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There exist no treatment guidelines for spontaneously ruptured hepatocellular carcinoma (srHCC) and its prognosis remains controversial.Patients were retrospectively enrolled and grouped based on hemodynamics and tumor resectability. The 30-day mortality, 5-year overall survival (OS), progression-free survival (PFS), peritoneal metastasis (PM) and intrahepatic metastasis (IM) rates were compared.In general, 239 patients were classified into four groups: patients with stable hemodynamics underwent semi-elective hepatectomy (n = 119), and those with unstable hemodynamics received emergent hepatectomy (n = 17), sequential hemostatic-transcatheter arterial chemoembolization (TACE)/-laparotomy with late hepatectomy (n = 49), or TACE only (n = 54). Hepatectomy was safer and provided better OS and PFS than TACE both before and after propensity score matching. Emergent hepatectomy was associated with higher 30-day mortality (6.2%, P 0.05) and poorer prognosis whereas semi-elective hepatectomy and sequential treatment had comparable mortality (both 0%) and survival (36.3% vs 45.2%, P 0.05). Compared with hemostatic TACE in the sequential treatment group, early surgical intervention (semi-elective hepatectomy, emergent hepatectomy, and sequential laparotomy with late hepatectomy) decreased PM (13.6% vs 34.2%, P = 0.003) whereas had higher IM (68.0% vs 50.0%, P = 0.039), but neither procedure had affected OS. In srHCC patients with high risk of recurrence (multiple tumors, micro- and macro-vascular invasion), postoperative adjuvant TACE improved OS.Hepatectomy could provide better prognosis than TACE for srHCC patients while semi-elective hepatectomy and sequential hemostatic-TACE with staged hepatectomy are viable options for srHCCs with stable and unstable hemodynamics, respectively.

Background: This study aimed to evaluate the role of plasma microRNA panel (miR-122, miR-192, miR-21, miR-223, miR-26a, miR-27a and miR-801) for prediction and surveillance of early tumor recurrence in hepatocellular carcinoma (HCC) patients who had undergone liver transplantation (LT). Methods: The expression of plasma microRNA panel was assayed in 193 HCC patients (training cohort, n =151; validation cohort, n = 42). Sensitivity and specificity for detecting post-transplant HCC recurrence, and the relationship of microRNA panel expression with clinical characteristics were analyzed accordingly. The prognostic value of microRNA panel was compared with that of AFP (alpha-fetoprotein) and DCP (Des-gamma-carboxyprothrombin). Cox regression analyses were used to evaluate independent prognostic factors. Results: In the training cohort, the rate of positive plasma microRNA panel status at 7-14 days after LT (late phase; 44.2%) decreased than that before (76.2%, P < 0.001) and 1-6 days after LT (early phase; 78.5%, P < 0.001). At late phase, positive microRNA panel status correlated with higher early tumor recurrence rate (one year after LT) than negative status (45.9% vs 10.7%; P < 0.001). Patients with persistent positive microRNA panel status both before and after LT had the highest early tumor recurrence rate in this cohort (54.9%, P < 0.001). The results were consistent in the validation cohort. Cox regression analysis found that positive plasma microRNA panel status at late phase was the only independent risk factor for early recurrence (HR: 4.903, 95% CI = 2.195 - 10.951; P < 0.001). Dynamic monitoring demonstrated plasma microRNA panel status changed from negative to positive earlier than AFP and DCP upon recurrence, and the median time between positivity of plasma microRNA and imaging evidence of recurrence was 2.4 (0.5-10.0) months. Conclusions: Plasma microRNA panel could be a noninvasive biomarker for prediction and surveillance of early tumor recurrence in HCC patients who have undergone LT.

