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The principal aim of the present study was to develop and validate a nomogram predicting overall survival (OS) in patients with α-fetoprotein (AFP)-negative hepatocellular carcinoma (AFP-NHCC) who experience dynamic changes in AFP level after hepatectomy. A cohort of 870 patients were enrolled and randomly assigned into a training cohort (n=600) and a validation cohort (n=270) at a 7:3 ratio. The key variables contributing to the nomogram were determined through random survival forest analysis and multivariate Cox regression. The discriminative ability of the nomogram was evaluated using time-dependent receiver operating characteristic curves and the area under the curves. Furthermore, the nomogram was comprehensively assessed using the concordance index (C-index), calibration curves and clinical decision curve analysis (DCA). Kaplan-Meier (KM) curves analysis was employed to discern survival rates across diverse risk strata of patients. Ultimately, the nomogram incorporated critical factors including sex, tumor size, globulin levels, gamma-glutamyl transferase and fibrinogen levels. In the training and validation cohorts, the C-indexes were 0.72 [95% confidence interval (CI): 0.685-0.755) and 0.664 (95% CI: 0.611-0.717], respectively, attesting to its predictive validity. The nomogram demonstrated excellent calibration and DCA further confirmed its clinical usefulness. Additionally, KM curve analysis unveiled statistically significant differences in OS among three distinct risk groups. In conclusion, the present study successfully formulated a nomogram predicting 3-, 5- and 8-year OS in patients with AFP-NHCC with dynamic changes in AFP level post-local resection. This model serves as a valuable tool for clinicians to promptly identify high-risk patients, thereby facilitating timely interventions and potentially enhancing patient survival outcomes.

Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has high morbidity and mortality rates. It is essential to search new biomarkers to improve the accuracy of early HCC diagnosis. Therefore, we evaluated the diagnostic value of prothrombin induced by vitamin K deficiency or antagonist- II (PIVKA-II) as a potential biomarker that complements α-fetoprotein (AFP) in HCC by detecting the serum PIVKA-II levels. Methods Serum PIVKA-II levels were compared in 168 HCC patients, 150 benign liver disease patients and 153 healthy controls to investigate the PIVKA-II potential to be a HCC biomarker. Receiver operating characteristic curve (ROC) analysis was used to evaluate the value of PIVKA-II in the diagnosis of HCC and its complementary role of AFP. The correlation between serum PIVKA-II levels and clinicopathological characteristics was analyzed to study the value of PIVKA-II in assessing HCC progression and prognosis. Finally, the ability of PIVKA-II in assessing the surgical treatment effects of HCC was studied by comparing the pre- and post-operative serum PIVKA-II levels in 89 HCC patients. Results Serum PIVKA-II levels in HCC patients were significantly higher than that in patients with benign liver disease and healthy controls. The PIVKA-II performance in the diagnosing HCC as an individual biomarker was remarkable. The combined detection of PIVKA-II and AFP improved the diagnostic efficiency of HCC. PIVKA-II retained significant diagnosis capabilities for AFP-negative HCC patients. Significant correlations were found between PIVKA-II expression levels and some clinicopathological characteristics, including tumor size, tumor stage, tumor metastasis, differentiation degree and complications. PIVKA-II expression obviously decreased after surgical resection. Conclusions PIVKA-II is a promising serum biomarker for the HCC diagnosis that can be used as a supplement for AFP. The combined diagnosis of the two markers greatly improved the diagnostic efficiency of HCC. The PIVKA-II levels in HCC patients were widely associated with clinicopathological characteristics representing tumor cell dissemination and/or poor prognosis. PIVKA-II can be used to evaluate the curative effects of HCC resection.

