Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas that can develop either de novo or as a result of malignant transformation of neurofibromas. Diagnostic modalities of choice, such as MRI or 18F-FDG PET/CT, show high sensitivity for the detection of MPNSTs but moderate specificity, as MPNSTs and benign peripheral nerve sheath tumors (BPNSTs) can initially present similar clinical and radiologic pictures. PET/CT with 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) showed specific uptake in sarcomas and enabled differentiation of benign and malignant lesions in other entities. Here, we analyzed the ability of 68Ga-FAPI PET/CT to differentiate between MPNSTs and BPNSTs. Methods: Twenty-six patients with suspected or histologically confirmed peripheral nerve sheath tumors who were scheduled to have surgical resection/biopsy underwent 68Ga-FAPI-46 PET/CT with static and dynamic acquisition. SUVmax, SUVmean, maximum and mean tumor-to-background ratios, and time-activity curves were evaluated using volume-of-interest-based analysis (isocontour 50%). Time to peak was derived from time-activity curves. Statistical analyses were performed, and receiver-operating-characteristic curves were calculated. Exemplary target validation by fibroblast activation protein immunohistochemistry was performed in 13 cases. Results: Eighteen patients (4 with MPNSTs, 5 with neurofibromas, 9 with schwannomas) were included in the final analysis. MPNSTs showed significantly higher 68Ga-FAPI uptake compared with BPNSTs. Neurofibromas showed higher 68Ga-FAPI uptake compared with schwannomas. In dynamic imaging, time to peak of MPNSTs and neurofibromas was prolonged compared with schwannomas. Analysis of receiver-operating-characteristic curves displayed high sensitivity (100%) and specificity (92.86%) of 68Ga-FAPI PET/CT for discrimination of MPNSTs and BPNSTs, for an exploratory SUVmax cutoff value of 7.53. Fibroblast activation protein expression was strong in MPNSTs and moderate in BPNSTs. Conclusion: 68Ga-FAPI PET/CT may aid in differentiating between MPNSTs and BPNSTs, thereby improving lesion characterization in indeterminate MRI or 18F-FDG PET/CT scenarios.

The pathologies pancreatic ductal adenocarcinomas, inflammatory lesions of the pancreas, postpancreatectomy reactive tissue, and recurrent pancreatic ductal adenocarcinomas all express fibroblast activation protein and are hardly distinguishable by static PET using [68Ga]Ga-labeled fibroblast activation protein inhibitors (FAPIs) combined with CT. Dynamic imaging allows full [68Ga]-Ga-FAPI kinetic profile analysis, highlighting differences among these pathologies. Here, we applied a voxel-level digital biopsy approach combined with network analysis and clustering to characterize healthy, nonmalignant pathologic, and malignant pathologic kinetic signatures. Methods: This monocentric, retrospective study included 47 patients (>18 y) with morphologically unclear pancreatic lesions on CT or MRI and supplemental [68Ga]Ga-FAPI-46 PET/CT in a primary (31 patients) or recurrent (16 patients) setting. Lesions were classified according to biopsy results (primary cases) or CT appearance and clinical course (recurrent cases). Digital biopsy samples (300 voxels) of pancreatic lesions and control organs (muscle, fat, kidneys, liver, and blood) were taken and then masked and imported into an open source visual analytics application. Voxel networks were created with multiple digital biopsy samples from a single scan or digital biopsy samples combined from multiple scans, with a minimum Pearson correlation value of 0.7. A k-nearest-neighbor edge reduction was applied before Markov clustering. Datasets were then unmasked for interpretation. Static PET parameters (SUVmax and SUVmean) and time to peak of pancreatic lesions and control tissues were extracted from isotropic volumes and analyzed by a t test (threshold for significance, P = 0.05). Results: This work created 47 individual networks and 2 combined networks. Within individual networks, voxels tended to arrange and cluster within the sampled volume of interest (VOI; left and right kidneys strongly coclustered). Networks typically arranged into healthy controls, elimination organs, and pathologic (malignant and nonmalignant) regions. Pathologies tended to cluster with high purity (>95% from the same VOI), with multiple clusters per VOI, indicating intralesional heterogeneity. Our analysis approach could differentiate between malignant and nonmalignant pathologies in the primary and recurrence settings. This differentiation was driven by slower FAPI clearance within malignant voxels. Conclusion: The kinetics of [68Ga]Ga-FAPI-46 across the different tissues, coupled with this sampling and analysis approach, allowed the separation and identification of healthy, nonmalignant pathologic, and malignant pathologic clusters and kinetic features that may facilitate diagnosis and warrant further investigation.

