Radiotheranostics in oncology: Making precision medicine possible.

A quintessential setting for precision medicine, theranostics refers to a rapidly evolving field of medicine in which disease is diagnosed followed by treatment of disease-positive patients using tools for the therapy identical or similar to those used for the diagnosis. Against the backdrop of only-treat-when-visualized, the goal is a high therapeutic index with efficacy markedly surpassing toxicity. Oncology leads the way in theranostics innovation, where the approach has become possible with the identification of unique proteins and other factors selectively expressed in cancer versus healthy tissue, advances in imaging technology able to report these tissue factors, and major understanding of targeting chemicals and nanodevices together with methods to attach labels or warheads for imaging and therapy. Radiotheranostics-using radiopharmaceuticals-is becoming routine in patients with prostate cancer and neuroendocrine tumors who express the proteins PSMA (prostate-specific membrane antigen) and SSTR2 (somatostatin receptor 2), respectively, on their cancer. The palpable excitement in the field stems from the finding that a proportion of patients with large metastatic burden show complete and partial responses, and this outcome is catalyzing the search for more radiotheranostics approaches. Not every patient will benefit from radiotheranostics; but, for those who cross the target-detected line, the likelihood of response is very high.

TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia.

Hypoglycemia triggers autonomic and endocrine counter-regulatory responses to restore glucose homeostasis, a response that is impaired in patients with diabetes and its long-term complication hypoglycemia-associated autonomic failure (HAAF). We show that insulin-evoked hypoglycemia is severely aggravated in mice lacking the cation channel proteins TRPC1, TRPC4, TRPC5, and TRPC6, which cannot be explained by alterations in glucagon or glucocorticoid action. By using various TRPC compound knockout mouse lines, we pinpointed the failure in sympathetic counter-regulation to the lack of the TRPC5 channel subtype in adrenal chromaffin cells, which prevents proper adrenaline rise in blood plasma. Using electrophysiological analyses, we delineate a previously unknown signaling pathway in which stimulation of PAC1 or muscarinic receptors activates TRPC5 channels in a phospholipase-C-dependent manner to induce sustained adrenaline secretion as a crucial step in the sympathetic counter response to insulin-induced hypoglycemia. By comparing metabolites in the plasma, we identified reduced taurine levels after hypoglycemia induction as a commonality in TRPC5-deficient mice and HAAF patients.

Fibroblast activation protein inhibitor-positron emission tomography in aortitis: fibroblast pathology in active inflammation and remission.

OBJECTIVES: Epigenetically modified fibroblasts contribute to chronicity in inflammatory diseases. Reasons for the relapsing character of large vessel vasculitis (LVV) remain obscure, including the role of fibroblasts, in part due to limited access to biopsies of involved tissue.68Ga FAPI-46 (FAPI)-PET/CT detects activated fibroblasts in vivo. In this exploratory pilot study, we tested the detection of fibroblast activation in vessel walls using FAPI-PET/CT in LVV with aortitis. METHODS: Eight LVV patients with aortitis and eight age- and gender-matched controls were included. The distribution of FAPI uptake was evaluated in the aorta and large vessels. FAPI-uptake was compared with MRI inflammatory activity scores. Imaging results were compared with clinical parameters such as serum inflammatory markers, time of remission and medication. RESULTS: Three aortitis patients were clinically active and five in remission. Irrespective of activity, FAPI uptake was significantly enhanced in aortitis compared with controls. Patients in remission had a mean duration of remission of 2.8 years (range 1-4 years), yet significant FAPI uptake in the vessel wall was found. In remitted aortitis, MRI inflammatory scores were close to be negative, while in 4/5 patients visually identifiable FAPI uptake was observed. CONCLUSIONS: This pilot feasibility study shows significant tracer uptake in the aortic walls in LVV. FAPI positivity indicates ongoing fibroblast pathology in clinically remitted LVV.

