Screening for Occult Transthyretin Amyloidosis in Patients with Severe Aortic Stenosis and Amyloid Red Flags.

AIMS: The optimal strategy to identify transthyretin-type cardiac amyloidosis (ATTR-CA) in patients with aortic stenosis (AS) is still unclear. This study aimed to investigate if targeted screening for ATTR-CA in patients with severe AS and amyloid red flags is associated with higher detection rates. METHODS: The study prospectively enrolled patients ≥65 years with severe AS. Patients who fulfilled ≥1 major (carpal tunnel syndrome (CTS), ruptured biceps tendon, spinal stenosis, N-terminal pro B-type natriuretic peptide ≥1000 pg/mL, cardiac troponin >99th percentile) or ≥2 minor criteria (diastolic dysfunction ≥2 grade/lateral e' <10 cm/s, atrial fibrillation, atrioventricular conduction disease/pacemaker) received bone scintigraphy and biochemical analysis for light chain amyloidosis. Hypertensive patients (>140/90 mmHg) and those with interventricular septal thickness (IVSd) ≤13 mm were excluded. RESULTS: Overall, 264 patients were screened, of whom 85 were included in the analysis. Tracer uptake Perugini grade ≥1 was detected in nine patients (11%). An endomyocardial biopsy was additionally performed in four of nine patients, yielding a prevalence of 7% (n = 6). All patients with dual AS-ATTR were male. Syncope was more commonly reported in AS-ATTR patients (50% vs. 6%, p = 0.010), who also tended to have more severe hypertrophy (IVSd of 18 vs. 16 mm, p = 0.075). Pericardial effusion and CTS were more common in patients with dual pathology (67% vs. 8%, p < 0.001, and 83% vs. 24%, p = 0.003, respectively). CONCLUSION: Targeted screening for ATTR-CA in patients with AS and amyloid red flags does not yield higher detection rates than those reported previously in all comers with AS.

Changes in tumor-to-blood ratio as a prognostic marker for progression-free survival and overall survival in neuroendocrine tumor patients undergoing PRRT.

BACKGROUND: Historically, patient selection for peptide receptor radionuclide therapy (PRRT) has been performed by virtue of somatostatin receptor scintigraphy (SRS). In recent years, somatostatin receptor positron emission tomography (SSTR-PET) has gradually replaced SRS because of its improved diagnostic capacity, creating an unmet need for SSTR-PET-based selection criteria for PRRT. Tumor-to-blood ratio (TBR) measurements have shown high correlation with the net influx rate Ki, reflecting the tumor somatostatin receptor expression, to a higher degree than standardized uptake value (SUV) measurements. TBR may therefore predict treatment response to PRRT. In addition, changes in semiquantitative SSTR-PET parameters have been shown to predate morphological changes, making them a suitable metric for response assessment. METHODS: The institutional database of the Department of Nuclear Medicine (University Hospital Essen) was searched for NET patients undergoing ≥ 2 PRRT cycles with available baseline and follow-up SSTR-PET. Two blinded independent readers reported the occurrence of new lesions quantified tumor uptake of up to nine lesions per patient using SUV and TBR. The association between baseline TBR and changes in uptake/occurrence of new lesions with progression-free survival (PFS) and overall survival (OS) was tested by use of a Cox regression model and log-rank test. RESULTS: Patients with baseline TBR in the 1st quartile had a shorter PFS (14.4 months) than those in the 3rd (23.7 months; p = 0.03) and 4th (24.1 months; p = 0.02) quartile. Similarly, these patients had significantly shorter OS (32.5 months) than those with baseline TBR in the 2nd (41.8 months; p = 0.03), 3rd (69.2 months; p < 0.01), and 4th (42.7 months; p = 0.03) quartile. Baseline to follow-up increases in TBR were independently associated with shorter PFS when accounting for prognostic markers, e.g., RECIST response (hazard ratio = 2.91 [95%CI = 1.54-5.50]; p = 0.01). This was confirmed with regard to OS (hazard ratio = 1.64 [95%CI = 1.03-2.62]; p = 0.04). Changes in SUVmean were not associated with PFS or OS. CONCLUSIONS: Baseline TBR as well as changes in TBR were significantly associated with PFS and OS and may improve patient selection and morphological response assessment. Future trials need to assess the role of TBR for therapy monitoring also during PRRT and prospectively explore TBR as a predictive marker for patient selection.

