Development of pre and post-operative models to predict early recurrence of hepatocellular carcinoma after surgical resection

It is well-documented that early recurrence of hepatocellular carcinoma following liver transplantation can markedly impact patient survival. Accurately identifying patients at risk for early recurrence, followed by timely interventions, could greatly improve the long-term efficacy of liver transplantation. The Milan criteria, the clinical gold standard for selecting patients with a low risk of post-transplant recurrence, fails to exclude high-risk patients with biologically aggressive hepatocellular carcinoma. Accordingly, there is an urgent need to develop and validate an improved model for predicting hepatocellular carcinoma post-liver transplantation. Herein, we established a new model to stratify the risk of early hepatocellular carcinoma recurrence following liver transplantation and facilitate decision-making regarding adjuvant therapy. Our newly established nomogram could predict early recurrence post-liver transplantation more effectively than the Milan criteria. Importantly, we found that adjuvant therapy could significantly benefit high-risk recipients but did not significantly affect low-risk recipients. Based on the new stratification criteria, adjuvant therapy should be actively considered for high-risk patients post-liver transplantation, whereas postoperative follow-up and observation are recommended for low-risk patients. Early recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) can adversely affect long-term patient survival. The Milan criteria (MC) have limited capacity to predict early HCC recurrence, and no consensus regarding prophylactic adjuvant therapy (AT) after LT has been established. Herein, we developed an accurate model for predicting early HCC recurrence following LT to guide decision-making on AT. Overall, 364 patients with HCC from three transplantation centers in China were included and followed up for one-year post-LT. Baseline data were used to construct a nomogram, comparing performance with the MC. The efficacy of AT was compared between patients stratified into low- and high-risk subgroups based on nomogram scores.The nomogram included tumor burden score, alpha-fetoprotein level, platelet-to-lymphocyte ratio, pathological differentiation, and microvascular invasion as independent predictive factors. The concordance index and the area under the curve of the nomogram were 0·768 (95% confidence interval, 0·753-0·781) and 0·809, respectively, exceeding those of the MC. The results of the calibration curve and decision curve analysis were also satisfactory. Considering the high-risk subgroups, the AT group considerably outperformed the No-AT group in terms of 1-year recurrence-free survival (45·0 vs. 23·0%, P < 0·001). However, the low-risk AT and No-AT groups did not significantly differ (78·5 vs. 83·9%). In patients with HCC, the new nomogram predicted early recurrence post-LT more effectively than the MC. Based on the new stratification criteria, high-risk patients may benefit from AT, whereas AT is not recommended for low-risk patients.

Presurgical identification of patients at high risk for early recurrence of hepatocellular carcinoma (HCC) after resection could warrant additional therapies. F-fluorodeoxyglucose (FDG) uptake by the tumour on preoperative PET can predict HCC recurrence after resection as effectively as poor differentiation or presence of microvascular invasion (MVI) on postsurgical histology. A better sensitivity for the detection of HCC nodules has been reported with F-fluorocholine (FCH), a PET tracer of lipid metabolism. This pilot study aimed to compare preoperative FDG and FCH PET/CT for predicting early recurrence of unifocal HCC, occurring within 6 months after surgical resection. FDG and FCH tumour uptakes were assessed on preoperative PET/CT by two masked readers. On FCH PET/CT, a photopenic lesion and a hot focus were considered as indicative of malignancy. During postoperative follow-up, recurrence was searched for by regularly performing CT and MRI. In 11 consecutive HCC patients, the detection rate was greater with FCH (80%) than with FDG (27%). After resection, the overall recurrence rate was 55%. Early recurrence occurred in four patients, who were the only ones with an FDG-positive and FCH-photopenic tumour, with a significant reduction in disease-free survival. On postsurgical histology, those four patients also presented with MVI and satellite nodules. Histological differentiation and capsule disruption appeared less accurate than PET/CT or MVI in predicting early recurrence. In unifocal HCC, the FCH photopenic pattern was associated with MVI and predicted early HCC recurrence after surgical resection as accurately as did an FDG uptake. Larger studies with FCH are warranted.

