Included Hepatocellular Carcinoma Patients Research Articles

Stereotactic body radiation therapy combined with atezolizumab and bevacizumab for hepatocellular carcinoma with extrahepatic metastasis: Preliminary result of a single-arm study.

e16205 Background: IMbrave150 study confirmed the clinical benefit of atezolizumab and bevacizumab in patients with advanced hepatocellular carcinoma (HCC). However, patients with extrahepatic metastasis (EHS) had a poorer prognosis. Studies suggested “abscopal effect” of synchronous radiotherapy and immunotherapy may improve antitumor activity. This study aimed to evaluate efficacy and safety of stereotactic body radiation therapy (SBRT) combined with atezolizumab and bevacizumab in HCC patients with EHS. Methods: This single-arm study included HCC patients with EHS from January 2022 to November 2023 in Fudan University Shanghai Cancer Center. Prior tyrosine kinase inhibitor and/or immune checkpoint inhibitor treatment were eligible. After first dose atezolizumab and bevacizumab, SBRT was performed with a total dose of 25-50 Gy. The primary endpoint was objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), and duration of response (DOR). Results: Thirty-nine patients were included. Fourteen patients were treated as first-line therapy and 25 patients were treated as later-line therapy. The mean age was 56.69±11.21 years and 89.7% were male. Of these patients, 66.7% had hepatitis viral infection and 25.6% had vascular invasion. 53.8% of patients had ≥2 extrahepatic spread lesions. In addition, 33.3% of patients had received prior immunotherapy and 23.1% of patients had received tyrosine kinase inhibitor therapy. The median follow-up was 6.50 (range: 1.43-22.17) months. The ORR and DCR were 43.6% and 92.3%, respectively. The ORR was 57.1% and 36.0% in first-line subgroup and later-line subgroup, respectively. The 12-month OS rates was 54.7%. The median PFS, median TTP and median DOR were 6.73 months, 8.67 months, and 7.17 months, respectively. The incidence of all grade TRAE and grade ≥3 TRAE were 38.5% and 12.8%, respectively. The most common grade ≥3 TRAEs were decreased platelet count (7.7%), decreased white blood cell count (2.6%), pruritus (2.6%) and rectal bleeding (2.6%). No serious adverse events occurred. Conclusions: SBRT combined with systemic atezolizumab and bevacizumab showed encouraging efficacy with manageable safety profile for HCC patients with EHS regardless of prior treatment. Further studies are warranted. Clinical trial information: NCT05396937 . [Table: see text]

Potential impact of malnutrition on patients with hepatocellular carcinoma undergoing liver transplantation: A nationwide analysis.

e16233 Background: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer mortality worldwide. Liver transplantation is the ideal treatment for HCC, and the Milan criteria, which has been the international gold standard, provided the opportunity for HCC patients to undergo liver transplantation with favorable outcomes. On the other hand, malnutrition is a prevalent condition, and carries a substantial burden on health and social-care systems. In this study, we aim to look at the potential impact of malnutrition on in-hospital mortality and other outcomes in HCC patients undergoing liver transplantation. Methods: The United States Nationwide Inpatient Sample (NIS) was used to extract hospitalization data of patients admitted between 2016 to 2018. Using ICD10 revision codes, we identified adults with a diagnosis of HCC, with or without cirrhosis, who underwent liver transplantation with concomitant malnutrition. The control group included HCC patients without malnutrition. The primary outcome was the in-hospital mortality. Secondary outcomes included length of stay (LOS), acute kidney injury (AKI) and hyponatremia. Multivariate logistic regression was used to adjust for relevant variables. Results: An estimated 33,321 patients were admitted with HCC during the study period. 503 of them underwent liver transplantation, and of those, 75 patients had the diagnosis of malnutrition. In this group of patients, the mean age was 60.3 years. 30% were females and 60% were Caucasians. When adjusted to other relevant variables, malnutrition was associated with increased in-hospital mortality (OR 2.42; P-value 0.033). It was also associated with increased chance of developing an AKI (OR 1.95; P-value 0.014). Moreover, it was associated with increased LOS (OR 1.18) and increased chance of liver transplant rejection (OR 1.47), however, these were not statistically significant. Other factors associated with increased in-hospital mortality in HCC patients undergoing liver transplantation are described in the table. Conclusions: Malnutrition is a potentially treatable condition, however, when untreated it may contribute to poor health and economic outcomes. In this study, HCC patients with malnutrition who underwent liver transplantation, have an increased chance of in-hospital mortality. Furthermore, they had an increased odds of developing an AKI which in turn can prolong the hospital length of stay and total charges. We recommend that clinicians pay more attention to identify patients with or at increased risk for malnutrition in order to treat and optimize them prior to liver transplantation, and therefore to prevent such complications. [Table: see text]

