Search Results (396)

Background/Objectives: Reliable biomarkers for longitudinal surveillance of neuroendocrine tumors (NETs) remain an unmet clinical need. Chromogranin A (CgA), the most widely used circulating biomarker, is limited by low sensitivity, substantial biologic variability, and poor concordance with radiologic progression. NETest2.0^® is a blood-based multigene transcriptomic liquid biopsy designed to dynamically assess NET biologic activity. This study compared serial NETest2.0^® measurements with CgA for monitoring disease progression in a real-world registry cohort. Methods: Patients with histologically confirmed NETs enrolled in the RegisterNET program (NCT02270567) who had paired blood samples and contemporaneous clinical assessment were included. NETest2.0^® scores were derived from quantitative RT-PCR analysis of a 51-gene transcript panel and expressed on a 0–100 scale. Serum CgA levels were measured using standard clinical immunoassays. Imaging-based disease assessment was performed using CT, MRI, and/or ⁶⁸Ga-somatostatin receptor PET/CT with RECIST 1.1 criteria applied where appropriate. Longitudinal percentage changes (Δ) between sequential measurements were evaluated using predefined NETest2.0^® thresholds and compared with the conventional CgA threshold (>50%). NETest2.0 Δ thresholds of >0% and >5% were evaluated a priori: >0% as a high-sensitivity threshold capturing any upward transcriptomic drift, and >5% as a more conservative threshold intended to reduce minor biological or analytical fluctuation. Receiver operating characteristic (ROC) analysis, operating characteristics, multivariable analysis (MVA), and logistic regression analysis (LRA) were performed. Results: A total of 191 patients were analyzed. Exploratory ROC analysis demonstrated superior discrimination for progression using serial NETest2.0^® changes compared with changes in CgA (AUC: 0.893 vs. 0.538; p < 0.0001). In the primary surveillance analysis, NETest2.0^® thresholds of >0% and >5% achieved AUCs of 0.860 (95% CI: 0.803–0.906) and 0.822 (95% CI: 0.760–0.873), respectively, both significantly superior to CgA (AUC: 0.553, 95% CI: 0.480–0.625; both p < 0.0001). NETest2.0^® >0% demonstrated the highest sensitivity (86.4%), whereas NETest2.0^® >5% achieved the optimal balance of sensitivity (70.5%), specificity (93.9%), and overall accuracy (88.5%). In multivariable and logistic regression analyses, changes in NETest2.0^® were the strongest independent predictor of progression (all p < 0.0001; odds ratios: 52.99–61.26), whereas CgA did not significantly contribute to progression prediction. Conclusions: Serial NETest2.0^® assessment significantly outperformed CgA for monitoring NET disease activity and progression. These findings support the integration of NETest2.0^® into molecularly informed surveillance strategies to complement imaging and improve longitudinal monitoring of patients with NETs. Full article

Background/Objectives: Acromegaly is a chronic endocrine disorder caused mainly by GH-secreting pituitary adenomas, leading to excess GH and elevated IGF-1. Although surgery is first-line therapy, many patients require medical treatment, and remission is often not achieved with first-generation somatostatin receptor ligands (SRLs). Pasireotide, a second-generation SRL, offers superior biochemical and tumor control but is associated with hyperglycemia. This study aimed to evaluate real-world outcomes associated with pasireotide treatment in patients with acromegaly inadequately controlled on first-generation SRLs, with IGF-1 normalization as the primary endpoint. Secondary outcomes included GH control, tumor response, and glycemic safety. Methods: We conducted a historical cohort study of adults with acromegaly treated at Clínica Imbanaco (Cali, Colombia) between 2017 and 2024. Eligible patients had residual tumors and persistently elevated GH and/or IGF-1 levels above the age-adjusted upper limit of normal despite treatment with clinically adequate doses of first-generation SRLs, as well as 12 months of continuous pasireotide treatment and follow-up after pasireotide initiation. Demographic, biochemical, imaging, and glycemic data were collected. Statistical analysis included paired and independent Student’s t-tests, Wilcoxon signed-rank tests, McNemar’s test, and Fisher’s exact test, with significance set at p < 0.05. Results: Fourteen patients (50% female; mean age 52.1 ± 14.5 years) were included. After 12 months, mean IGF-1 decreased from 2.73 ± 0.73 to 0.99 ± 0.56 × ULN, and 50% achieved IGF-1 normalization. Additionally, 35.7% achieved GH < 1 ng/mL, and 14.3% achieved combined control. Mean tumor diameter decreased by −3.26 mm (95% CI −4.56 to −1.95; p < 0.001). HbA1c increased from 5.56% to 6.05%, while type 2 diabetes mellitus prevalence rose from 14.3% to 35.7%. No patient discontinued pasireotide due to metabolic adverse events. Conclusions: Pasireotide was associated with favorable biochemical and tumor responses in patients with acromegaly inadequately controlled on first-generation SRLs under real-world conditions. Although treatment was associated with higher HbA1c and increased diabetes incidence, proactive monitoring and early management of hyperglycemia may have supported treatment persistence. Full article

