholar,21Levi Tzakis AG Martin end-stage era.J 210: 727-734Crossref Currently, more needs thorough patients.5Halazun Scholar,6Lee Scholar,8Mehta Scholar,10Mazzaferro Of various indicators known surgery, serum levels objective reproducible.22Toso Asthana Bigam DL al.Reassessing prior utilizing scientific registry database.Hepatology. 49: 832-838Crossref (272) 23Merani Majno Kneteman NM al.The waiting list changes 2011; 55: 814-819Abstract 24Kim HS Park Jang JS al.Prognostic hepatitis virus-related prospective study.J Clin 43: 482-488Crossref might HCC.15Kim time, knowledge, examinations combining results. reviewing 1000 recurrence: PET/CT, diameter, pretransplant workup held Though multicenter single-center merit research uniformly achieved surgical despite technically complicated procedures, minimized surgery-related confounding posttransplant outcome. good discrimination power candidates able stratify risks ranging less 6% (SNAPP score; 0-2) 75% higher). NYCA MoRAL scores. potentially affects practice There greater need organs, especially countries.25Chen CL. Living-donor perspective.Transplantation. 2003; 75: S1Crossref Furthermore, benefit recipient currently outweighs potential major hepatectomy innovation technique.26Lee complete technique challenges expand patients.Am 15: 17-38Crossref (95) rationally extended, prognosis becoming increasingly important. belonging “acceptable 3-4 points)” 77% RFS More 70% satisfactory when studies.27Clavien P-A Lesurtel Bossuyt PMM al.Recommendations International Consensus Conference Report.Lancet 2012; 13: E11-E22Abstract (733) 28Pomfret EA Washburn Wald al.Report National allocation United States.Liver 16: 262-278Crossref (325) 29Ioannou GN Perkins JD Carithers RL. survival.Gastroenterology. 134: 1342-1351Abstract (214) 26.2% 164) 23.5% 189) “high-risk group” (5 more) 56% 91/164) 65% 122/189) Totally 60.3% 213) excluded period obtained 5). experiences, definitely us future prognosis. replace institution.TABLE 5Classification within/above recurrenceMilan criteriaWithinAboveDevelopment 463)Validation 617)Development 164)Validation 189)0-2Low80%86%17%10%3-4Acceptable16%12%27%25%5 moreHigh4%1%56%65%Abbreviations: (PIVKA-II), (PET). One important advantages simple, unlike use complex formulas. example, 11xPIVKA-II+2xAFP (median 108.3, range: 33.7-3928.3).6Lee They both simultaneously improve accuracy, environments, outpatient’s clinic, difficult apply immediately. evaluation enables intuitively item. High correlation led perform specially procedures minimize such “Hilar dissection without mobilizing HCC” “No-touch en-bloc IVC replacement.”30Moon al.No-touch en bloc right lobe inferior vena cava replacement close retrohepatic cava: report.Transplant 3135-3139Crossref limitation did analyze effect locoregional institution tertiary medical transferred hospitals sufficient treatment. combined treatment, rather complicate decide assessed just conclusion, decision pertinent post-LDLT surveillance strategies advance. addition, make plan purpose minimizing