Background: PSMA-based alpha therapy using ²²⁵Ac-PSMA-I&T provides treatment for metastatic castration-resistant prostate cancer (mCRPC), even after the failure of ¹⁷⁷Lu-PSMA radioligand therapy (RLT). In clinical routine, the total tumor volume (TTV) on PSMA PET impacts therapy outcomes and plays an increasing role in mCRPC patients. Hence, we aimed to assess TTV and its changes during ²²⁵Ac-PSMA-I&T RLT. Methods: mCRPC patients undergoing RLT with ²²⁵Ac-PSMA-I&T with available ¹⁸F-PSMA-1007 PET/CT prior to therapy initiation were included. TTV was assessed in all patients using established cut-off values. Image derived, clinical and biochemistry parameters (PSA, LDH, AP, pain score) were analyzed prior to and after two cycles of ²²⁵Ac-PSMA. Changes in TTV and further parameters were directly compared and then correlated with established response criteria, such as RECIST 1.1 or mPERCIST. Results: 13 mCRPC patients were included. The median overall survival (OS) was 10 months. Prior to ²²⁵Ac-PSMA RLT, there was no significant correlation between TTV with other clinical parameters (p > 0.05 each). Between short-term survivors (STS, 0.05 each). In two patients, new PET-avid lesions were detected on ¹⁸F-PSMA-1007 PET/CT. However, TTV and PSA were decreasing or stable. Conclusion: PET-derived assessment of TTV is an easily applicable imaging biomarker independent of other established parameters prior to ²²⁵Ac-PSMA RLT in these preliminary follow-up data. Even after the failure of ¹⁷⁷Lu-PSMA, patients with extensive TTV seem to profit from RLT. All but one patient who was eligible for ≥2 cycles of ²²⁵Ac-PSMA-RLT demonstrated drastic TTV decreases without direct correlation to other biomarkers, such as serum PSA changes. Changes in TTV might hence improve the response assessment compared to standard classifiers by reflecting the current tumor load independent of the occurrence of new lesions.

In renal cell carcinoma (RCC), accurate imaging methods are required for treatment planning and response assessment to therapy. In addition, there is an urgent need for new therapeutic options, especially in metastatic RCC. One way to combine diagnostics and therapy in a so-called theranostic approach is the use of radioligands directed against surface antigens. For instance, radioligands against prostate-specific membrane antigen (PSMA) have already been successfully used for diagnosis and radionuclide therapy of metastatic prostate cancer. Recent studies have demonstrated that PSMA is expressed not only in prostate cancer but also in the neovasculature of several solid tumors, which has raised hopes to use PSMA-guided theranostic approaches in other tumor entities, too. However, data on PSMA expression in different histopathological subtypes of RCC are sparse. Because a better understanding of PSMA expression in RCC is critical to assess which patients would benefit most from theranostic approaches using PSMA-targeted ligands, we investigated the expression pattern of PSMA in different subtypes of RCC on protein level. Immunohistochemical staining for PSMA was performed on formalin-fixed, paraffin-embedded archival material of major different histological subtypes of RCC (clear cell RCC (ccRCC)), papillary RCC (pRCC) and chromophobe RCC (cpRCC). The extent and intensity of PSMA staining were scored semi-quantitatively and correlated with the histological RCC subtypes. Group comparisons were calculated with the Kruskal–Wallis test. In all cases, immunoreactivity was detected only in the tumor-associated vessels and not in tumor cells. Staining intensity was the strongest in ccRCC, followed by cpRCC and pRCC. ccRCC showed the most diffuse staining pattern, followed by cpRCC and pRCC. Our results provide a rationale for PSMA-targeted theranostic approaches in ccRCC and cpRCC.