Study of the effect of ACYP2 single nucleotide polymorphisms rs843711 and rs843706 in Egyptian patients with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a multifactorial disease with both genetic and environmental factors contributing to its pathogenesis. ACYP2 is a gene that is related to cell differentiation, apoptosis and prevention of malignant tumors. The ACYP2 gene also affects telomere length. The aim of this study was to evaluate the association between ACYP2 single nucleotide polymorphisms (SNPs) (rs843711), and (rs843706) and incidence of HCC in Egyptian HCC patients. The study included 30 patients with HCC and 30 normal controls. Detection of ACYP2 gene SNPs rs843711, and rs843706 in all study participants was done using real time polymerase chain reaction (RT-PCR). The results showed that all participants including HCC patients and controls carried the heterozygous CA (100%) of the rs843706 SNP (p> 0.05). As for the rs843711, 3.3% of HCC patients had the homozygous TT genotype, 46.7% had the heterozygous CT genotype and 50% had the wild CC genotype, while in the control group, 60% had the heterozygous CT genotype and 40% had the wild CC genotype with no significant difference between both groups (p>0.05). We concluded that there was no association between SNPs ACYP2 rs843706 and rs843711 and occurrence of HCC.

Abstract 6175: Deep learning-based survival prediction for hepatocellular carcinoma using whole slide images

Abstract There is an increasing need for classifiers to effectively stratify prognosis in patients with hepatocellular carcinoma (HCC). Deriving interpretable prognostic features using deep-learning (DL)-based prognostic models from pathology images remains a challenge. In this study, we developed a computational approach based on DL to predict the overall survival (OS) of HCC patients from formalin-fixed paraffin-embedded histopathology whole slide images. A DL model for classifying good and poor prognosis was developed on a total of 460 patients with 2 independent cohorts from Seoul St. Mary's Hospital. The primary outcome was OS. The training set (SSM1, n = 292) included HCC patients that had undergone surgical resection. The classifier was then independently tested on the second HCC dataset (SSM2, n = 168). The area under the curve (AUC) for the receiver operating characteristic (ROC) curves was 0.850 and 0.781 for SSM1 and SSM2 datasets, respectively. In addition, we have tried to establish DL model for prediction of OS based on clinicopathological features, including Edmondson-Steiner grade, pT stage, vascular invasion, Ki-67 index, and cytokeratin 19 immunohistochemical expression. Random forest model was applied to classify the good and poor prognosis groups and The AUROCs for the random forest was 0.705 for the SSM1 dataset, which are inferior to that of DL prediction. These findings suggest that the DL techniques can be applied to refine the prognostic prediction of HCC patients. Citation Format: Sung Hak Lee, Hyun-Jong Jang. Deep learning-based survival prediction for hepatocellular carcinoma using whole slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6175.

Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model.

Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.

Diagnostic performance of hepatic CT and chemical-shift MRI to discriminate lipid-poor adrenal adenomas from hepatocellular carcinoma metastases.