Improved pharmacokinetics and enhanced efficacy of the vancomycin derivative FU002 using a liposomal nanocarrier.

Antibiotic resistance still represents a global health concern which diminishes the pool of effective antibiotics. With the vancomycin derivative FU002, we recently reported a highly potent substance active against Gram-positive bacteria with the potential to overcome vancomycin resistance. However, the translation of its excellent antimicrobial activity into clinical efficiency could be hampered by its rapid elimination from the blood stream. To improve its pharmacokinetics, we encapsulated FU002 in PEGylated liposomes. For PEG-liposomal FU002, no relevant cytotoxicity on liver, kidney and red blood cells was observed. Studies in Wistar rats revealed a significantly prolonged blood circulation of the liposomal antibiotic. In microdilution assays it could be demonstrated that encapsulation does not diminish the antimicrobial activity against staphylococci and enterococci. Highlighting its great potency, liposomal FU002 exhibited a superior therapeutic efficacy when compared to the free form in a Galleria mellonella larvae infection model.

FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease.

Gallium 68 (68Ga)-labeled fibroblast activation protein (FAP) inhibitor (FAPI) PET is based on the molecular targeting of the FAP, which is known to be highly expressed in the major cell population in tumor stroma, termed cancer-associated fibroblasts. Among many FAP-targeted radiopharmaceuticals developed so far, 68Ga-FAPI exhibits rapid tracer accumulation in target lesions and low background signal, which results in excellent imaging features. FAPI PET can be integrated in the clinical workflow and enables the detection of small primary or metastatic lesions, especially in the brain, liver, pancreas, and gastrointestinal tract due to the low tracer accumulation in these organs. Moreover, the DOTA (1,4,7,10-tetraazacylclododecane-1,4,7,10-tetrayl tetraacetic acid) chelator in the molecular structure allows coupling of the FAPI molecules with therapeutic emitters such as yttrium 90 for theranostic applications. This review provides an overview of the state of the art in FAP imaging, summarizes the current knowledge of relevant cancer biology, and highlights the latest findings in the clinical use of 68Ga-FAPI PET and other current FAPI tracers. Published under a CC BY 4.0 license.

PSMA PET/CT: joint EANM procedure guideline/SNMMI procedure standard for prostate cancer imaging 2.0.

Here we aim to provide updated guidance and standards for the indication, acquisition, and interpretation of PSMA PET/CT for prostate cancer imaging. Procedures and characteristics are reported for a variety of available PSMA small radioligands. Different scenarios for the clinical use of PSMA-ligand PET/CT are discussed. This document provides clinicians and technicians with the best available evidence, to support the implementation of PSMA PET/CT imaging in research and routine practice.

Joint EANM/SNMMI procedure guideline for the use of 177Lu-labeled PSMA-targeted radioligand-therapy (177Lu-PSMA-RLT).

Prostate-specific membrane antigen (PSMA) is expressed by the majority of clinically significant prostate adenocarcinomas, and patients with target-positive disease can easily be identified by PSMA PET imaging. Promising results with PSMA-targeted radiopharmaceutical therapy have already been obtained in early-phase studies using various combinations of targeting molecules and radiolabels. Definitive evidence of the safety and efficacy of [177Lu]Lu-PSMA-617 in combination with standard-of-care has been demonstrated in patients with metastatic castration-resistant prostate cancer, whose disease had progressed after or during at least one taxane regimen and at least one novel androgen-axis drug. Preliminary data suggest that 177Lu-PSMA-radioligand therapy (RLT) also has high potential in additional clinical situations. Hence, the radiopharmaceuticals [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T are currently being evaluated in ongoing phase 3 trials. The purpose of this guideline is to assist nuclear medicine personnel, to select patients with highest potential to benefit from 177Lu-PSMA-RLT, to perform the procedure in accordance with current best practice, and to prepare for possible side effects and their clinical management. We also provide expert advice, to identify those clinical situations which may justify the off-label use of [177Lu]Lu-PSMA-617 or other emerging ligands on an individual patient basis.