Oncological treatment in a substantial portion of patients with cancer of unknown primary (CUP) remains challenging due to limitations of conventional imaging and positron emission tomography/computed tomography with 18Fluor-fluorodeoxyglucose (18F-FDG-PET/CT). In head and neck-like CUP (HNCUP), several studies found significantly higher tracer-uptake and detection rates of primary tumors in 68Gallium-labeled fibroblast activation protein inhibitor-PET/CT (68Ga-FAPI-PET/CT). Here, we address a gap in CUP literature by retrospectively evaluating the diagnostic accuracy of both tracer in a head-to-head comparison of patients with single-site and oligometastatic extra-cervical CUP. 13 patients with extra-cervical CUP underwent both 18F-FDG- and 68Ga-FAPI-PET/CT. Suspicious PET-positive lesions were delineated using the volume of interest-technique (50

Purpose:Whether FDG-PET-guided de-escalation of elective target volumes in radiotherapy of the head and neck reduces late toxicity remains uncertain. Therefore, we compared predicted toxicity of two de-escalation strategies-reduced elective nodal irradiation (RNI) and involved node irradiation (INI)-with standard elective nodal irradiation (ENI). Materials and Methods:In a within-patient plan comparison (n = 26), we generated RNI and INI plans using the same FDG-PET informed high-/intermediate-risk targets as ENI. RNI limited elective volumes to within 2 cm cranio-caudal from gross disease; INI omitted elective treatment. Proton plans were created in representative oropharyngeal cases. Co-primary outcomes were six-month normal-tissue complication probabilities (NTCPs) for dysphagia, feeding-tube dependence, and xerostomia. Results:Median total planning target volume decreased from 540 cm3 (ENI) to 418 cm3 (RNI) and 173 cm3 (INI). RNI and INI reduced modeled dysphagia risk by 5.9 percentage points (pp) (95% CI 2.3 to 9.6 pp; padj = 0.005) and 11.0 pp (6.9 to 15.2 pp; padj < 0.001), feeding-tube dependence by 2.8 pp (1.2 to 4.5 pp; padj = 0.005) and 4.2 pp (2.5 to 6.0 pp; padj < 0.001), and xerostomia by 2.8 pp (0.0 to 5.7 pp; padj = 0.054) and 8.8 pp (5.5 to 12.2 pp; padj < 0.001), respectively. Predicted benefits were greatest in hypopharyngeal and laryngeal cancers. In selected cases, de-escalated proton therapy further reduced organ-at-risk dose. Conclusions:FDG-PET-guided volumetric de-escalation was associated with lower modeled late swallowing-related toxicity. These findings support the rationale for ongoing and future trials investigating volumetric de-escalation strategies.

Targeted therapies are applied to increase the efficiency of antitumor treatment by simultaneously decreasing side effects. This can be achieved using carrier molecules which specifically bind to target structures or areas with remodeling activity. These carrier molecules may be coupled to chemotherapeutic drugs or to radioactive isotopes. In most cases, these carrier molecules are antibodies against tumor antigens, peptides, or small molecules which are binders for overexpressed receptors on tumor cells. The paradigm of endoradiotherapy is exemplified by the peptidic tracer DOTATOC which binds to somatostatin receptors and recently also small molecule inhibitors with high affinity for the prostate-specific membrane antigen.

