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PurposeFAPI 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 MethodsThis 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).ResultsA 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.ConclusionQuantitative 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.

Background Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTRs), which is the molecular basis for 68 Ga-DOTATOC positron-emission tomography (PET) and radiopeptide therapy (PRRT). However, SSTR expression fluctuates and can be subject to treatment-related changes. The aim of this retrospective study was to assess, which changes in PET and apparent diffusion coefficient (ADC) occur for different treatments and if pre-therapeutic 68 Ga-DOTATOC-PET/MRI was able to predict treatment response to PRRT. Methods Patients with histopathologically confirmed NET, at least one liver metastasis > 1 cm and at least two 68 Ga-DOTATOC-PET/MRI including ADC maps were eligible. 68 Ga-DOTATOC-PET/MRI of up to 5 liver lesions per patients was subsequently analyzed. Extracted features comprise conventional PET parameters, such as maximum and mean standardized uptake value (SUVmax and SUVmean) and ADC values. Furthermore, textural features (TFs) from both modalities were extracted. In patients with multiple 68 Ga-DOTATOC-PET/MRI a pair of 2 scans each was analyzed separately and the parameter changes between both scans calculated. The same image analysis was performed in patients with 68 Ga-DOTATOC-PET/MRI before PRRT. Differences in PET and ADC maps parameters between PRRT-responders and non-responders were compared using Mann-Whitney test to test differences among groups for statistical significance. Results 29 pairs of 68 Ga-DOTATOC-PET/MRI scans of 18 patients were eligible for the assessment of treatment-related changes. In 12 cases patients were treated with somatostatin analogues between scans, in 9 cases with PRRT and in 2 cases each patients received local treatment, chemotherapy and sunitinib. Treatment responders showed a statistically significant decrease in lesion volume and a borderline significant decrease in entropy on ADC maps when compared to non-responders. Patients treated with standalone SSA showed a borderline significant decrease in mean and maximum ADC, compared to patients treated with PRRT. No parameters were able to predict treatment response to PRRT on pre-therapeutic 68 Ga-DOTATOC-PET/MRI. Conclusions Patients responding to current treatment showed a statistically significant decrease in lesion volume on ADC maps and a borderline significant decrease in entropy. No statistically significant changes in PET parameters were observed. No PET or ADC maps parameters predicted treatment response to PRRT. However, the sample size of this preliminary study is small and further research needed.

The fibroblast activation protein α (FAP)-directed radiotracer [68Ga]Ga-FAPI-46 for PET–CT has shown promising diagnostic accuracy in cancer staging in retrospective studies. We aim to investigate the positive predictive value (PPV) of [68Ga]Ga-FAPI-46 PET for detecting FAP-expressing tumours and the potential association between PET radiotracer uptake intensity and immunohistochemical FAP expression. This single-centre, single-arm, interventional, phase 2 trial was conducted at the University Hospital Essen, Essen, Germany. Adults aged 18 years or older undergoing initial staging or restaging were eligible if they had at least one measurable tumour lesion (>1 cm) and a confirmed or suspected diagnosis of breast cancer, colorectal cancer, endometrial cancer, oesophageal cancer, head and neck cancer, ovarian cancer, pancreatic ductal adenocarcinoma (PDAC), prostate cancer, thyroid cancer, glioma, hepatocellular carcinoma, lymphoma, multiple myeloma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), sarcoma, seminoma, cancer of unknown primary origin, or other tumour types; had a planned or recent surgery or biopsy within 8 weeks before or after enrolment; and an ECOG performance status of 2 or less. Key exclusion criteria were previous external beam radiotherapy to the target lesion and receiving systemic cancer therapy within 1 month before enrolment. PET–CT images were acquired at a median of 11 min (IQR 10–14) after an intravenous injection of a median of 145 Megabecquerel (MBq; 124–154) of [68Ga]Ga-FAPI-46 and analysed by three independent, masked readers. The study concluded on day 30 of follow-up if histopathological confirmation and archived tumour tissue were already available, or on the day of biopsy or surgery within 8 weeks of receiving [68Ga]Ga-FAPI-46 PET–CT. Immunohistochemical FAP expression (score 0–3) was evaluated by an independent masked pathologist. The primary endpoint was the PPV of [68Ga]Ga-FAPI-46 PET for detecting immunohistochemical FAP-positive tumours (histopathologically confirmed) on a per-patient and per-region basis, with a predefined threshold of PPV of at least 75%, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05160051, and is complete. Between Dec 1, 2021, and Feb 6, 2024, 158 eligible participants were enrolled and three were excluded. 98 (63%) of 155 participants who received [68Ga]Ga-FAPI-46 PET–CT were male and 57 (37%) were female. One (1%) participant was African, two (1%) were Asian, and 152 (98%) were White. The median age of participants was 62 years (IQR 55–70). The median follow-up was 29 days (29–30). The patient-based PPV of [68Ga]Ga-FAPI-46 PET for detecting FAP-positive tumours based on immunohistochemical FAP staining was 90% (95% CI 84–95) and region-based PPV was 92% (85–96) in 127 (88%) of 144 participants with histopathological validation. Five (6%) of 90 adverse events were classified as possibly related to [68Ga]Ga-FAPI-46. Seven (8%) adverse events were serious, none related to [68Ga]Ga-FAPI-46. One participant died due to disease progression. These results confirm the safety and potential of [68Ga]Ga-FAPI-46 PET as an imaging biomarker for the detection of FAP-expressing tumours. Further studies are warranted to refine the specificity and define the role of [68Ga]Ga-FAPI-46 PET in clinical practice. SOFIE Biosciences.