[68 Ga]Ga-FAPI uptake correlates with the state of chronic kidney disease.

PURPOSE: Kidney fibrosis leads to a progressive reduction in kidney function ultimately resulting in kidney failure. Diagnostic tools to detect kidney fibrosis are all invasive in nature requiring kidney biopsies with subsequent histological validation. In this retrospective study, the diagnostic value of three different radiotracers for the noninvasive prediction of kidney fibrosis was analyzed, taking into account the glomerular filtration rate (GFR) and the intra-renal parenchymal radiotracer uptake. METHODS: In 81 patients receiving either one of the following molecular imaging probes, [68 Ga]Ga-FAPI, [68 Ga]Ga-PSMA, or [68 Ga]Ga-DOTATOC, kidney function parameters were correlated with SUVmax and SUVmean of the renal parenchyma and background activity measured in lung parenchyma, myocardium, gluteal muscle, and the abdominal aorta. Patients were clustered according to their grade of chronic kidney disease (CKD), and a regression analysis and one-way ANOVA were conducted in this retrospective analysis. RESULTS: We found a negative correlation between GFR and [68 Ga]Ga-FAPI uptake for both SUVmax and SUVmean values, whereas background activity showed no correlation with GFR. [68 Ga]Ga-DOTATOC and [68 Ga]Ga-PSMA did not correlate between CKD stage and intra-renal parenchymal radiotracer uptake. Only [68 Ga]Ga-PSMA background activity exhibited a positive correlation with GFR suggesting an unspecific binding/retention potentially due to longer circulation times. CONCLUSION: There is a significant negative correlation between renal parenchymal [68 Ga]Ga-FAPI uptake and GFR, which was not the case for [68 Ga]Ga-DOTATOC and [68 Ga]Ga-PSMA. This correlation suggests a specific binding of FAPI rather than a potential unspecific retention in the renal parenchyma, underlining the potential value of [68 Ga]Ga-FAPI for the noninvasive quantitative evaluation of kidney fibrosis.

Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model.

PURPOSE: Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. METHODS: PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. RESULTS: [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. CONCLUSION: This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

Effects of Different Basal Cell Culture Media upon the Osteogenic Response of hMSCs Evaluated by 99mTc-HDP Labeling.

The osteogenic differentiation of mesenchymal stem cells is now a standard procedure in modern bone tissue engineering. As this is a promising field for future clinical applications, many cell culture media exist to promote osteogenic differentiation. Prior to differentiation, cells must be expanded to obtain sufficient numbers for experiments. Little evidence is available regarding the optimal media combination for expansion and differentiation to maximize the osteogenic response. Therefore, human BM-MSCs (n = 6) were expanded in parallel in DMEM (Dulbecco's Modified Eagle Medium) LG (Low Glucose) and α-MEM (Minimum Essential Media alpha-modification), followed by simultaneous monolayer differentiation toward the osteogenic lineage in: 1. DMEM LG (Low Glucose), 2. DMEM HG (High Glucose), 3. α-MEM, 4. "Bernese medium", and 5. "Verfaillie medium", with a corresponding negative control (total 20 groups). As a marker for osteogenic differentiation, hydroxyapatite was accessed using radioactive 99mTc-HDP labeling and quantitative alizarin red staining. The results indicate that all media except "Bernese medium" are suitable for osteogenic differentiation, while there was evidence that DMEM LG is partly superior when used for expansion and differentiation of BM-hMSCs. Using "Verfaillie medium" after DMEM LG expansion led to the highest grade of osteogenic differentiation. Nevertheless, the difference was not significant. Therefore, we recommend using DMEM LG for robust osteogenic differentiation, as it is highly suitable for that purpose, economical compared to other media, and requires little preparation time.

