EJNMMI Research最新文献

Background: Fibroblast activation protein (FAP) is an attractive target for cancer theranostics. Although FAP-targeted nuclear imaging demonstrated promising clinical results, only sub-optimal results are reported for targeted radionuclide therapy (TRT). Preclinical research is crucial in selecting promising FAP-targeted radiopharmaceuticals and for obtaining an increased understanding of factors essential for FAP-TRT improvement. FAP is mainly expressed by cancer-associated fibroblasts in the tumor stroma and less on cancer cells themselves. Therefore, other (complex) factors impact FAP-TRT efficacy compared to currently clinically applied TRT strategies. For accurate evaluation of these aspects, selection of a representative preclinical model is important. Currently mainly human cancer cell lines transduced to (over)express FAP are applied, lacking clinical representation. It is unclear how these and more physiological FAP-expressing models compare to each other, and whether/how the model influences the study outcome. We aimed to address this by comparing FAP tracer behavior in FAP-transduced HT1080-huFAP and HEK293-huFAP cells, and endogenous FAP-expressing U-87 MG cancer cells and PS-1 pancreatic stellate cells. [¹¹¹In]In-FAPI-46 and a fluorescent FAP-targeted tracer (RTX-1370S) were used to compare tracer binding/uptake and localization in vitro and ex vivo. Additionally, FAP expression was determined with RT-qPCR and anti-FAP IHC.

Results: Although FAP expression was highest in HEK293-huFAP cells and cell line derived xenografts, this did not result in the highest tracer uptake. [¹¹¹In]In-FAPI-46 uptake was highest in HT1080-huFAP, closely followed by HEK293-huFAP, and a 6-10-fold lower uptake for U-87 MG and PS-1 cells. However, ex vivo U-87 MG xenografts only showed a 2-fold lower binding compared to HT1080-huFAP and HEK293-huFAP xenografts, mainly because the cell line attracts murine fibroblasts as demonstrated in our RT-qPCR and IHC studies.

Conclusions: The interaction between FAP and FAP-targeted tracers differs between models, indicating the need for appropriate model selection and that comparing results across studies using different models is difficult.

Background: Prostate cancer recurrence following primary treatment poses a significant clinical challenge, particularly when detected through biochemical recurrence at low PSA levels. Conventional imaging modalities often fail to localize the disease at this early stage. PSMA PET has demonstrated superior sensitivity in detecting recurrent lesions, even in patients with low PSA. Concurrently, liquid biopsy, through analysis of cell-free DNA (cfDNA), offers a minimally invasive approach for monitoring disease. There is scarce evidence about the association between liquid biopsy and PSMA PET/CT findings. This study aimed to assess the correlation between liquid biopsy and tumor burden assessed by PSMA PET/CT in early recurring prostate cancer patients.

Results: PSMA PET/CT and liquid biopsies of 32 patients in biochemical recurrence were analyzed. 12 patients (37.5%) had no PSMA PET-measurable disease. Four patients (12.5%) presented local recurrence, seven (21.9%) had recurrence in pelvic lymph nodes, one of whom also had local recurrence. Nine patients (28.1%) presented metastatic recurrence, with or without local or nodal recurrence. PSA levels correlated with molecular imaging data (p < 0.05), including whole body PSMA-TV, whole body PSMA-TL, whole body SUVmean and whole body SUVmax. The mean cfDNA fragment size fraction was inversely correlated with tumour burden measured with whole body PSMA-TV, with a Spearman correlation coefficient of -0.451 and a p-value of 0.009. No correlation was found between cfDNA concentration and PET-PSMA data.

Conclusion: This prospective study demonstrated a statistically significant negative correlation between cfDNA fragmentation patterns and PSMA PET/CT volumetric parameters in patients with presumed localized prostate cancer with early biochemical recurrence. These findings underscore the potential of liquid biopsy as a biomarker and a complementary tool to PSMA PET/CT to assess disease progression during the follow-up of these patients.

Background: PET imaging of activated microglia has improved our understanding of the pathology behind disability progression in MS, and pro-inflammatory microglia at 'smoldering' lesion rims have been implicated as drivers of disability progression. The P2X ₇R is upregulated in the cellular membranes of activated microglia. A single-tissue dual-input model was applied to quantify P2X ₇R binding in the normal appearing white matter, perilesional areas and thalamus among progressive MS patients, healthy controls and newly diagnosed relapsing MS patients.