The fibroblast activation protein (FAP) has emerged as a compelling theranostic target because it is highly expressed in the tumour microenvironment of many solid malignancies, predominantly on cancer-associated fibroblasts and, in selected tumour types, also on tumour cells. Following the rapid clinical expansion of FAP-targeted PET imaging, FAP-targeted radionuclide therapy (FAP-TRT) is now being explored as a predominantly stromal-directed therapeutic strategy across a broad range of solid malignancies. However, unlike established theranostic paradigms, such as prostate-specific membrane antigen- and somatostatin receptor-directed radioligand therapies, FAP-TRT faces distinct biological and translational challenges, including stromal heterogeneity, variable patterns of FAP expression, and limited tumour retention of many early radioligands. This review outlines the biological rationale, mechanistic basis, radiopharmaceutical development, and emerging clinical evidence for FAP-TRT. We highlight the recent ligand-engineering strategies aimed to improve tumour residence time and absorbed dose, and to summarise the current clinical data with particular focus on dosimetry, safety, and early efficacy signals. We also discuss key future directions, including disease-focused clinical development and rational combination strategies with immune checkpoint inhibitors, DNA damage response inhibitors, and chemotherapy. Overall, the available data support the feasibility of FAP-TRT but also underscore the need for improved ligand design and biologically informed clinical development to define its role within the evolving theranostic landscape. Full article

Acromegaly is a rare chronic endocrine disorder characterized by delayed diagnosis, multisystem comorbidity, and heterogeneous therapeutic response. We aimed to describe the clinical characteristics, tumor profile, treatment patterns, biochemical control, pituitary insufficiencies, and comorbidity burden in an endocrinology tertiary center in northeastern Romania. This observational retrospective study included 87 adult patients admitted for general inpatient evaluation between December 2023 and November 2024, with retrospective data collected from diagnosis and follow-up assessed through the last available hospital visit at St. Spiridon Clinical Emergency Hospital. Clinical, hormonal, imaging, and therapeutic data were analyzed using descriptive statistics and inferential statistical tests. Most patients were diagnosed in middle adulthood, with a female predominance. Macroadenomas and extrasellar extension were common, consistent with advanced tumor stage at presentation. Treatment was predominantly multimodal, with surgery as the main therapeutic intervention and somatostatin receptor ligands as the main medical treatment backbone. Biochemical improvement was observed over time, although complete remission was achieved only in a subset of patients. These findings describe the clinical and therapeutic complexity of acromegaly in a single tertiary-center inpatient cohort and support the need for individualized long-term monitoring. Full article

Background/Objectives: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor that often expresses somatostatin receptors (SSTRs). While various PET radiopharmaceuticals were used, there is no universal consensus on the optimal imaging modality for whole-body assessment of MTC. This study aims to evaluate the detection rate (DR) and clinical management impact of SSTR PET/CT imaging in patients with MTC. Methods: A systematic search was conducted across PubMed/MEDLINE, Scopus, and Embase. A total of 14 studies (comprising 350 patients) were eligible for quantitative meta-analysis. Pooled DRs were calculated using a random-effects model, and methodological quality was assessed via the QUADAS-2 tool. Results: Our analysis revealed an overall DR of 75.1% (95% CI: 67.6–82.6%) for recurrent or metastatic MTC, showing moderate significant heterogeneity (I² = 65.41%). Clinical impact of SSTR PET/CT was demonstrated in 16.6–100% of cases, primarily by identifying candidates for Peptide Receptor Radionuclide Therapy. Only a few studied investigated the relationship between serum calcitonin levels and the detection rate of SSTR PET/CT, finding a significant correlation. Conclusions: The DR of SSTR PET/CT in recurrent/metastatic MTC was high. SSTR PET/CT may have a positive impact on clinical management in a significant number of cases. Full article