99mTc-HDP Labeling-A Non-Destructive Method for Real-Time Surveillance of the Osteogenic Differentiation Potential of hMSC during Ongoing Cell Cultures.

99-Metastabil Technetium (99mTc) is a radiopharmaceutical widely used in skeletal scintigraphy. Recent publications show it can also be used to determine the osteogenic potential of human mesenchymal stem cells (hMSCs) by binding to hydroxyapatite formed during bone tissue engineering. This field lacks non-destructive methods to track live osteogenic differentiation of hMSCs. However, no data about the uptake kinetics of 99mTc and its effect on osteogenesis of hMSCs have been published yet. We therefore evaluated the saturation time of 99mTc by incubating hMSC cultures for different periods, and the saturation concentration by using different amounts of 99mTc activity for incubation. The influence of 99mTc on osteogenic potential of hMSCs was then evaluated by labeling a continuous hMSC culture three times over the course of 3 weeks, and comparing the findings to cultures labeled once. Our findings show that 99mTc saturation time is less than 0.25 h, and saturation concentration is between 750 and 1000 MBq. Repeated exposure to γ-radiation emitted by 99mTc had no negative effects on hMSC cultures. These new insights can be used to make this highly promising method broadly available to support researchers in the field of bone tissue engineering using this method to track and evaluate, in real-time, the osteogenic differentiation of hMSC, without any negative influence on the cell viability, or their osteogenic differentiation potential.

Nomograms to predict outcomes after 177Lu-PSMA therapy in men with metastatic castration-resistant prostate cancer: an international, multicentre, retrospective study.

BACKGROUND: Lutetium-177 (177Lu) prostate-specific membrane antigen (177Lu-PSMA) is a novel targeted treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Predictors of outcomes after 177Lu-PSMA to enhance its clinical implementation are yet to be identified. We aimed to develop nomograms to predict outcomes after 177Lu-PSMA in patients with mCRPC. METHODS: In this multicentre, retrospective study, we screened patients with mCRPC who had received 177Lu-PSMA between Dec 10, 2014, and July 19, 2019, as part of the previous phase 2 trials (NCT03042312, ACTRN12615000912583) or compassionate access programmes at six hospitals and academic centres in Germany, the USA, and Australia. Eligible patients had received intravenous 6·0-8·5 GBq 177Lu-PSMA once every 6-8 weeks, for a maximum of four to six cycles, and had available baseline [68Ga]Ga-PSMA-11 PET/CT scan, clinical data, and survival outcomes. Putative predictors included 18 pretherapeutic clinicopathological and [68Ga]Ga-PSMA-11 PET/CT variables. Data were collected locally and centralised. Primary outcomes for the nomograms were overall survival and prostate-specific antigen (PSA)-progression-free survival. Nomograms for each outcome were computed from Cox regression models with LASSO penalty for variable selection. Model performance was measured by examining discrimination (Harrell's C-index), calibration (calibration plots), and utility (patient stratification into low-risk vs high-risk groups). Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. FINDINGS: Between April 23, 2019, and Jan 13, 2020, 414 patients were screened; 270 (65%) of whom were eligible and were divided into development (n=196) and validation (n=74) cohorts. The median duration of follow-up was 21·5 months (IQR 13·3-30·7). Predictors included in the nomograms were time since initial diagnosis of prostate cancer, chemotherapy status, baseline haemoglobin concentration, and [68Ga]Ga-PSMA-11 PET/CT parameters (molecular imaging TNM classification and tumour burden). The C-index of the overall survival model was 0·71 (95% CI 0·69-0·73). Similar C-indices were achieved at internal validation (0·71 [0·69-0·73]) and external validation (0·72 [0·68-0·76]). The C-index of the PSA-progression-free survival model was 0·70 (95% CI 0·68-0·72). Similar C-indices were achieved at internal validation (0·70 [0·68-0·72]) and external validation (0·71 [0·68-0·74]). Both models were adequately calibrated and their predictions correlated with the observed outcome. Compared with high-risk patients, low-risk patients had significantly longer overall survival in the validation cohort (24·9 months [95% CI 16·8-27·3] vs 7·4 months [4·0-10·8]; p<0·0001) and PSA-progression-free survival (6·6 months [6·0-7·1] vs 2·5 months [1·2-3·8]; p=0·022). INTERPRETATION: These externally validated nomograms that are predictive of outcomes after 177Lu-PSMA in patients with mCRPC might help in clinical trial design and individual clinical decision making, particularly at institutions where 177Lu-PSMA is introduced as a novel therapeutic option. FUNDING: Prostate Cancer Foundation.