Molecular Imaging Biomarkers in Cardiooncology: A View on Established Technologies and Future Perspectives.

Novel therapeutic options have significantly improved survival and long-term outcomes in many cancer entities. Unfortunately, this improvement in outcome is often accompanied by new and increasingly relevant therapy-related cardiovascular toxicity. In this context, cardiooncology has emerged as a new field of interdisciplinary individual patient care. Important tasks are pretherapeutic risk stratification and early detection and treatment of cardiotoxicity, which comprises cardiac damage in relation to cardiovascular comorbidities, the tumor disease, and cancer treatment. Clinical manifestations can cover a broad spectrum, ranging from subtle and usually asymptomatic abnormalities to serious acute or chronic complications. Typical manifestations include acute and chronic heart failure, myo- and pericarditis, arrythmias, ischemia, and endothelial damage. They can be related to almost all current cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, hormonal therapy, and radiotherapy. Molecular imaging biomarkers can aid in pretherapeutic cardiooncologic assessment for primary prevention and personalized surveillance, detection, and differential diagnosis of cardiotoxic complications. Potential advantages over conventional diagnostics are the higher detection sensitivity for subtle changes in cardiac homeostasis, higher reproducibility, and better observer independence. Hybrid imaging with highly sensitive PET/MRI may be particularly suited for early diagnosis. Important technologies that are encouraged in current multidisciplinary guidelines are equilibrium radionuclide angiography for evaluation of ventricular function and chamber morphology, as well as myocardial perfusion imaging for additional detection of ischemia. Novel modalities that may detect even earlier signs of cardiotoxicity comprise 123I-metaiodobenzylguanidine SPECT to visualize sympathetic innervation, 18F-FDG and somatostatin receptor (68Ga-DOTATOC/DOTATATE) PET to indicate a metabolic shift and inflammation, and 68Ga-fibroblast activation protein inhibitor PET to monitor cardiac remodeling. In addition, PET imaging of mitochondrial function has recently been introduced in preclinical models and will potentially broaden the field of application through higher sensitivity and specificity and by enabling higher individualization of diagnostic concepts.

Quantification performance of silicon photomultiplier-based PET for small 18F-, 68Ga- and 124I-avid lesions in the context of radionuclide therapy planning.

PURPOSE: The aim of this study was to investigate conditions for reliable quantification of sub-centimeter lesions with low18F,68Ga, and124I uptake using a silicon photomultiplier-based PET/CT system. METHODS: A small tumor phantom was investigated under challenging but clinically realistic conditions resembling prostate and thyroid cancer lymph node metastases (6 spheres with 3.7-9.7 mm in diameter, 9 different activity concentrations ranging from about 0.25-25 kBq/mL, and a signal-to-background ratio of 20). Radionuclides with different positron branching ratios and prompt gamma coincidence contributions were investigated. Maximum-, contour-, and oversize-based partial volume effect (PVE) correction approaches were applied. Detection and quantification performance were estimated, considering a ±30 % deviation between imaged-derived and true activity concentrations as acceptable. A standard and a prolonged acquisition time and two image reconstruction algorithms (time-of-flight with/without point spread function modelling) were analyzed. Clinical data were evaluated to assess agreement of PVE-correction approaches indicating lesion quantification validity. RESULTS: The smallest 3.7-mm sphere was not visible. If the lesions were clearly observed, quantification was, except for a few cases, acceptable using contour- or oversized-based PVE-corrections. Quantification accuracy did not substantially differ between 18F, 68Ga, and 124I. No systematic differences between the analyzed reconstruction algorithms or shorter and larger acquisition times were observed. In the clinical evaluation of 20 lesions, an excellent statistical agreement between oversize- and contour-based PVE-corrections was observed. CONCLUSIONS: At the lower end of size (<10 mm) and activity concentration ranges of lymph-node metastases, quantification with reasonable accuracy is possible for 18F, 68Ga, and 124I, possibly allowing pre-therapeutic lesion dosimetry and individualized radionuclide therapy planning.

