Alpha-fetoprotein Research Articles

The current status of tumor markers as biomarkers in the era of immunotherapy for hepatocellular carcinoma: alpha-fetoprotein alone is not sufficient.

Rapid development of systemic treatments has resulted in improved prognosis for unresectable hepatocellular carcinoma (uHCC) patients. Since immune therapy shows a favorable therapeutic efficacy, use of tumor markers as biomarkers for monitoring treatment response is necessary. This study aimed to elucidate changes in positive rates of 3 available tumor markers in Japan, including alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and lens culinaris agglutinin-reactive AFP (AFP-L3) in uHCC patients treated with systemic therapies over time. From 2009 to 2023, 1470 uHCC patients with data of tumor markers before starting treatment were enrolled. The positivity cut-off value for AFP was 20 ng/mL, for AFP-L3 was 10%, and for DCP was 40 mAU/mL. After dividing the 15 years examined into three periods of five years each (period I, II, III), clinical features of the enrolled patients were evaluated, retrospectively. The percentage of Barcelona Clinic Liver Cancer stage B patients who received systemic therapy increased from period I to III (27.7%, 38.5%, 46.6%, respectively, P<0.001), which was also seen for HCC patients with a non-viral etiology (alcohol and others) (29.9%, 39.7%, 49.6%, respectively P<0.001). Positive rates for AFP (67.8%, 62.1%, 50.8%, respectively) and DCP (84.1%, 80.5%, 72.7%, respectively) were decreased (each P<0.001), while the AFP-L3 rate did not show a significant change (54.4%, 57.7%, 51.9%, respectively P=0.390). Among the AFP-negative patients, the rate of positive for DCP or AFP-L3 was increased (24.4%, 28.1%, 35.4%, respectively, P=0.002). Based on introduction of systemic treatment in an early stage and increasing numbers of HCC cases with a non-viral etiology, the positive rate of AFP level has been declining. Thus, determination of DCP and AFP-L3 in addition to AFP as markers should be more actively utilized in clinical practice, as well as clinical trials for monitoring and evaluating treatment response in this era of combination immunotherapy as a powerful treatment.

AFP shields hepatocellular carcinoma from macrophage phagocytosis by regulating HuR-mediated CD47 translocation in cellular membrane.

Alpha fetoprotein(AFP) overexpression connecting with macrophage dysfunction remain poorly defined. In this study, explore AFP regulates macrophage immunomodulation in hepatocellular carcinoma(HCC) through comprehensive in vitro and in vivo studies. Immunohistochemical and immunofluorescence staining was used to analyze the relativity of AFP and cellular membrane CD47 expression in clinical 30 HCC tissues, and the expression of AFP and CD47 in HCC cells. The intelligent living-cell high-throughput imaging analyzer was applied to dynamically track and image of macrophages to phagocytize HCC cells. The effect of AFP on regulating the level of CD47 in cellular membrane and growth of tumor in vivo was performed by animal experiment. The association of AFP and CD47 in HCC cells was detected by single cell analysis. The present results indicated that AFP upregulated the localization of CD47 on the HCC cell surface. CD47 overexpression stimulates HCC to escape immune surveillance by transmitting "don't eat me" signals to macrophages, lead to inhibit macrophage to phagocytize HCC cells. Mechanistically, the results demonstrated that AFP enhanced CD47 membrane translocation by interacting with Hu-Antigen R(HuR), an RNA-binding protein that regulates mRNA stability and translation. AFP alters the subcellular distribution of HuR, increasing its cytoplasmic accumulation and binding to CD47 transcript. AFP enhanced CD47 membrane translocation by interacting with HuR. These findings proved that AFP could inhibit macrophage to phagocytize HCC cells by upregulating the localization of CD47 on the HCC cell surface. Combination of AFP with CD47 blockade may be a potential therapeutic strategy for HCC treatment.

Characterization of the real-world first line (1L) use of single dose tremelimumab regular interval durvalumab (STRIDE), for treatment of unresectable hepatocellular carcinoma (uHCC), using two electronic medical record (EMR) databases.

