Purpose: We report efficacy and safety of 90Y-labeled FAPI-46 (90Y-FAPI-46-RLT) in patients with advanced sarcoma, pancreatic cancer, and other cancer entities. Experimental Design: Up to four cycles of radioligand therapy (RLT) were offered to patients with (i) progressive metastatic malignancy, (ii) exhaustion of approved therapies, and (iii) high fibroblast activation protein (FAP) expression, defined as SUVmax ≥ 10 in more than 50% of tumor. Primary endpoint was RECIST response after RLT. Secondary endpoints included PET response (PERCIST), overall survival (OS), dosimetry, and safety of FAP-RLT. Results: Among 119 screened patients, 21 (18%) were found eligible [n = 16/3/1/1 sarcoma/pancreatic cancer/prostate/gastric cancer; 38% Eastern Cooperative Oncology Group (ECOG) ≥ 2] and received 47 90Y-FAPI-46-RLT cycles; 16 of 21 (76%) patients underwent repeat RLT. By RECIST, disease control was confirmed in 8 of 21 patients [38%; 8/16 (50%) of evaluable patients). There was one partial response (PR) and seven stable diseases after RLT. Disease control was associated with prolonged OS (P = 0.013). PERCIST response was noted in 8 of 21 patients [38%; 8/15 (53%) of evaluable patients]. Dosimetry was acquired in 19 (90%) patients. Mean absorbed dose was 0.53 Gy/GBq in kidney, 0.04 Gy/GBq in bone marrow, and <0.14 Gy/GBq in liver and lung. Treatment-related grade 3 or 4 adverse events were observed in 8 (38%) patients with thrombocytopenia (n = 6) and anemia (n = 6) being most prevalent. Conclusions: 90Y-FAPI-46-RLT was safe and led to RECIST PR in one case as well as stable disease in about one third of patients with initially progressive sarcomas, pancreatic cancer, and other cancers. Discontinuation after the first cycle and a low rate of PR requires future improvement of FAP-RLT.

Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease. We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4⁺ and CD8⁺ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure–volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity. Anti-PD1 immune checkpoint inhibitor therapy induces an immune-mediated disruption of cardiac integrity that can be prevented by blockade of tumour necrosis factor alpha.

Introduction: Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (⁶⁸Ga-FAPI-46) for PET imaging. Here, we report our initial experience in terms of feasibility and safety of ⁹⁰Y-labelled FAPI-46 (⁹⁰Y-FAPI-46) for radioligand therapy (RLT) of extensively pretreated patients with solid tumors. Methods: Patients were considered for ⁹⁰Y-FAPI-46 therapy in case of (a) exhaustion of all approved therapies based on multidisciplinary tumor board decision and (b) high FAP expression, defined as SUV_max ≥ 10 in more than 50% of all lesions. If tolerated, post-therapeutic ⁹⁰Y-FAPI-46 bremsstrahlung scintigraphy was performed to visually confirm systemic distribution and focal tumor uptake, and ⁹⁰Y-FAPI-46 PET scans at multiple time-points were performed to determine absorbed dose. Blood-based dosimetry was used to determine bone-marrow absorbed dose. Adverse Events were graded using CTCAE v.5.0. Results: Nine patients with either metastatic soft tissue or bone sarcoma (N = 6) and pancreatic cancer (N = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 (IQR 3.25-5.40) GBq for the first cycle and three patients received subsequent cycles with a median of 7.4 (IQR 7.3-7-5) GBq. Post-therapy ⁹⁰Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient ⁹⁰Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR 0.41-0.65) in kidney, 0.04 Gy/GBq (IQR 0.03-0.06) in bone marrow and below 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median 1.28 Gy/GBq). Hematologic G3/G4 toxicities were noted in four patients (44%), of which thrombocytopenia was most prevalent (N = 6; 67%), whereas other G3/G4 laboratory-based adverse events were N ≤ 2. No acute toxicities attributed to ⁹⁰Y-FAPI-46 were noted. Radiographic disease control was noted in three patients (33 %). Conclusion: FAP-targeted RLT with ⁹⁰Y-FAPI-46 was well tolerated with a low rate of attributable adverse events. Low radiation doses to organs at risk suggest feasibility of repeat cycles of ⁹⁰Y-FAPI-46. We observe signs of clinical activity, but further studies are warranted to determine efficacy and toxicity profile in a larger cohort.

