Search Results (196)

Background and Objectives: Peptide receptor radionuclide therapy (PRRT) using radiopharmaceuticals labelled with Lutetium-177 is currently a therapeutic option for patients with advanced neuroendocrine neoplasms overexpressing somatostatin receptors (SSTRs). One promising option that has gained interest for PRRT is using alpha-emitting radioisotopes such as Actinium-225. The aim of this study was to perform a systematic review and meta-analysis on the efficacy and safety of radioligand therapy with Actinium-225 DOTATATE in advanced, metastatic or inoperable neuroendocrine neoplasms. Materials and Methods: A comprehensive literature search of studies on radioligand therapy with Actinium-225 DOTATATE in neuroendocrine neoplasms was carried out. Three different bibliographic databases (Cochrane Library, Embase, and PubMed/MEDLINE) were screened up to May 2025. Eligible articles were selected, relevant data were extracted, and the main findings on efficacy and safety are summarized through a systematic review. Furthermore, proportional meta-analyses on the disease response rate and disease control rate were performed. Results: Five studies (153 patients) published from 2020 were included in the systematic review. The pooled disease response rate and disease control rate of radioligand therapy using Actinium-225 DOTATATE were 51.6% and 88%, respectively. This treatment was well-tolerated in most patients with advanced, metastatic or inoperable neuroendocrine neoplasms. Conclusions: Radioligand therapy with Actinium-225 DOTATATE in advanced, metastatic or inoperable neuroendocrine neoplasms is effective with an acceptable toxicity profile and potential advantages compared with SSTR-ligands labelled with Lutetium-177. Currently, the number of published studies on this treatment is still limited, and results from multicenter randomized controlled trials are needed to translate this therapeutic option into clinical practice. Full article

Well-differentiated neuroendocrine neoplasms (NENs) are characterized by hyperexpression on the cell membrane of somatostatin receptors (SSTRs). The demonstration of SSTRs, mainly the subtype 2 (SSTR2), is the prerequisite for diagnostic and therapeutic strategies with radiolabeled somatostatin analogs (SSAs). SSTRs can be routinely demonstrated in vivo by SSA-positron emission tomography/computed tomography (SSA-PET/CT) and in vitro by immunohistochemistry (IHC). This systematic review and meta-analysis aimed to gather evidence from the available literature on the correlation between the in vivo PET/CT and in vitro IHC SSTR expression in NEN patients. A systematic review and meta-analysis were conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines. A comprehensive literature search was performed in PubMed/MEDLINE and Cochrane Library, selecting studies correlating SSTR expression in NENs via IHC and SSA-PET/CT. Data extraction, quality assessment, and statistical analysis were performed. Eleven studies met the inclusion criteria for systematic review (345 patients). Of these, eight studies (299 patients) provided sufficient quantitative data for meta-analysis. The pooled concordance between SSA-PET/CT and IHC was 76% (95% CI: 67.7–84.2), indicating a good correlation between in vivo and in vitro SSTR2 expression. Heterogeneity among studies was moderate (I² = 65%), reflecting different patient cohorts and methodologies regarding both SSA-PET/CT and IHC. No significant publication bias was detected. Our results confirmed good agreement between in vivo tumor uptake with SSA-PET/CT and in vitro SSTR2 expression with IHC, highlighting the potential of using IHC for clinical decision-making in NEN patients when SSA-PET/CT is not available. Full article

Neuroendocrine neoplasms (NENs) represent a heterogenous group of tumors with significant inter- and intra-patient variability. Once considered to be rare, neuroendocrine neoplasms are being increasingly recognized through the advent of advanced diagnostic techniques, which may be contributing to the significant increase in the incidence and detection rate of these tumors. NENs can be classified into well differentiated and poorly differentiated neuroendocrine tumors (NETs) or neuroendocrine carcinomas (NECs). The proliferation rate of NETs can vary from Ki-67 1–55%. In addition, the SSTR expression can vary significantly. Because of this high “heterogeneity”, their detection and characterization have become essential to disease management, leading to dual-tracer imaging, most commonly with FDG- and SSTR-targeted PET/CT. Because of the complexity of the disease, the optimal treatment of patients depends on a combination of imaging, serological biomarkers, and clinical information. There remains a significant portion of patients who do not respond as anticipated, and the management of their disease remains challenging with current techniques, necessitating the refinement of our technologies and the development of new ones. In addition to new biological targets, improved peptide vector targeting for the somatostatin receptor needs further development. This review aims to evaluate the existing imaging techniques utilized in the diagnosis, assessment, and treatment of NENs, as well as the emerging radiopharmaceuticals and technologies, which will expand our imaging repertoire as well as our management options. Full article