Interim [18F]FDG PET/CT can predict response to anti-PD-1 treatment in metastatic melanoma.

PURPOSE: In an attempt to identify biomarkers that can reliably predict long-term outcomes to immunotherapy in metastatic melanoma, we investigated the prognostic role of [18F]FDG PET/CT, performed at baseline and early during the course of anti-PD-1 treatment. METHODS: Twenty-five patients with stage IV melanoma, scheduled for treatment with PD-1 inhibitors, were enrolled in the study (pembrolizumab, n = 8 patients; nivolumab, n = 4 patients; nivolumab/ipilimumab, 13 patients). [18F]FDG PET/CT was performed before the start of treatment (baseline PET/CT) and after the initial two cycles of PD-1 blockade administration (interim PET/CT). Seventeen patients underwent also a third PET/CT scan after administration of four cycles of treatment. Evaluation of patients' response by means of PET/CT was performed after application of the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria and the PET Response Evaluation Criteria for IMmunoTherapy (PERCIMT). Response to treatment was classified into 4 categories: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). Patients were further grouped into two groups: those demonstrating metabolic benefit (MB), including patients with SMD, PMR, and CMR, and those demonstrating no MB (no-MB), including patients with PMD. Moreover, patterns of [18F]FDG uptake suggestive of radiologic immune-related adverse events (irAEs) were documented. Progression-free survival (PFS) was measured from the date of interim PET/CT until disease progression or death from any cause. RESULTS: Median follow-up from interim PET/CT was 24.2 months (19.3-41.7 months). According to the EORTC criteria, 14 patients showed MB (1 CMR, 6 PMR, and 7 SMD), while 11 patients showed no-MB (PMD). Respectively, the application of the PERCIMT criteria revealed that 19 patients had MB (1 CMR, 6 PMR, and 12 SMD), and 6 of them had no-MB (PMD). With regard to PFS, no significant difference was observed between patients with MB and no-MB on interim PET/CT according to the EORTC criteria (p = 0.088). In contrary, according to the PERCIMT criteria, patients demonstrating MB had a significantly longer PFS than those showing no-MB (p = 0.045). The emergence of radiologic irAEs (n = 11 patients) was not associated with a significant survival benefit. Regarding the sub-cohort undergoing also a third PET/CT, 14/17 patients (82%) showed concordant responses and 3/17 (18%) had a mismatch of response assessment between interim and late PET/CT. CONCLUSION: PET/CT-based response of metastatic melanoma to PD-1 blockade after application of the recently proposed PERCIMT criteria is significantly correlated with PFS. This highlights the potential ability of [18F]FDG PET/CT for early stratification of response to anti-PD-1 agents, a finding with possible significant clinical and financial implications. Further studies including larger numbers of patients are necessary to validate these results.

Dosing 225Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors: 5-year follow-up of hematological and renal toxicity.