Background: We previously demonstrated that intrinsic subtypes were associated with prognosis for early recurrence risk in patients (pts) with early-stage HER2-positive (HER2+) BC treated with trastuzumab (H) in the N9831 trial. Here, we evaluated the prognostic value of Intrinsic subtypes and 21-gene assay and the risk of early and late recurrence in the N9831 trial. Methods: NanoString custom code set, which included PAM50 and housekeeping genes, was used to quantify mRNA and generated intrinsic subtypes and risk of recurrence (ROR) score from the N9831 trial in Arms A and C: Arm A chemotherapy alone and arm C concurrent H. Quantitative RT-PCR of 21 genes, calculation of the axis, including estrogen axis (ER, PGR, BCL2, SCUBE2), HER2 axis (GRB7, HER2), proliferation axis (Ki67, STK15, Survivin, CCNB1, MYBL2), invasion axis (MMP11, CTSL2), and recurrence score (RS) risk group assignment (RS group 1 and 2: RS &amp;lt; 31 and RS group 3: RS ≥ 31) were performed using Oncotype DX assay. Cox regression models for RFS were used for analysis. Early recurrence was defined as a recurrence that occurred at ≤ 5 years, and late recurrence was defined as recurrence at &amp;gt; 5 years. Results: A total of 783 patients (Arm A 409 and Arm C 374) were included in this analysis. Using multivariate Cox regression analysis to evaluate the risk of early recurrence in patients who received chemotherapy alone in arm A, both invasion genes (MMP11 HR 1.23, 95%CI 1.05-1.44, p 0.01 and CTSL2 HR 1.36, 95%CI 1.1-1.69, p 0.005) and invasion axis (HR 1.64, 95%CI 1.26-2.13, p &amp;lt; 0.001) were associated with a higher rate of early recurrence. CD68 was associated with improved outcomes (HR 0.56, 95%CI 0.38-0.83, p 0.004). For the risk of early recurrence in patients treated with trastuzumab in arm C, ER (HR 0.85, 95%CI 0.74-0.97, p 0.02), PR (HR 0.78, 95%CI 0.64-0.94, p 0.008), and estrogen axis (HR 0.7, 95%CI 0.57-0.87, p 0.001) were associated with improved outcomes. Invasion axis (HR 1.61, 95%CI 1.08-2.41, p 0.02), Oncotype Dx risk group (3 vs. 1 and 2, HR 8.89, 95%CI 1.27-1124, p 0.02), and basal subtype (HR 2.77, 95%CI 1.1-5.95, p 0.03) were also significantly associated with worse outcomes. For risk of late recurrence, in arm A, ER (HR 1.22, 95%CI 1.04-1.44, p 0.02), PR (1.26, 95%CI 1.05-1.5, p 0.01), and estrogen axis (1.39, 95%CI 1.09-1.77, p 0.008) were associated with worse outcomes. Oncotype Dx risk group (3 vs. 1 and 2, HR 0.4, 95%CI 0.16-0.98, p 0.05) was associated with improved outcomes. However, neither individual gene, axis, nor intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Conclusions: For risks of early recurrence, the invasion genes/axis were associated with increased risks of recurrence in patients with early-stage HER2+ BC regardless of trastuzumab treatment. Among patients treated with trastuzumab, ER genes/axis, Oncotype Dx risk group, and intrinsic subtype were prognostic for risks of recurrence in the first five years. For risks of late recurrence, ER genes/axis and Oncotype Dx risk group were prognostic but only in patients treated with chemotherapy alone. The ER genes/axis were associated with less recurrence in the first five years but worse after five years, reflecting a higher risk of late recurrence in ER/PR+ HER2+ BC patients treated with chemotherapy alone. However, none of the individual gene, axis, or intrinsic subtypes were associated with the risk of late recurrence in patients treated with trastuzumab. Therefore, future studies are needed to identify biomarkers for the risk of late recurrence in HER2+ BC patients treated with adjuvant trastuzumab. Support: BCRF-19-161; U10CA180821, U10CA180882, Genentech. https://acknowledgments.alliancefound.org; Clinicaltrials.gov Identifier: NCT00005970 Citation Format: Saranya Chumsri, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Keith L. Knutson, Antonio C. Wolff, Edith A. Perez, E. A. Thompson. Effects of Intrinsic Subtypes and 21-gene Assay on the Early and Late Recurrence Risks in Patients with Early Stage HER2+ Breast Cancer: An Analysis of the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-05.

