Search Results (577)

Lung adenocarcinoma (LUAD) remains the leading cause of cancer-related mortality worldwide, highlighting the urgent need for novel therapeutic targets. While the role of the somatostatin receptor (SSTR) family is well established in neuroendocrine tumors, their expression patterns, clinical significance, and therapeutic potential in LUAD are not fully understood. In this study, comprehensive analyses of publicly available databases, including TCGA, GSCA, and TIMER, revealed that SSTR4 transcriptional expression is significantly downregulated in LUAD tissues compared to adjacent normal lung tissues. Moreover, low SSTR4 expression correlates with advanced tumor stage, remodeling of the immune microenvironment, and decreased overall survival in patients with LUAD. Using the PRESTO-Tango system, we identified tangeretin (TAN) as a potential ligand for SSTR4. Functional assays demonstrated that SSTR4 knockdown markedly enhanced TAN-mediated proliferative, migratory, and survival inhibitory effects in LUAD cells. Subsequent RNA sequencing and pathway enrichment analyses revealed that the loss of SSTR4 altered the effects of TAN from extracellular matrix remodeling to disruption of calcium homeostasis and energy metabolism disorders, elucidating the mechanism underlying the enhanced antitumor activity. Collectively, these findings establish SSTR4 as a critical tumor suppressor and prognostic biomarker in LUAD and highlight the therapeutic potential of targeting the TAN–SSTR4 signaling axis. These results provide novel insights into the biological functions of SSTR family members in LUAD. Full article

Recurrent brain tumors—including high-grade gliomas, brain metastases, and aggressive meningiomas—continue to carry a poor prognosis, with high mortality despite therapeutic advances. The aim of this narrative review is to summarize and critically discuss the current evidence on the role of intra-arterial radioligand therapy (RLT) in the treatment of recurrent brain tumors. RLT, a targeted form of radionuclide therapy, has gained increasing attention for its potential theranostic applications in neuro-oncology. A literature search was conducted using PubMed and Scopus, including clinical studies evaluating intra-arterial radioligand delivery in central nervous system tumors. Recent research has explored intra-arterial administration of radioligands targeting somatostatin receptors and prostate-specific membrane antigen (PSMA). Somatostatin receptors are overexpressed in meningiomas, while PSMA is highly expressed in the neovasculature of glioblastomas and brain metastases; both targets can be addressed using lutetium-177 (¹⁷⁷Lu)- or actinium-225 (²²⁵Ac)-labeled radiopharmaceuticals, traditionally delivered intravenously. Available evidence indicates that the intra-arterial route achieves markedly higher radionuclide uptake on ⁶⁸Ga-PSMA-11 and ⁶⁸Ga-DOTATOC PET, as well as increased absorbed doses in dosimetric models. Dosimetric analyses consistently show greater tracer accumulation compared with intravenous administration, without evidence of significant peri-procedural toxicity. Uptake in healthy brain tissue is minimal, and no relevant differences have been reported in liver or salivary gland accumulation between intra-arterial and intravenous RLT. Although based on heterogeneous and limited data, intra-arterial RLT appears to be a promising therapeutic strategy for recurrent brain tumors. Future research should focus on improving radioligand delivery beyond the blood–brain barrier and enhancing effective tumor targeting. Full article