Background: There is limited data on somatostatin receptor (SSTR) expression of metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) using modern imaging techniques and stratifying by primary site and tumor grade (G). Understanding patterns of SSTR expression and tumor heterogeneity is essential when determining the relevance of cold and radiolabeled somatostatin analog treatments. Methods: A single-institutional retrospective analysis of metastatic well-differentiated G1-3 GEP-NET patients who underwent Gallium-68 ([⁶⁸Ga])-DOTATATE or Copper-64 ([⁶⁴Cu])-DOTATATE positron emission tomography (PET) imaging from September 2016 to June 2024 was performed. Results: A total of 1192 patients were considered eligible for this study. Among them, 26 (2.2%) were completely negative on SSTR PET/computed tomography (CT), and 27 (2.3%) had weak uptake (less or equal to the normal liver). Up to 40 (3.4%) had heterogeneous SSTR expression on PET/CT: 26 (2.2%) displayed the coexistence of strongly avid lesions with the absence or near absence of SSTR uptake in measurable tumors (heterogeneous strong), while 14 (1.2%) had a combination of absent and weakly expressing SSTR tumors (heterogeneous low). An additional nine cases with prior homogeneous expression (0.8%) developed new SSTR-negative tumors along with disease progression, potentially indicating dedifferentiation. The absent or heterogeneous SSTR expression rates were greater in NET G3 than G1/G2 and in tumors originating outside the small bowel (midgut). Most NETs with absent or heterogeneous SSTR expression were fluorodeoxyglucose-F-18 ([¹⁸F]FDG)-avid. Conclusions: The large majority of metastatic GEP-NETs demonstrate strong and relatively uniform SSTR expression, but approximately 8% are SSTR-negative, weak or heterogeneous on PET/CT. Higher than average rates of absent/heterogeneous/weak SSTR expression occur in G3 NETs and lower rates among small intestine primaries. Full article

Colorectal cancer (CRC) remains the leading cause of morbidity and mortality for both men and women worldwide. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) of solid tumors, including CRC. These macrophages are found in the pro-inflammatory M1 and anti-inflammatory M2 forms, with the latter increasingly recognized for its tumor-promoting phenotypes. Many signaling molecules and pathways, including AMPK, EGFR, STAT3/6, mTOR, NF-κB, MAPK/ERK, and HIFs, are involved in regulating TAM polarization. Consequently, researchers are investigating several potential predictive and prognostic markers, and novel TAM-based therapeutic targets, especially in combination therapies for CRC. Macrophages of the gastrointestinal tract, including the normal colon and rectum, produce growth hormone-releasing inhibitory peptide/somatostatin (SRIF/SST) and five SST receptors (SSTRs, SST1-5). While the immunosuppressive function of the SRIF system is primarily known for various tissues, its role within CRC-associated TAMs remains underexplored. This review focuses on the following three aspects of TAMs: first, the role of macrophages in the normal colon and rectum within the broader context of macrophage biology; second, the various bioactive factors and signaling pathways associated with TAM function, along with potential strategies targeting TAMs in CRC; and third, the interaction between the SRIF system and macrophages in both normal tissues and the CRC microenvironment. Full article

Background: Incidental brain imaging findings could be clinically relevant, and advancements in molecular imaging could lead to their more frequent identification. The aim of this review is to establish the prevalence and clinical significance of brain incidentalomas at PET (BIPs) using radiotracers other than [¹⁸F]FDG. Methods: A comprehensive literature search of studies about BIPs was carried out. Four different databases (PubMed/MEDLINE, EMBASE, the Cochrane library, and Google Scholar) were screened up to December 2024. Only original articles about BIPs using radiotracers other than [¹⁸F]FDG were selected. A proportion meta-analysis of the prevalence of BIPs was carried out using a random-effects model. Results: Fourteen studies were included in the review, using somatostatin receptor (SSTR) PET (n = 6), radiolabeled choline PET (n = 5), prostate-specific membrane antigen (PSMA) ligands PET (n = 1), [¹⁸F]Fluciclovine PET (n = 1), and [¹⁸F]FDOPA PET (n = 1). The pooled prevalence of BIPs was 4.6% for SSTR PET, 1.1% for choline PET, 1.2% for PSMA ligands PET, 2.5% for [¹⁸F]Fluciclovine PET, and 3.9% for [¹⁸F]FDOPA PET. When BIPs were further evaluated using MRI, meningiomas were the most frequent lesions detected, but both benign and malignant lesions could be incidentally diagnosed. Conclusions: BIPs using radiotracers other than [¹⁸F]FDG are not rare, in particular at SSTR PET, further justifying the extension of PET scans to the brain when radiotracers other than [¹⁸F]FDG are used. When detected, a BIP should be further evaluated using brain MRI. Both benign and malignant lesions could be incidentally detected in the brain. Further studies are warranted to better clarify the clinical impact of BIP detection. Full article