To evaluate the diagnostic performance of multiphase hepatic CT parameters (non-contrast attenuation, absolute and relative washout ratios [APW and RPW, respectively], and relative enhancement ratio [RER]) and chemical-shift MRI (CS-MRI) for discriminating lipid-poor adrenal adenomas (with non-contrast CT attenuation > 10 HU) from metastases in patients with hepatocellular carcinoma (HCC). This retrospective study included HCC patients with lipid-poor adrenal lesions who underwent multiphase hepatic CT between January 2010 and December 2021. For each adrenal lesion, non-contrast attenuation, APW, RPW, RER, and signal-intensity index (SI-index) were measured. Each parameter was compared between adenomas and metastases. The area under the receiver operating characteristic curves (AUCs) and sensitivities to achieve 100% specificity for adenoma diagnoses were determined. 104 HCC patients (78 men; mean age, 71.8 ± 9.6years) with 63 adenomas and 48 metastases were identified; CS-MRI was performed in 66 patients with 49 adenomas and 21 metastases within one year of CT. Lipid-poor adenomas showed lower non-contrast attenuation (22.9 ± 7.1 vs. 37.9 ± 9.4 HU) and higher APW (40.5% ± 12.8% vs. 23.7% ± 17.4%), RPW (30.0% ± 10.2% vs. 12.4% ± 9.6%), RER (329% ± 152% vs. 111% ± 43.0%), and SI-index (43.3 ± 20.7 vs. 10.8 ± 13.4) than HCC metastases (all p < .001). AUC for non-contrast attenuation, APW, RPW, RER, and SI-index were 0.894, 0.786, 0.904, 0.969, and 0.902, respectively. The sensitivities to achieve 100% specificity were 7.9%, 25.4%, 30.2%, 63.5%, and 24.5%, respectively. Combined RER and APW achieved the highest sensitivity of 73.0%. Multiphase hepatic CT allows for better discrimination between lipid-poor adrenal adenomas and metastases relative to CS-MRI, especially when combined with RER and washout parameters.

Clinical efficacy and safety evaluation of camrelizumab plus lenvatinib in adjuvant therapy after hepatocellular carcinoma surgery.

To assess the efficacy and safety of camrelizumab plus different targeted drugs in adjuvant therapy after hepatocellular carcinoma (HCC) surgery. This retrospective cohort study included HCC patients who, after undergoing failed postoperative adjuvant lenvatinib therapy, received intravenous camrelizumab 200 mg every 3 weeks (C group, n = 97), camrelizumab plus oral apatinib 250 mg daily (C+A group, n = 125), camrelizumab plus oral lenvatinib 12 mg daily (for bodyweight ≥60 kg)/lenvatinib 8 mg daily (for bodyweight <60kg) (C+L group, n = 120), or camrelizumab plus oral sorafenib 400 mg bi-daily (C+S group, n = 114) between October 2020 and October 2021. The outcomes including the objective response rate (ORR) and disease control rate (DCR) were evaluated by RECIST 1.1 and iRECIST. The median progression-free survival (mPFS), median overall survival (mOS), 6-month OS rate, 12-month OS rate, and adverse events were evaluated. As of 31 May 2022 with last follow-up time, the ORR was 17.2% for the C group, 44.6% for the C+A group, 47.9% for the C+L group, and 36.3% for the C+S group. The DCR was 72.0% for the C group, 81.8% for the C+A group, 85.5% for the C+L group, and 77.9% for the C+S group. The mPFS was 11.0 months (10.1-12.8) for the C group, 14.0 months (12.7-16.5) for the C+A group, 18.0 months (16.9-20.1) for the C+L group, and 12.0 months (9.7-14.4) for the C+S group. The mOS was 13.0 months (11.6-15.3) for the C group, 17.0 months (15.8-19.4) for the C+A group, 19.0 months (17.7-20.2) for the C+L group, and 15.0 months (14.1-17.3) for the C+S group. Grade 3 or 4 treatment-related adverse events occurred in 14 patients (14.4%) for the C group, 10 patients (8.0%) for the C+A group, 5 patients (4.2%) for the C+L group, and 11 patients (9.6%) for the C+S group. The most common adverse events were fatigue and transaminitis. Camrelizumab combined with lenvatinib as adjuvant therapy showed promising efficacy and manageable safety in HCC patients. It might be a potential adjuvant therapy or second-line treatment for these patients.

Refinement and validation of a comprehensive clinical diagnostic model (GAMAD) based on gender, age, multitarget circulating tumour DNA methylation signature and commonly used serological biomarkers for early detection of hepatocellular carcinoma: a multicentre, prospective observational study protocol

IntroductionPrompt detection of hepatocellular carcinoma (HCC) in patients with chronic liver diseases is critical for enhancing prognosis. Existing imaging techniques and serum markers fall short of clinical needs. This study...

