Search Results (661)

Background: The sensitivity of ultrasound plus alpha-fetoprotein (AFP) for early-stage hepatocellular carcinoma (HCC) detection remains suboptimal, prompting interest in blood-based biomarkers as an alternative strategy. The ASAP [age, sex, AFP, PIVKA-II] score has promising performance, although validation in contemporary Western populations is needed. Methods: We conducted a case–control study in which the cases were patients with HCC and the controls had cirrhosis without HCC. AFP, PIVKA-II, LG2m, and GP73 were measured using the Abbott Alinity platform, and ASAP scores were calculated. Sensitivity and specificity for early-stage HCC (BCLC stage 0/A) were compared between ASAP and ultrasound plus AFP using McNemar’s chi-square test. Results: Among 294 patients (median age of 61 years, 67.7% men), 50.7% had HCC (69.1% BCLC 0/A), and 49.3% had cirrhosis. The performance of individual biomarkers for early-stage HCC was moderate to poor (AUROC: AFP 0.71, PIVKA-II 0.73, LG2m 0.51, and GP73 0.53). ASAP, at a cutoff of ≥0.526, demonstrated a sensitivity of 88.3% for early-stage HCC, with specificity of 54.5%. Sensitivity was higher in men and viremic HCV, whereas specificity was higher in younger individuals, women, and Child–Pugh A cirrhosis. In subgroup analysis (n = 178), ASAP had comparable sensitivity to ultrasound plus AFP (85.5% vs. 90.3%; p = 0.51) but lower specificity (53.4% vs. 93.1%; p < 0.001). Using the Youden-optimized cutoff (≥0.804) improved specificity to 83.4% while maintaining a sensitivity of 68.0% for early-stage HCC. Conclusions: ASAP demonstrated high sensitivity for early-stage HCC detection but low specificity. These findings suggest a need for optimized cutoffs prior to implementation in clinical practice. Full article

(1) Background: The Hepatitis B virus (HBV) is characterized by extensive genetic diversity, including low-frequency variants that contribute to disease progression. We aimed to characterize low-frequency variants and evaluate their potential clinical impact. (2) Methods: We utilized 104 HBV near-full-length sequences generated using next-generation sequencing (NGS) from people living with HIV (PLHIV). We used an in-house bioinformatics suite (HBVgenomeR v5.9.7) to filter for low-frequency variants (5–50%), which were compared to escape and drug resistance mutations (DRMs) and hepatocellular carcinoma (HCC)-associated mutations reported at the consensus level. Unclassified variants were characterized by HBV open reading frames (ORFs) to determine mutation frequency per genomic region. (3) Results: A total of six escape mutations were detected in 8/104 (7.7%) sequences, with _surfaceN131T being the most prevalent (5/8). We also observed six DRMs in 30/104 (28.8%), with _rtV173L being the most prevalent (21/30). Truncation mutations were also observed with _rtA181T/_sW172* and _rtM204I/_sW196L being the most prevalent. A total of 8/104 (7.7%) sequences had four variants associated with HCC. The _xP46S was the highest observed HCC-associated mutation at 5/8. We report 1152 unique uncharacterized variants across all ORFs, and these were found in 94/104 (90.4%) sequences. The RNaseH domain had the highest burden (330/1152, 28.6%). (4) Conclusions: Deep sequencing results identified clinically significant mutations, including those below the 20% detection limit of traditional sequencing, that would go unreported. This highlights the possible underreporting of mutational burden in people living with HBV/HIV, indicating the importance of deep sequencing to aid in HBV/HIV understanding and management. Full article

Contrast-enhanced low-mechanical-index endoscopic ultrasound (CELMI-EUS) extends the diagnostic capabilities of endoscopic ultrasound by enabling real-time assessment of hepatic microvascularization and perfusion using intravenous ultrasound contrast agents. Owing to its close proximity to the liver and high spatial resolution, CELMI-EUS is particularly suited for the detection and characterization of small or otherwise inconspicuous focal liver lesions. This review summarizes the technical principles of CELMI-EUS, contrast agent usage, vascular phase interpretation, and standardized assessment of benign and malignant focal liver lesions, including the potential and provisional application of CEUS Liver Imaging Reporting and Data System (LI-RADS) terminology in patients at risk for hepatocellular carcinoma, while acknowledging that dedicated validation for CELMI-EUS is lacking. Typical enhancement patterns of common benign lesions such as hemangioma, focal nodular hyperplasia, hepatocellular adenoma, biliary hamartomas, and abscesses are discussed, as well as malignant entities including metastases, hepatocellular carcinoma, and cholangiocarcinoma. In addition, the role of CELMI-EUS in lesion detection, interventional guidance, and its limitations and pitfalls are addressed. Integrated into a multimodality imaging approach alongside transcutaneous CEUS and cross-sectional imaging, CELMI-EUS represents a valuable complementary tool that improves diagnostic confidence and supports optimized management of patients with focal liver lesions. Full article