Objectives: Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) commonly relies on somatostatin receptor subtype 2 (SSTR2) agonists such as DOTA-TOC/TATE, which may show limited efficacy due to high hepatic uptake and therapy resistance in some patients. SSTR2 antagonists have demonstrated superior tumor targeting. This study aimed to establish the production and quality control of the Actinium-225-labeled SSTR2 antagonist [²²⁵Ac]Ac-DOTA-LM3 and to report in-human clinical experience with targeted alpha therapy (TAT). Methods: [²²⁵Ac]Ac-DOTA-LM3 was produced by radiolabeling DOTA-LM3 with Actinium-225 under validated conditions. Radiochemical conversion, purity, yield, and stability were assessed using radio-TLC, fractionated radio-HPLC combined with gamma spectroscopy, and in vitro serum stability testing. Clinical feasibility and therapeutic response were evaluated in a patient with metastatic neuroendocrine pancreatic neoplasm refractory to prior ¹⁷⁷Lu-based PRRT. Results: Radiolabeling achieved reproducibly high radiochemical purity (>97%) and decay-corrected yields exceeding 80%. The radiopharmaceutical showed high in vitro stability with minimal release of free Actinium-225 over five days. Fractionated radio-HPLC enabled indirect purity assessment. In the reported patient, [²²⁵Ac]Ac-DOTA-LM3 therapy resulted in partial remission without clinically relevant hematologic, renal, or hepatic toxicity and was associated with marked clinical improvement. Conclusions: [²²⁵Ac]Ac-DOTA-LM3 can be produced with high purity and stability using clinically applicable procedures. In-human results suggest promising efficacy and safety, supporting further clinical investigation of Actinium-225-labeled SSTR2 antagonists for advanced NETs. Full article

Meningiomas are the most common primary intracranial tumors, showing highly heterogeneous behavior and clinical outcomes. While the majority are benign, about one in five meningiomas are classified as higher grade (WHO Grade II–III), characterized by a more aggressive, treatment-resistant pathology. Although surgical resection remains the first-line therapy, peptide receptor radionuclide therapy is emerging as a novel and promising option for advanced, multifocal, or recurrent disease. The theranostic paradigm allows simultaneous detection and treatment of somatostatin receptor-expressing lesions using a single radiopharmaceutical. In this review, we explore the evolving role of PRRT in the management of meningiomas. We provide an integrated overview of preclinical findings—including radiosensitization mechanisms—and summarize the rapidly expanding clinical literature, which in recent years has grown both in patient numbers and in methodological sophistication. Particular emphasis is placed on advances in dosimetry, quantitative imaging, and radiomics, which are beginning to refine patient selection and improve response prediction. Together, current evidence highlights the therapeutic potential of radionuclide therapy in aggressive or refractory meningiomas and underscores the need for further prospective trials to define its optimal clinical application. Full article

Background/Objectives We re-analyzed publicly available gene expression profiles from the male mouse cortex under conditions of sleep deprivation (SD) using tensor decomposition-based unsupervised feature extraction, originally proposed by one of the authors in 2017. Methods We focused on two distinct expression patterns: genes whose levels were altered in SD and failed to normalize during recovery sleep (RS), and genes that overshot normal levels during RS. This selection excluded the expected “altered in SD and recovered in RS” pattern, which was not significantly observed. These two gene sets showed substantial overlap but were still distinct from each other. Results The analysis revealed that the selected gene sets were enriched in various brain regions as evidenced through clustering in the Allen Brain Atlas. This suggests that the successful selection identified biologically meaningful genes. Furthermore, somatostatin (Sst)-expressing neuronal clusters were among the most highly enriched. Conclusions Given that sst is already implicated in SD and RS, our fully data-driven transcriptomic analysis successfully identified the activity of sst during SD and RS. These findings reveal that Sst-expressing neurons may play a key role in SD. These results were further validated using AlphaGenome by uploading the selected genes to it. Full article