Effective molecular imaging and targeted cancer therapy rely on receptor-specific targeted delivery systems that are both metabolically stable and kinetically inert for optimal in vivo performance. Until now, no single metal complexing agent has demonstrated the versatility to coordinate metals across the periodic table while maintaining the kinetic inertness required for clinical theranostic applications. Therefore, enhancing the in vivo kinetic stability of radiolabeled, cell-targeting, biologically active compounds remains a critical goal to minimize unintended accumulation of radioactivity in collateral tissues. This review describes the usage of NOTA [NOTA = 1,4,7-triazacyclononane-1,4,7-triacetic acid] and derivatives of NOTA, a metal complexing agent that has been found to have the ability to effectively coordinate with a wide range of radiometals, including metal-radiohalogens, to form stable complexes. This enables the development of new cell-targeting small molecule and peptide conjugates with the potential to resist demetallation in vivo, thereby reducing radionuclide uptake in non-target tissues. Herein, we discuss the design and development of NOTA-based, cell-targeting, small molecules having very high affinity and selectivity for the GRPR (Gastrin-Releasing Peptide Receptor), the SSTR2 (Somatostatin Receptor Subtype 2), and the MC1R (Melanocortin-1) receptors that are present on the surfaces of numerous solid primary human tumors and their metastatic counterparts. Full article

(1) Background: GEP-NETs are frequently diagnosed at advanced stage. For well-differentiated somatostatin receptor-positive (SSTR+) NETs, SSA are the preferred first-line therapy. However, in newly diagnosed patients with G2/G3 and a high tumor burden, SSA alone might not be enough; (2) Methods: We conducted a retrospective analysis to assess the effectiveness of combining oxaliplatin–fluoropyrimidine chemotherapy with SSA as an upfront strategy in newly diagnosed metastatic G2/G3 GEP-NET patients treated with oxaliplatin–fluoropyrimidine-based chemotherapy; (3) Results: Between March 2017 and October 2023, 32 pts (19 males, 13 females; M:F = 1.5:1; median age 54 years, range 31–82) were deemed eligible to receive oxaliplatin–fluoropyrimidine chemotherapy in addition to SSA; 14 received XELOX and 18 FOLFOX. After a median follow-up of 26 mo., each patient had completed at least two cycles of chemotherapy. The ORR was 25%, with a median DoR of 21.3 mo. The DCR was 87.5%. Notably, 28.1% of patients experienced tumor shrinkage sufficient for radical surgery on residual tumor lesions, encompassing both primary tumors and metastases; (4) Conclusions: Upfront treatment with the combination of oxaliplatin–fluoropyrimidine and SSA demonstrated effectiveness and safety. This approach may be considered to facilitate conversion surgery in eligible patients. Full article

Auger electrons are low-energy, high-linear-energy-transfer particles that deposit their energy over nanometers distances. Their biological impact depends heavily on where the radionuclide is localized within the cell. To verify the hypothesis that the cell membrane may be a better molecular target than the cytoplasm in Auger electron therapy, we investigated whether the radiotoxicity of ^99mTc varied depending on its location in the cell. The behavior of peptide radiopharmaceuticals ^99mTc-TECANT-1 targeted the cell membrane was compared with ^99mTc-TEKTROTYD directed to the cytoplasm. Our findings confirmed that ^99mTc-TECANT-1 displayed greater binding to AR-42-J cells than ^99mTc-TEKTROTYD. Additionally, it was demonstrated that the receptor agonist ^99mTc-TEKTROTYD is localized in more than 90% of the cytoplasm, while ^99mTc-TECANT-1 is found in 60–80% of the cell membrane. When evaluating cell survival using the MTS assay, we observed that toxicity was significantly higher when ^99mTc was targeted to the membrane compared to the cytoplasm. This indicates that, for ^99mTc, as with ¹⁶¹Tb, the membrane is a more sensitive target for Auger electrons than the cytoplasm. Our results also suggest that receptor antagonists labelled with therapeutic doses of ^99mTc may be effective in treating certain cancers. However, further detailed studies, particularly dosimetric investigations, are necessary to validate these findings. Full article