Regression of Myocardial 99mTc-DPD Uptake After Tafamidis Treatment of Cardiac Transthyretin Amyloidosis.

Cardiac transthyretin amyloidosis is an infiltrative cardiomyopathy with high mortality. To date, there are no specific biomarkers to directly assess disease activity and response to specific treatments. Our aim was to evaluate scintigraphic changes after treatment with the transthyretin stabilizer tafamidis. Methods: We included patients who had undergone 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy before tafamidis initiation and after at least 9 mo. Tracer activity was assessed visually and quantitatively as SUVmax Results: The study included 14 patients who were on tafamidis for 44 ± 14 mo. We observed regression of Perugini grade in 5 patients, unchanged grade in 9 patients, and regression of mean heart-to-contralateral-lung ratio (P = 0.015) and SUVmax (P = 0.005). There were no changes in N-terminal pro-B-type natriuretic peptide or echocardiographic measures. Conclusion: Treatment with tafamidis results in regression of myocardial 99mTc-DPD uptake. 99mTc-DPD scintigraphy may provide useful imaging biomarkers to assess response to treatment.

Brainstem Infarction in Immunodeficiency Identified as Adenosine Deaminase 2 Deficiency: Case Report.

PURPOSE: We present the case of a 24-year-old male with CNS granulomatosis due to an immunodeficiency syndrome which was identified as deficiency of adenosine deaminase 2 (DADA2) as a cause of brainstem infarction. METHODS: Case report and detailed description of the clinical course of diagnosis and treatment. CASE: The patient's medical history consisted of an unknown immunodeficiency syndrome. Based on former findings, common variable immunodeficiency (CVID) was diagnosed. The patient suffered from three consecutive brainstem strokes of unknown etiology within 3 years. An MRI scan detected gadolinium-enhancing, granulomatous-suspect lesions in the interpeduncular cistern, temporal lobe, and tegmentum. Laboratory analysis was compatible with CVID, with leukopenia and immunoglobulin deficiency. Because granulomatous CNS inflammation was suspected, the patient received methylprednisolone immunosuppressive therapy, which led to partially regressive MRI lesions. However, in contrast to imaging, the patient showed a progressive cerebellar syndrome, indicating plasma exchange therapy and immunoglobulin treatment, which led to rapid symptom amelioration. After a relapse and a further stroke, expanded analysis confirmed DADA2 (and not CVID) as the inflammatory cause for recurrent stroke. After starting the therapy with immunoglobulins and adalimumab, no further strokes occurred. CONCLUSION: We present the case of a young adult with diagnosis of DADA2 as a cause for recurrent strokes due to vasculitis. This stroke etiology is rare but should be considered as a cause of recurrent stroke of unknown origin in young patients to avoid a disabling disease course by disease-specific treatment options.

68Ga-FAPI PET/CT Interobserver Agreement on Tumor Assessment: An International Multicenter Prospective Study.

68Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on 68Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Methods: 68Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [n = 10], colorectal cancer [n = 10], pancreatic adenocarcinoma [n = 10], genitourinary cancer [n = 10], and other types of cancer [n = 10]). Fifteen masked observers reviewed and interpreted the images using a standardized approach for local, local nodal, and metastatic involvement. Observers were grouped by experience as having a low (<30 prior 68Ga-FAPI PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 5). Two independent readers with a high level of experience and unmasked to clinical information, histopathology, tumor markers, and follow-up imaging (CT/MRI or PET/CT) served as the standard of reference (SOR). Observer groups were compared by overall agreement (percentage of patients matching SOR) and Fleiss κ with mean and corresponding 95% CI. We defined acceptable agreement as a κ value of at least 0.6 (substantial or higher) and acceptable accuracy as at least 80%. Results: Highly experienced observers agreed substantially on all categories (primary tumor: κ = 0.71; 95% CI, 0.71-0.71; local nodal involvement: κ = 0.62; 95% CI, 0.61-0.62; distant metastasis: κ = 0.75; 95% CI, 0.75-0.75), whereas observers with intermediate experience showed substantial agreement on primary tumor (κ = 0.73; 95% CI, 0.73-0.73) and distant metastasis (κ = 0.65; 95% CI, 0.65-0.65) but moderate agreement on local nodal stages (κ = 0.55; 95% CI, 0.55-0.55). Observers with low experience had moderate agreement on all categories (primary tumor: κ = 0.57; 95% CI, 0.57-0.58; local nodal involvement: κ = 0.51; 95% CI, 0.51-0.52; distant metastasis: κ = 0.54; 95% CI, 0.53-0.54). Compared with SOR, the accuracy for readers with high, intermediate, and low experience was 85%, 83%, and 78%, respectively. In summary, only highly experienced readers showed substantial agreement and a diagnostic accuracy of at least 80% in all categories. Conclusion: The interpretation of 68Ga-FAPI PET/CT for cancer imaging had substantial reproducibility and accuracy among highly experienced observers only, especially for local nodal and metastatic assessments. Therefore, for accurate interpretation of different tumor entities and pitfalls, we recommend training or experience with at least 300 representative scans for future clinical readers.

Diagnostic significance of MRI versus CT using identical PET data in patients with recurrent differentiated thyroid cancer: A PET/MRI study.

In this retrospective study we compared magnet resonance imaging (MRI) and computed tomography (CT) each combined with identical 2-deoxy-2-[18F] fluoro-D-glucose or 2-[18F] F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) data in patients with recurrent differentiated thyroid cancer (DTC). In total 42 patients with DTC were examined. All patients underwent FDG PET/MRI and CT, the latter originating from one of the following examinations: I-131 single photon emission computed tomography/CT (32/42), low dose FDG PET/CT (5/42) or diagnostic FDG PET/CT (5/42). Two readers assessed FDG PET/MRI as well as FDG PET/CT, with the latter CT coming from one of the above examinations performed at a maximum temporal interval of 5 days from PET/MRI. Local recurrence, cervical lymph node - and pulmonary metastases were assessed in a consensus read. Lesions rated with a high malignancy score (score 4 or 5) were further analyzed. Every malignant lesion was verified if it was identified by one of both or by both modalities. In 20 of 42 patients altogether 100 malignant lesions were present. In 11/20 patients in total 15 local recurrences (15 in MRI/ 9 in CT: 9 CT/MRI, 6 MRI only, 0 CT only; P = .04) were found with a statistically significant better performance of MRI. Regarding lymph node metastases, in total 13 lesions (12 in MRI/ 8 in CT: 7 CT/MRI, 5 MRI only, 1 CT only; P = .22) in 8/20 patients were found with no significant difference between both modalities. Furthermore, in 9/20 patients in total 72 lung lesions (40 in MRI/ 63 in CT: 31 CT/MRI, 9 MRI only, 32 CT only; P = .001) were found with a statistically significant better performance of CT. In 33/42 patients follow up was available and supported the observations. In patients with recurrent DTC, PET/MRI showed superiority compared to PET/CT in evaluation of the neck region. PET/MRI was inferior to PET/CT in evaluation of the lung. PET/MRI in combination with a low dose CT of the lung may thus represent the ideal staging tool in patients with recurrent DTC.

