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PubMed2026

Marked response to dabrafenib plus trametinib in a patient with BRAF V600E-mutant pancreatic hepatoid carcinoma: a case report and systematic analysis of 57 cases.

BACKGROUND: Pancreatic hepatoid carcinoma (PHC) is an extremely rare pancreatic malignancy characterized pathologically by hepatocellular-like differentiation. Some patients may present with elevated serum alpha-fetoprotein (AFP). Owing to the limited number of reported cases, the clinical features, molecular characteristics, and systemic treatment strategies for PHC remain poorly defined. BRAF V600E is an actionable alteration with established therapeutic value in several solid tumors; however, its clinical significance in PHC remains unclear. CASE PRESENTATION: We report the case of a 64-year-old man with advanced PHC who presented with painless jaundice, dark urine, and recent weight loss. Laboratory tests showed marked cholestatic liver injury and significantly elevated AFP. Imaging revealed a pancreatic head-neck mass with portal vein tumor thrombus and regional lymph node metastases, corresponding to cT4N1M1, stage IV disease. Percutaneous transhepatic biliary drainage was first performed to relieve obstructive jaundice. Biopsy of the pancreatic lesion showed poorly differentiated carcinoma. Based on hepatoid morphology, immunophenotype, elevated serum AFP, imaging findings, and exclusion of primary hepatocellular carcinoma, the patient was diagnosed with PHC. Comprehensive genomic profiling identified a BRAF V600E mutation with a variant allele frequency of 31.89%, together with MDM2 and MYC amplification. The molecular profile was characterized by microsatellite stability, low tumor mutational burden, MGMT promoter methylation, and low PD-L1 expression. After two cycles of pembrolizumab-based first-line therapy combined with paclitaxel, S-1, and lenvatinib, AFP continued to increase and imaging showed rapid tumor enlargement, consistent with immune checkpoint inhibitor-related hyperprogressive disease. The treatment was then switched to dabrafenib plus trametinib. AFP declined rapidly and returned to the normal range within approximately two months. Imaging showed marked regression of the pancreatic primary lesion, disappearance of the portal vein tumor thrombus and metastatic lymph nodes, and conversion of peripheral blood minimal residual disease to negative. The best response was partial response. After approximately six months of targeted therapy, occult disease progression emerged. Subsequent addition of cetuximab, replacement of the MEK inhibitor, and dose escalation of targeted therapy did not restore sustained systemic disease control, although local disease remained manageable with subsequent treatment adjustments. Proton radiotherapy was then delivered to the residual pancreatic lesion, followed by CyberKnife radiotherapy for a newly detected 2.3-cm metastasis in the caudate lobe of the liver. As of April 2026, the patient's AFP level remained close to normal at 14 ng/mL, local lesions were well controlled, peripheral blood minimal residual disease had turned positive, and the patient remained in a stable tumor-bearing state. SYSTEMATIC ANALYSIS: We further summarized 57 previously reported cases of PHC. The median age was 54 years, and 66.7% of patients were male. Tumors occurred at different pancreatic sites, including the pancreatic head in 21 cases, body in 8 cases, tail in 13 cases, and multifocal lesions in 15 cases. More than half of the patients had metastatic disease at initial diagnosis. The immunophenotype of PHC was highly heterogeneous. Regarding treatment, 47 patients underwent surgery, 20 received chemotherapy, and 6 received targeted therapy. The 1-year and 3-year overall survival rates were 70.7% and 43.1%, respectively, indicating an overall poor prognosis. CONCLUSION: This case suggests that BRAF V600E may represent a clinically actionable driver alteration in PHC. Dabrafenib plus trametinib induced a rapid and deep response in this patient with advanced BRAF V600E-mutant PHC. Microsatellite stability, low tumor mutational burden, low PD-L1 expression, and MDM2 amplification may be associated with limited benefit from immunotherapy and a risk of hyperprogression. After resistance to targeted therapy, local radiotherapy may serve as an important strategy for controlling oligoresidual and oligometastatic lesions. Together with the literature review, this case supports early comprehensive molecular profiling and individualized multidisciplinary management for advanced PHC.

