Susanne Lütje

PSMA PET/CT imaging biomarkers are increasingly investigated as predictors of response and survival outcomes following [¹⁷⁷Lu]Lu-PSMA radioligand therapy in prostate cancer. This review summarizes the current evidence and clinical relevance of these biomarkers. As [¹⁷⁷Lu]Lu-PSMA radioligand therapy is increasingly being introduced into earlier treatment lines of prostate cancer management, the identification of reliable imaging biomarkers for response prediction and outcome assessment is becoming increasingly important. Quantitative PSMA PET/CT parameters such as whole-body (WB) mean standardized uptake value (SUV_mean), WB PSMA-positive tumor volume, and tumor load, as well as qualitative features including disease distribution and phenotype (e.g., visceral metastases and FDG-avid, PSMA-negative discordant lesions), have been associated with treatment response, progression-free survival, and overall survival. However, the clinical utility of these imaging biomarkers is limited by heterogeneous study designs, small cohorts, and a lack of standardization in image acquisition, quantification, and cutoff definitions. This review critically appraises available data on baseline PSMA PET/CT-based prognostic and potentially predictive biomarkers for RLT and identifies the methodological barriers that must be addressed before these biomarkers can be implemented in clinical practice.

Background Prostate-specific membrane antigen (PSMA)-targeted radioguided surgery (PSMA-RGS) is a promising intraoperative technique for improving lesion localization and surgical accuracy in prostate cancer (PCa), particularly in high-risk or recurrent cases. Objective To systematically evaluate the diagnostic performance of PSMA-RGS in PCa using multilevel meta-analysis. Methods Following PRISMA 2020 guidelines, we searched PubMed, Embase, and Web of Science for clinical studies published between January 2016 and May 2025, with the final search performed on May 1, 2025, and identified 28 eligible studies. Diagnostic accuracy was assessed at the patient, lesion, region, and lymph node levels, using pooled sensitivity, specificity, likelihood ratios, and diagnostic odds ratios (DOR). Random-effects meta-analyses were conducted and risk of bias was evaluated with the ROBINS-I tool. Results Ex vivo PSMA-RGS demonstrated the highest specificity (up to 100%), while in vivo PSMA-RGS showed excellent sensitivity (90–97%) and specificity (90–99%), particularly at the lymph node level. Across all evaluated anatomical levels, PSMA-RGS consistently outperformed preoperative imaging (log DOR: 5.77 vs. 2.99; p < 0.0001). All diagnostic results were confirmed by histopathology as the reference standard. Meta-regression identified in vivo PSMA-RGS, lymph node–based analysis, and γ-probes combined with high-purity germanium detectors—used for post-resection confirmation—as independent predictors of improved diagnostic performance. Conclusion PSMA-RGS demonstrates robust diagnostic accuracy across multiple analytical levels, including per-patient, per-lesion, and per-node assessments. Initial evidence suggests that intraoperative γ-probes guidance may enable real-time localization of otherwise undetected nodal metastases. In high-risk prostate cancer surgery, this approach may help refine intraoperative decision-making, improve resection completeness, and reduce recurrence.