Corneal confocal microscopy identifies corneal nerve loss and increased Langerhans cells in presymptomatic carriers and patients with hereditary transthyretin amyloidosis.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare, but life-threatening protein misfolding disorder due to TTR gene mutations. Cardiomyopathy (ATTRv-CM) and polyneuropathy (ATTRv-PN) with early small nerve fibre involvement are the most common manifestations. Timely diagnosis and treatment initiation are key to limiting progression of disease. Corneal confocal microscopy (CCM) is a non-invasive method to quantify corneal small nerve fibres and immune cell infiltrates in vivo. METHODS: This cross-sectional study investigated the utility of CCM in 20 patients with ATTRv amyloidosis (ATTRv-CM, n = 6; ATTRv-PN, n = 14) and presymptomatic carriers (n = 5) compared to 20 age- and sex-matched healthy controls. Corneal nerve fibre density, corneal nerve fibre length, corneal nerve branch density, and cell infiltrates were assessed. RESULTS: Corneal nerve fibre density and nerve fibre length were significantly lower in patients with ATTRv amyloidosis compared to healthy controls regardless of the clinical phenotype (ATTRv-CM, ATTRv-PN) and corneal nerve fibre density was significantly lower in presymptomatic carriers. Immune cell infiltrates were only evident in patients with ATTRv amyloidosis, which correlated with reduced corneal nerve fibre density. CONCLUSIONS: CCM identifies small nerve fibre damage in presymptomatic carriers and symptomatic patients with ATTRv amyloidosis and may serve as a predictive surrogate marker to identify individuals at risk of developing symptomatic amyloidosis. Furthermore, increased corneal cell infiltration suggests an immune-mediated mechanism in the pathogenesis of amyloid neuropathy.

Efficacy and Safety of 124I-MIBG Dosimetry-Guided High-Activity 131I-MIBG Therapy of Advanced Pheochromocytoma or Neuroblastoma.

We aim to evaluate the efficacy and safety of 124I-metaiodobenzylguanidine (MIBG) dosimetry-guided high-activity 131I-MIBG therapy of advanced pheochromocytoma or neuroblastoma. Methods: Fourteen patients with advanced pheochromocytoma or neuroblastoma, age 9-69 y, underwent 124I-MIBG PET scans and whole-body retention measurements to assess the whole-body dose as a surrogate of bone marrow toxicity and tumor (absorbed) dose per unit of administered activity. Dosimetry results together with individual patient characteristics were combined to guide a single therapeutic activity to achieve a high tumor dose without exceeding toxicity threshold. Toxicity was assessed for hematologic, hepatic, and renal function. Response was evaluated by RECIST, International Society of Pediatric Oncology Europe Neuroblastoma-like score, change in PET uptake, and quantitative PET parameters (SUVmax, SUVpeak, metabolic tumor volume, total lesion glycolysis), as well as visual decrease in number or in visual intensity of lesions on baseline to follow-up 124I-MIBG PET/CT. Results: The average therapeutic activity was 14 GBq. Eleven of 14 patients (79%) received each more than 10 GBq. One male patient was treated with a single activity of 50 GBq. Three patients were treated with lower activities between 3.5 and 7.0 GBq. Median overall survival was 85 mo (95% CI), and median progression-free survival was 25 mo (95% CI). Four (29%) and 5 (36%) patients demonstrated response (complete response or partial response) by RECIST and functional imaging, respectively. One patient exceeded whole-body dose of 2 Gy and demonstrated grade 3 hematologic toxicity, which resolved spontaneously within 12 mo after the therapy without the need for further treatment. Three patients (21%) demonstrated transient grade 1 renal toxicity. Conclusion: 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy in patients with advanced pheochromocytoma or neuroblastoma resulted in durable responses with a low rate of manageable adverse events. Efficacy of 124I-MIBG-guided activity escalation should further be assessed in a prospective setting.

Nuclear medicine in the assessment and prevention of cancer therapy-related cardiotoxicity: prospects and proposal of use by the European Association of Nuclear Medicine (EANM).

Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity.

Reduction of emission time for [68Ga]Ga-PSMA PET/CT using the digital biograph vision: a phantom study.