534 Background: In October 2022, the US FDA approved the STRIDE (Single Dose Tremelimumab Regular Interval Durvalumab) regimen, comprising tremelimumab 300 mg for 1 dose plus durvalumab 1500 mg every 4 weeks, for the 1L treatment of uHCC in adults aged ≥18 years. Thus far there is limited data characterizing STRIDE's 1L use in the real world. This observational study aims to describe patient characteristics, and clinical profiles of a 1L STRIDE cohort. Methods: A retrospective cohort study was conducted using EMR data from two community oncology practice networks, Florida Cancer Specialists and American Oncology Network, from January 1, 2018, to March 31, 2024. Adults with HCC who received ≥1 administration of the STRIDE regimen as 1L treatment following diagnosis were included. Patients with evidence of other cancers or systemic therapies pre-index date were excluded, to establish a cancer-naïve cohort at index. Index date was first administration of STRIDE. The analysis described the patient characteristics and clinical profile at index date. Patient demographics, severity indicators (cancer stage, albumin-bilirubin index (ALBI), alpha fetoprotein (AFP), Eastern Cooperative Oncology Group (ECOG)) and lab data were assessed on or closest to index date. Results: 79 patients initiated the 1L STRIDE regimen. The median (P25, P75) age at index was 70 (63.2-76.4) years. 72.2% were males, 64.6% were white, and 69.6% were overweight or obese patients. 95% had their first HCC diagnosis between 2022-2024 and the mean time from diagnosis to index date was 3.8 months (SD: 10.2). Among patients with reported cancer stage (n=57), most (82.5%, n=47) were diagnosed with stages IIIA to IVB. 18% had ECOG scores ≥2. 86% had ALBI grades between 2-3; 42.1% had AFP level ≥400 ng/ml; 30.4% had cirrhosis (among those that reported comorbidities) and 24.1% received any loco-regional therapy. Conclusions: Our study provides a real-world profile of patients on 1L STRIDE. Compared to the HIMALAYA trial, these findings suggest that patients in this real-world study tend to be older, diagnosed at late-stage, have a poor liver profile, and potentially worse prognosis over time. Further research is required to explore treatment pathways after index date, over a long follow-up, which may provide more insight into the continuity and effectiveness of IL STRIDE in the real-world.

Washingtonia robusta H. Wendl Leaf Metabolites Potentiate the Radiosensitivity of Hepatocellular Carcinoma Through Ki67 and PARP Inhibition.

Hepatocellular carcinoma (HCC) represents the third-most prevalent cancer in humans worldwide. The current study's objective is to search for the potentiality of Washingtonia robusta H. Wendl (W. robusta) leaf extract in a nanoemulsion (NE) form in enhancing radiotherapy against HCC induced in rats using diethylnitrosamine (DEN). The metabolic composition of the bioactive extract of W. robusta leaves was investigated by LC-MS. Oral epithelial (OEC) and liver carcinoma (HepG2) cell lines were used to examine the safety and anticancer activity of the NE, respectively. In the in vivo study, HCC was induced in male albino rats through administration of DEN in drinking water for 8 weeks, then treatment with NE (100 mg/kg) until the experiment's ending. Rats were irradiated by a fractionated dose of 2Gy*4. NE exerted remarkable cytotoxicity in comparison to the parent extract and the standard doxorubicin on the HepG2 cell line. Besides, the NE administration and/or γ-irradiation (IRR) significantly reduced the elevated alanine aminotransferase (ALT), total proteins, and albumin levels in HCC-induced rats. Likewise, the tumor markers alpha-fetoprotein (AFP) and gamma-glutamyl transferase (GGT) levels were considerably reduced in HCC rats. In addition, NE treatment before IRR significantly decreased the expression of the poly ADP ribose polymerase-1 (PARP1) enzyme and Ki67. Furthermore, the histological investigations strongly confirmed the combined effect of NE and IRR in fighting DEN-induced HCC. NE of W. robusta extract may possess a radiosensitizing novel impact and provide a new strategy to combat HCC in clinical practices.

Development and validation of the SPEAR scoring model and predicting overall survival in unresectable hepatocellular carcinoma patients treated with TACE, molecular targeted therapies, and immune checkpoint inhibitors.

533 Background: To develop and validate a predictive model to identify hepatocellular carcinoma (HCC) patients likely to benefit from combined treatment of transarterial chemoembolization (TACE), molecular targeted therapies (MTTs), and immune checkpoint inhibitors (ICIs). Methods: Data from 500 patients with unresectable HCC treated with TACE, MTTs, and ICIs (2019-2023) were analyzed. Patients were divided into a training set (241 from Nanfang Hospital) and a validation set (259 from various hospitals). Key prognostic variables were identified using random forest survival analysis, and the top five were used to construct a Cox proportional hazards model. Model performance was assessed using time-dependent AUC values, calibration curves, clinical decision curves (DCA), and net reclassification improvement (NRI) indices. Risk scores and optimal cut-off values for risk stratification were determined and validated. Results: Five key survival variables were identified: serum alpha-fetoprotein (AFP), red cell distribution width coefficient of variation (RDW-CV), aspartate aminotransferase (AST), platelet-to-lymphocyte ratio (PLR), and extrahepatic metastasis (EHM). The Cox model had a C-index of 0.694 in the training and 0.691 in the validation set. The training set's 1-year, 2-year, 2.5-year, and 3-year AUC values were 0.77, 0.73, 0.73, and 0.72, respectively, and 0.74, 0.74, 0.76, and 0.66 in the validation set. The ARAPE model demonstrated a more significant net benefit than existing models. Median overall survival (mOS) was 33.9 months for low-risk, 20.4 months for intermediate-risk, and 14.2 months for high-risk groups in the training set; in the validation set, mOS was 30.8, 18.7, and 10.5 months, respectively. Conclusions: The SPEAR model (Serum AFP, PLR, EHM, AST, and RDW-CV) model effectively stratifies risk for HCC patients receiving TACE combined with MTTs and ICIs, aiding in personalized treatment decisions.