Background: Radiolabeled fibroblast activation protein inhibitors (FAPIs) have emerged as novel radiopharmaceutical agents for tumor diagnosis. Compared with [¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG), which reflects glucose uptake in metabolically active regions, FAPIs mainly bind to the fibroblast activation protein (FAP), which is highly expressed in tumor-associated fibroblasts, forming a pronounced signal. Several studies suggested potential superiority of FAPI tracers above [¹⁸F]FDG-based imaging in a variety of tumor entities. In this systematic review, we focus on the comparison of FAPI-PET/CT and [¹⁸F]FDG-PET/CT in upper-abdominal tumors. Methods: Original research published from 1 January 2021 to 22 December 2024 was collected from the PubMed and Web of Science databases (CRD42025648267). This research included only clinical studies, excluding conference abstracts and case reports. The risk of bias was assessed with the QUADAS-2 tool, and all evaluation steps performed independently by three independent reviewers. A systematic quality assessment of the included studies was conducted based on the imaging performance of FAPI-PET/CT and [¹⁸F]FDG-PET/CT for pancreatic, liver, and gastric cancers. The meta-analysis used relative risk (RR) as the effect size, with bias assessed via the Peters test (p-value > 0.05). Cochran’s Q test and I-squared value are used to comprehensively evaluate the magnitude of heterogeneity. Analyses and data visualization were performed in R language. Results: The database search identified 3272 articles. After screening, 31 studies were included in this analysis. The original studies enrolled 1377 participants (M/F: 850/527; ages predominantly between 50 and 70). Of these, 939 patients were ultimately diagnosed with tumors (five cancer subtypes) and included in this analysis. Meta-analysis results showed that FAPI-PET/CT significantly surpassed [¹⁸F]FDG-PET/CT in the detection of primary lesions (RRs = 1.20 and 1.17), lymph nodes (RRs = 1.18 and 1.24), distant metastases (RRs = 1.22 and 1.51), peritoneal metastases (RRs = 1.31 and 2.22), and bone metastases (RRs = 1.16 and 1.23). The two imaging methods exhibit clear differences in diagnostic performance (sensitivity: 98% vs. 79%; specificity: 83% vs. 87%), and FAPI-PET/CT demonstrates high and stable diagnostic performance (RRs = 1.20 and 1.17). Conclusions: Compared with [¹⁸F]FDG-PET/CT, FAPI-PET/CT demonstrates significant advantages in detecting primary lesions, lymph nodes, distant metastases, and peritoneal and bone metastases in pancreatic, liver, and gastric cancers (RR > 1.0). Overall, FAPI-PET/CT shows better diagnostic performance (RR > 1.0).

Background/Objectives: To evaluate the efficacy, safety, and symptom impact of yttrium-90 selective internal radiation therapy (Y-90 SIRT) for neuroendocrine liver metastases (NELM) through an updated systematic review and meta-analysis integrated with our institutional data. Methods: We retrospectively analyzed 12 patients with NELM treated with Y-90 resin microspheres between 2019 and 2024. Outcomes included overall survival (OS), hepatic progression-free survival (HPFS), symptom improvement, and adverse events. Concurrently, a systematic review and meta-analysis of 43 studies (including our institutional cohort; total n = 2221; 2008–2025) was conducted following PRISMA guidelines. Pooled estimates for survival, tumor response, symptom improvement, and adverse events were derived using random- or fixed-effects models, with publication bias assessed by standard methods. Results: In our cohort, the median OS and HPFS were 33.3 and 15.3 months; 71.4% of symptomatic patients reported improvement, with no grade ≥ 3 toxicities. In the meta-analysis, pooled OS rates were 82%, 66%, 52%, and 34% at 1, 2, 3, and 5 years, and HPFS rates were 64%, 41%, and 29% at 1, 2, and 3 years. The pooled objective response rate (ORR) and disease control rate (DCR) were 40% and 87% by RECIST, and 56% and 91% by mRECIST. Patients treated with resin microspheres (ORR 38%, DCR 86%) and glass microspheres (ORR 39%, DCR 83%) showed comparable responses. Symptom improvement was observed in 77% of symptomatic patients, while reported grade ≥ 3 toxicities for individual adverse events were each below 5%. Conclusions: Y-90 SIRT is associated with promising survival outcomes, high disease control rates, and substantial symptom improvement in NELM with acceptable toxicity, suggesting its potential value as a liver-directed therapy option.

Molecularly targeted therapies are increasingly relevant in clinical oncology, as they enable the selective modulation of specific biologic targets—such as enzymes or receptors—by inhibiting or enhancing their function. Nectin cell adhesion molecule 4 (nectin-4), a tumor-associated antigen, is overexpressed in various malignancies and has been linked to tumor progression and poor clinical outcomes. Its role has recently gained significant attention, particularly in urothelial carcinoma, where nectin-4–targeted antibody–drug conjugates have demonstrated promising therapeutic efficacy. These findings have positioned nectin-4 not only as a relevant target for noninvasive tumor characterization and cancer therapy but also as a valuable biomarker for molecular imaging. This review provides an overview of the recent developments in nectin-4–directed molecular theranostics, on the basis of a literature analysis, with a focus on the design, preclinical validation, and clinical translation of novel radiotracers in nuclear medicine. Multiple nectin-4–targeted radiotracers—comprising antibody- and peptide-based agents—have demonstrated high specificity and strong affinity for nectin-4–overexpressing tumors, particularly in urothelial carcinoma and triple-negative breast cancer. Exploratory preclinical and clinical data consistently showed comparable diagnostic accuracy to standard molecular imaging methods (e.g., [¹⁸F]FDG-based PET), enhanced detection of metastatic lesions, and effective monitoring of therapeutic response and eventual treatment resistance to nectin-4–targeted antibody–drug conjugates. Visual Abstract

