Preclinical Evaluation of 68Ga- and 177Lu-Labeled Integrin αvß6-Targeting Radiotheranostic Peptides.

The integrin αvß6, an epithelium-specific cell surface receptor, is overexpressed on numerous malignancies, including the highly lethal pancreatic ductal adenocarcinomas. Here, we developed and tested a novel αvß6-targeting peptide, DOTA-5G (1) radiolabeled with 68Ga, for PET/CT imaging and 177Lu for treatment. With the goal to develop a radiotheranostic, further modifications were made for increased circulation time, renal recycling, and tumor uptake, yielding DOTA-albumin-binding moiety-5G (2). Methods: Peptides 1 and 2 were synthesized on solid phase, and their affinity for αvß6 was assessed by enzyme-linked immunosorbent assay. The peptides were radiolabeled with 68Ga and 177Lu. In vitro cell binding, internalization, and efflux of 68Ga-1 and 177Lu-2 were evaluated in αvß6-positive BxPC-3 human pancreatic cancer cells. PET/CT imaging of 68Ga-1 and 68Ga-2 was performed on female nu/nu mice bearing subcutaneous BxPC-3 tumors. Biodistribution was performed for 68Ga-1 (1 and 2 h after injection), 68Ga-2 (2 and 4 h after injection), and 177Lu-1 and 177Lu-2 (1, 24, 48, and 72 h after injection). The 177Lu-2 biodistribution data were extrapolated for human dosimetry data estimates using OLINDA/EXM 1.1. Therapeutic efficacy of 177Lu-2 was evaluated in mice bearing BxPC-3 tumors. Results: Peptides 1 and 2 demonstrated high affinity (<55 nM) for αvß6 by enzyme-linked immunosorbent assay. 68Ga-1, 68Ga-2, 177Lu-1, and 177Lu-2 were synthesized in high radiochemical purity. Rapid in vitro binding and internalization of 68Ga-1 and 177Lu-2 were observed in BxPC-3 cells. PET/CT imaging and biodistribution studies demonstrated uptake in BxPC-3 tumors. Introduction of the albumin-binding moiety in 177Lu-2 resulted in a 5-fold increase in tumor uptake and retention over time. Based on the extended dosimetry data, the dose-limiting organ for 177Lu-2 is the kidney. Treatment with 177Lu-2 prolonged median survival by 1.5- to 2-fold versus controls. Conclusion: 68Ga-1 and 177Lu-2 demonstrated high affinity for the integrin αvß6 both in vitro and in vivo, were rapidly internalized into BxPC-3 cells, and were stable in mouse and human serum. Both radiotracers showed favorable pharmacokinetics in preclinical studies, with predominantly renal excretion and good tumor-to-normal-tissue ratios. Favorable human dosimetry data suggest the potential of 177Lu-2 as a treatment for pancreatic ductal adenocarcinoma.

Radioembolization Dosimetry with Total-Body 90Y PET.

Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive 90Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity before treatment and image it after treatment. 90Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging 90Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE 90Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose-volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10- and 13-mm diameters, consistent with its high spatial resolution and system sensitivity. The total liver-absorbed dose showed excellent agreement between the uEXPLORER and the mCT for both patients, with differences lower than 0.2%. Larger differences of up to 60% were observed when comparing the liver segment doses. All dose-volume histograms were in good agreement, with narrower tails for the uEXPLORER in all segments, indicating lower image noise. Conclusion: This patient study is compelling for the use of total-body 90Y PET for liver dosimetry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT, especially in lower-count regions of interest, which is expected to improve dose quantification and tumor dosimetry.

Multiparametric cardiac18F-FDG PET in humans: pilot comparison of FDG delivery rate with82Rb myocardial blood flow.

Myocardial blood flow (MBF) and flow reserve are usually quantified in the clinic with positron emission tomography (PET) using a perfusion-specific radiotracer (e.g.82Rb-chloride). However, the clinical accessibility of existing perfusion tracers remains limited. Meanwhile,18F-fluorodeoxyglucose (FDG) is a commonly used radiotracer for PET metabolic imaging without similar limitations. In this paper, we explore the potential of18F-FDG for myocardial perfusion imaging by comparing the myocardial FDG delivery rateK1with MBF as determined by dynamic82Rb PET in fourteen human subjects with heart disease. Two sets of FDGK1were derived from one-hour dynamic FDG scans. One was the original FDGK1estimates and the other was the correspondingK1values that were linearly normalized for blood glucose levels. A generalized Renkin-Crone model was used to fit FDGK1with Rb MBF, which then allowed for a nonlinear extraction fraction correction for converting FDGK1to MBF. The linear correlation between FDG-derived MBF and Rb MBF was moderate (r= 0.79) before the glucose normalization and became much improved (r> 0.9) after glucose normalization. The extraction fraction of FDG was also similar to that of Rb-chloride in the myocardium. The results from this pilot study suggest that dynamic cardiac FDG-PET with tracer kinetic modeling has the potential to provide MBF in addition to its conventional use for metabolic imaging.