BACKGROUND: The aim of this phantom study was to optimize the [68Ga]Ga-PSMA PET/CT examination in terms of scan time duration and image reconstruction parameters, in combination with PSF and TOF modelling, in a digital Biograph Vision PET/CT scanner. METHODS: Three types of phantoms were used: 1) soft-tissue tumor phantom consisting of six spheres mounted in a torso phantom; 2) bone-lung tumor phantom; 3) resolution phantom. Phantom inserts were filled with activity concentrations (ACs) that were derived from clinical data. Phantom data were acquired in list-mode at one bed position. Images with emission data ranging from 30 to 210 s in 30-s increments were reconstructed from a reference image acquired with 3.5-min emission. Iterative image reconstruction (OSEM), point-spread-function (PSF) and time-of-flight (TOF) options were applied using different iterations, Gaussian filters, and voxel sizes. The criteria for image quality was lesion detectability and lesion quantification, evaluated as contrast-to-noise ratio (CNR) and maximum AC (peak AC), respectively. A threshold value of CNR above 6 and percentage maximum AC (peak AC) deviation range of ±20% of the reference image were considered acceptable. The proposed single-bed scan time reduction was projected to a whole-body examination (patient validation scan) using the continuous-bed-motion mode. RESULTS: Sphere and background ACs of 20 kBq/mL and 1 kBq/mL were selected, respectively. The optimized single-bed scan time was approximately 60 s using OSEM-TOF or OSEM-TOF+PSF (four iterations, 4.0-mm Gaussian filter and almost isotropic voxel size of 3.0-mm side length), resulting in a PET spatial resolution of 6.3 mm for OSEM-TOF and 5.5 mm for OSEM-TOF+PSF. In the patient validation, the maximum percentage difference in lesion quantification between standard and optimized protocol (whole-body scan time of 15 vs. 5 min) was below 19%. CONCLUSIONS: A reduction of single-bed and whole-body scan time for [68Ga]Ga-PSMA PET/CT compared to current recommended clinical acquisition protocols is postulated. Clinical studies are warranted to validate the applicability of this protocol.

Quantitative 99mTc-DPD-SPECT/CT assessment of cardiac amyloidosis.

INTRODUCTION: Transthyretin (ATTR) amyloidosis is responsible for the majority of cardiac amyloidosis (CA) cases and can be reliably diagnosed with bone scintigraphy and the visual Perugini score. We aimed to implement a quantification method of cardiac amyloid deposits in patients with suspected cardiac amyloidosis and to compare performance to visual scoring. METHODS AND MATERIALS: 136 patients received 99mTc-DPD-bone scintigraphy including SPECT/CT of the thorax in case of suspicion of cardiac amyloidosis. Imaging phantom studies were performed to determine the scaling factor for standardized uptake value (SUV) quantification from SPECT/CT. Myocardial tracer uptake was quantified in a whole heart volume of interest. RESULTS: Forty-five patients were diagnosed with CA. A strong relationship between cardiac SUVmax and Perugini score was found (Spearman r 0.75, p < 0.0001). Additionally, tracer uptake in bone decreased with increasing cardiac SUVmax and Perugini score (p < 0.0001). ROC analysis revealed good performance of the SUVmax for the detection of ATTR-CA with AUC of 0.96 ± 0.02 (p < 0.0001) with sensitivity 98.7% and specificity 87.2%. CONCLUSION: We demonstrate an accessible and accurate quantitative SPECT approach in CA. Quantitative assessment of the cardiac tracer uptake may improve diagnostic accuracy and risk classification. This method may enable monitoring and assessment of therapy response in patients with ATTR amyloidosis.

Lesion Quantification Accuracy of Digital 90Y PET Imaging in the Context of Dosimetry in Systemic Fibroblast Activation Protein Inhibitor Radionuclide Therapy.