BRAF V600E↗

PubMed2025

The correlation of DPM1 overexpression with immune infiltration and poor prognosis in hepatocellular carcinoma.

BACKGROUND: The DPM1 gene, crucial for glycosylation processes, has shown abnormal expression in various cancers, raising interest in its potential oncogenic role and as a biomarker in hepatocellular carcinoma (HCC). METHODS: Transcriptomic data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. DPM1 expression levels were compared between HCC tissues and adjacent normal tissues. Clinical correlations were assessed using statistical analyses, including survival analysis and multivariate Cox regression. Immune microenvironment profiling was conducted to evaluate associations between DPM1 expression and immune cell infiltration patterns. RESULTS: Elevated DPM1 levels were associated with advanced tumor stages (P < 0.001), higher pathologic T stage (P < 0.001), increased histologic grade (P < 0.001), tumor positivity (P < 0.001), tissue inflammation (P < 0.001), and elevated alpha-fetoprotein levels (AFP > 400 ng/mL, P < 0.05). Multivariate Cox regression analysis identified DPM1 as an independent prognostic factor for reduced overall survival (HR = 1.990, 95% CI 1.390-2.848). Immunological analysis revealed that DPM1 expression was positively correlated with T helper cells (R = 0.268, P < 0.001) and Th2 cells (R = 0.295, P < 0.001), and negatively correlated with plasmacytoid dendritic cells (R=-0.291, P < 0.001) and cytotoxic cells (R=-0.284, P < 0.001). CONCLUSIONS: DPM1 serves as a promising prognostic biomarker in HCC, with its expression correlating with unfavorable clinical outcomes and immune landscape alterations. Future studies should further validate DPM1's impact on ferroptosis and immune evasion in HCC, and explore its potential as a therapeutic target.

DPM1↗

PubMed2025

Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene.

Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16 kb on chromosome 9 (chr9:132,295,852-132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11-15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.

Humans↗

PubMed2026

Integrated genomic and biochemical diagnosis of a novel homozygous start-loss variant in AKR1D1 associated with neonatal cholestasis.

INTRODUCTION: Congenital bile acid synthesis defects are rare autosomal recessive disorders that typically present in early infancy with cholestasis, progressive liver dysfunction, and, in severe cases, acute liver failure. These conditions may mimic other metabolic diseases detected in newborn screening, complicating early diagnosis. The AKR1D1 gene encodes Δ4-3-oxosteroid 5β-reductase, a key enzyme in primary bile acid synthesis, and pathogenic variants cause bile acid synthesis defect type 2 (OMIM #235555). CASE DESCRIPTION: We report a 3-month-old male infant with severe neonatal cholestasis and a history of elevated tyrosine levels in newborn screening. Pregnancy was high risk and unmonitored, with birth outside a hospital. Parental consanguinity was first-degree. Early metabolic evaluation showed transient normalization of tyrosine levels, but subsequent analyses revealed recurrent hyper-tyrosinemia. Urinary organic acids showed increased 4-hydroxyphenyl metabolites, with absent succinylacetone, excluding tyrosinemia type I. Progressive cholestasis developed, accompanied by coagulopathy, hyperbilirubinemia, hyperammonemia, and markedly elevated alpha-fetoprotein. Imaging revealed no structural liver abnormalities. Clinical exome sequencing identified a novel homozygous start-loss variant in AKR1D1, likely abolishing functional enzyme production. Metabolic studies confirmed increased urinary excretion of 3-oxocholenoic acids consistent with abnormal bile acid synthesis and supporting a diagnosis of bile acid synthesis defect type 2. Oral cholic acid therapy led to stabilization and improvement in clinical and biochemical parameters. DISCUSSION/CONCLUSION: This case illustrates the diagnostic complexity of neonatal cholestasis, particularly when initial metabolic findings suggest alternative etiologies. It highlights the importance of newborn screening as a tool for broader diagnostic suspicion and the critical role of early molecular diagnosis and multidisciplinary care. Timely recognition and targeted therapy can improve outcomes, prevent liver transplantation, and enable accurate genetic counseling, especially in consanguineous families.