Chronic stress is a major risk factor contributing to cellular changes in the brain that precipitate the emergence of various behavioral changes, including anxiety and anhedonia—symptoms relevant to mood disorders including major depression—however the sequence and trajectory of early molecular changes is poorly characterized. Using the chronic restraint stress (CRS) model in mice (N = 6–8/sex/group), we assessed the impact of 0, 7, 14, 21, 28, or 35 days of CRS at the behavioral level on the emergence of anxiety-like and anhedonia-like phenotypes. While 7 days of CRS was sufficient to induce anxiety-like behaviors in the PhenoTyper test, anhedonia-like deficits in the sucrose consumption test were only observed after 35 days of CRS. We also investigated the underlying molecular changes in the prefrontal cortex, a limbic brain region highly sensitive to stress, using Western blot and qPCR. We found that protein or RNA levels of several markers known to be implicated in the pathology of depression, and markers of synapses (post synaptic density protein 95 (PSD95), synapsin-1 (SYN1), vesicular glutamate transporter-1 (VGLUT1), and gephyrin (GPHN)); GABAergic inhibitory interneurons (somatostatin (SST), parvalbumin (PV), glutamic acid decarboxylase-67 (GAD67), and vasoactive intestinal peptide (VIP)); and astroglia (glial fibrillary acidic protein (GFAP), glutamate transporter-1 (GLT1), and glutamine synthase (GS)) were gradually reduced by CRS. Interestingly, all three astroglial markers were negatively correlated with anhedonia-like behaviors, while SYN1 and GPHN negatively correlated with anxiety-like behaviors. GLT1, VGLUT1, SYN1, and GAD67 negatively correlated with Z-emotionality scores. Exploratory between-marker correlations and integrative network analyses revealed that CRS effects might be driven by different compartments (synaptic, GABAergic and astroglial) depending on sex. Our study demonstrates that CRS induces dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, may experience different underlying pathologies. Full article

Glomerular filtration rate (GFR) is a key indicator of renal function. Traditional methods for GFR measurement have limitations including invasiveness, low spatial resolution, and lengthy protocols. Positron emission tomography (PET) radiotracers have emerged as promising tools for non-invasive, accurate, and dynamic renal function assessment. Objectives: This systematic literature review evaluates the clinical utility, and current evidence surrounding PET radiotracers used for GFR measurement in humans, emphasizing advances over conventional renal imaging modalities. Methods: A systematic literature search was conducted in PubMed, Web of Science, and Scopus, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, from database inception to November 2024. The search identified studies evaluating PET-based measurement of glomerular filtration rate (GFR) and renal perfusion. Inclusion criteria encompassed human studies using PET radiotracers (e.g., ⁶⁸Ga, ¹⁸F) with comparisons to reference standards (estimated GFR or serum creatinine). Two authors independently screened titles/abstracts, extracted data, and assessed bias using Quality Assessment of Diagnostic Accuracy Studies tool (QUADAS-2). Exclusions included animal studies, reviews, and non-English articles. Results: Eleven studies met inclusion criteria, with ⁶⁸Ga-EDTA showing the highest validation against reference standards such as ⁵¹Cr-EDTA plasma clearance, demonstrating strong correlation. PET imaging offered superior spatial–temporal resolution, enabling accurate split renal function assessment and quantitative analysis of both filtration and perfusion. ⁶⁸Ga-somatostatin analogues exhibited moderate correlations between renal SUV and estimated GFR, with post-PRRT uptake changes indicating early nephrotoxicity. Among novel tracers, ⁶⁸Ga-FAPI showed a strong inverse SUV–GFR relationship, reflecting renal fibrosis and suggesting potential as a chronic kidney disease (CKD) biomarker but requires further clinical validation. Limitations across studies include small sample sizes, retrospective designs, and variability in reference standards. Conclusions: PET radiotracers, particularly ⁶⁸Ga-EDTA, represent a significant advancement for non-invasive, quantitative GFR measurement with improved precision and renal anatomical detail compared to traditional methods. Future prospective, large-scale human studies with standardized protocols are needed to establish these PET tracers as routine clinical tools in nephrology. Integration of hybrid PET/MRI and novel tracer development may further enhance renal diagnostic capabilities. Full article