We developed and evaluated a modified albumin-bilirubin grade and α-fetoprotein (mALF) score, a nutritional and oncological assessment tool for patients with hepatocellular carcinoma (HCC) after surgical resection. Patients (n = 480) who underwent R0 resection between 2010 and 2020 were analyzed retrospectively. The mALF score assigned one point for a modified albumin-bilirubin (mALBI) grade 2b or 3 and one point for an α-fetoprotein (AFP) level ≥ 100 ng/mL. Patients were classified by mALF scores of 0 (mALBI grade 1/2a, AFP < 100 ng/mL), 1 (mALBI grade 2b/3 or AFP ≥ 100 ng/mL), or 2 (mALBI grade 2b/3, AFP ≥ 100 ng/mL) points. Liver reserve deteriorated and cancer progressed with increasing score. Postoperative complications (Clavien–Dindo classification ≥ 3) differed significantly among groups. The 5-year recurrence-free survival (RFS) rates were 34.8%, 11.2%, and 0.0% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The 5-year overall survival (OS) rates were 66.0%, 29.7%, and 17.8% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The mALF score was an independent prognostic predictor of RFS and OS. In HCC, the mALF score was effective for predicting postoperative complications and long-term survival.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal causes of cancer-related death worldwide. The treatment of HCC remains challenging and is largely predicated on early diagnosis. Surveillance of high-risk groups using abdominal ultrasonography, with or without serum analysis of α-fetoprotein (AFP), can permit detection of early, potentially curable tumours, but is limited by its insensitivity. Reviewed here are two current approaches that aim to address this limitation. The first is to use old re-emerged empirically derived biomarkers such as AFP, now applied within statistical models. The second is to use circulating nucleic acid biomarkers, which include cell-free DNA (for example, circulating tumour DNA, cell-free mitochondrial DNA and cell-free viral DNA) and cell-free RNA, applying modern molecular biology-based technologies and machine learning techniques closely allied to the underlying biology of cancer. Taken together, these approaches are likely to be complementary. Both hold considerable promise for achieving earlier diagnosis as well as offering additional functionalities including improved monitoring of therapy and prediction of response thereto.Surveillance of hepatocellular carcinoma (HCC), one of the most lethal solid cancers globally, is insensitive for the detection of early-stage tumours. In this Review, the authors discuss HCC biomarkers that can improve early diagnosis, therapy monitoring and prediction of therapy response.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Surveillance for HCC is critical for early detection and treatment, but fewer than one-quarter of individuals at risk of HCC undergo surveillance. Multiple failures across the screening process contribute to the underutilization of surveillance, including limited disease awareness among patients and health-care providers, knowledge gaps, and difficulty recognizing patients who are at risk. Non-alcoholic fatty liver disease and alcohol-associated liver disease are the fastest-rising causes of HCC-related death worldwide and are associated with unique barriers to surveillance. In particular, more than one-third of patients with HCC related to non-alcoholic fatty liver disease do not have cirrhosis and therefore lack a routine indication for HCC surveillance on the basis of current practice guidelines. Semi-annual abdominal ultrasound with measurement of α-fetoprotein levels is recommended for HCC surveillance, but the sensitivity of this approach for early HCC is limited, especially for patients with cirrhosis or obesity. In this Review, we discuss the current status of HCC surveillance and the remaining challenges, including the changing aetiology of liver disease. We also discuss strategies to improve the utilization and quality of surveillance for HCC.In this Review, Huang et al. discuss the current status of hepatocellular carcinoma surveillance, the remaining challenges, including the changing aetiology of liver disease, and strategies to improve the utilization and quality of surveillance.