Humans↗

PubMed2026

A multi-analyte cfDNA-based blood test for early detection of hepatocellular carcinoma.

BACKGROUND & AIMS: Patients at high risk for hepatocellular carcinoma (HCC) are recommended to undergo biannual abdominal ultrasound surveillance; however, ultrasound has low sensitivity for small HCC nodules and is associated with poor adherence. To address these limitations, the multianalyte HelioLiver Dx blood test was developed to aid in the detection of HCC in patients with cirrhosis who are at high risk for HCC. METHODS: The performance of the HelioLiver Dx test and ultrasound for the detection of HCC in adults with cirrhosis was evaluated in a cross-sectional, prospective, blinded, multicenter validation study. All participants provided blood specimens for the HelioLiver Dx test and underwent ultrasound. All participants also underwent multiphasic MRI, which served as the reference standard for determining HCC status. RESULTS: Of 1,268 evaluable participants, 46 (3.6%) were considered to have HCC as determined by MRI, with many (46%) having small HCC lesions ≤2 cm in diameter. The HelioLiver Dx test had a sensitivity of 47.8% (95% CI 32.9-63.1) for all HCC lesions and 28.6% (95% CI 11.3-52.2) for HCC lesions ≤2 cm. In contrast, ultrasound demonstrated a lower sensitivity of 28.3% (95% CI 16.0-43.5) for all HCC lesions and failed to detect any (0%; 95% CI 0.0-16.1) HCC lesions ≤2 cm. The specificity of HelioLiver Dx and ultrasound were 87.6% (95% CI 85.6-89.4) and 93.9% (95% CI 92.5-95.2), respectively. The HelioLiver Dx test met prespecified co-primary endpoints for superior sensitivity and non-inferior specificity compared to ultrasound. CONCLUSION: Compared with ultrasound and alpha-fetoprotein, the HelioLiver Dx test identified more HCC lesions overall, including more small lesions. A convenient and accurate blood-based test may improve HCC surveillance by facilitating earlier detection and reducing patient barriers to testing. GOV IDENTIFIER: NCT03694600 IMPACT AND IMPLICATIONS: There is a significant, unmet clinical need for more sensitive and accessible methods for the early detection of hepatocellular carcinoma (HCC) in high-risk patient populations. The current study is the first blinded, multicenter, prospective study to evaluate the performance of a multianalyte blood test compared to abdominal ultrasound for the detection of HCC among patients with cirrhosis. The multianalyte HelioLiver Dx test met prespecified co-primary endpoints for superior sensitivity and non-inferior specificity compared to ultrasound for detection of HCC lesions. The availability of a more accessible, convenient and sensitive blood test to aid in the detection of HCC may improve utilization and consequently clinical outcomes for high-risk patients via reduction of care barriers and improved early HCC detection. CLINICALTRIALS: gov identifier: NCT03694600.

Humans↗

PubMed2026

Identification of a G-quadruplex-forming cell-free DNA fragment as a biomarker for the precise diagnosis of hepatocellular carcinoma.

Early detection of hepatocellular carcinoma (HCC) remains challenging, as the currently recommended surveillance strategy based on ultrasound combined with alpha-fetoprotein (AFP) is limited by suboptimal sensitivity and accessibility. Cell-free DNA (cfDNA) provides a minimally invasive avenue for cancer detection. However, most existing cfDNA-based approaches either perform unreliably in low-input samples or require analytically complex workflows. Here, we systematically profiled serum cfDNA from individuals with HCC and without HCC and identified a high-abundance tumor-associated single cfDNA fragment at the FAM230F genomic region. Integrative analysis of liver assay for transposase-accessible chromatin with sequencing (ATAC-seq) data revealed consistent tumor-specific chromatin accessibility at this locus, suggesting a tumor-derived origin. Structural characterization further demonstrated enrichment of G-quadruplex (G4) features within the target sequence, which may increase resistance to serum nuclease degradation and promote its preferential retention in circulation. Based on these properties, we established a qPCR-based detection workflow with clinical accessibility. In a validation cohort independent of the discovery cohort, a ΔC t cutoff of 2 was selected by maximizing the Youden index within the same cohort. The assay showed a sensitivity of 94.5% and a specificity of 90.5% for distinguishing HCC from non-HCC. Collectively, our study identifies FAM230F as a structurally stable tumor-associated cfDNA fragment and establishes a simple and scalable qPCR-based assay for HCC detection, providing a practical framework for translating cfDNA fragment analysis into clinical biomarkers.