Inflammatory Bowel Diseases (IBD) comprise ulcerative colitis (UC) and Crohn’s disease (CD). Management of IBD requires assessment of disease activity, severity, extent and complications. Here, we describe the signal behavior of both CD and UC in 68Gallium- fibroblast activation protein inhibitor-based radiopharmaceuticals-46-positron emission tomography (68Ga-FAPI-46-PET) and evaluate the potential of 68Ga-FAPI-46-PET for activity assessment in IBD. This analysis includes data of 43 IBD patients and 43 control patients examined by 68Ga-FAPI-46-PET/computed tomography (CT). Disease activity of IBD patients was assessed by colonoscopy. FAPI-positive gastrointestinal tract (GIT)-findings and healthy appearing GI structures were contoured. Non-IBD related FAPI-positive GIT-findings were ruled out by interdisciplinary consensus. Static and dynamic PET-parameters of FAPI-positive IBD lesions and healthy appearing GI structures were extracted and PET signalling was analyzed with respect to IBD subtype and disease activity. We examined 20 CD patients and 23 UC patients (29 with active, 14 with inactive disease). FAPI-uptake in most healthy appearing GI structures of IBD patients was significantly increased compared to controls. Of 80 FAPI-positive GIT-findings, 14 were ruled out as non-IBD related and 66 FAPI-positive IBD lesions were analyzed. We observed equally high lesional FAPI-uptake in CD and UC. All patients with active disease showed at least one intensively FAPI-positive IBD lesion, while only 4/14 patients with inactive disease showed any FAPI-positive IBD lesion. Lesional and patientwise FAPI-uptake was significantly higher in active than in inactive disease. FAPI-positive IBD lesions showed a characteristic kinetic behaviour with two types of uptake patterns – one showing a continuous increase and the other an early peak followed by a plateau. 68Ga-FAPI-46-PET/CT appears promising for assessing disease activity in terms of fibroblast activation in both CD and UC.

Abstract Purpose Differential diagnoses of primary pancreatic lesions include pancreatic ductal adenocarcinomas (PDAC) and inflammatory lesions of the pancreas (ILP). Post-pancreatic surgery, differentiation of postoperative reactive tissue (PRT) and PDAC-recurrence challenges oncological imaging. Static 68Ga-FAPI-PET/CT uptake is increased in all of these lesions with marked overlap in signal intensity, hampering their FAPI-PET-based assessment. Here, we evaluated static and parametric imaging parameters for discrimination of pancreatic lesions in primary and post-pancreatic surgery scenarios. Methods 55 Patients with pancreatic lesions (36 primary, 19 post-pancreatic surgery) underwent static and dynamic 68Ga-FAPI-46-PET/CT. Primary lesions were classified either by histology following PET/CT or follow-up (> 6 months). Post-surgery, PRT and PDAC-recurrence were classified by CT- and clinical course (> 18 months). Parametric maps (1 tissue compartment (1TC), 2TC and Logan plot (LP)) from dynamic PET-data were generated via image-based aortic input function using PMOD-software. Pancreatic lesions (PDAC, ILP, PRT, PDAC-recurrence) were then delineated using VOI-technique (30–70% isocontour) and signal intensities were analyzed. SPSS was used to detect outliers, unpaired t-tests was applied for comparison of static and parametric imaging parameters. Receiver-operating-characteristic curves for differentiating PDAC/ILP or recurrent PDAC/PRT were generated. Results 42 patients were included in the final analysis: in primary setting, 16 PDAC and 10 ILP; in post-surgery setting 9 PDAC-recurrences and 7 PRT. In the primary setting, although PDAC showed higher SUVmax/mean than ILP, no significant differences in maximum/mean signal values neither in static imaging nor in parametric maps were detected. With regard to the differentiation of PDAC-recurrences versus postoperative tissue, LPmax were significantly higher in PDAC-recurrences compared to PRT (4.74 vs. 2.40, p-value 0.020) with AUC 82.5% (95-CI 0.62-1.0) and a possible diagnostic threshold at > 3,49 (LR + 5.44), while differences in static imaging or other parametric maps were not statistically significant. Conclusion Differentiating pancreatic lesions remains challenging. While LPmax significantly distinguished PDAC-recurrence from PRT, other parametric mapping parameters yielded no significant results. Larger studies and additional dynamic data analysis methods should be explored.

Immune checkpoint inhibitors have shown promising results in the neoadjuvant treatment of resectable non-small cell lung cancer. This open-label, single-arm, prospective, monocentric trial evaluated the efficacy and safety of neoadjuvant atezolizumab plus carboplatin/nab-paclitaxel in patients with resectable non-squamous non-small cell lung cancer. Patients with previously untreated, pathologically confirmed, non-squamous non-small cell lung cancer in stage II, IIIA, and select IIIB (T3N2 only) were treated with atezolizumab and carboplatin/nab-paclitaxel for 3 cycles followed by curative intent surgery. Major pathologic response (MPR) was defined as primary endpoint. 20 patients with histologically confirmed pulmonary adenocarcinoma in TNM-stage IIA (n = 1, 5%), stage IIB (n = 7, 35%), and stage IIIA (n = 12, 60%) were enrolled and treated according to the study protocol. 151 treatment-related adverse events were recorded, and 13 patients (65%) had treatment-related adverse events of grade 3 or higher. There were no grade 5 events. All patients underwent complete anatomical resection (R0). MPR was observed in 9 patients (45%), including 5 (25%) patients with complete pathological response. The proportion of remaining viable tumor showed a significant but weak association to the relative tumor size change in CT (p = 0.018) and the relative change in SUVmax (p = 0.006). In conclusion, neoadjuvant chemoimmunotherapy with atezolizumab achieved a promising MPR-rate of 45% while being well tolerated and allowing a safe and complete surgical resection. These results strongly support the further investigation of atezolizumab as preoperative therapy in resectable non-small cell lung cancer and underline the continued need to develop biomarkers of response.