Regorafenib combined with immunotherapy and prognosis of unresectable hepatocellular carcinoma.

541 Background: To investigate the prognosis and influencing factors of patients with unresectable hepatocellular carcinoma (uHCC) receiving regorafenib in different treatment modes. Methods: A total of 227 patients with uHCC who received at least 2 cycles of regorafenib treatment in the Affiliated Hospital of Qingdao University between June 2018 and August 2022 were retrospectively collected through the Hospital Information System (HIS). 204 patients were finally enrolled by inclusion and exclusion criteria after screening. Results: The median follow-up was 25.9 (4.5-69.7) months. The median overall survival (OS) of 204 patients with uHCC was 27.7 (95%CI 21.98-33.42) months. The 1, 2, 3 and 5-year OS were 80.9%, 55.9%, 41.4% and 26.7%, respectively. Univariate analysis showed that combination with immune checkpoint inhibitor (ICI) and metabolic-associated complications were independent factors for survival benefit of regorafenib, while the Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) scale = 2, undecreased Alpha-fetoprotein (AFP), macrovascular invasion and extrahepatic metastasis were independent risk factors for poor prognosis (P&lt;0.05). Compared with 60 patients receiving regorafenib alone, 144 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 16.9 vs. 31.5 months, respectively, P=0.006). The median OS of 153 patients receiving second-line therapy with regorafenib was 30.3 months. Among 51 patients receiving third or more lines of therapy with regorafenib, compared with 4 patients receiving regorafenib alone, 47 patients receiving regorafenib combined with ICI had a significant survival benefit (median OS, 9.4 vs. 24.1 months, respectively, P=0.000). Among 148 patients receiving local treatment, the median OS of patients with regorafenib combined with ICI (n=115) or without ICI (n=33) was 33.2 and 16.5 months, respectively (P=0.005). Conclusions: Regorafenib has a good prognosis in second-line treatment of uHCC. The OS of patients with regorafenib combined with ICI were significantly better than that of patients without ICI. The OS benefit of regorafenib combined with ICI was also equivalent in patients with third or more lines. The benefit of regorafenib combined with ICI was better for patients receiving local treatment.

The impact of adherence to NCCN and BCLC treatment guidelines on survival in HCC: A single center study.

561 Background: Hepatocellular carcinoma (HCC) is a prevalent and lethal disease in Saudi Arabia, and globally. Guidelines such as Barcelona Clinic Liver Cancer (BCLC) and National Comprehensive Cancer Network (NCCN) are used to guide therapy for this disease. Adherence to these guidelines should lead to better outcomes. We aim to examine the adherence to guidelines and its impact on survival in a real world setting. Methods: This retrospective cross-sectional study was conducted at the Ministry of National Guard for Health Affairs, Riyadh, Saudi Arabia. Study included all adult patients with HCC who were diagnosed between 2020 and 2023, and presented at our HCC multidisciplinary tumor board (MDT). Data extracted included demographics, clinical and disease characteristics, treatment modalities, and survival status. Chi-square tests, and Kaplan-Meier survival analysis were used to explore relationships between tumor characteristics, adherence to NCCN and BCLC guidelines, and survival outcomes. Adherence to guidelines were assessed by two independent physicians. Results: The study included 208 patients with HCC, the majority were males (73%) with a mean age of 73 years. Less than half of the patients (41.7%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Tumor staging showed that 35% of the patients had BCLC stage D. Child pugh class A and B were equally present in 45% of the patients. Moreover, 24% of the patients had distant metastases or vascular invasion (in portal vein) placing them in BCLC stage C. It is noteworthy that Alpha-Fetoprotein (AFP) was abnormal (&gt;8ng/ml) in 58% of the patients, 18% of them had AFP of more than 400ng/ml. Additionally, the prevalence of comorbid conditions were remarkable for liver cirrhosis being present in 85% of patients, while diabetes mellitus and hypertension each present in 63% of patients. Finally, survival analysis showed a median survival of 16.8 months in all patients with HCC (range 0-47.8 months). Adherence to guidelines were high, with 97.6% (n=203) following NCCN guidelines and 70.7% (n=147) following BCLC guidelines. Following both guidelines showed better survival with mean of 37 months (SD=1.841) in patients with child pugh class A (n=53), and mean survival of 24 months (SD=2.251) in patients with child pugh class B (n=74). Conclusions: Adherence to NCCN guidelines was high in our MDT presented patients compared to BCLC guidelines adherence which was lower, but with comparable survival outcomes.