The study aims to investigate the presence of physiological prostate-specific membrane antigen (PSMA)-ligand uptake on positron-emission-tomography (PET) in cervical, coeliac and sacral ganglia of the sympathetic trunk as a pitfall for lymph node metastases in prostate cancer imaging. Methods: 407 patients who underwent “Glu-NH-CO-NH-Lys” radio-labeled with [⁶⁸Ga]gallium N,N-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N-diacetic acid (⁶⁸Ga-PSMA-HBED-CC) PET (combined with a diagnostic computed tomography (CT)) were retrospectively analyzed. The number of PSMA PET-positive cervical, coeliac and sacral ganglia was determined and the configuration and maximum standardized uptake value (SUV_max) of each ganglion was measured. In addition, the configuration and SUV_max of adjacent lymph node metastases in the respective region (cervical, coeliac or sacral) were determined. Results: PSMA-ligand uptake above background was detected in 401 (98.5%) patients in any peripheral ganglia, in 369 (92%) patients in cervical ganglia, in 363 (89%) patients in coeliac ganglia, and in 183 (46%) patients in sacral ganglia. The PSMA-ligand uptake was highest in coeliac (mean SUV_max 2.9±0.8 vs. cervical (mean SUV_max 2.4±0.6) and sacral (mean SUV_max 1.7±0.5), both p<0.0001) ganglia. Intra-individually there was a statistically significant, but weak to moderate correlation between the PSMA-ligand uptake in cervical vs. coeliac ganglia (R=0.34, p<0.0001), cervical vs. sacral (R=0.52, p<0.0001) and coeliac vs. sacral (R=0.16, p<0.05). The PSMA-ligand uptake was significantly more intense in adjacent lymph node metastases compared to the respective ganglia (cervical: 18.0±16.2 vs. 2.4±0.6, p<0.0001; coeliac: 13.5±12.3 vs. 2.9±0.8, p<0.0001; sacral: 13.4±11.6 vs. 1.7±0.5, p<0.0001). Furthermore, ganglia predominantly exhibit a band-shaped (71.2%), followed by a teardrop (26.8%) and only rarely a nodular configuration (2.0%). Conversely, lymph node metastases are only rarely band-shaped (1.1%), but more often show teardrop (40.3%) or nodular appearance (58.6%) (p<0.00001). Conclusion: PSMA-ligand uptake in ganglia along the sympathetic trunk as assessed by ⁶⁸Ga-PSMA-HBED-CC PET represents an important pitfall in prostate cancer PET imaging. The PSMA-ligand uptake is higher in coeliac ganglia compared to cervical or sacral ganglia and the level of PSMA-ligand uptake seems to be patient-related. For the differentiation between lymph node metastases and sympathetic ganglia both intensity of PSMA-ligand-uptake as well as exact localization and configuration of the respective lesion should be examined carefully.

Background Fibroblast activation protein (FAP) as a specific marker of activated fibroblasts can be visualized by positron emission tomography (PET) using Ga-68-FAP inhibitors (FAPI). Gallium-68-labeled FAPI is increasingly used in the staging of various cancers. In addition, the first cases of theranostic approaches have been reported. In this work, we describe the phenomenon of myocardial FAPI uptake in patients who received a Ga-68 FAPI PET for tumor staging. Method and results Ga-68 FAPI PET examinations for cancer staging were retrospectively analyzed with respect to cardiac tracer uptake. Standardized uptake values (SUV) were correlated to clinical covariates in a univariate regression model. From 09/2018 to 11/2019 N = 32 patients underwent FAPI PET at our institution. Six out of 32 patients (18.8%) demonstrated increased localized myocardial tracer accumulation, with remote FAPI uptake being significantly higher in patients with vs without localized focal myocardial uptake (SUV_max 2.2 ± .6 vs 1.5 ± .4, P < .05 and SUV_mean 1.6 ± .4 vs 1.2 ± .3, P < .05, respectively). Univariate regression demonstrated a significant correlation of coronary artery disease (CAD), age and left ventricular ejection fraction (LVEF) with remote SUV_mean uptake, the latter with a very strong correlation with remote uptake (R² = .74, P < .01). Conclusion Our study indicates an association of CAD, age, and LVEF with FAPI uptake. Further studies are warranted to assess if fibroblast activation can be reliably measured and may be used for risk stratification regarding early detection or progression of CAD and left ventricular remodeling.

Purpose: Restoration of iodine incorporation (redifferentiation) by MAPK inhibition was achieved in previously radioiodine-refractory, unresectable thyroid carcinoma (RR-TC). However, results were unsatisfactory in BRAFV600E-mutant (BRAF-MUT) RR-TC. Here we assess safety and efficacy of redifferentiation therapy through genotype-guided MAPK-modulation in patients with BRAF-MUT or wildtype (BRAF-WT) RR-TC. Patients and Methods: In this prospective single-center, two-arm phase II study, patients received trametinib (BRAF-WT) or trametinib + dabrafenib (BRAF-MUT) for 21 ± 3 days. Redifferentiation was assessed by 123I-scintigraphy. In case of restored radioiodine uptake, 124I-guided 131I therapy was performed. Primary endpoint was the redifferentiation rate. Secondary endpoints were treatment response (thyroglobulin, RECIST 1.1) and safety. Parameters predicting successful redifferentiation were assessed using a receiver operating characteristic analysis and Youden J statistic. Results: Redifferentiation was achieved in 7 of 20 (35%) patients, 2 of 6 (33%) in the BRAF-MUT and 5 of 14 (36%) in the BRAF-WT arm. Patients received a mean (range) activity of 300.0 (273.0–421.6) mCi for 131I therapy. Any thyroglobulin decline was seen in 57% (4/7) of the patients, RECIST 1.1 stable/partial response/progressive disease in 71% (5/7)/14% (1/7)/14% (1/7). Peak standardized uptake value (SUVpeak) < 10 on 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET was associated with successful redifferentiation (P = 0.01). Transient pyrexia (grade 3) and rash (grade 4) were noted in one patient each. Conclusions: Genotype-guided MAPK inhibition was safe and resulted in successful redifferentiation in about one third of patients in each arm. Subsequent 131I therapy led to a thyroglobulin (Tg) decline in more than half of the treated patients. Low tumor glycolytic rate as assessed by FDG-PET is predictive of redifferentiation success. See related commentary by Cabanillas et al., p. 4164