Biliary-tract-carcinomas (BTC), pancreatic-ductal-adenocarcinomas (PDAC) and adenoidcystic-carcinomas (AC) have in common that they are traditionally treated with large clinical-target-volumes (CTV). The aim of this study is to examine the impact of pretreatment-[ 68 Ga]FAPI-PET/CT on target-volume-definition and posttreatment-[ 68 Ga]FAPI-PET/CT-response-assessment for BTC-, PDAC- and AC-patients referred to radiation-therapy. All consecutive BTC-, PDAC-, and AC-patients who received pretreatment-[ 68 Ga]FAPI-PET/CT±[ 18 F]FDG-PET/CT were included from 01.01.2020 to 01.03.2022. MTV and SUV max were separately generated based on [ 68 Ga]FAPI- and [ 18 F]FDG-PET/CT-images. A [ 68 Ga]FAPI- and [ 18 F]FDG-based-CTV was defined. Treatment-plans were compared. Treatment-response was reassessed by a second [ 68 Ga]FAPI-PET/CT and [ 18 F]FDG-PET/CT after treatment-completion. Intermodality comparison of lesion-to-background-ratios [SUV max_lesion /SUV mean_background ] for individual timepoints t 1 and t 2 revealed significant higher values for [ 68 Ga]FAPI compared to [ 18 F]FDG ( t 1 , p  = 0.008; t 2 , p  = 0.005). Intermodality comparison of radiation-therapy-plans showed that [ 68 Ga]FAPI-based planning resulted in D100% = 97.2% and V95% = 98.8% for the [ 18 F]FDG-MTV. [ 18 F]FDG-based-planning resulted in D100% = 35.9% and V95% = 78.1% for [ 68 Ga]FAPI-MTV. [ 18 F]FDG-based-planning resulted only in 2 patients in V95% > 95% for [ 68 Ga]FAPI-MTV, and in 1 patient in D100% > 97% for [ 68 Ga]FAPI-MTV. GTV-coverage in terms of V95% was 76.4% by [ 18 F]FDG-based-planning and 99.5% by [ 68 Ga]FAPI-based-planning. Pretreatment [ 68 Ga]FAPI-PET/CT enhances radiation-treatment-planning in this particular group of patients. While perilesional and tumoral follow-up [ 18 F]FDG-uptake behaved uniformly, perilesional and tumoral reaction may differ in follow-up [ 68 Ga]FAPI-imaging. Complementary [ 68 Ga]FAPI- and [ 18 F]FDG-imaging enhance treatment-response-assessment.