Systemic therapies have improved the management of hepatocellular carcinoma, but there is still a need to further enhance overall survival in first-line advanced stages. This study aimed to evaluate the addition of pembrolizumab to lenvatinib versus lenvatinib plus placebo in the first-line setting for unresectable hepatocellular carcinoma. In this global, randomised, double-blind, phase 3 study (LEAP-002), patients aged 18 years or older with unresectable hepatocellular carcinoma, Child Pugh class A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment were enrolled at 172 global sites. Patients were randomly assigned (1:1) with a central interactive voice-response system (block size of 4) to receive lenvatinib (bodyweight <60 kg, 8 mg/day; bodyweight ≥60 kg, 12 mg/day) plus pembrolizumab (200 mg every 3 weeks) or lenvatinib plus placebo. Randomisation was stratified by geographical region, macrovascular portal vein invasion or extrahepatic spread or both, α-fetoprotein concentration, and Eastern Cooperative Oncology Group performance status. Dual primary endpoints were overall survival (superiority threshold at final overall survival analysis, one-sided p=0·019; final analysis to occur after 532 events) and progression-free survival (superiority threshold one-sided p=0·002; final analysis to occur after 571 events) in the intention-to-treat population. Results from the final analysis are reported. This study is registered with ClinicalTrials.gov, NCT03713593, and is active but not recruiting. Between Jan 17, 2019, and April 28, 2020, of 1309 patients assessed, 794 were randomly assigned to lenvatinib plus pembrolizumab (n=395) or lenvatinib plus placebo (n=399). Median age was 66·0 years (IQR 57·0–72·0), 644 (81%) of 794 were male, 150 (19%) were female, 345 (43%) were Asian, 345 (43%) were White, 22 (3%) were multiple races, 21 (3%) were American Indian or Alaska Native, 21 (3%) were Native Hawaiian or other Pacific Islander, 13 (2%) were Black or African American, and 46 (6%) did not have available race data. Median follow up as of data cutoff for the final analysis (June 21, 2022) was 32·1 months (IQR 29·4–35·3). Median overall survival was 21·2 months (95% CI 19·0–23·6; 252 [64%] of 395 died) with lenvatinib plus pembrolizumab versus 19·0 months (17·2–21·7; 282 [71%] of 399 died) with lenvatinib plus placebo (hazard ratio [HR] 0·84; 95% CI 0·71–1·00; stratified log-rank p=0·023). As of data cutoff for the progression-free survival final analysis (April 5, 2021), median progression-free survival was 8·2 months (95% CI 6·4–8·4; 270 events occurred [42 deaths; 228 progressions]) with lenvatinib plus pembrolizumab versus 8·0 months (6·3–8·2; 301 events occurred [36 deaths; 265 progressions]) with lenvatinib plus placebo (HR 0·87; 95% CI 0·73–1·02; stratified log-rank p=0·047). The most common treatment-related grade 3–4 adverse events were hypertension (69 [17%] of 395 patients in the lenvatinib plus pembrolizumab group vs 68 [17%] of 395 patients) in the lenvatinib plus placebo group), increased aspartate aminotransferase (27 [7%] vs 17 [4%]), and diarrhoea (25 [6%] vs 15 [4%]). Treatment-related deaths occurred in four (1%) patients in the lenvatinib plus pembrolizumab group (due to gastrointestinal haemorrhage and hepatorenal syndrome [n=1 each] and hepatic encephalopathy [n=2]) and in three (1%) patients in the lenvatinib plus placebo group (due to gastrointestinal haemorrhage, hepatorenal syndrome, and cerebrovascular accident [n=1 each]). In earlier studies, the addition of pembrolizumab to lenvatinib as first-line therapy for advanced hepatocellular carcinoma has shown promising clinical activity; however, lenvatinib plus pembrolizumab did not meet prespecified significance for improved overall survival and progression-free survival versus lenvatinib plus placebo. Our findings do not support a change in clinical practice. Eisai US, and Merck Sharp & Dohme, a subsidiary of Merck.

BackgroundTo explore the changes of pre- and short-term-post-ablative two-dimensional shear wave elastography (2D-SWE) measurements, and to assess the feasibility of using pre- and short-term-post-ablative indicators, including 2D-SWE measurement, to predict hepatocellular carcinoma (HCC) recurrence.Methods161 chronic hepatitis B-related HCC patients were consecutively enrolled and were divided into a training group (n =107) and a validation group (n =56). Data, including 2D-SWE measurement value (Emean), were collected within one week of pre-ablation and at the scheduled on-patient or telephone post-ablative follow-ups for up to three years. The association between variables and recurrence was analysed using multivariate Cox proportional hazards regression analysis and a recurrence prediction model was established.ResultsThe median follow-up time was 12 months (range 1 - 36 months) and recurrence occurred in 36 (22.4%) patients. Compared to the pre-ablative Emean, the one-month-post-ablative Emean decreased in 40 (24.8%) patients, while increased in 71 (44.1%) patients and not significantly changed in 50 (31.1%). Cox regression analysis indicated that the pre-ablative prothrombin time (PT; p =0.014, HR =1.54, 95% CI =1.09 - 2.17), one-month-post-ablative alpha-fetoprotein (AFP; p =0.014, HR =1.01, 95% CI =1.00 - 1.01), and the categorized Emean change between pre-ablative and one-month-post-ablative period (when comparing the decrease and the not-significant-change, p =0.096, HR =0.38, 95% CI =0.12 - 1.19; when comparing the decrease and the increase, p =0.014, HR =0.22, 95% CI =0.06 - 0.73) were the independent predictor of progression-free survival. The longer pre-ablative PT, higher one-month-post-ablative AFP, and decreased one-month-post-ablative Emean implied a shorter progression-free survival. The Cox model was found with a significant ability to predict progress-free survival in both the training group (p <0.001, HR =2.10, 95% CI =1.52 – 2.91) and the validation group (p =0.009, HR =1.17, 95% CI =1.04 – 1.31).ConclusionsThe changes in 2D-SWE measurement from pre- to one-month post-ablative periods, the pre-ablative PT, and the one-month-post-ablative AFP could help to predict post-ablative recurrence in CHB-related HCC. The changes in 2D-SWE measurement might be a new predictor of HCC recurrence.