Background: Neuroendocrine tumors—are relatively rare but increasingly diagnosed malignancies originating from diffuse neuroendocrine cells, most commonly affecting the gastroenteropancreatic system. Due to their long asymptomatic development and low incidence, pose a diagnostic and therapeutic challenge for physicians. Recently, the role of nuclear medicine has been growing not only in the diagnostic stage but also in treatment. Systemic radionuclide therapy using somatostatin analogs labelled with the radioisotope lutetium-177 is becoming increasingly common in patients with advanced-stage disease. Currently, most patients receive a standard activity of therapeutic radiopharmaceuticals. Recent clinical studies provide increasing evidence of a close relationship between the absorbed radiation dose in pathological lesions and the therapeutic effect of radioisotope therapy. Internal dosimetry is used to measure the doses of ionising radiation absorbed by the patient after administration of the radiopharmaceutical. The lack of individual internal dosimetry prior to therapy means that only a small fraction of patients receive optimal doses of radioactivity, which is markedly different from external beam radiotherapy planning. Methods: A narrative literature review was conducted using the PubMed/MEDLINE and Embase databases, focusing primarily on publications from the last years. The search strategy included combinations of keywords related to peptide receptor radionuclide therapy and dosimetry, such as “Lutetium-177”, “neuroendocrine tumors”, “dosimetry”, “PRRT”, “systemic radionuclide therapy” and “artificial intelligence”. Particular emphasis was placed on recent prospective clinical studies, multicenter investigations, systematic reviews and consensus documents published by major nuclear medicine societies, including the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). Seminal earlier publications considered essential for understanding the development of dosimetry concepts and clinical implementation were also included. Results: This study confirms the existence of a clinically significant dose-response relationship in ¹⁷⁷Lu-PRRT. Higher absorbed doses to tumour lesions are associated with longer progression-free survival. The lack of individualized internal dosimetry prior to therapy means that only a small proportion of patients receive optimal radiation doses. Simplified dosimetric approaches with a reduced number of imaging time points, together with emerging artificial intelligence–based tools, appear promising for reducing the complexity of the dosimetry process. Conclusions: The aim of this study was to analyse the current literature on the role of internal dosimetry in the treatment of neuroendocrine tumors using the radioisotope lutetium-177. Available data support the clinical relevance of individualized dosimetry and highlight its potential to optimize both therapeutic efficacy and treatment safety. Full article

Nectin-4 has emerged as a clinically relevant target in muscle-invasive bladder cancer (MIBC), primarily because of its role in antibody–drug conjugate-based therapies. However, the broader biological context of Nectin-4 expression and its association with tumor-promoting signaling pathways in MIBC remain insufficiently characterized. In this single-institution study, Nectin-4 expression (H-score 0–300) was assessed by immunohistochemistry in two independent MIBC cohorts. Associations between Nectin-4 expression and key markers related to growth signaling, metabolic regulation, and inflammation were analyzed alongside clinicopathological characteristics. Nectin-4 expression was significantly higher in malignant tissue than in non-malignant tissue (p = 0.0016 and p = 0.0302, respectively). Nectin-4 expression was not associated with demographic or clinicopathological parameters; however, a trend toward lower expression in more advanced disease stages was observed. Significant positive correlations were identified between Nectin-4 expression and protein kinase B (p = 0.0004), cytoplasmic (p = 0.0115) and membranous somatostatin receptor 2 (p = 0.0125), insulin receptor substrate 1 (p = 0.03), and interleukin-1 receptor antagonist (IL-1RA; p = 0.0045). In contrast, a negative correlation was observed with the IL-1β/IL-1RA ratio (p = 0.0246). Although Nectin-4 expression was not significantly associated with cancer-specific or overall survival, a trend toward shorter relapse-free survival was observed in patients with lower Nectin-4 expression (p = 0.0531). In multivariate analysis, patient age, but not Nectin-4 expression, emerged as an independent prognostic factor. Although Nectin-4 expression does not appear to have independent prognostic value, its biological associations suggest that it reflects an integrated tumor-related signaling context. These findings support further investigation of Nectin-4 as part of rational, biology-driven therapeutic strategies in bladder cancer. Full article