Background The efficacy of current bone-targeting agents, notably bisphosphonates, in the treatment of bone metastases remains limited by their systemic toxicity and excessively long half-life. This study aims to develop bone-targeting agents inspired by osteotropic peptides involved in the bone mineralization process. These agents are intended to provide an innovative alternative to bisphosphonates for precision bone targeting. Results Osteotropic peptides and phosphopeptides were obtained by solid-phase synthesis and conjugated to DOTA. The peptides were radiolabeled with gallium-68 or lutetium-177, and their binding affinity to bone was tested in vivo. Osteopontin and matrix extracellular phosphoglycoprotein (MEPE) derived peptides did not show strong binding to bone. Systematic variations in oligoglutamic acid chain length, as well as the positioning and clustering of phosphorylated serine residues, enabled the identification of an optimized phosphopeptide. Clustering phosphorylated sites within the peptide sequence provided significant advantages over phosphorylated moieties scattered throughout the peptide sequence. DOTA-pS(4)E(8) showed the strongest affinity for bone, comparable to the clinically used bone targeting agent methylene bisphosphonate (MBP). Conclusions The novel phosphopeptides match the outstanding bone-targeting capabilities of bisphosphonates and show comparable pharmacokinetics. Owing to their peptidic nature and the consequently anticipated favorable toxicological profile, these agents warrant further investigation as versatile bone-targeting vectors.

Prostate-specific membrane antigen (PSMA)-targeting strategies in prostate cancer have evolved rapidly from early antibody-based approaches to highly effective diagnostic and therapeutic agents. While PSMA remains a central benchmark in metastatic disease, biological heterogeneity and therapy resistance underscore the need for continued innovation and rational combination strategies.

BACKGROUND:The phase II NEOMUN trial was conducted to investigate the therapeutic effect of preoperative programmed death receptor-1 inhibitor pembrolizumab for treating non-small cell lung cancer (NSCLC). Herein, we report the final efficacy, safety, and long-term survival results. METHODS:Patients with resectable stage II/IIIA NSCLC were included. Two cycles of pembrolizumab (200 mg intravenously once every 3 weeks) were administered before surgery. The primary objectives were to assess the feasibility and safety of neoadjuvant treatment and evaluate antitumor activity. We analyzed the clinical parameters and pathologic, radiological, and metabolic tumor response data. RESULTS:29 patients with NSCLC were enrolled. NSCLC histology revealed adenocarcinoma and squamous cell carcinoma in 24 and in 5 patients, respectively. 93.1% of patients were treated with two therapy cycles. 73 adverse events were reported, of which 18 were treatment-related. Complete tumor resection rate was 100%. Major (≤10% vital tumor cells) and complete pathologic response rates were 24.1% and 13.8%, respectively. Tumor response increased with higher programmed death-ligand 1 tumor proportion scores (TPS) and high pretherapeutic tumor mutational burden (≥10 mut./Mb). The metabolic response, quantified non-invasively using positron emission tomography/CT, predicted the pathologic tumor response. The disease-free survival was 75.9% at 24 and 36 months, and the overall survival was 82.7% at 24 and 36 months. CONCLUSIONS:Neoadjuvant immunotherapy with pembrolizumab appears safe and feasible and is associated with a remarkable major pathologic response rate. Preoperative TPS, change in maximal standardized uptake value during the induction phase, and high mutational burden might be suitable clinical parameters for predicting pathologic response in surgical candidates. TRIAL REGISTRATION NUMBER:NCT0319746.