αvß6-Targeted Molecular PET/CT Imaging of the Lungs After SARS-CoV-2 Infection.

The true impact and long-term damage to organs such as the lungs after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain to be determined. Noninvasive molecularly targeted imaging may play a critical role in aiding visualization and understanding of the systemic damage. We have identified αvß6 as a molecular target; an epithelium-specific cell surface receptor that is low or undetectable in healthy adult epithelium but upregulated in select injured tissues, including fibrotic lung. Herein we report the first human PET/CT images using the integrin αvß6-binding peptide (18F-αvß6-BP) in a patient 2 mo after the acute phase of infection. Minimal uptake of 18F-αvß6-BP was noted in normal lung parenchyma, with uptake being elevated in areas corresponding to opacities on CT. This case suggests that 18F-αvß6-BP PET/CT is a promising noninvasive approach to identify the presence and potentially monitor the persistence and progression of lung damage.

Personalized Dosimetry for Liver Cancer Y-90 Radioembolization Using Computational Fluid Dynamics and Monte Carlo Simulation.

Yttrium-90 (Y-90) transarterial radioembolization uses radioactive microspheres injected into the hepatic artery to irradiate liver tumors internally. One of the major challenges is the lack of reliable dosimetry methods for dose prediction and dose verification. We present a patient-specific dosimetry approach for personalized treatment planning based on computational fluid dynamics (CFD) simulations of the microsphere transport combined with Y-90 physics modeling called CFDose. The ultimate goal is the development of a software to optimize the amount of activity and injection point for optimal tumor targeting. We present the proof-of-concept of a CFD dosimetry tool based on a patient's angiogram performed in standard-of-care planning. The hepatic arterial tree of the patient was segmented from the cone-beam CT (CBCT) to predict the microsphere transport using multiscale CFD modeling. To calculate the dose distribution, the predicted microsphere distribution was convolved with a Y-90 dose point kernel. Vessels as small as 0.45 mm were segmented, the microsphere distribution between the liver segments using flow analysis was predicted, the volumetric microsphere and resulting dose distribution in the liver volume were computed. The patient was imaged with positron emission tomography (PET) 2 h after radioembolization to evaluate the Y-90 distribution. The dose distribution was found to be consistent with the Y-90 PET images. These results demonstrate the feasibility of developing a complete framework for personalized Y-90 microsphere simulation and dosimetry using patient-specific input parameters.

Multiparametric Cardiac 18F-FDG PET in Humans: Kinetic Model Selection and Identifiability Analysis.

Cardiac 18F-FDG PET has been used in clinics to assess myocardial glucose metabolism. Its ability for imaging myocardial glucose transport, however, has rarely been exploited in clinics. Using the dynamic FDG-PET scans of ten patients with coronary artery disease, we investigate in this paper appropriate dynamic scan and kinetic modeling protocols for efficient quantification of myocardial glucose transport. Three kinetic models and the effect of scan duration were evaluated by using statistical fit quality, assessing the impact on kinetic quantification, and analyzing the practical identifiability. The results show that the kinetic model selection depends on the scan duration. The reversible two-tissue model was needed for a one-hour dynamic scan. The irreversible two-tissue model was optimal for a scan duration of around 10-15 minutes. If the scan duration was shortened to 2-3 minutes, a one-tissue model was the most appropriate. For global quantification of myocardial glucose transport, we demonstrated that an early dynamic scan with a duration of 10-15 minutes and irreversible kinetic modeling was comparable to the full one-hour scan with reversible kinetic modeling. Myocardial glucose transport quantification provides an additional physiological parameter on top of the existing assessment of glucose metabolism and has the potential to enable single tracer multiparametric imaging in the myocardium.

Relational and Spiritual Coping Among Emerging and Young Adult Cancer Survivors.