Chronic hepatitis B and C are major causes of cirrhosis, hepatocellular carcinoma, and liver-related mortality worldwide. The genetic diversity of hepatitis B virus (HBV) and hepatitis C virus (HCV) influences disease progression, diagnosis, vaccine response, and antiviral treatment. Periods of healthcare disruption, such as the COVID-19 pandemic, reinforce the importance of molecular surveillance to monitor viral genotypes and clinically relevant mutations. This study described the distribution of HBV and HCV genotypes and mutations in Rio de Janeiro, Brazil, during the COVID-19 pandemic. A cross-sectional study included 25 patients (15 HBV and 10 HCV) recruited between 2020 and 2022. Viral nucleic acids were amplified and sequenced by Sanger methodology, and mutations were analyzed using the Geno2pheno platform. HBV genotype A predominated (67%), comprising subgenotypes A1 (40%) and A2 (27%), followed by the rare genotypes B1 (13%), F2 (13%), and G (7%). Among HCV-infected individuals, genotypes 1a (40%) and 1b (30%) predominated, followed by genotypes 4 (20%) and 2 (10%). HBV immune escape mutations (Y100C and T126S) and unusual insertions in the S and RT domains were identified. In HCV, the substitutions C316Y, C316N, and S282R were detected. These findings highlight the importance of molecular surveillance for detecting clinically relevant viral variants. Full article

Heme oxygenase-1 (HO-1), encoded by HMOX1, catalyzes the rate-limiting step of heme degradation and generates biliverdin, carbon monoxide, and ferrous iron, thereby linking heme turnover with redox regulation and stress-associated signaling. In birds, biliverdin is retained as a major heme-derived product, but the cellular consequences of HMOX1 perturbation remain insufficiently defined. Here, CRISPR/Cas9-mediated editing was used to generate a heterogeneous HMOX1-edited population in Chicken hepatocellular carcinoma-derived cells. The selected sgRNA reduced HO-1 protein abundance by approximately 47%, and no detectable cleavage was observed at the seven predicted high-risk off-target loci examined. Compared with vector-control cells, HMOX1-edited cells exhibited intracellular heme accumulation, reduced biliverdin levels, increased oxidation-sensitive fluorescence, and reduced CCK-8 absorbance values, indicating disruption of heme–biliverdin metabolic and redox homeostasis. RNA sequencing identified 2650 differentially expressed genes, including 951 upregulated and 1699 downregulated genes. Downregulated genes were mainly enriched in immune, cytokine, MAPK/stress, and extracellular signaling-associated pathways, whereas DNA replication and cell-cycle-related genes were increased. Enrichment-term association and STRING functional-association analyses further identified a coordinated module involving IL1B, JUN, NFKBIA, IRF1, TGFB1, IL10, CCL5, and PTGS2. Independent RT-qPCR analysis confirmed selected expression trends. These findings show that heterogeneous HMOX1 editing and reduced HO-1 abundance are associated with disruption of the avian heme–biliverdin metabolic axis and coordinated remodeling of basal immune, stress, extracellular signaling, and cell-cycle-associated transcriptional programs in Chicken hepatocellular carcinoma-derived cells. Full article