Therapy with 90Y-labeled fibroblast activation protein inhibitors (90Y-FAPIs) was recently introduced as a novel treatment concept for patients with solid tumors. Lesion and organ-at-risk dosimetry is part of assessing treatment efficacy and safety and requires reliable quantification of tissue uptake. As 90Y quantification is limited by the low internal positron-electron pair conversion rate, the increased effective sensitivity of digital silicon photomultiplier-based PET/CT systems might increase quantification accuracy and, consequently, allow for dosimetry in 90Y-FAPI therapy. The aim of this study was to explore the conditions for reliable lesion image quantification in 90Y-FAPI radionuclide therapy using a digital PET/CT system. Methods: Two tumor phantoms were filled with 90Y solution using different sphere activity concentrations and a constant signal-to-background ratio of 40. The minimum detectable activity concentration was determined, and its dependence on acquisition time (15 vs. 30 min per bed position) and smoothing levels (all-pass vs. 5-mm gaussian filter) was investigated. Quantification accuracy was evaluated at various activity concentrations to estimate the minimum quantifiable activity concentration using contour-based and oversized volume-of-interest-based quantification approaches. A ±20% deviation range between image-derived and true activity concentrations was regarded as acceptable. Tumor dosimetry for 3 patients treated with 90Y-FAPI is presented to project the phantom results to clinical scenarios. Results: For a lesion size of 40 mm and a clinical acquisition time of 15 min, both minimum detectable and minimum quantifiable activity concentrations were 0.12 MBq/mL. For lesion sizes of greater than or equal to 30 mm, accurate quantification was feasible for detectable lesions. Only for the smallest 10-mm sphere, the minimum detectable and minimum quantifiable activity concentrations differ substantially (0.43 vs. 1.97 MBq/mL). No notable differences between the 2 quantification approaches were observed. For the investigated tumors, absorbed dose estimates with reliable accuracy were achievable. Conclusion: For lesion sizes and activity concentrations that are expected to be observed in patients treated with 90Y-FAPI, quantification with reasonable accuracy is possible. Further dosimetry studies are needed to thoroughly investigate the efficacy and safety of 90Y-FAPI therapy.

Clinical Decision Support for Axillary Lymph Node Staging in Newly Diagnosed Breast Cancer Patients Based on 18F-FDG PET/MRI and Machine Learning.

In addition to its high prognostic value, the involvement of axillary lymph nodes in breast cancer patients also plays an important role in therapy planning. Therefore, an imaging modality that can determine nodal status with high accuracy in patients with primary breast cancer is desirable. Our purpose was to investigate whether, in newly diagnosed breast cancer patients, machine-learning prediction models based on simple assessable imaging features on MRI or PET/MRI are able to determine nodal status with performance comparable to that of experienced radiologists; whether such models can be adjusted to achieve low rates of false-negatives such that invasive procedures might potentially be omitted; and whether a clinical framework for decision support based on simple imaging features can be derived from these models. Methods: Between August 2017 and September 2020, 303 participants from 3 centers prospectively underwent dedicated whole-body 18F-FDG PET/MRI. Imaging datasets were evaluated for axillary lymph node metastases based on morphologic and metabolic features. Predictive models were developed for MRI and PET/MRI separately using random forest classifiers on data from 2 centers and were tested on data from the third center. Results: The diagnostic accuracy for MRI features was 87.5% both for radiologists and for the machine-learning algorithm. For PET/MRI, the diagnostic accuracy was 89.3% for the radiologists and 91.2% for the machine-learning algorithm, with no significant differences in diagnostic performance between radiologists and the machine-learning algorithm for MRI (P = 0.671) or PET/MRI (P = 0.683). The most important lymph node feature was tracer uptake, followed by lymph node size. With an adjusted threshold, a sensitivity of 96.2% was achieved by the random forest classifier, whereas specificity, positive predictive value, negative predictive value, and accuracy were 68.2%, 78.1%, 93.8%, and 83.3%, respectively. A decision tree based on 3 simple imaging features could be established for MRI and PET/MRI. Conclusion: Applying a high-sensitivity threshold to the random forest results might potentially avoid invasive procedures such as sentinel lymph node biopsy in 68.2% of the patients.