Metastases to the breast from non-mammary malignancies are rare, accounting for 0.1–5% of all breast malignancies. Neuroendocrine tumors (NETs) rarely metastasize to the breast. PET-CT somatostatin receptor imaging plays a pivotal role in the staging and follow-up of NETs, leveraging tracers like 68Ga-DOTATOC that bind to somatostatin receptors (SSTRs) expressed on tumor cells. While both primary and metastatic NETs express SSTRs, primary breast tumors may also exhibit an uptake of 68Ga-somatostatin analogs, making the differential diagnosis between primary breast tumors and neuroendocrine metastases challenging. Additionally, imaging characteristics of breast metastases from NETs are poorly documented in the literature, posing a diagnostic challenge that extends to pathology, particularly when in the absence of clinical suspicion. Misdiagnosis in such cases can lead to inappropriate therapeutic interventions. We report the case of a 75-year-old female patient with a history of pancreatic NET who presented to our breast clinic for further evaluation of a breast mass after a PET-CT scan revealed moderate 68Ga-DOTATOC uptake. Multimodality breast examination, including mammography and multiparametric US with B-mode, Color Doppler, Strain Elastography (SE), Shear Wave Elastography (SWE), and contrast-enhanced US (CEUS), was performed. Following a core biopsy, the lesion underwent surgical excision, revealing the diagnosis of NET metastasis. This case highlights a rare instance of neuroendocrine tumor metastasis to the breast, assessed using various ultrasound techniques, with detailed imaging and quantitative analysis. The comprehensive multimodal assessment contributes to the limited body of literature and provides elements for the differential diagnosis of a rare breast lesion that should always be considered in the presence of a known primary NET. Full article

Background/Objectives: Meningiomas are the most common intracranial tumors. Surgery and radiation therapy are the cornerstones of treatment and no standard of care therapy exists for refractory meningiomas. This manuscript aims to provide a comprehensive review of novel diagnostic and therapeutic approaches against these tumors. Methods: A search for the existing literature on systemic therapies for meningiomas was performed on PubMed and a search for presently accruing clinical trials was performed on ClinicalTrials.gov. Results: Systemic treatments, including chemotherapy, somatostatin analogs, anti-hormone therapy, and anti-angiogenic therapy, have been extensively studied with marginal success. Targeted therapies are actively being studied for the treatment of meningiomas, including focal adhesion kinase (FAK), sonic hedgehog signaling pathway, phosphoinositide-3-kinase (PI3K), and cyclin-dependent kinases (CDK) inhibitors. These driver mutations are present only in a subset of meningiomas. In stark contrast, somatostatin receptor 2 (SSTR2) is ubiquitously expressed in meningiomas and was formerly targeted with somatostatin analogs with modest success. Theranostic SSTR2-targeting via [⁶⁸Ga]DOTATATE for PET imaging and β-emitting [¹⁷⁷Lu]DOTATATE for the treatment of meningiomas are currently under active investigation. Conclusions: A nuanced approach is needed for the treatment of refractory meningiomas. Targeted therapies show promise. Full article

Some plants belonging to the Leontodon sect. Asterothrix were collected from southern Albania. They were compared with the closest taxon (L. albanicus s.str.) from morphological and molecular (AFLPseq fingerprinting) points of view. Uni- and multivariate statistical analyses of morphological data revealed distinctive discontinuities—especially in terms of the characteristics of the indumentum–that are paralleled by separation into two genetic clusters in AFLPseq fingerprinting. Following an integrated taxonomic approach based on morphological, genetic, and geographical sources of evidence, we show that the newly discovered population should be regarded as a new subspecies named Leontodon albanicus subsp. acroceraunicus. The new taxon is described and illustrated, and its relationship with L. albanicus subsp. albanicus is also discussed. We have no data to assess conservation status according to IUCN categories and criteria; however, considering that it is probably limited to the Acroceraunian Mountains, it deserves particular conservation interest. Full article

Meningiomas account for approximately 40% of all primary brain tumors, of which 1.5% are classified as grade 3. Whilst meningiomas are discovered on imaging with high-grade meningiomas being associated with certain imaging features, the final diagnosis is based on histopathology in combination with molecular markers. According to the latest World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), grade 3 should be assigned based on criteria for anaplastic meningiomas, which comprise malignant cytomorphology (anaplasia) that resembles carcinoma, high-grade sarcoma or melanoma; elevated mitotic activity; a TERT promoter mutation and/or a homozygous CDKN2A and/or CDKN2B deletion. Surgery remains the mainstay treatment modality for grade 3 meningiomas, followed by radiotherapy. Limited data are available on the effect of stereotactic radiosurgery and systemic therapy for grade 3 meningiomas; however, studies are underway. Despite optimal treatment, the estimated recurrence rate ranges between 50% and 95% with a 5-year survival rate of 66% and a 10-year estimated survival rate of 14% to 24%. Full article