Background: Neutrophil extracellular traps (NETs) promote tumor progression and immune evasion across multiple cancers. However, the mechanisms governing NET formation (NETosis) within the tumor immune microenvironment remain incompletely understood. Low P2RY13 expression is associated with the pro-tumor activity of neutrophils in lung adenocarcinoma. Methods: Pan-cancer bioinformatics analyses were performed, including differential gene expression, prognostic, tumor-infiltrating immune cell, and NET scoring analyses. Single-cell profiling was conducted using the Tumor Immune Single-cell Hub 2 database. Immunohistochemical (IHC) and multiplex immunofluorescence (mIF) staining of tissue microarrays (TMAs) was performed to validate findings in lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), and colorectal cancer (CRC). In vitro validation was conducted using gene modulation, tumor-cell-conditioned medium (CM) education, tumor-associated macrophage (TAM)-like macrophage CM transfer, immunofluorescence staining, and ELISA. Results: Bioinformatics analyses suggested that P2RY13 is frequently dysregulated in multiple cancers and that low P2RY13 expression is associated with poor prognosis and reduced immunotherapy responsiveness. Single-cell analyses revealed that P2RY13 is predominantly expressed in TAMs rather than tumor cells. Macrophages without detectable P2RY13 transcripts were markedly enriched in tumor tissues compared with paired normal tissues, and their high infiltration appeared to be associated with elevated NET scores. Tissue microarray-based IHC and mIF analyses further validated this infiltration pattern in LUAD, LIHC, and CRC. In vitro, CM from P2RY13-silenced, tumor-educated TAM-like macrophages enhanced neutrophil NETosis, whereas P2RY13 re-expression attenuated this effect. Furthermore, TMA staining indicated a positive correlation between P2RY13⁻CD68⁺ TAM infiltration and NET expression in the three malignancies. Conclusions: We identified a potentially conserved NETosis-regulating pattern in multiple cancers in which P2RY13-negative TAMs promote NET formation and are associated with adverse clinical outcomes. These findings suggest a previously unrecognized tumor-promoting mechanism and highlight potential therapeutic targets for cancer treatment. Full article

Aflatoxin B₁ (AFB₁), a dietary mycotoxin classified as a Group 1 carcinogen and a risk factor for hepatocellular carcinoma (HCC), has seen limited biomarker-based evidence linking it to HCC in South America despite favorable regional contamination conditions. Utilizing a newly validated isotope-dilution HPLC–MS/MS method to quantify AFB₁-Lysine (AFB₁-Lys) adducts, we conducted a cross-sectional study involving 92 HCC patients and 70 healthy controls across six South American nations. The primary case–control analysis, focusing on 64 HCC patients and 70 controls from Argentina and Colombia, revealed that AFB₁-Lys concentrations and positivity rates were significantly higher in HCC cases compared to controls (7.16 vs. 0.89 pg/mg albumin; 43% vs. 10%). Multivariable logistic regression demonstrated that detectable AFB₁-Lys was significantly and independently associated with HCC (adjusted OR = 3.72), with associations most pronounced, though based on small subgroups, in viral hepatitis-related and cryptogenic HCC. Furthermore, broader regional analysis indicated higher AFB₁-Lys positivity rates in HBV-positive patients than in HCV-positive or non-viral HCC cases. Ultimately, chronic dietary aflatoxin exposure shows a consistent, statistically significant association with hepatocarcinogenesis across diverse etiological backgrounds in South America, highlighting an urgent need for integrated regional food safety surveillance and expanded prospective studies. Full article

The progression and immune escape of HCC are closely regulated by endoplasmic reticulum stress (ERS). However, the associated ceRNA regulatory networks and their prognostic value remain to be systematically elucidated. Here, we sought to establish a prognostic signature derived from an ERS-associated ceRNA network and to investigate its relationship with the tumor immune microenvironment. We integrated TCGA-LIHC transcriptomic data with the MSigDB ERS gene set to identify ERS-associated differentially expressed genes and construct a ceRNA regulatory network. Using a forward search strategy with 10-fold cross-validation, we screened candidate genes to select the optimal prognostic combination and constructed a multigene Cox regression signature. External validation was performed in the independent microarray cohort GSE14520. By integrating single-cell transcriptomics, CIBERSORT, ESTIMATE, TIDE, and drug sensitivity analyses, we revealed immune microenvironment characteristics associated with this signature. Based on the ceRNA network’s eight core ERS mRNAs, an optimal three-gene signature comprising STC2, CKS1B, and PSAT1 was selected via forward search. The signature demonstrated robust prognostic discrimination in the TCGA training cohort (C-index = 0.653) and was independently corroborated in the external GSE14520 dataset (C-index = 0.584, log-rank p = 0.008). The signature was confirmed as an independent prognostic indicator by multivariable Cox regression. Functional enrichment analysis demonstrated a marked accumulation of cell-cycle-related pathways in the high-risk group, notably DNA replication and the spindle assembly checkpoint. Single-cell transcriptomic profiling showed that STC2 and CKS1B were predominantly expressed by tumor epithelial cells, whereas CCL2 and ATF3 were mainly detected in macrophages and fibroblasts. Drug sensitivity analysis indicated that the high-risk group was more sensitive to drugs such as docetaxel and AZD5582, consistent with the upregulation of proliferation pathways in this group; in the low-risk group, VE-822 exhibited selective sensitivity. This study established a three-gene prognostic signature based on the ERS-associated ceRNA network. The signature demonstrated robust prognostic stratification capabilities in cross-platform validation and revealed molecular characteristics centered on uncontrolled cell-cycle progression, as well as an immunosuppressive microenvironment, in the high-risk group, providing an exploratory tool for prognostic assessment and treatment strategy selection in hepatocellular carcinoma (HCC). Full article