Heart failure with reduced ejection fraction (HFrEF) is marked by a shift in cardiac energy metabolism from fatty acid oxidation to glucose utilization. This “fuel switch” promotes accumulation of glucose byproducts that modify calcium-handling proteins and impair cardiac function, yet the initiating signals remain unclear. We identify Ca2+/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [18F]FDG-PET imaging showed a six-fold increase in myocardial glucose uptake after pressure overload in control mice, but not in cardiomyocyte-specific Camk2d/Camk2g double knockouts (cDKO), even before functional decline. cDKO hearts retained lipid reserves, indicating preserved fatty acid metabolism. Transcriptomics revealed strong CAMK2-dependent induction of Nr4a1 and early repression of genes for fatty acid uptake and β-oxidation preceding upregulation of genes for glucose utilization. Cardiomyocyte-specific Nr4a1 knockout mice closely mimicked the metabolic protection seen in cDKO, while NR4A1 overexpression in human iPSC-derived cardiomyocytes suppressed fatty acid metabolism. NR4A1 directly bound and repressed the FATP1 (Slc27a1) promoter, thereby secondarily enhancing glucose utilization. Together, these findings define a CAMK2–NR4A1 signaling axis that drives lipid depletion and metabolic remodeling, establishing it as a causal mechanism linking energy substrate switching to HFrEF. ### Competing Interest Statement The authors have declared no competing interest.

Ziel/Aim: With static 68Ga-FAPI-PET/CT, distinguishing pathologies like pancreatic ductal adenocarcinomas (PDAC), inflammatory lesions of the pancreas (ILP), post- pancreatectomy reactive tissue (PRT) and recurrent-PDAC (RPDAC) is a challenge due to their marked increase in signal intensity. Dynamic imaging allows 68Ga-FAPI kinetic profile analysis, highlighting differences between these pathologies. Heretofore, analysis of such dynamic PET data is challenging. The use of a voxel-level "digital biopsy" approach combined with network analysis and clustering could overcome this challenge. We hypothesise this approach will allow the identification of healthy, non- malignant pathological and malignant pathological kinetic signatures which could aid diagnosis.

Ziel/Aim: Ziel ist es zu untersuchen, inwiefern 68Ga-FAPI-46-PET-Texturparameter bei der Differenzierung zwischen Bronchialkarzinomen und benignen pulmonalen Läsionen helfen können.

Abstract Breast cancer presents a significant global health challenge, necessitating continued innovation in diagnostic and therapeutic approaches. Recent advances have led to the identification of cancer-associated fibroblasts, which are highly prevalent in breast cancers and express fibroblast activation proteins (FAPs), as critical targets. FAP-specific radiotracers, when used with PET/CT and SPECT/CT, have significant potential for improving early breast cancer detection, staging, treatment response monitoring, and therapeutic intervention. This review provides insight into FAP-targeted molecular imaging, exploring advanced techniques for protein status assessment, development of early-phase targeted therapies, and other emerging applications. The advent of FAP-targeted imaging stands to significantly enhance personalized oncologic care, leading to improved breast cancer management and overall patient outcomes.

The benefit that antibiotics confer to the welfare of mankind is threatened by bacterial resistance. Resistance to daptomycin, a cyclic lipopeptide frequently used for the treatment of complicated bacteremia, is a prime example of this alarming situation. As the restricted number of antibacterial drug targets limits de novo development, chemical modification of existing compounds represents an alternative development option for future antimicrobials. This approach involves altering compounds to target bacteria through multiple mechanisms and/or to reinforce them against resistant strains. Herein, the conjugation of polycationic peptides to daptomycin enhances its effectiveness against a highly daptomycin-resistant laboratory strain of Staphylococcus aureus and clinical isolates of Enterococcus faecium with reduced daptomycin sensitivity. Notably, unlike daptomycin, the activity of these conjugates does not necessarily depend on the calcium concentration. In addition to regaining bacteriolytic activity, the findings indicate the acquisition of an additional or amended mode of action as evidenced by pore formation and the disruption of membrane potential. The combination of enhanced in vitro potency, in vivo activity, and tolerability highlights the potential of this drug modification strategy in combating multidrug-resistant bacteria.

Ziel/Aim: Inflammatory Bowel Disease (IBD), comprise a complex spectrum of chronic inflammatory conditions of the gastrointestinal tract (GIT) including ulcerative colitis (UC) and Crohn´s disease (CD). Management and monitoring of IBD necessitate the use of various diagnostic modalities including enteroscopy and cross-sectional imaging to assess disease activity, extent, and complications. Given the role of fibroblast activation and tissue remodeling in the pathophysiology of IBD, we aimed to explore the potential of the application of 68Ga-FAPI-PET in the context of IBD.