FAP-ligands as novel cancer radiopharmaceuticals in nuclear medicine have been recently translated successfully into the clinical space. Particularly small molecules (i.e. FAPI-46, FAPI-74) and peptides (i.e. FAP-2286, DOTAGA.SA.FAPi) seem to be some of the most promising molecular probes for imaging and therapy. Back in 2019, there have been slight reservations about adopting this new imaging probe, after the decades of the solidly established role of FDG PET/CT in oncological imaging. At that time, it was expected that these novel ligands might challenge Onco-PET as new cornerstones in the individualized tumor staging and even beyond. However, FAP-targeted imaging is today not intended to replace FDG PET/CT, but rather to complement cancer imaging and therapy, where cancer subtypes exhibit low glucose metabolism which often leads to moderate or very insufficient FDG uptake. Recently, numerous FAP-imaging studies -ranging from single-case reports to larger patient cohorts and even prospective trials have reinforced the empirical understanding of FAP-imaging as a potentially "disruptive" modality compared to FDG PET/CT. The broader application of FAPI PET/CT has gained momentum, shaping a new narrative in oncological imaging and beyond. FAPI PET/CT is now increasingly recognized as a novel imaging agent that does not aim to replace FDG PET/CT, but rather supports it by enhancing diagnostic accuracy in specific sub-cohort of tumor entities, where FDG PET/CT tends to underperform. Several FAP-derivates- such as FAPI-04, FAPI-46, FAPI-74 for PET imaging as well as FAPI-34 for SPECT imaging were rapidly introduced into clinical practice. To date, FAP-imaging agents have steadily paved their way into clinical practice, particularly in tumor entities such as pancreatic ductal adenocarcinoma, gastroesophageal cancers, and hepatocellular carcinoma. Even in lung cancer, where FDG PET/CT has long held a well-established and clinically robust role, FAPI PET/CT has quickly emerged as a strong competitor, especially in case of lung adenocarcinoma. FAPI PET/CT has been gaining increasing acceptance beyond academic and scientific field as a tool for improved oncological imaging, while FAP theranostics is still in the elaboration and early translation. In contrast to imaging probes, FAP-derivates for therapy require a rather long residence (>48 h) time following successful target-binding at the cancer-associated fibroblast or FAP-positive tumor cells to enable the radiotoxic effect (beta- and alpha-emitter) and deliver enough LET to the cancer microenvironment. Meanwhile, FAP-based imaging probes are advancing into the clinical application, with Phase-II/III clinical trials expected as early as Q4/2025 (NCT07217704 & NCT07217717). In contrast, FAP-targeted therapeutics remain in the Phase-I or proof-of-concept stage but brings hope for patients with systemic disease who are left out and urgently need additional innovation drives beyond the standard care. This review article will give insight into the most recent developments in the FAP-Therapeutic applications of cancer treatments using several different promising FAP-derivates to improve FAP-theranostic in oncology.

Purpose: Radioligand therapy (RLT) targeting PSMA (prostate-specific membrane antigen) has transformed the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, bone marrow depletion remains a common side effect, particularly in patients with extensive bone metastases or prior myelotoxic therapies. This study evaluated [^99mTc]Tc-antigranulocyte scintigraphy to assess bone marrow reserve to guide myelotoxic treatment decisions. Methods: Ten mCRPC patients with extensive osseous tumor load on [¹⁸F]F-PSMA PET/CT underwent [^99mTc]Tc-antigranulocyte scintigraphy to assess bone marrow reserve and RLT eligibility (interval: 26.6 ± 18.5 days). Visual comparison of both modalities evaluated tumor-bone marrow overlap. Patients without significant co-localization received RLT ([¹⁷⁷Lu]Lu-PSMA or [²²⁵Ac]Ac-PSMA) with laboratory monitoring before and between the cycles. Results: No significant co-localization between viable bone marrow and PSMA-positive metastases was observed in 9/10 (90.0%) patients. Two other patients were excluded from RLT due to contraindications. Of the remaining seven patients, 2/7 (28.6%) underwent subsequent [¹⁷⁷Lu]Lu-PSMA therapy, 2/7 (28.6%) [²²⁵Ac]Ac-PSMA therapy and 2/7 (28.6%) [²²⁵Ac]Ac-[¹⁷⁷Lu]Lu-PSMA therapy. 1/7 (14.3%) received a single cycle of [¹⁷⁷Lu]Lu-PSMA, which was then followed by [²²⁵Ac]Ac-PSMA therapy. Follow-up laboratory results showed no significant changes from baseline (p > 0.05). Conclusion: [^99mTc]Tc-antigranulocyte scintigraphy may support the assessment of bone marrow reserve in patients with extensive bone metastases. Spatial mismatch was associated with no significant myelotoxicity, whereas high congruence may increase the risk. No fixed thresholds currently exist; thus, this method should be regarded as a supplementary tool in complex cases and future studies are needed to define the critical bone marrow volume.