A high-throughput test enables specific detection of hepatocellular carcinoma

High-throughput tests for early cancer detection can revolutionize public health and reduce cancer morbidity and mortality. Here we show a DNA methylation signature for hepatocellular carcinoma (HCC) detection in liquid biopsies, distinct from normal tissues and blood profiles. We developed a classifier using four CpG sites, validated in TCGA HCC data. A single F12 gene CpG site effectively differentiates HCC samples from other blood samples, normal tissues, and non-HCC tumors in TCGA and GEO data repositories. The markers were validated in a separate plasma sample dataset from HCC patients and controls. We designed a high-throughput assay using next-generation sequencing and multiplexing techniques, analyzing plasma samples from 554 clinical study participants, including HCC patients, non-HCC cancers, chronic hepatitis B, and healthy controls. HCC detection sensitivity was 84.5% at 95% specificity and 0.94 AUC. Implementing this assay for high-risk individuals could significantly decrease HCC morbidity and mortality.

Liver Transplantation Outcomes of HBV-, HCV-, and Alcohol-induced Hepatocellular Carcinoma in the United States: Analysis of National Inpatient Samples.

Liver transplantation is a current treatment option for hepatocellular carcinoma (HCC). The United States National Inpatient Sample database was utilized to identify risk factors that influence the outcome of liver transplantation, including locoregional recurrence, distant metastasis, and in-hospital mortality, in HCC patients with concurrent hepatitis B infection, hepatitis C infection, or alcoholic cirrhosis. This retrospective cohort study included HCC patients (n=2391) from the National Inpatient Sample database who underwent liver transplantation and were diagnosed with hepatitis B or C virus infection, co-infection with hepatitis B and C, or alcoholic cirrhosis of the liver between 2005 and 2014. Associations between HCC etiology and post-transplant outcomes were examined with multivariate analysis models. Liver cirrhosis was due to alcohol in 10.5% of patients, hepatitis B in 6.6%, hepatitis C in 10.8%, and combined hepatitis B and C infection in 24.3%. Distant metastasis was found in 16.7% of patients infected with hepatitis B and 9% of hepatitis C patients. Local recurrence of HCC was significantly more likely to occur in patients with hepatitis B than in those with alcohol-induced disease. After liver transplantation, patients with hepatitis B infection have a higher risk of local recurrence and distant metastasis. Postoperative care and patient tracking are essential for liver transplant patients with hepatitis B infection.

Above-Standard Survival of Hepatocellular Carcinoma as the Final Outcome of Comprehensive Hepatology Care Programs in a Remote HCV-Endemic Area

Early detection and prompt linkage to care are critical for hepatocellular carcinoma (HCC) care. Chang Gung Memorial Hospital (CGMH) Yunlin branch, a local hospital in a rural area, undertakes health checkup programs in addition to its routine clinical service. Patients with HCC are referred to CGMH Chiayi branch, a tertiary referral hospital, for treatment. This study enrolled 77 consecutive patients with newly diagnosed HCCs between 2017 and 2022, with a mean age of 65.7 ± 11.1 years. The screening group included HCC patients detected through health checkups, and those detected by routine clinical service served as the control group. Compared to the 24 patients in the control group, the 53 patients in the screening group had more cases with early stage cancer (Barcelona Clinic Liver Cancer or BCLC stage 0 + A 86.8% vs. 62.5%, p = 0.028), better liver reserve (albumin-bilirubin or ALBI grade I 77.3% vs. 50%, p = 0.031) and more prolonged survival (p = 0.036). The median survival rates of the 77 patients were >5 years, 3.3 years, and 0.5 years in the BCLC stages 0 + A, B, and C, respectively, which were above the expectations of the BCLC guideline 2022 for stages 0, A, and B. This study provides a model of HCC screening and referral to high-quality care in remote viral-hepatitis-endemic areas.

Association between early response of alpha-fetoprotein and treatment efficacy of systemic therapy for advanced hepatocellular carcinoma: A multicenter cohort study from China.