Results: Overall, tracer uptake in the MS brain was not significantly higher compared to HCs. In the 3 mm perilesional rim of all T1 lesions, tracer binding was higher among relapsing patients compared to progressive patients. Tracer binding was higher in males compared to females. Disease duration correlated with tracer binding in the normal appearing white matter. Age correlated negatively with tracer binding in the perilesional rims.

Conclusions: Even as binding estimates obtained with the dual-input model were consistent with the expected distribution of P2X ₇Rs in the MS brain, the small free fraction of the parent tracer may limit its accuracy and applicability, and binding estimates between subjects were highly variable. Conclusive evidence for the applicability of [¹¹C]SMW139 to detect MS-related diffuse smoldering inflammation was not obtained.

Background: Type 1 diabetes (T1D) is an autoimmune disease characterized by a progressive β-cell destruction. There are no clinically established methods for quantifying endocrine cells of the pancreas and current knowledge is almost exclusively based on autopsy material and functional measurements. Based on the expression of the γ-aminobutyric acid A receptors (GABA_ARs) in pancreatic islets and the fact that GABA_AR agonists are being explored as treatment for T1D, we hypothesized that the positron emission tomography (PET) tracer [¹¹C]flumazenil ([¹¹C]FMZ) could serve as a marker of the endocrine mass of the pancreas. The in vivo uptake of [¹¹C]FMZ in pig pancreas was evaluated by PET/CT, either tracer alone or after blockade of GABA_AR by unlabeled flumazenil. The pancreatic binding of [¹¹C]FMZ was investigated in vitro with frozen sections of pig pancreas as well as human organ donors, in addition to isolated mouse and human islets and exocrine preparations. The expression of GABA_AR subunits in pig, human and mouse pancreas was explored by immunohistochemistry.

Results: Strong specific in vivo uptake of [¹¹C]FMZ was observed in the pig brain as expected, but in the pancreas the signal was moderate and only partially reduced by blockade. In vitro experiments revealed a positive but weak and variable binding of [¹¹C]FMZ in islets compared to exocrine tissue in the mouse, pig and human pancreas. In pig and mouse pancreatic islets we identified the GABA_AR subunits β2 and γ2 but not α2. In the human pancreas from non-diabetic donors, we have identified the α2, β2 (although weak) and γ2 subunits, whereas from a T2D donor the α2 subunit was missing.

Conclusions: Our findings suggest that [¹¹C]FMZ bind to GABA_ARs in the islets, but not with a sufficient contrast or magnitude to be implemented as an in vivo PET marker for the endocrine mass of the pancreas. However, GABA_ARs with different subunits are widely expressed in the endocrine cells within the pancreas in pig, human and mouse. Hence, the GABA_AR could still be a potential imaging target for the endocrine cells of the pancreas but would require tracers with higher affinity and selectivity for individual GABA_AR subunits.

Background: Tumor-Associated Macrophages (TAMs) play a critical role in the pathogenesis and progression of ovarian cancer, a lethal gynecologic malignancy. [¹²⁴I]iodo-DPA-713 is a PET radiotracer that is selectively trapped within reactive macrophages. We have employed this radioligand here as well as a fluorescent analog to image TAMs associated with primary tumors, secondary pulmonary metastases and gastrointestinal tract-associated macrophages, associated with ascites accumulation in a syngeneic mouse model of metastatic ovarian cancer. Intact female C57BL/6 mice were engrafted with ID8-Defb29-VEGF tumor pieces. One month after engraftment, the mice were selected for positive bioluminescence to show primary and secondary tumor burden and were then scanned by PET/MRI with [¹²⁴I]iodo-DPA-713, observing a 24 h uptake time. PET data were overlayed with T₂-weighted MRI data to facilitate PET uptake tissue identity. Additionally, mice were imaged ex vivo using Near IR Fluorescence (NIRF), capturing the uptake and sequestration of DPA-713-IRDye800CW, a fluorescent analog of the radioligand used here. Additionally, cell culture uptake of DPA-713-IRDye680LT in ID8-DEFb29-VEGF, IOSE hTERT and RAW264.7 cells was conducted to measure tracer uptake in ovarian cancer cells, ovarian epithelial cells and macrophage.

Results: PET/MRI data show an intense ring of radiotracer uptake surrounding primary tumors. PET uptake is also associated with lung metastases, but not healthy lung. Mice displaying ascites also display PET uptake along the gastrointestinal tract while sham-operated mice show minimal gastrointestinal uptake. All mice show specific kidney uptake. Mice imaged by NIRF confirmed TAMs uptake mostly at the rim of primary tumors while 1 mm secondary tumors in the lungs displayed robust, homogeneous uptake of the radio- and fluorescent analog. Ex vivo biodistribution of [¹²⁴I]iodo-DPA-713 showed that contralateral ovaries in middle-stage disease had the highest probe uptake with tissues sampled in mid- and late-stage disease showing increasing uptake.