Surgical stress by hepatic ischaemia-reperfusion (I/R) is supposed to promote intra- and extrahepatic tumour recurrence. Treatment with prostaglandin E1 (PGE1) has been shown to attenuate hepatic I/R injury in liver transplant patients, but the potential anti-cancer effects have not been analysed. To evaluate the impact of PGE1 therapy on risk of hepatocellular carcinoma (HCC) recurrence in liver transplant patients. A retrospective review of 106 liver transplant patients with HCC was conducted. Fifty-nine patients underwent early post-liver transplantation (LT) treatment with the stable PGE1 analogue alprostadil. Administration of alprostadil was correlated with outcome in uni- and multivariate analysis. Subgroup analysis focused on patients with HCC beyond the Milan criteria (Milan Out) on radiographic imaging. Three- and 5-year recurrence-free survival rates were 87.9% and 85.7% in the PGE1-group, but only 65.3% and 63.1% in the non-PGE1-population (P= 0.003). Multivariate Cox regression analysis identified absence of PGE1-treatment (HR=11.42), along with presence of poor tumour grading (HR= 2.69) and microvascular tumour invasion (HR=35.8) to be independently associated with early (within 12months) HCC recurrence. In Milan Out-patients, only therapy with PGE1 (HR=5.09) and well/moderate tumour differentiation (HR=6.51) were independent promoters of recurrence-free survival. Treating hepatic ischaemia-reperfusion injury with alprostadil reduces the risk of early HCC recurrence following LT. In particular patients with HCC exceeding the Milan criteria seem to benefit from PGE1-treatment. The molecular mechanisms of the anti-tumour effects need to be further assessed.

To assess the predictive value of preoperative gadoxetic acid (GA)-enhanced magnetic resonance imaging (MRI) features and postoperative histopathological grading for early recurrence of hepatocellular carcinoma (HCC) without microvascular invasion (MVI) after curative hepatectomy. A total of 85 MVI-negative HCC cases were retrospectively analyzed. Cox analyses were used to identify the independent predictors of early recurrence (within a 24 months span). The clinical prediction Model-1 or Model-2 was established without or with postoperative pathological factor, respectively. Nomogram models were constructed and receiver operating characteristic (ROC) curve analysis was used to assess the models' predictive ability. Internal validation of the prediction models for early HCC recurrence was performed using a bootstrap re-sampling approach. In the multivariate cox regression analysis, Edmondson-Steiner grade, peritumoral hypointensity on hepatobiliary phase (HBP), and relative intensity ratio (RIR) in HBP were identified as independent variables associated with early recurrence. The C-index of the nomogram models and internal validation were both between 0.7 and 0.8, showing good model fitting and calibration effects. The area under the ROC curve (AUC) was 0.781 for Model-1 based on the two preoperative MRI factors. When a third factor, the Edmondson-Steiner grade, was included (Model-2), the AUC increased to 0.834, and the sensitivity increased from 71.4 to 96.4%. Edmondson-Steiner grade, peritumoral hypointensity on HBP, and RIR on HBP can help predict early recurrence of MVI-negative HCC. In comparison with Model-1 (only imaging features), Model-2 (imaging features + histopathological grades) increases the sensitivity in predicting early recurrence of HCC without MVI. Preoperative GA-enhanced MRI signs are of great value in predicting early postoperative recurrence of HCC without MVI, and a combined pathological model was established to evaluate the feasibility and effectiveness of this technique.