Highly stable SERS-based mirrored aptasensor for selective detection of alpha-fetoprotein.

Anaptasensor was developedbased on surface-enhanced Raman spectroscopy (SERS) to detect alpha-fetoprotein (AFP) using a mirror aptamer. AFP triggered and altered SERS signaling molecules through the release recognition mechanism as they are released. Two signaling molecules, cyanine 3 (Cy3) and 2-mercaptobenzimidazole-5-carboxylic acid (MBIA), were used to quantify AFP. The results showed that AFP could be reliably and sensitively detected in the concentration range 0.0038-100ng/mL (R2 = 0.9907), with a minimum detection limit of 3.8pg/mL. The sensor can be used for AFP detectionin cancer patient serum samples. This quantitative SERS technology provides a promising tool for biomedical research and clinical diagnosis.

Phosphoproteomics delineates hepatocellular carcinoma subtypes and pinpoints therapeutic targets.

Only a minority of patients could benefit from systemic therapy owing to the high heterogeneity of HCC. Therefore, a deeper understanding of the pathogenesis of HCC is essential for precision therapy. Genomic and proteomic studies of HCC have enhanced our understanding of HCC. However, phosphoproteomic characterization of HCC remains poorly understood. We conducted an in-depth analysis of a clinical cohort of HCC using high-coverage phosphoproteomic. Effective therapeutic targets were validated using liver cancer cell lines and HCC patient-derived xenograft (PDX) mouse models that correspond to the phosphoproteomic subtypes of HCC. Phosphoproteomic analysis classified HCC into three subtypes, A, B, and C, with increasing malignancy and correlation with clinical features, including patient prognosis, tumor staging, serum alpha fetoprotein (AFP) levels, tumor thrombus, and tumor size. Phosphoproteomic subtyping deeply reflected the biological characteristics and clinical features of HCC patients. The profiles of HCC dysregulated kinase activities inferred from the different phosphoproteomic subtypes, consistently identifying increased kinase activity related to cell proliferation. Subtype-C HCC patients showed the most significant dysregulation, indicating a potential therapeutic target. The corresponding drug, bosutinib, demonstrated efficacy in inhibiting the growth of subtype C tumors in liver cancer cell lines and HCC patient-derived xenograft (PDX) mouse models representative of the phosphoproteomic HCC subtypes. Our study provides a comprehensive exploration of the phosphoproteomic landscape of HCC, establishing new subtypes that match clinical features and identifying potential therapeutic targets for the most malignant C subtype.

Direct repeat region 3' end modifications regulate Cas12a activity and expand its applications.

CRISPR-Cas12a technology has transformative potential, but as its applications grow, enhancing its inherent functionalities is essential to meet diverse demands. Here, we reveal a regulatory mechanism for LbCas12a through direct repeat (DR)region3' end modifications and de-modifications, which can regulate LbCas12a's cis- and trans-cleavage activities. We extensively explored the effects of introducing phosphorylation, DNA, photo-cleavable linker, DNA modifications at the DR 3' end on LbCas12a's functionality. We find that the temporary inhibitory function of Cas12a can be reactivated by DR 3' end modification corresponding substances, such as alkaline phosphatase (ALP), immunoglobulin G (IgG), alpha-fetoprotein (AFP), DNA exonucleases, ultraviolet radiation, and DNA glycosylases, which greatly expand the scope of application of Cas12a. Clinical applications demonstrated promising results in ALP, AFP, and trace Epstein-Barr virusdetection compared to gold standard methods. Our research provides valuable insights into regulating LbCas12a activity through direct modification of DR and significantly expands its potential clinical detection targets, paving the way for future universal clustered regularly interspaced short palindromic repeats (CRISPR) diagnostic strategies.