Alpha-fetoprotein (AFP) is a well-identified biomarker in hepatocellular carcinoma (HCC). However, only limited AFP-related studies have evaluated its early response to systemic therapy. This study was performed with the aim of assessing the value of early AFP response in predicting overall survival (OS) and progression-free survival (PFS) in advanced HCC patients receiving systemic therapy. This cohort study included HCC patients with baseline AFP ≥ 200 ng/ml and no prior treatment history. A > 20% decline in the serum AFP level from baseline to the first follow-up (i.e., 4~6 weeks after treatment) was defined as an early AFP response. Patient demographic information, clinical characteristics, radiological response, and survival rates were compared between patients with early AFP response and patients without early AFP response. We further utilized multivariate Cox regression to seek characteristics related to OS and PFS. Among 154 patients, 69 patients (44.8%) showed an early AFP response. The disease control rate (76.8 vs. 54.1%; P = 0.003) and objective response rate (38.4 vs. 11.8%; P = 0.001) were significantly higher in patients with an early AFP response. By performing multivariate analysis, early AFP response remained a prognostic factor for longer PFS (HR 0.546; 95% CI 0.371-0.804; P = 0.002) and longer OS (HR 0.529; 95% CI 0.335-0.834; P = 0.006). An early AFP response is correlated with longer overall survival and progression-free survival for advanced HCC patients receiving systemic therapy. Moreover, an early AFP response is an independent prognostic factor for longer OS and PFS.

Potential Role of Tumor Cell Metabolic Subtype in the Clinical Course of Hepatocellular Carcinoma

INTRODUCTION: Tumor metabolism is critical in tumorigenesis and development. This study aims to evaluate the potential role and the prognostic value of tumor cell metabolism in the progression of hepatocellular carcinoma (HCC). METHODS: Systematic analyses were performed using genome, transcriptome, and clinical characteristics to evaluate the metabolic system in 673 HCC patients. We analyzed the impact of metabolism on the clinical course of HCC. Univariate and multivariate Cox proportional-hazards regression methods were used to screen overall survival (OS). RESULTS: Included HCC patients were categorized into cholesterogenic (25.3%), glycolytic (14.6%), mixed (10.4%), and quiescent (49.8%) types based on the glycolysis and cholesterol biosynthesis gene expression. The distribution of α-fetoprotein (AFP; <300 μg/L or ≥300 μg/L) but not TMN stages among the 4 metabolic subtypes showed significant differences (p < 0.05). The quiescent subtype was associated with a low AFP expression level (p < 0.05) and the glycolytic subtype was associated with a higher AFP level (p < 0.01). The mixed type and glycolytic type had a shorter median OS (p < 0.0001). And the metabolic subtype emerged as an independent predictor of HCC patients’ survival in multivariate analyses. CONCLUSION: These results suggest that the metabolic subtypes were consistent with AFP expression and may play a prognostic role in HCC patients. And the glycolytic metabolism-related genes may induce tumor progression in HCC.

Impact of alcohol consumption on treatment outcome of hepatocellular carcinoma patients with viral hepatitis who underwent transarterial chemoembolization.

BACKGROUNDAlcohol consumption increases the risk of hepatocellular carcinoma (HCC) in patients with pre-existing liver disease, including viral hepatitis. However, studies on the impact of alcohol consumption on the outcomes of HCC are limited. We hypothesized that alcohol had an additional effect with chronic viral hepatitis infection on treatment outcomes after transarterial chemoembolization (TACE) in patients with intermediate-stage HCC (Barcelona Clinical Liver Cancer [BCLC] -B).AIMTo evaluate the additional effect of alcohol on treatment outcomes of TACE among HCC patients with viral hepatitis.METHODSThis study, conducted at Hatyai Hospital in Thailand, included HCC patients over 18 years of age with chronic viral hepatitis. Records of HCC patients with viral hepatitis classified as BCLC-B who underwent TACE as the first treatment modality between 2014 and 2019 were retrospectively reviewed. Patients with chronic viral hepatitis only were categorized under group A, and those with chronic viral hepatitis and concurrent alcohol consumption were categorized under group B. Both groups were compared, and the Cox proportional-hazards model was used to identify the survival-influencing variables.RESULTSOf the 69 patients, 53 were categorized in group A and 16 in group B. There were no statistically significant differences in tumor characteristics between the two patient groups. However, Group A had a statistically significantly higher proportion of complete response (24.5% vs 0%, P = 0.030) and a higher median survival rate (26.2 mo vs 8.4 mo; log-rank P = 0.012) compared to group B. Factors associated with decreased survival in the proportional-hazards model included alcohol consumption (hazards ratio [HR], 2.377; 95% confidence interval [CI], 1.109-5.095; P = 0.026), presence of portal hypertension (HR, 2.578; 95%CI, 1.320–5.037; P = 0.006), largest tumor size > 5 cm (HR, 3.558; 95%CI, 1.824-6.939; P < 0.001), and serum alpha-fetoprotein level > 100 ng/mL (HR, 2.536; 95%CI, 1.377-4.670; P = 0.003).CONCLUSIONIn HCC BCLC B patients with chronic viral hepatitis, alcohol consumption is an independent risk factor for increased mortality and decreases the rate of complete response and survival after TACE.