Purpose: In somatostatin receptor (SSTR)-expressing tumors, theranostics with SSTR-directed imaging and therapy showed promising results regarding disease control. This study evaluated the use of PET imaging with [ ¹⁸ F]SiTATE in pheochromocytoma and paraganglioma (PPGL) patients, focusing on eligibility for peptide radioreceptor therapy (PRRT) and therapy monitoring. Methods: Five patients with metastatic paraganglioma (n = 3) or pheochromocytoma (n = 2) were included. Eligibility for PRRT was assessed by [ ¹⁸ F]SiTATE applying the Krenning score and baseline SUV _max . Treatment response was analyzed by RECIST 1.1 criteria, total tumor volume (PET-based TTV), and Chromogranin A (CgA). Results: At baseline, all patients showed high lesional uptake, with the highest in the bone (mean SUV _max 41.4 ± 87.3) and a high Krenning Score of 3–4, Suggestive for PRRT eligibility. At the follow up, 2.5 months after completion of PRRT, all patients presented with stable disease (RECIST 1.1) and decreasing or stable CgA levels, whereas TTV increased in three patients and thus showed heterogenous response. Conclusion: In metastatic PPGL, [ ¹⁸ F]SiTATE effectively visualizes tumor burden and supports patient selection and response assessment for PRRT. Notably, the data revealed a heterogenous response across PET-based, CT-based, and biochemical assessments. The underlying mechanisms of these discrepancies remain unclear and warrant further investigation.

Background: Somatostatin receptor (SSTR)-targeted PET is valuable for meningioma imaging due to high SSTR expression. [ ¹⁸ F]SiTATE, a novel tracer, is not only promising for imaging neuroendocrine tumors but also for meningiomas. Standardized delineation methods on [ ¹⁸ F]SiTATE PET are lacking. This study correlates CT-based volumes with PET-based delineation approaches to identify a threshold for standardized [ ¹⁸ F]SiTATE PET volume assessment. Methods: Patients with well-delineated, extraosseous meningioma on CT (≥ 1mL) who underwent [ ¹⁸ F]SiTATE PET/CT were included. Volumes were assessed on contrast-enhanced CT and correlated with PET-based delineation approaches: (I) fixed SUV threshold, (II) isocontour thresholding relative to SUV _max (SUV%), and thresholds relative to (III) bone marrow (SUV _BM ), (IV) parotid gland (SUV _parotis ) and (V) pituitary gland (SUV _sella ). Results: 19 meningiomas in 17 PET/CT scans (16 patients) were included. A fixed SUV of 4.0 ( r = 0.783, p < 0.001) showed good correlation with CT volumes without skewed distribution on Bland-Altman-Plot analysis. Using isocontour-based thresholds, 45% SUV _max ( r = 0.496, p = 0.031) showed the highest concordance. Best reference-based approaches were achieved by 150% SUV _BM ( r = 0.859, p < 0.001), 250% SUV _parotis ( r = 0.460, p = 0.047) and 70% SUV _sella ( r = 0.819, p < 0.001). However, background-based approaches showed a trend towards overestimation of PET-volumes in larger meningiomas as assessed on Bland-Altman-Plot analyses. Uptake intensities of reference tissues (SUV _BM, SUV _parotis and SUV _sella ) were not inter-correlated ( p > 0.05 each). Conclusion: A fixed SUV threshold of 4.0 showed strong agreement with CT-based volumes in well-delineated, extraosseous meningiomas which offers a simple, clinically applicable method without technical requirements. Reference tissue-based methods showed similar correlations but tended to overestimate volumes in larger lesions.