Journal Article↗

PubMed2025

Phosphoproteomics delineates hepatocellular carcinoma subtypes and pinpoints therapeutic targets.

BACKGROUND AND AIMS: 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, the phosphoproteomic characterization of HCC remains poorly understood. APPROACH AND RESULTS: 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 mouse models that correspond to the phosphoproteomic subtypes of HCC. Phosphoproteomic analysis classified HCC into 3 subtypes, A, B, and C, with increasing malignancy and correlation with clinical features, including patient prognosis, tumor staging, serum alpha-fetoprotein levels, tumor thrombus, and tumor size. Phosphoproteomic subtyping deeply reflected the biological characteristics and clinical features of patients with HCC. The profiles of HCC-dysregulated kinase activities inferred from the different phosphoproteomic subtypes consistently identify 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 mouse models representative of the phosphoproteomic HCC subtypes. CONCLUSIONS: 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.

Carcinoma, Hepatocellular↗

PubMed2026

Multi-Target HCC Blood Test Demonstrates Consistent Performance Across Subgroups of Patients with Chronic Liver Disease.

BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is critical for improving patient outcomes; however, ultrasound-based surveillance has limited sensitivity and variable performance across patient populations. We evaluated the performance of a multitarget HCC blood test (mt-HBT), incorporating methylated DNA markers, alpha-fetoprotein (AFP), and patient sex, across clinically relevant subgroups. METHODS: We performed a subgroup analysis of a multicenter, prospective case-control study that included 159 patients with early-stage HCC (Barcelona Clinic Liver Cancer Stage 0/A) and 649 control patients with cirrhosis or chronic hepatitis B without HCC. The mt-HBT combined methylated HOXA1, TSPYL5, and B3GALT6 markers with AFP and sex. Sensitivity and specificity were evaluated overall and according to age, sex, obesity, liver disease etiology, Child Pugh class, and tumor size. Performance was compared with AFP and GALAD. RESULTS: Overall sensitivity and specificity of mt-HBT for early-stage HCC detection were 76.7% (95% CI, 69.6-82.6) and 87.5% (95% CI, 84.8-89.8), respectively. Sensitivity was significantly higher than that of AFP (35.2%, p < 0.001) and comparable to that of GALAD (78.6%, p = 0.56), whereas specificity was lower than that of AFP (98.5%, p < 0.001) but higher than that of GALAD (76.9%, p < 0.001). Sensitivity was maintained across key subgroups, including patients with obesity (68.9%), Child Pugh B cirrhosis (75.0%), hepatitis C (80.0%), hepatitis B (72.2%), alcohol-associated liver disease (80.5%), and metabolic dysfunction-associated steatotic disease (69.0%) (all p > 0.05 between subgroups). Specificity exceeded 80% in all examined populations and was significantly higher in women than in men (92.5% vs. 83.9%, p < 0.001). Sensitivity increased with tumor size, ranging from 60.0% for tumors < 2 cm to 100% for tumors > 5 cm. CONCLUSIONS: The mt-HBT demonstrated robust, consistent performance for early-stage HCC detection across diverse patient populations, including subgroups in which ultrasound surveillance commonly underperforms. These findings support the prospective validation of mt-HBT as a blood-based surveillance strategy for HCC.

liver cancer↗

PubMed2026

Circulating Methylated SEPT9 for Detection of Hepatocellular Carcinoma in Cirrhosis.