Background. Neuroendocrine neoplasms (NENs) represent a heterogeneous group of tumors that pose significant therapeutic challenges due to their potential for progression, metastasis, and hormonal syndromes. Somatostatin analogs (SSAs) have emerged as a cornerstone in NEN treatment, offering both antisecretory and antiproliferative effects by targeting somatostatin receptors (SSTRs). Despite their proven efficacy, intrinsic and acquired resistance mechanisms, including receptor downregulation, tumor heterogeneity, and microenvironmental influences, limit their long-term effectiveness. Recent advances, including high-dose SSA regimens and novel formulations, have aimed to optimize their therapeutic utility and address these limitations. Body of the review. This review explores the cellular and molecular mechanisms underlying the antitumor effects of SSAs, including receptor-mediated signaling pathways, cell cycle arrest, apoptosis induction, and antiangiogenesis. The role of SSAs in combination therapies with mTOR inhibitors and peptide receptor radionuclide therapy (PRRT) is analyzed, emphasizing their synergistic potential. Key clinical trials, such as RADIANT-2, EVERLAR, and NETTER-1, support the efficacy of these approaches, demonstrating improved outcomes when SSAs are combined with targeted agents or radiolabeled therapies. Emerging strategies include high-dose SSA regimens, particularly in progressive cases with low Ki67 indices. Finally, novel formulations, including oral octreotide, paltusotine, and subcutaneous depot formulations like CAM2029, offer improved pharmacokinetics, bioavailability, and patient adherence. Ongoing clinical trials, including SORENTO, further evaluate their efficacy and safety profiles. Conclusions. This paper provides a comprehensive analysis of the cellular and molecular mechanisms of SSAs. SSAs remain integral to the management of NENs, providing effective tumor stabilization and symptom control. However, resistance mechanisms and tumor heterogeneity necessitate innovative approaches, including high-dose regimens, combination strategies, and next-generation formulations. Future research should focus on refining these strategies to optimize patient outcomes, enhance long-term efficacy, and expand the therapeutic landscape for NENs. Full article

Knowledge of how novel antigens or dietary stimuli affect stomach development and function in pigs remains limited. This study aimed to investigate stomach characteristics, parietal cell numbers, and the expression of genes essential to the functioning of the fundic and pyloric gland regions at weaning compared to seven days post-weaning and to examine whether maternal probiotic supplementation or piglet dietary tryptophan (Trp) levels influence these stomach parameters. This study has a 2 × 3 factorial design, with 48 sows assigned to one of two diets: basal or basal supplemented with Bacillus subtilis and Bacillus amyloliquefaciens. Their litters received creep diets containing 0.22, 0.27, or 0.33% standardized ileal digestible (SID) Trp. In total, 96 pigs were sacrificed for gastric sampling, 48 on the day of weaning and 48 on day 7 post-weaning. At 7 days post-weaning, pigs had an increased number of parietal cells and expression of parietal cell activity and digestive enzyme (PGA5 and CHIA) genes in the fundic gland region (p < 0.05), although the expression of signaling molecules involved in the regulation of acid secretion was unchanged in the fundic gland region (p > 0.05) and reduced in the pyloric gland region (p < 0.05), compared to the day of weaning. Overall, maternal probiotic supplementation had a significant impact on gene expression in the fundic gland region of the offspring, elevating several genes related to parietal cell activity (CLIC6, HRH2, KCNE1, KCNQ1, CHRM3, CCKBR, and SSTR2) (p < 0.05). Additionally, there were time × maternal interactions, where certain acid secretion pathway (ATP4A and HDC), chitinase enzyme (CHIA), and ghrelin (GHRL) genes were increased in offspring from probiotic sows compared to control sows at weaning (p < 0.05), but not at 7 days post-weaning (p > 0.05). Maternal probiotic supplementation did not influence growth performance pre-weaning or during the 7-day post-weaning period. There was a limited effect of creep Trp level or maternal × creep interactions on performance, gene expression, or parietal cell counts. Low pre-weaning creep intake may have confounded this analysis. In conclusion, maternal probiotic supplementation accelerated the maturation of the offspring’s stomach, particularly in terms of the expression of genes linked to acid secretion from parietal cells. Full article