Background and Clinical Significance: Carcinoid heart disease (CHD) is an uncommon valvular manifestation of neuroendocrine tumours, usually affecting right-sided cardiac valves. Left-sided involvement is rare and is generally associated with bronchopulmonary carcinoid, right-to-left shunting, or markedly elevated circulating vasoactive substances. Therapeutic decision-making is particularly challenging in advanced disease when severe tricuspid regurgitation occurs in patients at prohibitive surgical risk. Case Presentation: We report the case of a 61-year-old male patient with progressive dyspnoea, abdominal distension, lower-limb oedema, facial flushing, and 15 kg of unintentional weight loss. Transthoracic and transoesophageal echocardiography demonstrated torrential tricuspid regurgitation caused by thickened, retracted, and immobile leaflets, with additional mitral and aortic valve involvement, raising strong suspicion of CHD. An agitated-saline contrast study demonstrated delayed right-to-left shunting without patent foramen ovale, suggesting an extracardiac, likely intrapulmonary, shunt. Somatostatin receptor PET/CT identified a pancreatic lesion with metastatic disease, and bone marrow biopsy confirmed neuroendocrine tumour infiltration. Owing to prohibitive surgical risk, as reflected by a Tricuspid Regurgitation Impact Score (TRI-SCORE) with an estimated in-hospital mortality of 65%, unfavourable tricuspid anatomy for repair, and refractory venous congestion, heterotopic bicaval valve implantation was performed (TricValve system -P&F). Discussion: This case highlights the role of echocardiography in recognising the characteristic phenotype of CHD, detecting occult right-to-left shunting, and supporting selection of a palliative transcatheter intervention. It also illustrates the value of a multimodality diagnostic strategy integrating echocardiography, functional oncological imaging, and histopathology in tumour-related cardiac disease. Conclusions: In selected inoperable patients with advanced carcinoid-related tricuspid regurgitation, heterotopic bicaval valve implantation may represent a feasible strategy for reducing venous congestion and improving functional status. Full article

Background: Radioiodine (Na[¹³¹I]I) therapy is the cornerstone of systemic treatment for differentiated thyroid cancer (DTC), exploiting sodium–iodide symporter (NIS) expression for durable control. Up to 30–40% of advanced cases develop radioiodine-refractory disease (RAI-R DTC), marked by impaired iodine uptake, aggressive behavior, and poor response to Na[¹³¹I]I. Locoregional treatments, multikinase inhibitors (MKIs), and selective targeted agents improve progression-free survival but are not curative and carry cumulative toxicity, motivating precision-based alternatives. The primary objective of this review is to clarify the evolving theranostic paradigm in RAI-R DTC; the secondary objectives are to appraise redifferentiation and iodine-based theranostics for restoring or exploiting iodine avidity and to evaluate non-iodine theranostic strategies for cases where iodine biology is absent, impaired, or unreliable. Methods: This narrative review synthesizes contemporary evidence on theranostic strategies in RAI-R DTC, drawn from available studies, clinical trials, and current guidelines, with an emphasis on redifferentiation and non-iodine approaches; a systematic search protocol was not applied. Results: Theranostics couples target-specific molecular imaging with matched radionuclide therapy and response-adapted sequencing. Its most transformative application is redifferentiation, in which pharmacologic modulation of oncogenic signaling can restore iodine avidity and enable renewed, dosimetry-guided Na[¹³¹I]I treatment. Beyond iodine, somatostatin receptor (SSTR) imaging and peptide receptor radionuclide therapy (PRRT) have re-emerged in very selected cases, whereas alpha emitters remain investigational. Refractoriness is increasingly viewed as a reversible continuum rather than a fixed state. Conclusions: Theranostics can individualize RAI-R DTC treatment, restoring or exploiting iodine biology where possible and shifting to non-iodine targets where it is unreliable. Patient selection, timing, and integration with systemic therapy are central, and prospective validation is needed. Full article

Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by fibroblast growth factor 23 (FGF-23)-secreting tumors, typically of mesenchymal origin, leading to renal phosphate wasting and severe bone demineralization and fragility fractures. Diagnosing TIO remains a significant clinical challenge, particularly when coexisting mineral metabolism disorders, such as hypercalcemic hyperparathyroidism, are masking its clinical presentation. Case Presentation: A 74-year-old woman with fragility fractures, generalized bone pain, and nephrolithiasis was initially diagnosed with primary hyperparathyroidism due to concomitant hypercalcemia, hypophosphatemia, and elevated parathyroid hormone (PTH). Despite a successful parathyroidectomy, which normalized calcium levels, severe hypophosphatemia persisted due to renal phosphate wasting. High FGF-23 levels and subsequent functional imaging indicating a somatostatin receptor-positive lesion in the left popliteal fossa led to the diagnosis of TIO. Surgical resection immediately normalized FGF-23 levels, leading to a slower rise in phosphorus during follow-up. Histopathology revealed a tophaceous-like giant cell granulomatous reaction, recalling the earlier report by Prader. Conclusions: This case highlights that parathyroid disorders can coexist with TIO, and they may delay its diagnosis. In this circumstance, a high index of clinical suspicion is represented by the persistence of hypophosphatemia post-parathyroidectomy. Full article

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with increasing incidence, particularly within the gastroenteropancreatic (GEP) system. The liver represents the most common site of metastasis, and neuroendocrine liver metastases (NELMs) significantly impact prognosis, symptom burden, and therapeutic decision-making. Surgical management remains a cornerstone in the treatment of NELMs and encompasses a spectrum of strategies, including curative liver resection, cytoreductive surgery, and, in selected cases, liver transplantation (LT). Hepatic resection, although potentially curative when technically feasible, is applicable only to a highly selected subset of patients, and its benefits in terms of long-term survival and symptom control remain limited by recurrence rates and patient-related factors. Cytoreductive surgery has emerged as a valuable alternative in patients with unresectable disease, with increasing evidence supporting a ≥70% debulking threshold as sufficient to achieve meaningful clinical benefit. This approach may improve survival and quality of life, notably in symptomatic patients, and can be combined with parenchymal-sparing techniques and locoregional therapies. Liver transplantation represents a radical but potentially curative strategy for highly selected patients with liver-only disease, favorable tumor biology, and stable disease. Outcomes are strongly dependent on strict selection criteria, and appropriate patient selection remains critical. The incorporation of systemic treatments, such as somatostatin analogues, targeted therapies, and peptide receptor radionuclide therapy (PRRT), has broadened the available therapeutic options and contributed to redefining current treatment strategies. Overall, the management of NELMs requires a multidisciplinary, individualized approach guided by tumor biology, disease distribution, and patient-specific factors, with the goal of optimizing survival outcomes and preserving quality of life. Full article

Background/Objectives: Histone deacetylase (HDAC) inhibitors have been shown to prime the response to immunotherapy (IMT) treatment by inducing immune activation and infiltration to target tumor cells. Many studies primarily focus on adaptive immune cells and their expression of pro-inflammatory markers, like somatostatin receptor 2 (SSTR2); however, macrophages are known to help mediate key tumor microenvironment changes. The goal of this study is to evaluate the effects of HDAC inhibitors and IMT on macrophages, their expression of SSTR2, and their impact on the treatment response in triple-negative breast cancer (TNBC). Methods: Cytotoxic effects of HDAC inhibitors on 4T1 mouse mammary carcinoma cells, including suberoylanilide hydroxamic acid (SAHA), were evaluated using flow cytometry. Bone marrow-derived macrophages (BMDMs) were stimulated to M1-like and M2-like phenotypes and treated with SAHA to explore the effects on SSTR2 expression in different macrophage phenotypes. 4T1-tumor-bearing BALB/c mice were used to evaluate the therapy response to four treatments: saline control, SAHA, anti-PD-1 + anti-CTLA-4 checkpoint blockade IMT, or a combination of SAHA + IMT. Additional cohorts of 4T1-tumor-bearing BALB/c mice and NOD SCID mice, which lack adaptive immune cells, were euthanized for early evaluation of tumor-associated macrophage (TAM) populations via flow cytometry and cytokine analysis. One-way independent ANOVAs and log-rank tests were used to compare group differences. Results: SAHA promotes SSTR2 expression on M1-like BMDMs in vitro. SAHA promotes M2-like TAMs in vivo and stimulates pro-inflammatory, anti-tumor cytokine production in combination with IMT. Conclusions: SAHA drives SSTR2 expression and anti-tumor innate immune responses with additive effects in combination with immunotherapy in preclinical TNBC. Full article