IMPORTANCE: Hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis remains suboptimal, with inadequate early-stage detection. α-Fetoprotein (AFP) demonstrates insufficient sensitivity. Circulating methylated septin 9 (SEPT9) has shown diagnostic promise. OBJECTIVE: To determine whether methylated SEPT9 improves detection of HCC when combined with AFP in patients with cirrhosis undergoing surveillance. DESIGN, SETTING, AND PARTICIPANTS: In this prospective, cross-sectional, diagnostic accuracy study, patients with cirrhosis undergoing routine HCC surveillance with ultrasonography and AFP were enrolled at 2 French academic centers from February 2018 through October 2024. HCC was diagnosed per international guidelines with centralized radiologic review, blinded to methylated SEPT9 results. Data were analyzed from October 2025 to January 2026. EXPOSURES: Plasma methylated SEPT9 was analyzed from 3 independent plasma aliquots and classified by number of positive replicates (single-positive, double-positive, or triple-positive). Serum AFP was evaluated at a threshold of 20 ng/mL. Biomarkers were evaluated individually and in combination using disjunction logic (tier 1; maximizing sensitivity) or conjunction logic (tier 2; maximizing specificity). MAIN OUTCOMES AND MEASURES: The primary outcome was the presence of HCC at enrollment. The primary end point was comparison of the area under the receiver operating characteristic curve (AUROC) between methylated SEPT9 and AFP. Secondary end points included diagnostic performance stratified by Barcelona Clinic Liver Cancer (BCLC) stage. RESULTS: Among 574 participants, 414 (72.1%) were male, and the median (IQR) age was 63 (57-70) years. A total of 118 had HCC, including 51 (43.2%) with BCLC stage 0-A. Methylated SEPT9 outperformed AFP (AUROC: 0.79 [95% CI, 0.74-0.84] vs 0.71 [95% CI, 0.66-0.76], respectively; P = .002; posterior probability of superiority >99.8%). Tier 1a (at least single-positive methylated SEPT9 or AFP >20 ng/mL) achieved 87.8% (95% CI, 81.6-93.5) sensitivity and a negative likelihood ratio of 0.2 (95% CI, 0.1-0.3). Among 64 HCC cases missed by AFP, tier 1a recovered 50 (78%). For BCLC 0-A disease, tier 1a sensitivity was 74.5% (95% CI, 62.2-86.5) vs 23.5% (95% CI, 12.5-35.8) for AFP, 3.2-fold increase. Tier 2 (triple-positive methylated SEPT9 and AFP >20 ng/mL) achieved 99.6% (95% CI, 98.9-100) specificity, a positive likelihood ratio of 76.0 (95% CI, 26.9-181.0), and a diagnostic odds ratio of 112.1 (95% CI, 37.8-294.7). CONCLUSIONS AND RELEVANCE: In this diagnostic study, combining methylated SEPT9 with AFP substantially improved HCC detection in patients with cirrhosis, particularly for early-stage disease amenable to curative treatment. Prospective studies are needed to determine whether improved detection translates into survival benefit.

Humans↗

PubMed2026

Serum Olink Proteomics Reveals Novel Biomarkers for Early Diagnosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly prevalent malignant tumor in China, and early diagnosis critically affects the prognosis. Current imaging and pathological biopsy techniques have limitations, including high invasiveness and limited accessibility, while the insufficient sensitivity of serum biomarkers (such as AFP) restricts their use in early screening. In this study, using the Olink proteomics platform based on the proximity extension assay (PEA), we screened for hepatocellular carcinoma-related differentially expressed proteins (DEPs) and constructed a multiprotein diagnostic model. In the discovery cohort, we included 15 patients with newly diagnosed HCCs and 16 healthy controls. DEPs were identified using Olink, and their diagnostic performance was analyzed to identify the candidate biomarkers. In an independent validation cohort, including 116 HCC patients (50 early stage, 66 late stage) and 83 healthy controls, we further validated the expression levels and diagnostic performance of identified proteins─C1QA and GFER. The C1QA and GFER expression levels were significantly higher in the serum of patients with early and late HCC stages compared to healthy controls. By constructing a multiprotein diagnostic model, we identified C1QA, GFER, and AFP as the optimal diagnostic combination, demonstrating a combined diagnostic AUC of 0.92 and 0.99 for early-stage and advanced-stage HCC, respectively.

Humans↗