Background/Objectives: Intraoperative ultrasound (IOUS) has become an integral component of modern hepatic oncology surgery, providing real-time imaging guidance during liver resections for hepatocellular carcinoma, colorectal liver metastases, and other primary or secondary hepatic malignancies. Despite substantial improvements in preoperative imaging modalities, occult lesions, disappearing metastases after chemotherapy, and complex vascular relationships continue to represent major intraoperative challenges. This structured narrative review aimed to evaluate the contemporary role of IOUS in hepatic oncology surgery, with particular emphasis on contrast-enhanced intraoperative ultrasound (CE-IOUS), minimally invasive liver surgery, navigation-assisted hepatectomy, and emerging artificial intelligence-based technologies. Methods: A structured literature review was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar databases. Peer-reviewed studies, international guidelines, consensus statements, systematic reviews, and technological reports addressing IOUS applications in liver surgery were analyzed. Particular focus was placed on studies evaluating lesion detection, intraoperative strategy modification, disappearing colorectal liver metastases, parenchymal-sparing hepatectomy, laparoscopic and robotic liver surgery, navigation systems, augmented reality integration, and AI-assisted imaging technologies. Results: Contemporary evidence demonstrates that IOUS continues to significantly influence intraoperative decision-making despite advances in magnetic resonance imaging and multidetector computed tomography. CE-IOUS improves the detection of occult hepatic lesions and residual disease after systemic chemotherapy, particularly in disappearing colorectal liver metastases. IOUS-guided anatomical and parenchymal-sparing resections contribute to the preservation of functional liver parenchyma while maintaining oncologic radicality. In minimally invasive liver surgery, laparoscopic ultrasound remains essential for lesion localization and vascular mapping. Recent developments integrating navigation systems, augmented reality platforms, and AI-assisted image recognition suggest a progressive transition toward digitally integrated precision liver surgery. Conclusions: IOUS remains a cornerstone of modern hepatic oncology surgery and continues to evolve from a localization tool into a comprehensive platform for precision-guided liver resection. The integration of CE-IOUS, navigation technologies, and artificial intelligence may further enhance intraoperative accuracy, oncologic safety, and individualized surgical planning in the future. Full article