Purpose: Zollinger–Ellison syndrome (ZES) is the most frequent, functional, malignant pancreatic neuroendocrine tumor syndrome (pNET), which is due to ectopic secretion of gastrin by a pNET/NET (i.e., gastrinomas) resulting in severe, refractory acid-peptic disease (ulcer, GERD). ZES has several unique management features, which lead to a number of unresolved controversies. Areas covered: Whereas both medical and surgical controversies exist, they have not been examined in detail for some time. This review contains an analysis of a number of the main current, medical controversies that are unresolved in ZES patients, including insights into the basis of these controversies and possible insights into their resolution from recent studies in patients with gastrinomas or from recent studies in other pNET syndromes or other neuroendocrine tumors (NETs). These include the following: controversies in the long-term control of acid secretion and acid antisecretory drug side-effects; controversies related to the difficulty in making the diagnosis of ZES; nonsurgical MEN1/ZES controversies related to the management of gastric carcinoids (Type II); nonsurgical MEN1/ZES controversies related to whether genotype–phenotype correlations exist in MEN1 patients including MEN1/ZES patients; nonsurgical MEN1/ZES controversies related to the roles of imaging/tumor localization in MEN1 patients for gastrinomas/pNETs in their initial/follow-up management; controversies related to the role of non-surgical tumor ablation for treatment of ZES/gastrinomas; and controversies related to medical treatment selection for advanced, metastatic disease in patients with ZES/gastrinomas/other malignant pNETs. Conclusions: In this paper, the basis for the development of each of these unique ZES-related controversies is discussed and insights into progress that could lead to their resolution are reviewed. Full article

Background/Objectives: Cardiac metastases (CM) represent a rare manifestation of neuroendocrine neoplasms (NEN). Detailed clinical characteristics and significance remain understudied. Methods: We retrospectively evaluated 1201 patients with NEN treated at an ENETS Center of Excellence to determine prevalence, clinical features, and outcomes of cardiac metastases. CM were identified in 15 patients (prevalence 1.25%) through multimodal imaging, incorporating somatostatin receptor positron emission tomography/computed tomography (SSTR PET/CT). Metachronous CM occurrence accounted for 93% of cases. Results: The majority of patients showed well-differentiated tumors (G1/G2), with ileum being the most frequent site of origin. Clinical symptoms attributable to CM were observed in 27% of affected patients. Following CM detection, therapeutic management was adjusted in 73% of cases, most frequently by initiating peptide receptor radionuclide therapy (PRRT) n = 8, 53%. Median overall survival (OS) from CM diagnosis was 95 months, with an estimated 5-year survival rate of 77%, with a 5-year OS from NEN diagnosis of 87%. Conclusions: CM in NEN are rare and often clinically silent, with SSTR PET/CT proving essential for detection. While treatment adjustments were frequently observed, particularly with PRRT, OS remained favorable, indicating that the presence of CM in NEN serves as an indicator of metastatic spread rather than a standalone diagnostic determinant of survival. Larger, prospective studies are needed to further validate these findings and to better define the clinical implications of CM in NEN. Full article

Background/Objectives: For completely resected well differentiated (WD) gastroenteropancreatic (GEP) NET, guidelines differ in recommendations for utilization of SSTR-based functional imaging in post-operative surveillance. While ¹¹¹In-Octreotide has previously been the standard of care, imaging with ⁶⁸Ga-labelled peptides has expanded in recent years due to increased sensitivity to detect smaller volume diseases and reduced costs. Though many centres have widely adopted imaging with ⁶⁸Ga-labelled peptides, its role in surveillance of resected GEP NET has not been well defined. We sought to characterize current utilization of imaging with ⁶⁸Ga-DOTATATE PET CT (⁶⁸Ga-DOTA) for post-operative surveillance of WD GEP NET and assess the impact on clinical management. Methods: We conducted a retrospective review of all ⁶⁸Ga-DOTA scans performed from April 2019 to August 2024. Inclusion criteria were age ≥ 18 years with WD grade 1 and 2 GEP NET that had undergone curative-intent surgery, had Stage I-III disease at diagnosis, and had ⁶⁸Ga-DOTA post-operatively. Results: Forty-six scans met the inclusion criteria. We identified four indications for ⁶⁸Ga-DOTA: (1) post-operative assessment (n = 12); (2) routine surveillance (n = 18); (3) recurrence suspected based on cross-sectional imaging (n = 10); and (4) recurrence suspected based on biochemical monitoring (n = 6). Avidity for each indication was observed in 45%, 8%, 50%, and 80%, respectively. Initiation of long-acting somatostatin analogue was the most common management following avidity. Conclusions: ⁶⁸Ga-DOTA best informed clinical decision making when there was clinical suspicion for residual or metastatic disease post-operatively or based on cross-sectional imaging or biochemistry. The utility of this modality for routine surveillance appears limited. Full article