PURPOSE: The aim of this retrospective analysis is to estimate the most appropriate single cycle and cumulative doses of 225Ac-DOTATOC in patients treated for somatostatin-receptor-expressing cancers. METHODS: 225Ac-DOTATOC was administered to thirty-nine patients with various somatostatin-receptor-positive tumors. Baseline and follow-up 68Ga-DOTATOC PET/CT, lab tests, and renal scintigraphy were obtained. Patients received long-term follow-up either at the local cancer center or in close collaboration with external oncologists. Acute and chronic hematological toxicity was evaluated quantitatively over time. Long-term follow-up of creatinine was used to approximate the annual loss of estimated GFR (eGFR). RESULTS: Dose-dependent acute hematological toxicity was seen at single doses above 40 MBq or repeated doses greater than approximately 20 MBq 225Ac-DOTATOC at 4 month intervals. Treatment-related kidney failure occurred in 2 patients after a delay of >4 years but was independent of administered radioactivity, and other clinical risk factors were important contributors to renal decline. In general, the annual decline of eGFR among patients did not follow a clear dose-effect relationship even in patients with previous ß-therapy. An average eGFR-loss of 8.4ml/min (9.9%) per year was observed which is similar to the experience with ß-therapy studies. CONCLUSION: Treatment activities of approx. 20 MBq per cycle (4 monthly repetition) and cumulative doses up to 60-80 MBq generally avoided both acute and chronic grade 3/4 hematotoxicity in patients with advanced stage malignancies. Chronic renal toxicity was observed at these doses, but pre-existing renal risk factors were important co-factors. These data represent a starting point for additional research to more precisely define safety thresholds of 225Ac-DOTATOC.

Performance of [68Ga]Ga-PSMA-11 PET/CT in patients with recurrent prostate cancer after prostatectomy-a multi-centre evaluation of 2533 patients.

PURPOSE: To evaluate the performance of [68Ga]Ga-PSMA-11 PET/CT in the diagnosis of recurrent prostate cancer (PC) after prostatectomy in a large multicentre cohort. METHODS: The centres, which contributed to this study, were the departments of nuclear medicine of Heidelberg (Germany), Technical University of Munich (Germany) and Albert Einstein Hospital of São Paulo (Brazil). A total of 2533 patients who were scanned with [68Ga]Ga-PSMA-11 PET/CT at 1 h p.i. due to recurrent PC after prostatectomy were included in this retrospective analysis. Exclusion criteria were as follows: patients with untreated primary tumour, previous chemotherapy or Xofigo®; those previously treated with exclusively external beam radiation therapy or HIFU; those referred for PSMA-therapy; and those treated with ADT (including first- and second-generation ADT) within the last 6 months. Potential influences of different factors such as PSA level, PSA doubling-time (PSADT), PSA velocity (PSAVel), Gleason Score (GSC, including the separate analysis of 7a and 7b), age and amount of injected tracer were evaluated in a multivariable analysis. RESULTS: The rate of pathologic PET/CT-scans was 43% for PSA ≤ 0.2 ng/ml, 58% for PSA > 0.2 to ≤ 0.5, 72% for PSA > 0.5 to ≤ 1.0 and increased to a maximum of 93% for PSA > 10 ng/ml. A pathological PET/CT was significantly (p = 0.001) associated with PSA level and higher GSC. Amount of injected tracer, age, PSADT and PSAVel were not associated with a higher probability of a pathological scan. CONCLUSION: [68Ga]Ga-PSMA-11 PET/CT at 1 h p.i. confirmed its high performance in the largest patient cohort yet analysed. Tumour detection showed a clear association with higher PSA and higher GSC. No association was found between a pathological [68Ga]Ga-PSMA-11 PET/CT and age, amount of injected tracer, PSADT or PSAVel.

High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics.