Background and Aims The overall survival (OS) of hepatocellular carcinoma (HCC) remains dismal. Bioinformatic analysis of transcriptome data could identify patients with poor OS and may facilitate clinical decision. This study aimed to develop a prognostic gene model for HCC. Methods GSE14520 was retrieved as a training set to identify differential expressed genes (DEGs) between tumor and adjacent liver tissues in HCC patients with different OS. A DEG-based prognostic model was then constructed and the TCGA-LIHC and ICGC-LIRI datasets were used to validate the model. The area under the receiver operating characteristic curve (AUC) and hazard ratio (HR) of the model for OS were calculated. A model-based nomogram was established and verified. Results In the training set, differential expression analysis identified 80 genes dysregulated in oxidation-reduction and metabolism regulation. After univariate Cox and LASSO regression, eight genes (LPCAT1, DHRS1, SORBS2, ALDH5A1, SULT1C2, SPP1, HEY1 and GOLM1) were selected to build the prognostic model. The AUC for 1-, 3- and 5-year OS were 0.779, 0.736, 0.754 in training set and 0.693, 0.689, 0.693 in the TCGA-LIHC validation set, respectively. The AUC for 1- and 3-year OS were 0.767 and 0.705 in the ICGC-LIRI validation set. Multivariate analysis confirmed the model was an independent prognostic factor (training set: HR=4.422, p

Lenvatinib is one of the first-line treatments for unresectable hepatocellular carcinoma (HCC). However, data are lacking on lenvatinib in the postoperative setting.This retrospective analysis enrolled 242 patients with HCC who underwent liver transplantation (LTx). Eligible patients were divided into 2 groups according to their use of adjuvant lenvatinib following LTx (lenvatinib, n=42; control, n=200). The primary outcome measures were overall survival (OS), time to recurrence (TTR), and safety. Kaplan-Meier analysis was applied to calculate the OS, while a competing risk model was used to estimate the cumulative incidence of recurrence.The lenvatinib group showed more advanced tumors and a higher proportion of HCC beyond the Milan criteria (P0.001) than the control group. There were no significant differences in both the OS and TTR between the 2 groups. After focusing on the patients with HCC beyond the Milan criteria, baseline characteristics were similar in the lenvatinib group (n=38) and the control group (n=102). Competing risk analysis showed lenvatinib significantly prolonged TTR after LTx versus the control group [sub-hazard ratio (sHR), 0.40; 95% confidence interval (CI): 0.17 to 0.93; P=0.031]. In the multivariate competing risk model, adjuvant lenvatinib was an independent protective factor for tumor recurrence after LTx in patients with HCC beyond the Milan criteria (sHR, 0.33; 95% CI: 0.13 to 0.83; P=0.018). The rate of early recurrence within t2 years after LTx was also significantly decreased in the lenvatinib group (15.8%Postoperative lenvatinib administration may provide clinical benefits and is well tolerated in patients with HCC beyond the Milan criteria who undergo LTx.

e16149 Background: Emerging data suggest that circulating tumor DNA (ctDNA) could detect minimal residual disease (MRD) and reflect tumor recurrence after radical resection in hepatocellular carcinoma (HCC). However, most reported ctDNA measurements are based on hotspot mutations and their predictive value in liver transplantation (LT) are still undetermined. We conducted a pilot study investigate ctDNA fingerprint as the detection marker of MRD in HCC patients undergoing LT. Methods: We enrolled 74 patients in HCC and monitored their ctDNA changes along the course of treatment at both pre- and post-operation by serial sampling of peripheral blood. All of the patents were treated by LT, and their ctDNA variations were used to assess the recurrence. We analyzed the correlation between ctDNA levels and recurrence-free survival (RFS) of the patients. Results: We monitored the ctDNA value of each patient before and after LT and found that the ctDNA-positive group was associated with higher recurrence rate (31.7% vs 11.5%), and has a shorter RFS than that of the ctDNA-negative group at baseline (preopreation) (HR, 3.25; CI 95% 1.18-8.97; p = 0.019). The conclusion also stands in patients at first timepoint follow-up after LT (postoperation) (recurrence rate, 46.2% vs 21.3%; HR, 4.26; CI 95% 1.62-11.2; p = 0.010). Moreover, changes of ctDNA were associated with RFS during the course after LT, both the ctDNA-decreased group and ctDNA-negative group have favorable clinical benefit than ctDNA-increased group. Conclusions: This study confirming the association between baseline levels of ctDNA and RFS in HCC undergoing LT. More importantly, it suggests the change of ctDNA level in plasma is a promising biomarker of MRD detection and patient prognosis in early HCC.