Predictive value of prenatal screening markers combined with serum placental growth factor in early pregnancy for preeclampsia

Objective: To observe the predictive value of prenatal screening markers combined with serum placental growth factor(PLGF) in early pregnancy for preeclampsia(PE). Methods: This was a prospective study. A total of 369 pregnant women undergoing early pregnancy examinations were selected at Jingmen Central Hospital from August 2024 to January 2025 and divided into the PE group(n=43) and the normal group(n=326) according to the presence of PE during the follow-up. The levels of prenatal screening markers alpha-fetoprotein(AFP), serum PLGF, β-human chorionic gonadotropin(β-hCG) and pregnancy-associated plasma protein-A(PAPP-A) were compared between the two groups. Results: There were 43 patients experiencing PE, with an incidence of 11.65%. The levels of PLGF, β-hCG and PAPP-A were significantly decreased in the PE group compared with those in the normal group, and the differences between the groups were statistically significant (all P&lt;0.05). Logistic regression analysis showed that increased prenatal screening markers AFP, serum PLGF, HCG and PAPP-A were independent risk factors for PE, with statistically significant differences between the groups (all P&lt;0.05). Finally, the results of ROC curve analysis showed that the AUCs of AFP, PLGF, β-hCG and PAPP-A were 0.618, 0.645, 0.690, and 0.645, respectively, and the AUC of combined prediction was 0.825, which was significantly increased compared with that of each marker alone, with statistically significant differences(P&lt;0.05). Conclusion: The development of PE in pregnancy is closely related to the levels of AFP, PLGF, β-hCG and PAPP-A. The predictive efficiency of combined detection of AFP, PLGF, β-hCG and PAPP-A for PE in pregnancy significantly increases. Project Title: sFlt-1/PlGF based combined early pregnancy prenatal screening marker Nursing Strategies and Application in Preeclampsia Risk Assessment, Project Number: 2024YFYB111, Year: 2024. doi: https://doi.org/10.12669/pjms.41.2.9794 How to cite this: Shu Z, Wang W. Predictive value of prenatal screening markers combined with serum placental growth factor in early pregnancy for preeclampsia. Pak J Med Sci. 2025;41(2)598-602. doi: https://doi.org/10.12669/pjms.41.2.9794 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Liver resection in stage 0-A HCC in segments 7/8: a propensity-matched analysis comparing open, laparoscopic, and robotic approach.

Both laparoscopic hepatectomy (LH) and robotic hepatectomy (RH) have been performed for tumors in nearly all liver segments. However, few studies have compared the outcomes of patients who underwent open hepatectomy (OH), LH and RH for the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A HCC in S7/8. The clinical data of patients who underwent S7/8 resection for the treatment of BCLC stage 0-A HCC in the First Affiliated Hospital of Guangxi Medical University from July 2017 to July 2023 were retrospectively collected. To minimize selection bias, propensity score matching (PSM) analysis was performed using American Society of Anesthesiology (ASA), tumor size, body mass index (BMI), alpha-fetoprotein (AFP), tumor location, age, number of tumors, platelet (PLT), and Viral hepatitis. A total of 401 patients met the study criteria.After PSM, 61 OH (28.6%), 74 LH (34.8%), and 78 RH (36.6%) were included. RH group had the least blood loss among the three groups (OH, 300 vs. LH, 215 vs. RH, 100mL,P < 0.001). Conversion rate was significantly lower in RH group compared to LH group [LH, 10 (13.5%) vs. RH, 1 (1.3%),P = 0.003]. Although minimally invasive group (RH + LH) took slightly longeroperativetime (OH, 233 vs. LH, 255.5 vs. RH, 257min,P = 0.068), there was no statistical difference. The minimally invasive group had fewer postoperative hospital stay (OH, 8 vs. LH, 6 vs. RH, 6days,P < 0.001). The minimally invasive group had lower rates of surgical complications (OH, 37.7% vs. LH, 20.3% vs. RH, 11.5%). However, there were no statistically significant variations observed in the disease-free survival or overall survival rates among the three groups. RH showed advantage over the OH and LH in short-term outcomes, and non-inferiority in survival outcomes for the treatment of BCLC stage 0-A HCC patients.

Rapid Detection of Alpha-Fetoprotein (AFP) with Lateral Flow Aptasensor

We present a lateral flow aptasensor for the visual detection of alpha-fetoprotein (AFP) in human serum. Leveraging the precise molecular recognition capabilities of aptamers and the distinct optical features of gold nanoparticles, a model system utilizing AFP as the target analyte, along with a pair of aptamer probes, is implemented to establish proof-of-concept on standard lateral flow test strips. It is the first report of an antibody-free lateral flow assay using aptamers as recognition probes for the detection of AFP. The analysis circumvents the numerous incubation and washing steps that are typically involved in most current aptamer-based protein assays. Qualitative analysis involves observing color changes in the test area, while quantitative data are obtained by measuring the optical response in the test zone using a portable strip reader. The biosensor exhibits a linear detection range for AFP concentrations between 10 and 100 ng/mL, with a minimum detection limit of 10 ng/mL. Additionally, it has been successfully applied to detect AFP in human serum samples. The use of aptamer-functionalized gold nanoparticle probes in a lateral flow assay offers great promise for point-of-care applications and fast, on-site detection.