Introduction The tumor immune response plays a vital role in cancer recurrence in patients with malignancies. We aim to clarify the risk factors for early recurrence and investigate the efficacy of blood-based biomarkers to predict the risk of early recurrence in early-stage hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI) after hepatectomy. Materials and methods A total of 101 cases of HCC with MVI who underwent liver resection were enrolled. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors of early recurrence. We calculated the area under the receiver operating characteristic curve to evaluate the performance of the four biomarkers identified as risk factors for early recurrence. Results Multiple logistic regression analysis indicated that complement (C)4, cluster of differentiation (CD)4+, immunoglobulin A (IgA), and hepatitis B virus (HBV) DNA of greater than 500 IU/mL were correlated with early recurrence of HCC. The area under the curve was greater for the combination model than for the HBV DNA, CD4+, IgA, or C4 models alone. Conclusion Preoperative serum CD4+, C4, IgA, and HBV DNA levels were linked with early recurrence of early-stage HCC with MVI and the combination model was of considerable predictive value for the prognosis of HCC with MVI.

This study aimed to evaluate the value of simultaneous multislice diffusion kurtosis imaging (SMS-DKI) for predicting early recurrence (within 2 years) in hepatocellular carcinoma (HCC) and to develop a predictive model. This prospective study included 67 HCC patients who underwent SMS-DKI on a 3-T MRI between June 2021 and January 2023. Diffusion parameters, including the apparent diffusion coefficient (ADC), SMS-mean kurtosis (SMS-MK), and SMS-mean diffusivity (SMS-MD), along with radiological features, were analyzed. Logistic regression models were used to predict early recurrence, internally validated using 10-fold cross-validation, and assessed using AUC, calibration curves, and decision curve analysis (DCA). Among 67 patients (58 males; mean age, 53.5 ± 9.9 years), 30 (44.8%) experienced early recurrence. The early recurrence had significantly lower ADC (1.12 vs 1.22 × 10-3 mm2/s) and SMS-MD (1.45 vs 1.70 × 10-3 mm2/s), and higher SMS-MK (0.91 vs 0.75). SMS-MK showed the highest AUC (0.90, 95% CI: 0.80-0.96). Multivariate analysis identified SMS-MK (OR = 3.43 [1.31-8.89]), tumor size (OR = 4.22 [1.58-7.76]), non-smooth tumor margin (OR = 2.68 [1.58-7.96]), and complete capsule (OR = 0.22 [0.02-0.79]) as independent predictors of early recurrence. Based on these four parameters, the final model achieved an AUC of 0.94 (95% CI: 0.88-1.00). Calibration curves and DCA confirmed clinical utility. SMS-DKI enhances early recurrence prediction in HCC. The predictive model, incorporating SMS-MK, tumor size, and key radiological features, demonstrated good prognostic value. Question Can SMS-DKI predict HCC early recurrence within 2 years post-surgery? Findings Higher SMS-MK, larger tumor size, non-smooth margins, and incomplete capsule predict HCC early recurrence (model AUC = 0.94). Clinical relevance Integrating preoperative SMS-DKI biomarkers (SMS-MK) with tumor size and capsule status stratifies early HCC recurrence risk, guiding surgical planning and postoperative management.