Aims The study aimed to investigate the prevalence, phenotypic characteristics, and predictors of atrial fibrillation (AF) in patients presenting with cardiac amyloidosis (CA) of light‐chain (AL) or transthyretin (ATTR) type. Methods and results Clinical, biochemical, and echocardiographic data of patients presenting with CA between 2005 and 2020 were retrospectively collected. CA staging was based on established biomarker systems. Binomial logistic regression was run to analyse the effects of clinical variables on the likelihood of AF. The study included 133 patients [53% AL, 41% wild‐type (wt) ATTR‐CA, & 6% hereditary ATTR‐CA]. Mean age was 71 years, and 80% were male patients. AF was diagnosed in 64 (48%) patients (28% in AL‐CA, 80% in wtATTR, 13% in hATTR, P < 0.001). Patients with AF were older (74 vs. 69 years, P < 0.001), more likely to have wtATTR‐CA (67 vs. 16%, P < 0.001), exhibited more often New York Heart Association ≥ III symptoms (66 vs. 45%, P = 0.02) and carried a higher burden of comorbidities. AF patients had lower left ventricular ejection fraction (47 vs. 53%, P < 0.005), higher left atrial volume index (54 vs. 46 mL/m2, P = 0.007), higher pulmonary artery pressure (42 vs. 31 mmHg, P = 0.008), and worse tricuspid annular plane systolic excursion values (17 vs. 20 mm, P = 0.01). Mitral regurgitation ≥ Grade 2 was more frequent in AF (56 vs. 25%, P < 0.001). Higher ATTR‐CA stage was associated with higher AF prevalence (47% vs. 74% vs. 94%, P < 0.001, for Stages I, II, & III, respectively). Higher AL‐CA stage was associated with lower AF prevalence (0% vs. 40% vs. 31% vs. 18%, P < 0.001, for Stages I, II, IIIa, & IIIb, respectively). Three independent predictors for AF were identified in a multivariate logistic regression model with 81.5% classification accuracy: AL type [odds ratio (OR) 0.1, confidence interval (CI) 0.01–0.29, P = 0.001], estimated glomerular filtration rate (OR 0.9, CI 0.93–0.99, P = 0.03), and body mass index (OR 1.3, CI 1.07–1.66, P = 0.01). ATTR amyloidosis was associated with a 10‐fold higher risk of AF. During 1 year follow‐up, only one episode of ischaemic stroke was reported. Conclusions Atrial fibrillation affects nearly half of all patients with CA. Patients presenting with AF have more severe symptoms and higher burden of comorbidities. ATTR type of amyloidosis is the strongest predictor of AF. Prospective screening for occult AF may be considered in ATTR‐CA.

The impact of inflammation on the outcome of many medical conditions such as cardiovascular diseases, neurological disorders, infections, cancer, and autoimmune diseases has been widely acknowledged. However, in contrast to neurological, oncologic, and cardiovascular disorders, imaging plays a minor role in research and management of inflammation. Imaging can provide insights into individual and temporospatial biology and grade of inflammation which can be of diagnostic, therapeutic, and prognostic value. There is therefore an urgent need to evaluate and understand current approaches and potential applications for imaging of inflammation. This review discusses radiotracers for positron emission tomography (PET) that have been used to image inflammation in cardiovascular diseases and other inflammatory conditions with a special emphasis on radiotracers that have already been successfully applied in clinical settings.