Background: Meta-analyses on the prevalence and clinical significance of breast incidental uptake (BIU) at PET/CT are available only for [¹⁸F]FDG, showing that BIU is rare but malignant in a substantial proportion of cases. This study aimed to update the pooled prevalence and malignancy risk of BIU using different PET radiotracers, expanding [¹⁸F]FDG-based evidence. Methods: A comprehensive literature search of studies on BIU was carried out in two bibliographic databases, and the literature was screened up to 25 May 2025. Only original articles reporting BIU were selected. A proportion meta-analysis was conducted on a patient-based analysis using a random-effects model to estimate pooled prevalence, malignancy rate, and histological distribution. Results: In total, 29 studies were included in the systematic review and meta-analysis. PET/CT was performed using [¹⁸F]FDG (n = 25), radiolabeled somatostatin analogues (SSAs) (n = 3), or [¹⁸F]fluorocholine (n = 1). The pooled prevalence of BIU was 0.5% for [¹⁸F]FDG PET/CT, 3.4% for SSA PET/CT, and 2.6% for [¹⁸F]fluorocholine. The pooled malignancy rate among BIUs (female patients) was 33.5% for [¹⁸F]FDG, 86.4% for SSA, and 70% for [¹⁸F]fluorocholine PET/CT. Histological data were mainly available for [¹⁸F]FDG PET/CT, showing ductal carcinoma as the most frequent malignant histotype (pooled value 42.2%) and fibroadenoma (pooled value 14.8%) as the most frequent benign histotype. Conclusions: Similar to the case for [¹⁸F]FDG, BIU using other PET radiopharmaceuticals is uncommon but often malignant. Therefore, BIU should prompt dedicated breast imaging and, when indicated, histopathological confirmation. Further well-designed studies are needed to clarify the clinical impact of BIU detection and the prevalence and clinical significance of BIU using tracers other than [¹⁸F]FDG. Full article

Pancreatic neuroendocrine neoplasms (PanNENs) are a diverse group of cancers with varying clinical presentations and prognoses due to differences in morphology and clinical stage. Most are non-functional tumors that express somatostatin receptors (SSTRs). Several treatment options have been established for patients with locally advanced or metastatic PanNETs, but the optimal choice of treatment approach and the sequence of available therapies are not yet clearly defined and are currently being studied in multiple ongoing clinical trials. Additionally, new drugs are being researched for PanNET treatment, including immune checkpoint inhibitors, next-generation peptide receptor radionuclide therapy, and other targeted biological therapies. To improve treatment outcomes for patients with PanNETs, a multidisciplinary team should evaluate systemic treatment options. The aim of this article is to review currently available therapies and discuss new and emerging systemic treatment strategies for patients with advanced PanNETs. Full article

Background: Somatostatin receptors (SSTRs), especially subtype 2 (SSTR2), are increasingly recognized as valuable molecular targets in the imaging of chronic inflammatory and immune-mediated diseases. Their expression on activated immune and stromal cells enables specific, non-invasive detection of inflammatory activity using radio-labeled somatostatin analogs. Objective: This review aims to summarize current evidence on SSTR-targeted imaging across a range of chronic inflammatory and immune-mediated diseases, compare its diagnostic value with ¹⁸F-FDG PET/CT, and discuss biological mechanisms, clinical applications, and remaining challenges. Methods: A literature-based narrative review was conducted, integrating preclinical studies, clinical trials, and comparative imaging research involving SSTR PET/SPECT tracers such as ⁶⁸Ga-DOTATATE, ⁶⁸Ga-DOTANOC, ⁹⁹ᵐTc-HYNIC-TOC, and ¹¹¹In-pentetreotide in diseases including vasculitis, sarcoidosis, autoimmune myocarditis, rheumatoid arthritis, and thyroid-associated ophthalmopathy. Results: SSTR-targeted imaging has shown promising specificity for inflammatory lesions and provides favorable lesion-to-background contrast, particularly in tissues with high physiological FDG uptake such as the myocardium and brain. In vasculitis and sarcoidosis, SSTR-targeted tracers may complement FDG PET by improving diagnostic confidence and inter-observer consistency in selected small studies. Mechanistically, SSTR2 expression is closely associated with cytokine-driven immune activation, predominantly involving M1 macrophages. However, current evidence remains limited by heterogeneous receptor expression, variable myocardial uptake, and the lack of standardized imaging protocols. Conclusions: SSTR-targeted molecular imaging represents a biologically grounded and clinically promising complementary approach for assessing immune-mediated inflammation. Future developments in tracer design, quantitative standardization, and multicenter clinical validation are warranted to establish its role in precision diagnostics. Full article