Recurrence of hepatocellular carcinoma (HCC) after curative resection remains a major cause of treatment failure and tumor-related death. Patterns of HCC recurrence can be categorized into early recurrence and late recurrence which have different underlying mechanisms. In this study, we investigated if simple inflammation-based clinical markers can distinguish patterns of recurrence after curative resection of HCC. A retrospective analysis of 223 patients who underwent curative hepatectomy for HCC was performed. Preoperative inflammation-based factors including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, gamma-glutamyl transferase/alanine aminotransferase ratio, aspartate aminotransferase/platelet ratio index (APRI) and prognostic nutritional index together with other clinicopathologic parameters were evaluated by univariate analysis and multivariate analysis to identify independent prognostic factors. By combining risk factors, predictive models were established to distinguish populations at high risk of early or late recurrence. Age ≤50 years, resection margin ≤1 cm, TNM stage III-IV, NLR>2.75, APRI>0.23 and positive alpha-fetoprotein were independent adverse prognostic factors for early recurrence. Patients with three or more risk factors were at significant higher risk of early recurrence. APRI>0.23 and positive hepatitis B e antigen (HBeAg) were independent risk factors of late recurrence, the coexistence of high APRI and positive HBeAg increased the risk of late recurrence. Preoperative inflammation-based prognostic factors predict early and late recurrence of HCC after curative resection. Different prognostic factor combinations distinguish high-risk populations of early or late HCC recurrence.

This study aims to evaluate the relationship between abdominal fat, as quantified by magnetic resonance imaging (MRI), and early postoperative recurrence (≤ 2 years) in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), with an emphasis on identifying potential mediators. We enrolled HCC patients with HBV infection who underwent preoperative MRI and hepatectomy between January 2015 and October 2021. The visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured at the third lumbar vertebra plane on T1-weighted images and compared between patients with and without early recurrence. Multivariate logistic regression models identified risk factors for early recurrence, which were then visualized in a nomogram. Mediation analysis assessed whether mediators explained the relationship between abdominal fat and early recurrence. The study included 146 HBV-related HCC patients from institution A (internal cohort) and 76 from institution B (external validation cohort). Results showed that patients with early recurrence had smaller VAT areas (Pinternal cohort=0.001, Pexternal validation cohort<0.001) compared to those without early recurrence. The nomogram identified VAT areas (OR 0.92; 95% CI 0.86, 1.00) and microvascular invasion (MVI) (OR 2.29; 95% CI 1.08, 4.85) as significant risk factors in the internal cohort, and VAT areas (OR 0.65; 95% CI 0.48, 0.88) and MVI (OR 13.47; 95% CI 1.33, 136.27) in the external cohort. Mediation analysis revealed that MVI and tumor size partially mediated the relationship between VAT and early recurrence. Reduced VAT areas influence early recurrence in HBV-related HCC, with MVI and tumor size acting as mediators.

Norman Kneteman, Tito Livraghi, David Madoff, Eduardo de Santibanez, and Michael Kew Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada; Department of Interventional Radiology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy; Division of Interventional Radiology, New York-Presbyterian/Weill Cornell Medical Center, New York, NY; General Surgery and Liver Transplant Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; and Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa

Early recurrence of liver cancer is significantly associated with poor prognosis. Further dissection of the cellular heterogeneity in the tumor microenvironment (TME) of patients at high risk of early recurrence after liver cancer surgery is highly necessary. This study integrated clinical data, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq data to reveal and verify a TME characteristic associated with high risk of early recurrence after liver cancer surgery. Clinical analysis of 402 patients identified neutrophil-to-lymphocyte ratio ≥3, alpha-fetoprotein ≥400ng/mL, and microvascular invasion as independent predictors of early recurrence. scRNA-seq of 28 hepatocellular carcinoma (HCC) samples revealed nine neutrophil subtypes, with SPP1⁺ neutrophils (enriched in TNFα/NF-κB, hypoxia, and TGF-β pathways) and exhausted CD8⁺ T cells (expressing PD-1 and CTLA-4) significantly infiltrating the TME of patients with early recurrence. These findings were corroborated in an independent validation cohort comprising scRNA-seq data from 17 HCC tissues and 7 matched peripheral blood samples. Spatial analysis demonstrated their co-localization at tumor margins, forming an immunosuppressive barrier. Ligand-receptor interaction analysis highlighted SPP1-CD44, TGFB1-TGFBR, and TNF-TNFRSF axes as key mediators of neutrophil-T cell crosstalk, inducing T cell dysfunction. Validation in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma cohort comprising 365 patients confirmed that high infiltration of SPP1⁺ neutrophils and exhausted CD8⁺ T cells was significantly correlated with shorter recurrence-free (P <0.0001) and overall survival (P <0.0001). This study shows that the infiltration of SPP1⁺ neutrophils and exhausted CD8⁺ T cells is associated with a high risk of early recurrence in HCC. SPP1⁺ neutrophils may serve as key mediator of immune suppression through spatial interactions with exhausted CD8⁺ T cells, suggesting that they could be potential therapeutic targets to mitigate early recurrence in HCC.

Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study

A simplified prediction model for early intrahepatic recurrence after hepatectomy for patients with unilobar hepatocellular carcinoma without macroscopic vascular invasion: An implication for adjuvant therapy and postoperative surveillance

BACKGROUNDEarly recurrence is an important factor affecting the prognosis of hepatocellular carcinoma (HCC), but its preoperative prediction remains challenging.AIMTo explore the value of a multimodal interpretable fusion model combining computed tomography (CT) habitat imaging (HI), radiomics, and clinical features in predicting early recurrence of HCC and analyze its correlation with pathological indicators.METHODSThe 191 HCC patients were categorized into early recurrence and non-early recurrence groups based on postoperative follow-up outcomes, and randomly divided into training and testing sets in a 7:3 ratio. Based on CT arterial phase and clinical data, the habitat model, radiomics model, clinical model, and fusion model were constructed and compared for their predictive ability in early recurrence of HCC. For the optimal model, SHapley Additive exPlanations (SHAP) analysis was performed to evaluate the contribution of different features in the model, and the correlation between HI and radiomics features with tumor microvascular invasion (MVI), Ki67 expression, GPC-3 expression, and pathological grading was analyzed.RESULTSThe fusion model demonstrated the best performance in predicting early recurrence of HCC, achieving the area under the curve of 0.933 on the validation set. The decision curve analysis curve indicated that the fusion model yielded the highest clinical net benefit. SHAP analysis provided valuable insights into explaining the fusion model's prediction of early HCC recurrence. Correlation analysis revealed significant associations between certain radiomics and Habitat features and pathological indicators such as MVI and Ki-67 expression in HCC.CONCLUSIONAn interpretable fusion model integrating clinical, radiomic, and habitat features can assist clinicians in identifying early postoperative recurrence of HCC, offering significant potential for prognosis prediction and clinical management.

To clarify the relationship between aldo-keto reductase family 1 member B10 (AKR1B10) expression and early hepatocellular carcinoma (HCC) recurrence, this study detected AKR1B10 expression in tumor and adjacent non-tumor tissues from 110 patients with hepatitis B virus (HBV)-related HCC underwent liver resection and analyzed its correlations with clinicopathological characteristics and prognosis of these patients. Detected by quantitative reverse transcription polymerase chain reaction, AKR1B10 mRNA expression showed significantly higher in HCC tissues than in adjacent non-tumor tissues, with a low level in normal liver tissues. Similar results was confirmed at the protein level using immunohistochemistry and Western blotting. High AKR1B10 expression was negatively correlated with serum alpha-fetoprotein level and positively correlated with HBV-DNA level. Patients with high AKR1B10 expression had significantly higher disease-free survival than those with low expression within 2 years after liver resection. Multivariate analysis also confirmed high AKR1B10 expression to be a predictor of low risk of early HCC recurrence. In addition, high AKR1B10 expression was found to be a favorable factor of overall survival. These results suggest that AKR1B10 is involved in HBV-related hepatocarcinogenesis, but its high expression could predict low risk of early tumor recurrence in patients with HBV-related HCC after liver resection.