PSMA-targeted radiopharmaceutical therapy (RPT) is a standard treatment for metastatic castration-resistant prostate cancer (PCa), exploiting PSMA overexpression to deliver cytotoxic radiation. Treatment with the β-emitter [¹⁷⁷Lu]Lu-PSMA-617, approved in 2022, has been associated with prolonged progression-free and overall survival in patients with PCa. However, resistance and heterogeneous patient responses limit its efficacy. Although immunotherapy is effective in several malignancies, PCa’s immunosuppressive microenvironment often reduces its impact. Combining targeted RPT with immune checkpoint inhibitors, particularly programmed cell death protein 1 and programmed cell death ligand 1 inhibitors, may enhance antitumor responses. This review explores the rationale behind this combination, evaluates preclinical and clinical evidence, and discusses future directions for integrating immune checkpoint blockade with targeted RPT. Visual Abstract

Purpose T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a novel immune checkpoint receptor implicated in tumor immune evasion. Non-invasive imaging of TIGIT expression holds potential for improving patient selection and monitoring in cancer immunotherapy. This systematic review aims to evaluate recent advancements in radiotracer development for non-invasive visualization of TIGIT. Methods A comprehensive literature search was conducted up to February 2025 using databases including PubMed and Web of Science. The search terms "TIGIT imaging", "TIGIT PET", "TIGIT SPECT", and "TIGIT visualization" were used, focusing on those reporting on the development, characterization, or application of immuno-PET tracers targeting TIGIT expression. Both preclinical and clinical studies were reviewed. Results Six studies met the inclusion criteria, exploring tracers targeting TIGIT expression on immune cells. These studies have focused on the development of TIGIT-targeted imaging agents, including radiolabeled antibodies, peptides, and nanobodies for positron emission tomography (PET) and single-photon emission tomography (SPECT) imaging. These agents demonstrated high specificity and enabled visualization of TIGIT expression in preclinical models and one exploratory clinical study. Conclusion Novel radiotracers for non-invasive imaging of TIGIT show potential for enhancing personalized cancer immunotherapy. TIGIT-targeted imaging agents allow for the visualization and quantification of TIGIT expression in tumors/tumor microenvironment, which in future might contribute to better patient selection and treatment monitoring. Further research and clinical validation are necessary to optimize these imaging techniques for routine clinical application.

Background: Glioblastoma is known for its highly immunosuppressive microenvironment, hindering the efficacy of immunotherapies. Noninvasive imaging like immuno-positron emission tomography (PET) offers the potential for visualizing immune dynamics within glioblastoma, potentially aiding in patient selection and treatment monitoring. This systematic review evaluates immuno-PET tracers currently under investigation for the noninvasive visualization of the immune environment in glioblastoma. Methods: A literature search was conducted in PubMed and Web of Science up to March 2025, using keywords related to glioblastoma, immuno-PET, immune compartments, and specific tracers. Studies were screened based on predefined inclusion and exclusion criteria, focusing on the development, characterization, or application of immuno-PET tracers targeting immune cells or immune checkpoint molecules in glioblastoma. Results: Nineteen studies met the inclusion criteria, exploring tracers targeting immune checkpoints and immune cell populations. Full-length antibodies demonstrated higher tumor specificity and retention compared to smaller fragments but showed longer circulation times. Peptide-based tracers and affibodies offered improved pharmacokinetics with rapid clearance and lower nonspecific uptake but encountered hurdles in ensuring adequate tumor targeting and retention. Advancements included dual-modal tracers combining PET and near-infrared fluorescence imaging for enhanced diagnostic and intraoperative applications. Conclusions: Significant progress has been made in developing immuno-PET tracers for noninvasive visualization of immune reactions in glioblastoma. Challenges persist in clinical translation due to issues like blood–brain barrier permeability and safety profiles. Continued research and clinical evaluations are essential to harness the potential of immuno-PET in improving glioblastoma diagnosis, assessment of treatment response, and guiding personalized immunotherapy strategies, ultimately aiming to enhance patient outcomes.