4103 Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, especially in Asian counties. Patients can be treated more effectively if detected earlier, however the current screening strategies with alpha-fetoprotein (AFP) or ultrasound it is largely suboptimal. We aimed to develop non-invasive and cost-effective assay to improve HCC early detection. Methods: HCC-specific DNA methylation markers were screened from tissue and plasma samples through a modified reduce representation bisulfite sequencing assaay,and optimized by a targeted methylation sequencing assay. The most informative markers were then integrated in a multi-locus qPCR assay, HepaQ. Results: Profiling DNA methylation pattern on 61 tissue samples (31 HCC tumor and 30 normal tissues) and 663 plasma samples (276 HCC and 393 control plasma samples) achieved an AUC of 0.99, which corresponds to 91% sensitivity at 94% specificity. The best-performance markers were further screened and analytically verified in additional tissues and plasmas after several rounds of marker selection. A multi-locus qPCR assay, designated as HepaQ, was then developed to incorporate the most effective markers. A cohort of 559 plasma samples including 293 HCC (84% of them at stage 0/A), 60 liver cirrhosis (LC), 36 chronic hepatitis B (CHB) and 170 healthy controls (CTRL), were used to train a classifier for HCC early detection. HepaQ classifier enables to detect 85.3% of HCC under a specificity of 88.3%, 91.7% and 92.4% in LC, CHB and CTRL, respectively. Finally, HepaQ classifier was validated in 374 plasma samples independently collected from multiple clinical centers to confirm its performance of 87.2% sensitivity in HCC and 86.8%,90.5% and 93.4% specificities in LC, CHB and CTRL respectively. Conclusions: We have developed and demonstrated a blood-based ctDNA methylation assay, HepaQ, that can detect early-stage HCC at high sensitivity and specificity. We proposed that HepaQ assay, a cost-effective qPCR assay, has the great potential to benefit the population at-risk for HCC early detection and screening.

Background: Lenvatinib is currently available as the first-line treatment for advanced unresectable hepatocellular carcinoma. The safety and efficacy of lenvatinib in preventing early recurrence after liver transplantation (LTx) beyond Milan criteria is still unclear. Methods: During August 2018 to September 2019, 181 patients who underwent LTx beyond Milan criteria at Zhongshan Hospital were retrospective analyzed. Among them, 30 patients were administered lenvatinib after LTx. Propensity score matching (PSM) strategy at 1:2 ratio was adopted to offset differences between two groups. Results: Before PSM, lenvatinib group (n = 30) tended to have more advanced tumors than control group (n = 151). In survival analysis, lenvatinib group showed comparable overall survival (OS) (P = 0.078) and time to recurrence (TTR) (P = 0.120) with control group. After PSM, the clinical baseline in lenvatinib group (n = 30) was similar with the control group (n = 60). We found that post-LTx lenvatinib administration could significantly reduce postoperative tumor recurrence and prolong median TTR (not reached vs. 14.60 months, P=0.019) after LTx, compared with untreated PSM controls. The rate of early recurrences (≤1 year) was also significantly deceased in the lenvatinib group (20.0% vs. 41.7%, p=0.041). We found that the patients with lenvatinib treatment had a propensity of improved OS compared with the matched control group (24-month OS, 92.5% vs 74.3%; P = 0.069). Multivariate regression analysis indicated that post-LTx lenvatinib was an independent protective factor for tumor recurrence after operation (HR = 0.388; 95%CI, 0.186-0.809; P = 0.012).We found that post-LTx lenvatinib administration could reduce tumor recurrence in the patients with tumor size>5cm (P=0.019), multiple tumor (P=0.016), tumor differentiation III-IV (P=0.033), without PVTT (P=0.009), and post-LTx AFP >20ng/ml (one month after LTx)(P=0.010). The treatment-related adverse events occurred in most patients (28/30, 93.3%) received post-LTx lenvatinib treatment, and grade 3 treatment-related adverse events occurred in nine (30.0%) patients. Apart from two (6.7%) patients withdrew lenvatinib due to unbearable adverse events and three (10.0%) patients get relieved after dose reduction, the other patients could tolerate adverse events after dealing with symptoms. Conclusion: Post-LTx lenvatinib could serve as a safety and effective therapy to reduce tumor recurrence after LTx in HCC patients beyond Milan criteria. Citation Format: Xin-Rong Yang, De-Zhen Guo, Jian Zhou, Jia Fan. The safety and efficacy of lenvatinib in preventing early recurrence after liver transplantation for hepatocellular carcinoma beyond Milan criteria: A single-center, retrospective, propensity-matched study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1456.