Introduction: Circulating cell-free DNA (cfDNA) has emerged as a promising minimally invasive biomarker in hepatocellular carcinoma (HCC), with potential applications in disease detection and prognostic stratification. This exploratory study aimed to evaluate the relationship between circulating cell-free DNA (cfDNA) concentration, liver dysfunction parameters, and hepatocellular carcinoma stage in an exploratory cohort: we sought to explore the extent to which cfDNA variability may be explained by the underlying liver disease environment and whether cfDNA concentration provides incremental information beyond routinely available markers of liver reserve for the discrimination between early- and late-stage hepatocellular carcinoma. Methods: Sixty-four newly diagnosed HCC patients were included. Clinical, laboratory, and staging data were collected. cfDNA was isolated from plasma, confirmed by on-chip electrophoresis, and quantified by fluorimetry. Logistic regression and ROC curve analyses were performed to assess the ability of several biomarker panels to discriminate early-stage HCC (BCLC 0–A) from intermediate/advanced-stage disease (BCLC B–D). Bootstrap resampling (2000 iterations) evaluated model robustness and coefficient stability. Additional linear regression analyses explored associations between cfDNA concentration and liver dysfunction parameters. Results: Linear regression demonstrated that liver dysfunction parameters explained approximately 53% of cfDNA variability, while HCC stage contributed minimally after adjustment. Models incorporating albumin, bilirubin, and platelet count as individual parameters demonstrated the best discriminatory performance after adjustment for liver disease etiology, achieving AUROCs up to 0.857. The only incremental value that cfDNA concentration added to the panel was an increase to its specificity (from 79.4% to 94.1%), while reducing sensitivity by 13.4%. Bilirubin and platelet count remained the most stable predictors after bootstrap, whereas cfDNA concentration was unstable. Limitations: The study was limited by its small sample size, cross-sectional design, and lack of longitudinal outcome assessment. External validation in larger prospective cohorts is necessary. Conclusion: A substantial proportion of cfDNA concentration variability (approximately 53%) was explained by routinely available liver dysfunction parameters, whereas HCC stage had minimal contribution. These findings suggest that circulating cfDNA concentration in patients with HCC may be influenced to a greater extent by the underlying cirrhotic liver environment and hepatocyte injury than by tumor burden alone. Integrated multimarker panels combining liver reserve parameters and liver disease etiology may be of interest for minimally invasive stratification of HCC. Although cfDNA concentration increased specificity for early- versus advanced-stage disease discrimination, its incremental value was low. Further validation in larger prospective cohorts is required. Full article

Background/Objectives: Arterial hypertension (AH) and hepatitis C virus (HCV) infection are interlinked, with AH increasing the risk of severe liver disease and HCV contributing to cardiovascular issues. Treating HCV in hypertensive patients is critical, though data on direct-acting antivirals (DAAs) in this group remain limited. Methods: This retrospective study evaluated the effects of DAAs in AH patients with HCV using data from the 2015–2023 EpiTer-2 project, a multicenter study in Poland. Results: Among the 18,968 HCV-infected DAA-treated patients, 5976 had AH. These patients were older, predominantly women, and had higher rates of obesity, comorbidities, cirrhosis, hepatocellular carcinoma, and genotype 1b infection. Sustained virologic response rates were high and comparable between the AH and non-AH groups in the intent-to-treat (94.8% vs. 94.2%) and per-protocol analyses (97.6% vs. 97.6%). AH was not independently associated with treatment failure (OR 0.87, 95% CI: 0.69–1.10). Predictors of failure included genotype 3, decompensated liver function, cirrhosis, thrombocytopenia, and treatment with asunaprevir + daclatasvir. While therapy discontinuation was more common in the AH patients, most completed treatment, with fatigue being the most frequent adverse event. Although not directly evaluated, the overall safety outcomes suggest that potential drug–drug interactions with antihypertensive therapies are unlikely to have a major clinical impact in routine practice. Conclusions: This study highlights the safety and efficacy of DAAs in AH patients and emphasizes the importance of early HCV detection and treatment in this population. Full article

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality worldwide, is driven by complex interactions between genetic mutations and reversible epigenetic alterations. Among these, aberrant DNA methylation, histone modifications, and dysregulated noncoding RNAs (ncRNAs) play central roles in hepatocarcinogenesis, tumor progression, and therapy resistance. Epigenetic changes not only regulate key oncogenic pathways, including JAK/STAT and RAS, but also contribute to tumor immune evasion and heterogeneity. Unlike genetic mutations, epigenetic alterations are reversible, offering unique opportunities for therapeutic targeting. This review highlights recent advances in understanding the epigenetic landscape of HCC, identifies promising biomarkers for early detection and prognosis, and evaluates emerging epigenetic therapies (including DNMT, HDAC, and BET inhibitors as well as ncRNA-based strategies). Although these therapies have shown tumor-suppressive or treatment-sensitizing effects in preclinical models, their clinical translation remains limited by modest efficacy, small early-phase trials, treatment-related adverse events, and insufficient biomarker-guided patient selection. These insights may support more precise diagnostic and therapeutic strategies for HCC. Full article