One of most important parts of the female genital tract is the uterine cervix, both from the anatomical as well as physiological points of view. As there is currently a lack of detailed information on the presence, distribution pattern(s), and the chemical coding of phoenixin (PNX)-containing dorsal root ganglia (DRG) neurons supplying the porcine uterine cervix, this study, using combined retrograde tracing and double-immunofluorescence techniques, was aimed at analyzing (i) the distribution pattern of uterine cervix-supplying sensory neurons (UC-SNs) at the particular spinal cord levels, (ii) their intraganglionic distribution, and (iii) the patterns of PNX co-expression with other biologically active substances. UC-SNs were identified by the presence of deposits of Fast Blue (FB), in DRG of thoracic (Th10–Th15), lumbar (L1–L5) and sacral (S2–S4) spinal cord segments. FB⁺/PNX⁺ neurons constitute approximately 33% of all UC-SNs, 73% at the L, and 27% at the S neuromeres. These neurons were mainly small sized (52%), with a slightly smaller population of medium-sized cells (40%), while large-diameter cells made up the least numerous population (8%). The vast majority of FB⁺/PNX⁺ neurons simultaneously contained calcitonin gene-related peptide (CGRP; 80.9%) or substance P (SP; 77.9%); one-third of them showed immunoreactivity toward neuronal nitric oxide synthase (nNOS; 34%), while PNX⁺ UC-SNs containing pituitary adenylate cyclase-activating polypeptide (PACAP), galanin (GAL), calretinin (CRT), or somatostatin (SOM) formed significantly smaller populations (21.4%, 7.4%, 3.1%, and 0.7%, respectively). The results of the present study demonstrate the presence of PNX in DRG UC-SNs, and its co-occurrence with numerous neurotransmitters suggesting a putative role for this neuropeptide in the transmission of various types of sensory information and possible effects on the functioning of this organ in the body. Full article

Neuroendocrine tumors (NETs) are heterogeneous neoplasms with different molecular characteristics and prognosis. Although slow-growing, NETs are often diagnosed at an advanced stage. The treatment choice depends on primary site, extent, grade, growth rate, somatostatin receptor status, functional status, performance status, and comorbidities. Precise knowledge of the biological and molecular features of NETs has led to the development of novel therapies. Therapeutic options include somatostatin analogs, multi-targeted tyrosine kinase inhibitors (e.g., sunitinib), or mammalian targets of rapamycin (mTOR) inhibitors (e.g., everolimus), telotristat ethyl, chemotherapy, and peptide-receptor radionuclide therapy. Pivotal studies that led to approval, treatment-related adverse events, and safety concerns, as demonstrated in clinical trials and real-world clinical practice. Questions, such as the optimal timing, selection, and sequence of therapies, and biomarkers that predict response to the novel agents in an individual patient, remain to be answered. We propose a stepwise approach for the management of advanced Gastro-entero-pancreatic (GEP)-NETs that utilizes a multidisciplinary team of experts. Biomarkers may assist in both the diagnosis and post-treatment follow-up in patients with GEP-NETs. The next decade of research on GEP-NETs is promising and should provide new insights into the molecular underpinnings of this disease, therapy selection, and the sequencing of the available therapies, along with the potential role of AL in NET pharmacotherapy. Full article