e16182 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancy with dismal outcomes. Recently, lenvatinib have been approved as the first-line therapy for unresectable HCC. However, the efficacy and safety of lenvatinib with the combination of other therapy such as transarterial chemoembolization (TACE) and immune checkpoint inhibitor (ICI) therapy was still unclear. Methods: A multicenter retrospective study was conducted and 158 HCC patients treated with lenvatinib from four medical centers were enrolled between November 2018 and December 2020. According to the treatment combined with lenvatinib, all patients were classified into four groups, including lenvatinib monotherapy (LEN) group, combined ICI (c-ICI) group, combined TACE (c-TACE) group and combined ICI and TACE (c-ICI-TACE) group. Objective response rate (ORR) and disease control rate (DCR) were assessed. Overall survival (OS) and time to progression (TTP) were calculated and compared among different groups. Results: All patients (n = 158) were classified into LEN group (n = 40), c-ICI group (n = 42), c-TACE group (n = 39) and c-TACE-ICI group (n = 37). In all patients, the ORR and DCR was 29.1% and 74.1%. The median OS and TTP were 21.8 and 6.2 months, respectively. Four groups showed significant differences in ORR and DCR rates. Specifically, c-ICI-TACE group have significantly higher ORR and DCR rate compared with LEN group (ORR: 12% vs. 38%, P = 0.002; DCR: 60% vs. 89%, P = 0.004). Kaplan-Meier analysis identified that LEN group, c-ICI group, c-TACE group and c-TACE-ICI group showed significantly different TTP (median TTP: 5.0 vs. 6.6 vs. 4.9 vs. 9.5 months; P = 0.021), but similar OS (median OS: 21.8 vs. 19.6 vs. 17.5 months vs. unreached; P = 0.180). Further investigation revealed lenvatinib combined with ICI could prolong TTP compare with lenvatinib without ICI (median TTP: 8.4 vs. 5.0 months; P = 0.019), but it had no significant impact on OS (median OS: unreached vs. 20.1 months; P = 0.300). c-ICI-TACE group showed both better TTP and improved OS compared with other three groups (median TTP: 9.5 vs. 5.2 months; P = 0.004; median OS: unreached vs. 20.1 months; P = 0.034). Univariate and multivariate analysis confirmed that c-ICI-TACE was an independent protective factor for OS (hazard ratio: 0.226; 95% confidence interval: 0.10-0.50; P < 0.001) and TTP (hazard ratio: 0.55; 95% confidence interval: 0.32-0.95; P = 0.032). Most patients (152/158, 96.2%) showed adverse events (AEs) during lenvatinib treatment and the grade 3 AE occurred in 45 patients (28.5%). No significant difference of AE (P = 0.569) and grade 3 AE (P = 0.572) was found among four groups. Conclusions: Lenvatinib was an effective treatment for patients with HCC. Lenvatinib combined ICI could prolong the TTP, while lenvatinib combined ICI and TACE could improve both TTP and OS. Combined therapy wouldn’t escalate the AE and grade 3 AE rates.