Deep learning for prediction of hepatocellular carcinoma recurrence after resection or liver transplantation: a discovery and validation study

BackgroundThere is a growing need for new improved classifiers of prognosis in hepatocellular carcinoma (HCC) patients to stratify them effectively.MethodsA deep learning model was developed on a total of 1118 patients from 4 independent cohorts. A nucleus map set (n = 120) was used to train U-net to capture the nuclear architecture. The training set (n = 552) included HCC patients that had been treated by resection. The liver transplantation (LT) set (n = 144) contained patients with HCC that had been treated by LT. The train set and its nuclear architectural information extracted by U-net were used to train the MobileNet V2-based classifier (MobileNetV2_HCC_class). The classifier was then independently tested on the LT set and externally validated on the TCGA set (n = 302). The primary outcome was recurrence free survival (RFS).ResultsThe MobileNetV2_HCC_class was a strong predictor of RFS in both LT set and TCGA set. The classifier provided a hazard ratio of 3.44 (95% CI 2.01–5.87, p < 0.001) for high risk versus low risk in the LT set, and 2.55 (95% CI 1.64–3.99, p < 0.001) when known prognostic factors, remarkable in univariable analyses on the same cohort, were adjusted. The MobileNetV2_HCC_class maintained a relatively higher discriminatory power [time-dependent accuracy and area under curve (AUC)] than other factors after LT or resection in the independent validation set (LT and TCGA set). Net reclassification improvement (NRI) analysis indicated MobileNetV2_HCC_class exhibited better net benefits for the Stage_AJCC beyond other independent factors. A pathological review demonstrated that tumoral areas with the highest recurrence predictability featured the following features: the presence of stroma, a high degree of cytological atypia, nuclear hyperchromasia, and a lack of immune cell infiltration.ConclusionA prognostic classifier for clinical purposes had been proposed based on the use of deep learning on histological slides from HCC patients. This classifier assists in refining the prognostic prediction of HCC patients and identifies patients who have been benefited from more intensive management.

Hepatocellular Carcinoma With Portal Vein Tumor Thrombus Treated With Transarterial Chemoembolization and Sorafenib vs. 125Iodine Implantation.