Prognostic Value of POST-Treatment Extent of Tumor (POSTTEXT) System in Patients with Hepatoblastoma.

To assess prognostic values of the POST-Treatment Extent of Tumor (POSTTEXT) system and clinical factors after neoadjuvant chemotherapy in hepatoblastoma patients and evaluate benefits of posttreatment imaging and clinical factors concomitant with Children's Hepatic Tumors International Collaboration-Hepatoblastoma Stratification (CHIC-HS) system. This single-center retrospective study of hepatoblastoma cases (2006-2022) included pediatric patients receiving ≥ 4 cycles of neoadjuvant chemotherapy, with pre- and post-treatment imaging and complete medical records. Clinical data included age, sex, and serum alpha-fetoprotein (AFP) levels. Cox regression analyses identified predictors of event-free survival (EFS). Time-dependent receiver operating characteristic curves assessed the predictive power of combining the CHIC-HS risk stratification with posttreatment factors. Inter-reader agreement was analyzed using weighted kappa. Among the 109 hepatoblastoma patients, 73 (mean age: 2.2 ± 2.7 years) met the inclusion criteria. Prognostic factors for EFS included AFP levels after the fourth cycle of neoadjuvant chemotherapy (HR, 1.233; 95% CI, 1.806-1.400; p=0.001), tumor size change ratio (HR, 0.654; 95% CI, 0.448-0.955; p=0.03), and POSTTEXT annotation factor M (HR, 5.209; 95% CI, 1.639-16.553; p=0.005). Incorporating AFP levels after the fourth cycle of neoadjuvant chemotherapy into the CHIC-HS improved predictive power (p=0.043). POSTTEXT system showed better inter-reader agreement than PRETEXT. Predictors of EFS in hepatoblastoma include AFP levels after the fourth cycle of neoadjuvant chemotherapy, tumor size change ratio, and metastasis (POSTTEXT M). Combining AFP levels after the fourth cycle of neoadjuvant chemotherapy to the CHIC-HS improved the predictive ability.

Comparative Efficacy of Lenvatinib Plus Immunotherapy and Regorafenib Plus Immunotherapy After Lenvatinib Failure for Advanced Hepatocellular Carcinoma: A Retrospective Study.

The combination of regorafenib and immune checkpoint inhibitor (ICI) has been the most popular second-line systemic therapy for advanced hepatocellular carcinoma (HCC). However, considering the good anti-tumor performance of lenvatinib, combined immunotherapy on the basis of lenvatinib after first-line lenvatinib failure is also popular in clinical practice. This study aimed to compare the efficacy and safety of regorafenib plus ICI (TACE-R-I) versus lenvatinib plus ICI (TACE-L-I) in patients with advanced HCC after lenvatinib failure. In this single-center retrospective study, 164 patients with advanced HCC were enrolled from January 2019 to March 2024 in China. All patients were aged ≥18 years, clinically or pathologically diagnosed with HCC. All patients received trans-arterial chemoembolization (TACE) as local treatment. Overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were compared between groups. The Cox regression model was used to analyze the factors associated with OS and PFS. We compared 77 patients from each group after propensity score matching (PSM). There was no significant difference in the OS (p=0.255) or PFS (p=0.387) between groups. However, in the subgroup (distant metastases, Barcelona Clinic Liver Cancer (BCLC) stage C or tumor thrombus), the TACE-R-I group showed better survival benefit than the TACE-L-I group. The multivariable Cox regression model suggested that BCLC stage and alpha-fetoprotein (AFP) were independently associated with OS. Distant metastases, tumor thrombus and Child-Pugh were independent associated factors for PFS (p<0.05). The frequency of grade ≥3 TRAEs was not significantly different between groups (p≥0.05). Our study demonstrated that in patients with greater tumor burden, the TACE-R-I group showed better OS and PFS benefits than the TACE-L-I group. However, in the overall population of HCC patients, there was no significant difference in efficacy and safety between the groups.

Antidiabetic Effects of Quercetin and Silk Sericin in Attenuating Dysregulation of Hepatic Gluconeogenesis in Diabetic Rats Through Potential Modulation of PI3K/Akt/FOXO1 Signaling: In Vivo and In Silico Studies.