BackgroundImmunotherapy-based regimens are now the standard first-line treatment for advanced gastric cancer; however, it remains unclear whether patients with alpha-fetoprotein-producing gastric cancer (AFPGC) benefit from this approach. In this study, we aimed to evaluate the predictive and prognostic value of serum AFP in patients with gastric cancer receiving first-line immunotherapy and to explore whether adding anti-angiogenic agents improves outcomes in AFPGC.MethodsClinicopathological data from patients with advanced gastroesophageal junction/gastric cancer (GEJ/GC) treated with first-line immunotherapy were analyzed retrospectively. Patients were stratified into HER2-negative and HER2-positive subgroups. AFP-positive GEJ/GC (AFP-GEJ/GC) was defined as serum AFP≥20 ng/ml or immunohistochemical positivity pretreatment.ResultsIn the HER2-negative cohort (n=246), the AFP-GEJ/GC group (n=16) had significantly shorter median PFS (mPFS, 5.4 vs. 7.0 months; p=0.02) and numerically shorter median OS (mOS, 11.4 vs. 16.8 months; p=0.24) compared with the AFP-negative group, despite similar ORR (50.0% vs. 45.2%; p=0.798) and the DCR (93.8% vs. 90.4%; p > 0.999). In the HER2-positive cohort (n=155), patients with AFP-GEJ/GC (n=133) showed numerically shorter mPFS (7.67 vs. 14.07 months; p = 0.26) and similar mOS (29.0 vs. 26.1 months; p = 0.36) compared with the AFP-negative group (n=22). Among HER2-negative AFP-GEJ/GC (n=47), patients receiving anti-angiogenic combination therapy (n=31) had longer mPFS (6.33 vs. 5.40 months; p=0.02) and mOS (15.7 vs. 11.4 months; p=0.15) than those receiving standard chemoimmunotherapy (n=16).ConclusionsElevated serum AFP may predict poorer efficacy and prognosis in patients with advanced GEJ/GC treated with immunotherapy, particularly in HER2-negative subgroups. Combining anti-angiogenic agents with first-line immunotherapy could improve treatment efficacy and survival in HER2-negative AFP-GEJ/GC.

IntroductionBiomarker combinations such as the GALAD, GAAD and HES scores have been proposed to aid detection of hepatocellular carcinoma (HCC), a common, debilitating primary liver cancer. A method is required to assess and compare the accuracy of the various combinations that are available.MethodsPredictive models were developed using logistic regression based on data from several large previously published datasets; for all 31 possible combinations of five biomarkers – alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), des-gamma-carboxy prothrombin (DCP), age and sex – area under the curve (AUC), sensitivity and specificity scores were generated to estimate HCC diagnostic performance.ResultsDCP was the most important single biomarker for predicting HCC (AUC=0.89). AFP was the second most important biomarker; combining DCP and AFP produced an AUC of 0.94. Addition of the third most important biomarker significantly improved AUC, as did addition of the fourth but there was no significant difference in AUC between the 4-biomarker and full 5-biomarker models.ConclusionsOur work suggests that biomarker combinations can be flexible to accommodate individual patient and healthcare provider needs. There is no statistical difference between the 4- and 5-biomarker models, indicating that the GALAD score is simply one of a family of models, all with similar performance characteristics. Our automated calculator easily assesses the AUC of all possible biomarker combinations and can be applied to biomarkers in other disease areas.