PURPOSE: To evaluate fibroblast-activation-protein (FAP) expression in different clinical stages of prostate cancer (PC) with regards to utility of [68 Ga]Ga-FAPI-04 PET/CT imaging in patients with castration-resistant PC (CRPC). METHODS: Tissue microarrays (TMAs) were constructed from prostatic tissue from 94 patients at different stages of PC (primary PC, patients undergoing neoadjuvant androgen deprivation therapy, CRPC, and neuroendocrine PC (NEPC)) and were stained with anti-FAP monoclonal antibody. A positive pixel count algorithm (H-Index) was used to compare FAP expression between the groups. Additionally, three men with advanced CRPC or NEPC underwent [68 Ga]Ga-FAPI-04 PET/CT, and PET positivity was analyzed. RESULTS: The mean H-index for benign tissue, primary PC, neoadjuvant androgen deprivation therapy before radical prostatectomy, CRPC, and NEPC was 0.018, 0.031, 0.042, 0.076, and 0.051, respectively, indicating a significant rise in FAP expression with advancement of disease. Corroborating these findings [68 Ga]Ga-FAPI-04 PET/CT was highly positive in men with advanced CRPC. CONCLUSION: Increased FAP tissue expression supports the use of FAP inhibitor (FAPI)-molecular theranostics in CRPC.

68Ga-FAPI-PET/CT in patients with various gynecological malignancies.

PURPOSE: 68Ga-FAPI (fibroblast activation protein inhibitor) is a novel and highly promising radiotracer for PET/CT imaging. The aim of this retrospective analysis is to explore the potential of FAPI-PET/CT in gynecological malignancies. We assessed biodistribution, tumor uptake, and the influence of pre- or postmenopausal status on tracer accumulation in hormone-sensitive organs. Furthermore, a comparison with the current standard oncological tracer 18F-FDG was performed in selected cases. PATIENTS AND METHODS: A total of 31 patients (median age 59.5) from two centers with several gynecological tumors (breast cancer; ovarian cancer; cervical cancer; endometrial cancer; leiomyosarcoma of the uterus; tubal cancer) underwent 68Ga-FAPI-PET/CT. Out of 31 patients, 10 received an additional 18F-FDG scan within a median time interval of 12.5 days (range 1-76). Tracer uptake was quantified by standardized uptake values (SUV)max and (SUV)mean, and tumor-to-background ratio (TBR) was calculated (SUVmax tumor/ SUVmean organ). Moreover, a second cohort of 167 female patients with different malignancies was analyzed regarding their FAPI uptake in normal hormone-responsive organs: endometrium (n = 128), ovary (n = 64), and breast (n = 147). These patients were categorized by age as premenopausal (<35 years; n = 12), postmenopausal (>65 years; n = 68), and unknown menstrual status (35-65 years; n = 87), followed by an analysis of FAPI uptake of the pre- and postmenopausal group. RESULTS: In 8 out of 31 patients, the primary tumor was present, and all 31 patients showed lesions suspicious for metastasis (n = 81) demonstrating a high mean SUVmax in both the primary (SUVmax 11.6) and metastatic lesions (SUVmax 9.7). TBR was significantly higher in 68Ga-FAPI compared to 18F-FDG for distant metastases (13.0 vs. 5.7; p = 0.047) and by trend for regional lymph node metastases (31.9 vs 27.3; p = 0.6). Biodistribution of 68Ga-FAPI-PET/CT presented significantly lower uptake or no significant differences in 15 out of 16 organs, compared to 18F-FDG-PET/CT. The highest uptake of all primary lesions was obtained in endometrial carcinomas (mean SUVmax 18.4), followed by cervical carcinomas (mean SUVmax 15.22). In the second cohort, uptake in premenopausal patients differed significantly from postmenopausal patients in endometrium (11.7 vs 3.9; p < 0.0001) and breast (1.8 vs 1.0; p = 0.004), whereas no significant difference concerning ovaries (2.8 vs 1.6; p = 0.141) was observed. CONCLUSION: Due to high tracer uptake resulting in sharp contrasts in primary and metastatic lesions and higher TBRs than 18F-FDG-PET/CT, 68Ga-FAPI-PET/CT presents a promising imaging method for staging and follow-up of gynecological tumors. The presence or absence of the menstrual cycle seems to correlate with FAPI accumulation in the normal endometrium and breast. This first investigation of FAP ligands in gynecological tumor entities supports clinical application and further research in this field.