Type 2 diabetes mellitus (T2DM) is an intricate disease correlated with many metabolic deregulations, including disordered glucose metabolism, oxidative stress, inflammation, and cellular apoptosis due to hepatic gluconeogenesis aberrations. However, there is no radical therapy to inhibit hepatic gluconeogenesis disturbances yet. We thus sought to probe the effectiveness and uncover the potential mechanism of quercetin (QCT) and silk sericin (SS) in mitigating hyperglycemia-induced hepatic gluconeogenesis disorder, which remains obscure. Administration of QCT and SS to diabetic male albino rats markedly restored the levels of glucose, insulin, advanced glycation end-products (AGEs), liver function enzymes, alpha-fetoprotein (AFP), globulin, and glycogen, in addition to hepatic carbohydrate metabolizing enzymes and gluconeogenesis in comparison with diabetic rats. Furthermore, treatment with QCT and SS modulated hepatic malondialdehyde (MD), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nitric oxide, tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β), in addition to serum interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), implying their effectiveness in safeguarding cells against oxidative impairment and inflammation. Remarkably, QCT and SS treatments led to the upregulation of expression of phosphatidylinositol 3-kinases (PI3K), phospho-Akt (p-Akt), and forkhead box-O1 (FOXO1) genes in hepatic tissues compared to diabetic rats, orchestrating these singling pathways for curtailing hyperglycemia and pernicious consequences in hepatic tissues. Importantly, immunohistochemical investigations exhibited downregulation of caspase-3 expression in rats treated with QCT and SS compared to diabetic animals. Beyond that, the histopathological results of hepatic tissues demonstrated notable correlations with biochemical findings. Interestingly, the in silico results supported the in vivo findings, showing notable binding affinities of QCT and SS to PI3K, GPx, and TNF-α proteins. These results imply that QCT and SS could mitigate oxidative stress and inflammation and regulate hepatic gluconeogenesis in diabetic rats. However, QCT revealed greater molecular interactions with the studied proteins than SS. Overall, our results emphasize that QCT and SS have significant therapeutic effects on attenuating hyperglycemia-induced hepatic gluconeogenesis, with QCT showing superior effectiveness.

Biochemical characteristics, genetic variants and treatment outcomes of 55 Chinese cases with neonatal intrahepatic cholestasis caused by citrin deficiency.

The diagnostic criteria of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) have not been established due to non-specific clinical manifestations, and our understanding on the treatment outcome is still limited. We aim to investigate the biochemical characteristics, genetic variants, and treatment outcome of NICCD patients. We compared the nutritional status and biochemical characteristics of 55 NICCD infants and 27 idiopathic neonatal cholestasis (INC) infants. SLC25A13 gene variant analysis was performed for definitive diagnosis of NICCD. NICCD infants received 12 months of lactose-free and/or medium-chain triglyceride-enriched (LF/MCT) formula treatment. The treatment efficacy was evaluated by comparing the outcome of NICCD with the 24 healthy infants that were selected as normal controls. All NICCD patients were followed up until death or at least 1 year of age. Compared to INC group, significant increase was found in levels of total bilirubin, indirect bilirubin, total bile acid, gamma-glutamyl transpeptidase, alkaline phosphatase, prothrombin time, thrombin time, international normalized ratio, alpha-fetoprotein (AFP), Vitamin D, and Vitamin E of NICCD group, while alanine aminotransferase, albumin, fibrinogen, glucose, and Vitamin A levels showed significant decrease in the NICCD group (P < 0.05). There were 7 novel variants among 19 SLC25A13 variant types. No significant differences were found between NICCD patients treated for 12 months and normal controls. In long term follow-up, 2 cases developed FTTDCD, 8 cases had special dietary habits, and 1 case died from cirrhosis. NICCD showed more severe impairments in liver, coagulation, and metabolic function than INC. Significantly increased AFP levels could provide reference for the differential diagnosis of NICCD. The newly discovered variants may be meaningful for the individualized treatment of NICCD patients. LF/MCT formula was recommended for NICCD patients.

Differentiating Liver Metastases from Primary Liver Cancer: A Retrospective Study of Imaging and Pathological Features in Patients with Histopathological Confirmation.