Cancer presents uncertainties for individuals of any age; however, emerging and young adults (EYA) are challenged to cope with developmental tasks in addition to cancer-related stressors. Guided by the double ABC-X model and biopsychosocial-spiritual framework, the current study investigates coping strategies used by this population and the role of psychological resources (perception of parental care/control and spirituality) on their coping ability. Recruited from online social media, 210 EYA cancer survivors self-reported demographic, medical information, and completed the Brief Cope scale. In addition, spirituality reliance, perceived parental care, and parental control were measured and examined in relation to coping ability. While nearly half of participants experienced positive adaptation in relation to multiple stressors, hierarchical multiple regression revealed the developmental nature of coping and indicated that higher spirituality reliance and higher degree of parental care were predictive of adaptive coping among EYA cancer survivors. Content analyses of the open-ended questions confirmed these results. In order to facilitate adaptive coping, attention must be paid to the unique biopsychosocial-spiritual and developmental needs of young cancer survivors while encouraging family support and spirituality reliance as significant tools in coping. Practical recommendations for nursing support and healthcare teams are discussed.

Opportunistic body composition evaluation in patients with esophageal adenocarcinoma: association of survival with 18F-FDG PET/CT muscle metrics.

OBJECTIVE: 18F-FDG PET is widely used to accurately stage numerous types of cancers. Although 18F-FDG PET/CT features of tumors aid in predicting patient prognosis, there is increasing interest in mining additional quantitative body composition data that could improve the prognostic power of 18F-FDG PET/CT, without additional examination costs or radiation exposure. The aim of this study was to determine the association between overall survival and body composition metrics derived from routine clinical 18F-FDG PET/CT examinations. METHODS: Patients who received baseline 18F-FDG PET/CT imaging during workup for newly diagnosed esophageal adenocarcinoma (EAC) were included. From these studies, psoas cross-sectional area (CSA), muscle attenuation (MA), SUVmean, and SUVmax were obtained. Correlation with overall survival was assessed using a Cox Proportional Hazards model, controlling for age, body mass index, 18F-FDG dose, glucose level, diabetes status, in-hospital status, and tumor stage. RESULTS: Among the 59 patients studied, psoas MA and SUVmax were found to be significant predictors of survival (HR 0.94, 95% CI 0.88-0.99, p = 0.04, and HR 0.37, 95% CI 0.14-0.97, p = 0.04, respectively) and remained independent predictors. Psoas CSA and SUVmean did not significantly influence survival outcomes. CONCLUSIONS: Characterization of psoas muscles as a surrogate marker for sarcopenia on baseline 18F-FDG PET/CT imaging is relatively easily obtained and may offer additional prognostic value in patients with EAC.

Understanding chondrodysplasia (cho): A comprehensive review of cho as an animal model of birth defects, disorders, and molecular mechanisms.

BACKGROUND: The mutant chondrodysplasia (cho) is a cartilage-targeting disorder in C57BL mice that results in dwarfing and other malformations stemming from this collagenopathy. Clarke Fraser made the discovery of the mutation accidentally in the early 1960s during the thalidomide tragedy. METHODS: For this review we identified key research on cho as since its discovery. Relevant data were compiled to make a comprehensive review that details discoveries associated with the cho mutation, that describes the associated phenotypes and molecular mechanisms, and that provides a discussion surrounding its current clinical relevance. RESULTS: Mechanistically, cho acts by hindering chondrogenesis and endochondral bone formation. The phenotype results from a 1-nt deletion in the gene encoding the alpha 1 chain of type XI collagen. For more than half a century, researchers have studied the pathogenesis of the cho mutation in relation to a variety of mouse models of human birth defects and disease. These studies have resulted in several discoveries linking cho with such human disorders as dwarfism, tracheal stenosis, cleft palate, pulmonary hypoplasia, and osteoarthritis (OA). CONCLUSION: The study of cho has led to numerous advances in understanding human birth defects, congenital disorders, and adult human disease. The most recent studies have suggested a role for the TGF-Beta, HtrA1, Ddr2, and Mmp-13 pathway in the degradation of articular cartilage and the development of OA in cho/+ mice. We have shown that the anti-hypertension drug Losartan is a TGF-Beta blocker that could be used to treat OA in Stickler syndrome, and thereby rescue the WT phenotype.

Preclinical Development and First-in-Human Imaging of the Integrin αvß6 with [18F]αvß6-Binding Peptide in Metastatic Carcinoma.