Background/Objectives: The glucocorticoid receptor (GR) is essential for regulating liver energy balance, metabolism, and inflammation. Stress and other factors can impair its function, resulting in glucocorticoid-resistant metabolic liver disease. GR mainly exists in two forms: the glucocorticoid-binding isoform, GRα, and the non-binding isoform, GRβ. The GRβ isoform typically exhibits minimal signaling activity beyond its role as a dominant-negative regulator of GRα, thereby decreasing glucocorticoid responsiveness and potentially causing resistance. Methods: To explore GRβ signaling independent of GRα, we developed mice with adenovirus-induced overexpression of GRβ (GRβ-Ad) and control mice with a vector (Vec-Ad). After five days on a standard diet, these mice received either vehicle or dexamethasone treatment. Liver tissues were collected, and we performed RNA sequencing and advanced PamGene kinome analysis to detect pathway changes in GRβ-Ad mice compared with controls. Results: Significant increases were observed in the expression of genes that inhibit fatty acid oxidation, inflammation, and liver cancer development. There was also a marked difference in serine/threonine kinase activity between GRβ-Ad and control mice. Conclusions: The findings suggest that elevated GRβ levels affect kinase pathways that modulate glucocorticoid signaling, disrupt liver lipid metabolism, and are associated with cancer pathways. Further research is needed to determine whether GRβ functions similarly in humans and to assess its potential contribution to hepatocellular carcinoma (HCC). Full article

Hepatocellular carcinoma (HCC) is a heterogeneous primary liver malignancy characterized by limited treatment options and low overall survival rates. Recent studies have explored the role of programmed death ligand 1 (PD-L1), tumor-associated macrophages (TAMs), and epithelial-mesenchymal transition (EMT) in modulating tumor progression and the response to immunotherapy. This study aimed to investigate the association among PD-L1 expression, TAMs, and EMT in HCC, highlighting the recently proposed immunophenotypic variant—gastric-type HCCs. A retrospective cohort of 50 surgically resected HCC patients was analyzed. Immunohistochemical staining was performed for PD-L1 (clones 28-8 and 22C3), CD68 (TAMs), and EMT markers (VSIG-1, TTF-1, and vimentin). PD-L1 expression was detected in 52% of the patients and was significantly associated with high TAM counts (p < 0.001). Compared with PD-L1-negative patients, those with gastric-type HCCs, which are characterized by VSIG-1 and TTF-1 co-expression and vimentin negativity, demonstrated improved survival outcomes (p = 0.03). Integration of immune and EMT profiling of tumor cells in routine diagnostics may guide prognosis and immunotherapeutic strategies in HCC. Further molecular validation is required to confirm the biological significance of the proposed gastric-type HCC immunophenotype. Full article

The widespread adoption of prostate-specific membrane antigen (PSMA)-targeted PET/CT has profoundly reshaped molecular imaging in prostate cancer and has substantially reduced the routine use of radiolabeled choline tracers. However, the transition from choline to PSMA imaging should not be interpreted simply as the replacement of one radiopharmaceutical by another, but rather as part of a broader evolution from metabolism-based imaging toward receptor-targeted and biology-driven imaging strategies. This narrative review critically reassesses the residual and emerging role of choline PET/CT in the PSMA era, with particular attention to the biological rationale of choline uptake, selected prostate cancer scenarios, and extra-prostatic applications. In prostate cancer, PSMA PET/CT remains the dominant imaging modality because of its superior diagnostic performance, particularly in biochemical recurrence; nevertheless, choline PET/CT may provide complementary metabolic information in highly selected settings, including PSMA-low or heterogeneous disease, aggressive or dedifferentiated variants, neuroendocrine transformation, equivocal PSMA findings, and limited PSMA availability. These prostate cancer applications, however, are supported mainly by biological rationale, indirect evidence, and limited clinical data and should therefore be regarded as exploratory rather than established indications. By contrast, ¹⁸F-fluorocholine PET/CT has emerged as a clinically established imaging modality in primary hyperparathyroidism, particularly after negative or inconclusive conventional imaging, with prospective studies and meta-analyses demonstrating high detection rates and superior performance compared with conventional scintigraphic techniques. Additional applications in hepatocellular carcinoma and selected neuro-oncologic settings remain exploratory and require further validation. Overall, choline PET/CT should not be considered obsolete in the PSMA era, but selectively repositioned within biology-driven and multiparametric imaging strategies, with its strongest evidence currently supporting primary hyperparathyroidism and its other applications requiring cautious interpretation and further prospective validation. Full article