Background and AimsThis study investigated the feasibility, safety, and efficacy of transarterial chemoembolization (TACE) combined with CT-guided 125iodine seed implantation for treatment of hepatocellular carcinoma (HCC) with first-branch portal vein tumor thrombosis (PVTT).MethodsThis prospective, controlled, multicenter study included HCC patients with Barcelona Clinic Liver Cancer stage C disease and PVTT in the right and/or left portal veins. Patients were treated with either TACE and sorafenib or TACE and CT-guided 125iodine seed implantation and regularly evaluated for clinical response and adverse events, with treatment termination resulting from declining clinical status, loss to follow-up, or death.ResultsThis study demonstrated a significant between-group difference in median overall survival (OS); therefore, it was terminated early. A total of 123 patients were included in this study, with 52 patients in the TACE-sorafenib group and 71 patients in the TACE-125iodine group, without significant differences in baseline characteristics between groups. The median OS was 8.3 months (95% CI: 6.105–10.495) in the TACE-sorafenib group and 13.8 months (95% CI: 9.519–18.081) in the TACE-125iodine group. In a subgroup analysis of type IIa versus type IIb PVTT, the median OS was 17.5 months for type IIa and 7.1 months for IIb in the TACE-125iodine group. The median OS was 9.3 months for IIa and 4.0 months for IIb in the TACE-sorafenib group. Univariate and multivariate analyses confirmed that the PVTT type and treatment strategy were significant independent factors affecting OS. The objective response rates (ORR) for intrahepatic lesions and PVTT showed significant differences between groups. Most patients in both groups experienced minor adverse events related to TACE. The overall incidence of sorafenib-related adverse events or toxic effects was 90.4% in TACE-sorafenib group. In the TACE-125iodine group, the incidence of pneumothorax and minor hepatic subcapsular hemorrhage were 7.04% and 9.86%, respectively.ConclusionsThis study showed that TACE-125iodine treatment significantly enhanced survival of patients with HCC and type II PVTT, especially subtype IIa, with minimal adverse events.Clinical Trial RegistrationChinese Clinical Trials Database, identifier ChiCTR-ONN-16007929.

Upper Limits of Downstaging for Hepatocellular Carcinoma in Liver Transplantation.

Simple SummaryCurrently, most transplant centres worldwide accept patients with hepatocellular carcinoma who underwent successful downstaging. Concurrently, the effectiveness of radiological and systemic therapies used for the downstaging of hepatocellular carcinoma are increasing. It is now more frequently observed that candidates for liver transplantation have an excellent response to downstaging, even if the baseline stage was well beyond the transplantable tumour. Downstaged patients have a higher risk of dropout from the waiting list and post-transplant recurrence if not transplanted in a short time. Since an increasing number of downstaged patients affects the waitlist dynamics, the definition of upper limits of downstaging is becoming a crucial issue. In this narrative review, we summarise current evidence on the downstaging of hepatocellular carcinoma for liver transplantation, including downstaging of patients with macrovascular invasion or extrahepatic metastasis at presentation and employment of the new systemic treatments for hepatocellular carcinoma.In Europe and the United States, approximately 1100 and 1800 liver transplantations, respectively, are performed every year for hepatocellular carcinoma (HCC), compared with an annual incidence of 65,000 and 39,000 new cases, respectively. Because of organ shortages, proper patient selection is crucial, especially for those exceeding the Milan criteria. Downstaging is the reduction of the HCC burden to meet the eligibility criteria for liver transplantation. Many techniques can be used in downstaging, including ablation, chemoembolisation, radioembolisation and systemic treatments, with a reported success rate of 60–70%. In recent years, an increasing number of patient responders to downstaging procedures has been included in the waitlist, generally with a comparable five-year post-transplant survival but with a higher probability of dropout than HCC patients within the Milan criteria. While the Milan criteria are generally accepted as the endpoint of downstaging, the upper limits of tumour burden for downstaging HCC for liver transplantation are controversial. Very challenging situations involve HCC patients with large nodules, macrovascular invasion or even extrahepatic metastasis at baseline who respond to increasingly more effective downstaging procedures and who aspire to be placed on the waitlist for transplantation. This narrative review analyses the most important evidence available on cohorts subjected to “extended” downstaging, including HCC patients over the up-to-seven criteria and over the University of California San Francisco downstaging criteria. We also address surrogate markers of biological aggressiveness, such as alpha-fetoprotein and the response stability to locoregional treatments, which are very useful in selecting responders to downstaging procedures for waitlisting inclusion.

Real-world study of hepatic artery infusion chemotherapy combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors for advanced hepatocellular carcinoma.

Aim: We investigated the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) combined with anti-PD-1 immunotherapy and tyrosine kinase inhibitors (TKIs) for advanced hepatocellular carcinoma (HCC). Method: This retrospective study included HCC patients treated with HAIC, TKIs and anti-PD-1 antibodies between May 2019 and November 2020 in our hospital. Primary end points were progression-free survivaland safety. Results: Twenty-seven advanced HCC patients were analyzed. The median follow-up was 12.9 months (range: 4.0-24.0 months)and the median progression-free survival was 10.6 months. The objective response rate and disease control rate were 63.0and 92.6%, respectively. No treatment-related deaths occurred. Conclusion: In patients withadvanced HCC, treatment with HAIC, anti-PD-1 antibodies and oral TKIs was effective and safe.