Purpose Radiolabelled fibroblast activation protein inhibitors (FAPIs) are becoming increasingly important for imaging various tumour diseases. However, it is essential to be aware of potential pitfalls. Here, we investigate FAP expression in the thyroid gland in autoimmune thyroiditis (AIT). Methods AIT patients with pathological thyroid uptake on [ 68 Ga]Ga-FAPI PET were compared with glucose metabolism on 2-[ 18 F]FDG PET in terms of SUV max /SUV peak /SUV mean /tissue-to-background ratio (TBR), and with a healthy control group. Results Between September 2019 and July 2021, 6 patients presented with a visually increased thyroid uptake and TBR on [ 68 Ga]Ga-FAPI PET. In the retrospective clinical work-up, all patients had known or newly diagnosed AIT. Compared to a matched healthy control group, FAP expression and glucose metabolism were significantly increased ([ 68 Ga]Ga-FAPI (SUV peak ): 7.0 vs. 1.7; p  = 0.004/(TBR bloodpool ): 6.8 vs. 1.7; p  = 0.002; 2-[ 18 F]FDG (SUV peak ): 3.9 vs. 1.4; p  = 0.004/(TBR bloodpool ): 4.0 vs. 1.2; p  = 0.041). However, there was no significant difference in median uptake between [ 68 Ga]Ga-FAPI and 2-[18F]FDG PET (SUV peak : 7.3 vs. 5.6; p  = 0.104). Conclusion Patients with AIT show higher thyroid uptake on [ 68 Ga]Ga-FAPI and 2-[ 18 F]FDG PET. Incidental thyroid uptake is another pitfall in the interpretation of [ 68 Ga]Ga-FAPI PET and should prompt a clinical work-up.

Background Hereditary transthyretin (ATTRv) amyloidosis is a rare, genetically heterogeneous and phenotypically variable systemic disease characterized by deposition of misfolded transthyretin fibrils in various tissues. ATTRv cardiomyopathy and progressive axonal polyneuropathy are the most common manifestations, leading to severe disability and ultimately death within approximately ten years. As disease-modifying treatment options evolve, timely diagnosis and treatment initiation are crucial to prevent rapid disease progression. Case presentation Here, we report on a 73-year old patient initially diagnosed with cardiac wild-type ATTR (ATTRwt) amyloidosis by endomyocardial biopsy. Molecular genetic analysis revealed a novel TTR sequence variant (p.Ala65Val) that is highly likely to be amyloidogenic in light of previously reported TTR mutations and the patient’s clinical presentation and family history. Conclusions Our findings expand the spectrum of known pathogenic TTR mutations and underline the importance of a thorough diagnostic workup in amyloidosis patients including careful genetic testing to avoid misdiagnosis and missing of treatment opportunities and to enable cascade testing and tracking of carriers.

Bone regeneration is typically a reliable process without scar formation. The endocrine disease type 2 diabetes prolongs and impairs this healing process. In a previous work, we showed that angiogenesis and osteogenesis-essential steps of bone regeneration-are deteriorated, accompanied by reduced proliferation in type 2 diabetic bone regeneration. The aim of the study was to improve these mechanisms by local application of adipose-derived stem cells (ASCs) and facilitate bone regeneration in impaired diabetic bone regeneration. The availability of ASCs in great numbers and the relative ease of harvest offers unique advantages over other mesenchymal stem cell entities. A previously described unicortical tibial defect model was utilized in diabetic mice (Lepr(db-/-)). Isogenic mouse adipose-derived stem cells (mASCs)(db-/db-) were harvested, transfected with a green fluorescent protein vector, and isografted into tibial defects (150,000 living cells per defect). Alternatively, control groups were treated with Dulbecco's modified Eagle's medium or mASCs(WT). In addition, wild-type mice were identically treated. By means of immunohistochemistry, proteins specific for angiogenesis, cell proliferation, cell differentiation, and bone formation were analyzed at early (3 days) and late (7 days) stages of bone regeneration. Additionally, histomorphometry was performed to examine bone formation rate and remodeling. Histomorphometry revealed significantly increased bone formation in mASC(db-/db-)-treated diabetic mice as compared with the respective control groups. Furthermore, locally applied mASCs(db-/db-) significantly enhanced neovascularization and osteogenic differentiation. Moreover, bone remodeling was upregulated in stem cell treatment groups. Local application of mACSs can restore impaired diabetic bone regeneration and may represent a therapeutic option for the future. This study showed that stem cells obtained from fat pads of type 2 diabetic mice are capable of reconstituting impaired bone regeneration in type 2 diabetes. These multipotent stem cells promote both angiogenesis and osteogenesis in type 2 diabetic bony defects. These data might prove to have great clinical implications for bony defects in the ever-increasing type 2 diabetic patient population.