PURPOSE: The study was undertaken to develop and evaluate the potential of an integrin αvß6-binding peptide (αvß6-BP) for noninvasive imaging of a diverse range of malignancies with PET. EXPERIMENTAL DESIGN: The peptide αvß6-BP was prepared on solid phase and radiolabeled with 4-[18F]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired αvß6-expressing and αvß6-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired αvß6-expressing and αvß6-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. RESULTS: [18F]αvß6-BP displayed excellent affinity and selectivity for the integrin αvß6 in vitro [IC50(αvß6) = 1.2 nmol/L vs IC50(αvß3) >10 µmol/L] in addition to rapid target-specific cell binding and internalization (72.5% ± 0.9% binding and 52.5% ± 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [18F]αvß6-BP was rapid, primarily via the kidneys. In patients, [18F]αvß6-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [18F]αvß6-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. CONCLUSIONS: The clinical impact of [18F]αvß6-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.

Particle disease on fluoride-18 (NaF) PET/CT imaging.

Particle disease is a loss of bone that commonly occurs about five years after arthroplasty. The cause is secondary to microabrasive wear and shedding of any portion of the prosthesis, and the microscopic foreign bodies activate inflammation which can lead to pain. This report describes the imaging findings of an 80-year-old female with particle disease detected with 18F-fluoride PET/CT.

Mediastinoscopy might not be necessary in patients with non-small cell lung cancer with mediastinal lymph nodes having a maximum standardized uptake value of less than 5.3.

OBJECTIVE: Accurate pretreatment staging in non-small cell lung cancer remains tantamount in formulating an appropriate treatment plan. The maximum standardized uptake value obtained with integrated fluorodeoxyglucose-positron emission tomography/computed tomography has been proposed to be a predictor of malignancy in mediastinal lymph nodes. A recent study has also suggested that accuracy of integrated fluorodeoxyglucose-positron emission tomography/computed tomography might be improved by increasing the maximum standardized uptake value used for calling a lymph node positive from 2.5 to 5.3. We tested the hypotheses that the maximum standardized uptake value is a predictor of individual lymph node metastasis in non-small cell lung cancer and that pathologic staging with mediastinoscopy might not be necessary in patients with a maximum standardized uptake value of less than 5.3 in their mediastinal lymph nodes. METHODS: This is a retrospective review of 765 lymph nodes sampled from 110 patients in a single institution with biopsy-proved non-small cell lung cancer. All patients underwent integrated fluorodeoxyglucose-positron emission tomography/computed tomography before biopsy or resection of their mediastinal lymph nodes. Surgical staging was the reference standard. All N2 lymph nodes were individually assessed according to station. Data were analyzed by using the Pearson chi(2) test. RESULTS: Twenty-one (19%) of 110 patients had N2 disease, and a total of 765 N2 lymph nodes were pathologically examined. The mean and median maximum standardized uptake values for N2 nodes with metastatic disease were 9.2 (95% confidence interval, 7.0-11.4) and 7.2 (range, 2.2-25.8), respectively. For benign N2 nodes, the mean and median maximum standardized uptake values were 1.5 (95% confidence interval, 1.4-1.6) and 1.0 (range, 1.0-9.6), respectively (P < .05). When integrated fluorodeoxyglucose-positron emission tomographic/computed tomographic scans were reinterpreted by using a maximum standardized uptake value of 5.3 as a cutoff for malignancy, sensitivity decreased from 93% to 81% (P = .15), specificity increased from 86% to 98% (P < .01), positive predictive value increased from 22% to 64% (P < .01), negative predictive value was unchanged at 99%, and overall accuracy of integrated positron emission tomography/computed tomography increased from 87% to 97% (P < .01). CONCLUSIONS: The maximum standardized uptake value is a predictor of individual lymph node metastasis in non-small cell lung cancer. Accuracy of integrated positron emission tomography/computed tomography is significantly improved by using a maximum standardized uptake value of 5.3 to assign malignancy, thereby dramatically decreasing the number of false-positive results. More importantly, these results suggest that some patients with non-small cell lung cancer with a maximum standardized uptake value less than 5.3 in their N2 lymph nodes might be able to forego mediastinoscopy and proceed directly to thoracotomy. This represents a significant change in the current management of standardized uptake value-positive mediastinal lymph nodes in non-small cell lung cancer.