Impact of COVID-19 Pandemic on Intervals and Outcomes of Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma

Background: Transarterial chemoembolization (TACE) may not be repeated “on-demand” timely for hepatocellular carcinoma (HCC) patients in the era of the novel coronavirus disease (COVID-19). We aim to evaluate the impact of the COVID-19 pandemic on the intervals and outcomes of TACE in HCC patients. Methods: This retrospective study included HCC patients who underwent TACE from Jan 1, 2020 to March 31, 2020 (study group) and Jan 1, 2019 to Mar 31, 2019 (control group) at two institutions in China. The endpoints included the TACE interval and the overall response rate (ORR). Uni- and multivariate logistic analyses were performed to identify independent risk factors associated with a worse ORR. The cut-off point was determined to divide repeated TACE time into long- and short- intervals. Findings: 154 patients (71 in the study group, 83 in the control group) were enrolled. The median TACE interval in the study group was 82·0 days (IQR, 61–109), longer than 66·0 days (IQR, 51–94) in the control group (p=0·004). The ORR was 23·9% in the study group, while 39·8% in the control group (p=0·037). The cut-off value was 95 days. The group (OR, 2·402; 95% CI, 1·040–5·546; p=0·040), the long interval (OR, 2·573; 95% CI, 1·022–6·478; p=0·045), and the stage system (OR, 2·500; 95% CI, 1·797–3·480; pInterpretation: For HCC patients, the COVID-19 pandemic results in a longer re-TACE schedule, which may further lead to a lower ORR. Patients with a TACE interval of more than 95 days may have a worse prognosis. Funding: This study was supported by the National Key Research and Development Project of China (2018YFA0704100), the National Natural Science Foundation of China (Major Scientific Research Instrument Development Program 81827805, 81441054, 81520108015, 81671796, 81901847), Jiangsu Provincial Medical Youth Talent Program (ZDRCA2016078), the Key Research and Development Project of Jiangsu Province (BE2019750), the Natural Science Foundation of Jiangsu Province (BK20190177), Innovation Platform of Jiangsu Provincial Medical Center (YXZXA2016005), and the Suzhou Science and Technology Youth Plan (KJXW2018003).Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: The study was approved by the institutional ethics review boards in two participating institutions and the requirement for written informed consent was waived due to its retrospective nature.

Pathological predictive factors for late recurrence of hepatocellular carcinoma in chronic liver disease.

Late recurrence of hepatocellular carcinoma (HCC) is regarded as de novo HCC from chronic hepatitis. This study investigated clinicopathological and molecular factors to develop a nomogram for predicting late HCC recurrence (>2years after curative resection). The training and validation cohorts included HCC patients with a major aetiology of hepatitis B who underwent curative resection. Clinicopathological features including lobular and porto-periportal inflammatory activity, fibrosis and liver cell change were evaluated. Proteins encoded by genes related to late recurrence were identified using a reverse phase protein array of 95 non-tumourous liver tissues. Immunoexpression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), plasminogen activator inhibitor-1, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) and spleen tyrosine kinase (SYK) was measured. Late recurrence occurred in 74/402 (18%) and 47/243 (19%) in the training and validation cohorts respectively. Cirrhosis, moderate/severe lobular inflammatory activity, and expression of pSTAT3, pERK1/2, and SYK proteins correlated to the gene signature of hepatocyte injury and regeneration were independently associated with late recurrence, with odds ratios (95% confidence intervals) of 2.0 (1.2-3.3), 21.1 (4.3-102.7) and 6.0 (2.1-17.7) respectively (P<.05 for all). A nomogram based on these variables (histological parameters and immunohistochemical marker combinations) showed high reliability in both the training and validation cohorts (Harrell's C index: 0.701 and 0.716; 95% confidence intervals: 0.64-0.76 and 0.64-0.79 respectively). The combination of pSTAT3, pERK1/2 and SYK immunoexpression with high lobular inflammatory activity and cirrhosis (fibrosis) predicts late HCC recurrence.