Background and Objectives: This study aimed to identify and analyze imaging and pathological features that differentiate liver metastases from primary liver cancer in patients with histopathological confirmation, and to evaluate the diagnostic accuracy of imaging modalities. Materials and Methods: This retrospective study included 137 patients who underwent liver biopsy or resection between 2016 and 2024, comprising 126 patients with liver metastases and 11 patients with primary liver cancer (hepatocellular carcinoma). Imaging features on contrast-enhanced MRI were evaluated, including lesion number, size, margins, enhancement patterns, presence of capsule, T1/T2 signal characteristics, diffusion-weighted imaging (DWI) signal, and portal vein thrombosis. Laboratory data such as liver function tests and alpha-fetoprotein (AFP) levels were collected. Pathological features recorded included tumor differentiation, vascular invasion, necrosis, and fibrosis. Statistical analyses were performed using chi-squared tests, t-tests, and logistic regression, with a significance level of p < 0.05. The diagnostic accuracy of imaging features was assessed using receiver operating characteristic (ROC) curve analysis. Results: Liver metastases were more likely to present as multiple lesions (82.5% vs. 27.3%, p < 0.001), had irregular margins (78.6% vs. 36.4%, p = 0.002), rim enhancement (74.6% vs. 18.2%, p < 0.001), and were hypointense on T1-weighted images (85.7% vs. 45.5%, p = 0.004). Primary liver cancers were more likely to be solitary (72.7% vs. 17.5%, p < 0.001), have smooth margins (63.6% vs. 21.4%, p = 0.002), exhibit arterial phase hyperenhancement (81.8% vs. 23.8%, p < 0.001), and portal venous washout (72.7% vs. 19.0%, p < 0.001). Vascular invasion was more common in primary liver cancer (45.5% vs. 11.1%, p = 0.01). AFP levels > 400 ng/mL were significantly associated with primary liver cancer (63.6% vs. 4.8%, p < 0.001). ROC curve analysis showed that a combination of imaging features had an area under the curve (AUC) of 0.91 for differentiating the two entities. Conclusions: Imaging features such as lesion number, margin characteristics, enhancement patterns, T1/T2 signal characteristics, and portal venous washout, along with pathological features like vascular invasion and AFP levels, can effectively differentiate liver metastases from primary liver cancer. The diagnostic accuracy of imaging is high when multiple features are combined.

Up-front resection for hepatocellular carcinoma: Assessing futility in the preoperative setting.

We sought to develop a predictive model to preoperatively identify patients with hepatocellular carcinoma (HCC) at risk of undergoing futile upfront liver resection (LR). Patients undergoing curative-intent LR for HCC were identified from a large multi-institutional database. Futile LR was defined by death or disease recurrence within six months postoperatively. Backward logistic regression was performed to identify factors associated with futility. Additionally, binary criteria were established for surgical candidacy, aiming to keep the likelihood of futility below 20%. Among 1633 patients with HCC, 264 (16.2%) underwent futile upfront LR. Tumor burden score (TBS) (coefficient: 0.083, 95%CI: 0.067-0.099), alpha-fetoprotein (AFP) (coefficient: 0.254, 95%CI: 0.195-0.310), and albumin-bilirubin (ALBI) grade 2/3 (coefficient: 0.566, 95%CI: 0.420-0.718) were independently associated with an increased risk of futile LR. The model demonstrated strong discrimination and calibration in both derivation and validation cohorts. Low, intermediate, and high-risk groups were determined based on the risk model, each with an escalating likelihood of futility, worse histological features, and worse survival outcomes. Six distinct conditions based on AFP-adjusted-to-TBS criteria were established, all with a futility likelihood of less than 20%. Patients fulfilling these criteria had significantly better long-term recurrence-free and overall survival. The futility risk model was made available online for wide clinical applicability: (https://altaf-pawlik-hcc-futilityofsurgery-calculator.streamlit.app/). A preoperative risk model and AFP-adjusted-to-TBS criteria were developed and validated to predict the likelihood of futile LR among patients with HCC. This pragmatic clinical tool may assist clinicians in preoperative decision-making, helping them avoid futile surgery unlikely to offer long-term benefits.

Membranous Overexpression of Fibronectin Predicts Microvascular Invasion and Poor Survival Outcomes in Patients with Hepatocellular Carcinoma.

Fibronectin (FN) has recently been identified as being overexpressed in patients with hepatocellular carcinoma (HCC) and deemed a promising biomarker of vascular invasion. The aim of this study was to examine the patterns of FN expression in HCC cells and their clinicopathological significance, such as their association with vascular invasion and angiogenesis patterns. Immunohistochemical analysis of FN was conducted using tissue microarrays from 258 surgically resected HCCs and matched nontumorous liver tissues. Three distinct FN expression patterns were observed: cytoplasmic, membranous, and sinusoidal. Moderate or strong expression was considered FN-positive. Cytoplasmic or sinusoidal FN expression was significantly more common in HCC cells than in the adjacent liver tissue (p<0.001). FN expression was detected in the membranes of HCC cells and absent in nonneoplastic hepatocytes (p<0.001). Overall survival and disease-free survival in patients with HCC cells with membranous FN expression were significantly shorter than those in patients without membranous FN expression. Membranous FN expression in HCC was significantly associated with high serum alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II) levels, infiltrative gross type, poor Edmondson-Steiner grade, major vessel invasion, microvascular invasion, macrotrabecular massive subtype, advanced T stage, and vessel-encapsulating tumor cluster pattern. Sinusoidal pattern of FN expression in HCC was significantly associated with high serum AFP and PIVKA-II levels, infiltrative gross type, large tumor size, microvascular invasion, macrotrabecular massive subtype, and vessel-encapsulating tumor cluster patterns. Evaluating FN expression in HCC cells may be useful for identifying aggressive cases of HCC with vascular invasion via biopsy.