Head-to-head intra-individual comparison of biodistribution and tumor uptake of 68Ga-FAPI and 18F-FDG PET/CT in cancer patients.

PURPOSE: FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of 68Ga-FAPI versus standard-of-care 18F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers. MATERIAL AND METHODS: This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both 68Ga-FAPI and 18F-FDG PET/CT within a median time interval of 10 days (range 1-89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ). RESULTS: A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. 68Ga-FAPI uptake in primary tumors and metastases was comparable to 18F-FDG in most cases. The SUVmax was significantly lower for 68Ga-FAPI than 18F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, 68Ga-FAPI TBRs were significantly higher than 18F-FDG TBRs in some sites, including liver and bone metastases. CONCLUSION: Quantitative tumor uptake is comparable between 68Ga-FAPI and 18F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for 68Ga-FAPI. Thus, 68Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological 18F-FDG uptake.

E-PSMA: the EANM standardized reporting guidelines v1.0 for PSMA-PET.

RATIONALE: The development of consensus guidelines for interpretation of Prostate-Specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) is needed to provide more consistent reports in clinical practice. The standardization of PSMA-PET interpretation may also contribute to increasing the data reproducibility within clinical trials. Finally, guidelines in PSMA-PET interpretation are needed to communicate the exact location of findings to referring physicians, to support clinician therapeutic management decisions. METHODS: A panel of worldwide experts in PSMA-PET was established. Panelists were selected based on their expertise and publication record in the diagnosis or treatment of PCa, in their involvement in clinical guidelines and according to their expertise in the clinical application of radiolabeled PSMA inhibitors. Panelists were actively involved in all stages of a modified, nonanonymous, Delphi consensus process. RESULTS: According to the findings obtained by modified Delphi consensus process, panelist recommendations were implemented in a structured report for PSMA-PET. CONCLUSIONS: The E-PSMA standardized reporting guidelines, a document supported by the European Association of Nuclear Medicine (EANM), provide consensus statements among a panel of experts in PSMA-PET imaging, to develop a structured report for PSMA-PET in prostate cancer and to harmonize diagnostic interpretation criteria.

Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging.

OBJECTIVES: To date, there is no valuable tool to assess fibrotic disease activity in humans in vivo in a non-invasive way. This study aims to uncouple inflammatory from fibrotic disease activity in fibroinflammatory diseases such as IgG4-related disease. METHODS: In this cross-sectional clinical study, 27 patients with inflammatory, fibrotic and overlapping manifestations of IgG4-related disease underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP; 68Ga-FAP inhibitor (FAPI)-04), 18F-fluorodeoxyglucose (FDG), MRI and histopathological assessment. In a longitudinal approach, 18F-FDG and 68Ga-FAPI-04 PET/CT data were evaluated before and after immunosuppressive treatment and correlated to clinical and MRI data. RESULTS: Using combination of 68Ga-FAPI-04 and 18F-FDG-PET, we demonstrate that non-invasive functional tracking of IgG4-related disease evolution from inflammatory towards a fibrotic outcome becomes feasible. 18F-FDG-PET positive lesions showed dense lymphoplasmacytic infiltration of IgG4+ cells in histology, while 68Ga-FAPI-04 PET positive lesions showed abundant activated fibroblasts expressing FAP according to results from RNA-sequencing of activated fibroblasts. The responsiveness of fibrotic lesions to anti-inflammatory treatment was far less pronounced than that of inflammatory lesions. CONCLUSION: FAP-specific PET/CT permits the discrimination between inflammatory and fibrotic activity in IgG4-related disease. This finding may profoundly change the management of certain forms of immune-mediated disease, such as IgG4-related disease, as subtypes dominated by fibrosis may require different approaches to control disease progression, for example, specific antifibrotic agents rather than broad spectrum anti-inflammatory treatments such as glucocorticoids.