Somatostatin is a potent endocrine regulator and neurotransmitter, exerting predominantly inhibitory effects in different tissues of the body, via G-protein coupled receptors. Five such specific receptors have been identified, with different effects and tissue distribution. The multifaceted actions and effects of somatostatin make it useful as a potential therapeutical means in various pathologies; however, in clinical practice, somatostatin analogues, namely octreotide, lanreotide and pasireotide, are commonly used instead, due to their increased half-life and increased receptor selectivity, with pasireotide showing a more extensive receptor binding profile and high affinity for somatotastin receptor (SSTR) 5, which may prove effective in cases of resistance to first-generation analogues. Apart from their many uses in neoplastic pathologies, somatostatin analogues represent viable treatment choices in some ocular pathologies, congenital hyperinsulinism, gastrointestinal bleedings and portal hypertension, acute pancreatitis, and dumping syndrome. They have also been used in some cases, with varying degrees of success, in patients with post-surgical gastrointestinal and lymphatic fistulas, refractory chronic diarrhoea and polycystic kidney disease; many applications in paediatric patients have also been documented. The aim of this review is to present the applications of somatostatin and its analogues as alternative or second-line therapies, along with insights into their effectiveness and future potential. Full article

Background: Somatostatin receptors (SSTRs) are pivotal diagnostic and therapeutic targets in well-differentiated neuroendocrine neoplasms (NENs). SSTR-directed treatment strategies rely on sufficient SSTR2 expression. Thus, receptor loss during dedifferentiation limits therapeutic efficacy. Preclinical data suggest pharmacologic modulation of SSTRs’ expression. However, there are no robust data on the effect of NEN-specific systemic treatments on SSTRs’ expression and function. Methods: We systematically evaluated the effects of six systemic agents commonly used in NEN therapy—isplatin, etoposide, 5-fluorouracil (5-FU), streptozotocin (STZ), temozolomide (TMZ), and everolimus—on SSTR2 and SSTR5 expression, as well as on uptake of ⁶⁸Ga-DOTATOC, in BON-1 and QGP-1 cells, as well as the MS-18 cell line. Analyses included qRT-PCR, Western blotting, immunohistochemistry, and radiopeptide uptake assays. Results: Systemic agents modulated SSTR expression and radioligand uptake in a drug- and cell line-dependent manner. Etoposide consistently upregulated SSTR2 expression and significantly increased radioligand uptake across all three cell lines. TMZ enhanced SSTR2 expression and uptake in BON-1 cells, but reduced uptake in QGP-1 and MS-18 cells. In contrast, 5-FU, STZ, cisplatin, and everolimus showed heterogeneous, compound- and cell line-specific effects on SSTR2 expression and ⁶⁸Ga-DOTATOC uptake, including both up- and downregulation depending on the model. Conclusions: All agents under investigation affect SSTR expression in vitro, while etoposide is identified as the most consistent enhancer of SSTR2’s expression and function across cellular NEN models. Our findings highlight both the potential and the risks of systemic therapy-induced receptor modulation and therefore support further investigation of treatment sequencing strategies to optimize SSTR-targeted approaches. However, further studies are required to translate these observations to a clinical setting. Full article

Antibodies directed against β-amyloid (Aβ) have been developed for the treatment of Alzheimer’s disease (AD). However, the in vivo central efficacy is reduced by the poor penetration of antibodies across the blood–brain barrier (BBB). In addition, these antibodies have been associated with adverse effects like amyloid-related imaging abnormalities. Thus, the development of new antibody-based therapies for AD with improved transport across the BBB may improve efficacy and reduce adverse effects. Antibodies targeting the BBB transferrin receptor (TfR) are able to cross the BBB through receptor-mediated transcytosis, producing a global distribution throughout the brain. Along the same line, bispecific antibodies directed to both the BBB TfR and Aβ showed enhanced brain uptake and pharmacological effects with diminished adverse side effects in experimental animal models of AD and in clinical trials. A generation of brain-penetrating fusion proteins targeting the BBB-TfR has been shown to represent novel treatments for AD, and this includes erythropoietin, tumor necrosis factor alpha inhibitors, neprilysin, somatostatin, oligonucleotides, and an antibody activating TREM2. The aim of this article is to review the progress made in the delivery of antibody-derived biologicals to the brain for AD, targeting the BBB-TfR. Full article