Conclusion: [¹²⁴I]iodo-DPA-713 and DPA-713-IRDye800CW sensitively identify and locate TAMs in a syngeneic mouse model of metastatic ovarian cancer.

Background: Epidemiological studies have indicated that patients with heart failure (HF) who experience cognitive impairment (CI) have a poor prognosis. While poor self-management and compliance are suggested as contributing factors, they do not fully explain the underlying mechanisms of high risk of cardiac events in HF patients with CI. Given the interconnectedness of CI and the autonomic nervous system (ANS), both regulated by the central nervous system, this study investigated the relationship among cognitive function, metabolism in ANS-related brain regions, and major arrhythmic events (MAEs) in patients with HF with reduced ejection fraction (HFrEF).

Results: We retrospectively enrolled 72 patients with HFrEF who underwent gated myocardial perfusion imaging, heart and brain ¹⁸F-FDG positron emission tomography/computed tomography imaging, and cognitive testing. Cognitive function was evaluated using the Mini-Mental State Examination. During the follow-up period, 13 patients (17.8%) experienced MAEs. Patients with MAEs exhibited decreased cognitive function across various domains, including orientation, registration, and language and praxis (all p < 0.05). Patients with CI displayed a prolonged heart rate-corrected QT (QTc) interval and hypometabolism in the left hippocampus and bilateral caudate nuclei (all p < 0.05). Significant correlations were observed between cognitive function, QTc interval, and metabolism in ANS-related brain regions (all p < 0.05). Cox regression model analysis showed that the predictive value of cognitive function is not independent of the QTc interval and there is a significant interaction. The mediation analyses suggested that a prolonged QTc interval resulting from ANS disorder increased risk of MAEs in HFrEF patients with CI. Patients with CI exhibited reduced central autonomic network (CAN) connectivity.

Conclusion: ANS dysfunction, exacerbated by reduced metabolism in ANS-related brain regions and CAN connectivity, contributed to an increased risk of MAEs in HFrEF patients with CI.

Background: We conducted a study on radiation exposure in patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) treated with [¹⁷⁷Lu]Lu-DOTA-TATE in China for the first time, aiming to provide guidance and reference for radiation protection in this regard. A total of 30 GEP-NENs patients who received [¹⁷⁷Lu]Lu-DOTA-TATE therapy were recruited in the study. We measured the external dose rate (EDR) values of each patient during the injection and 0-6 h post-administration period, as well as the radiation dose (RD) values to healthcare nurses and the surrounding environment. We performed a double exponential curve fitting and estimated the RD to the public from patients discharged at different times after [¹⁷⁷Lu]Lu-DOTA-TATE therapy.

Results: Among the 30 patients, 27 patients completed 4 cycles of [¹⁷⁷Lu]Lu-DOTA-TATE treatments, the estimated RD to the public indicated that for adult family members, children above 10 years old, children aged 3-10 and coworkers of the patients, patients could begin daily contact at least 24 h, 48 h, 144 h and 192 h after injection to ensure that the total RD values after four treatments not exceed the limit. During the hospitalization of patients receiving [¹⁷⁷Lu]Lu-DOTA-TATE, the cumulative dose received by the administering nurses and to the ward environment were both well below the national RD limits.

Conclusions: This study conducted a fitting analysis of the decay pattern of EDR values in GEP-NENs patients undergoing [¹⁷⁷Lu]Lu-DOTA-TATE therapy, in order to establish guidelines for patient discharge timing and provide recommendations for radiation protection for the general public after patient discharge. Trial registration A Study Comparing Treatment With Lutetium[177Lu] Oxodotreotide Injection to Octreotide LAR in Patients With GEP-NETs, NCT05459844. https://clinicaltrials.gov/study/NCT05459844?cond=NCT05459844&rank=1 . Registered 5 July 2022.

Background: Single-photon emission computed tomography (SPECT) analysis relies on qualitative visual assessment or semi-quantitative measures like total perfusion deficit that play a critical role in the non-invasive diagnosis of coronary artery disease by assessing regional blood flow abnormalities. Recently, machine learning (ML) -based analysis of SPECT images for coronary artery disease diagnosis has shown promise, with its utility in predicting long-term patient outcomes (prognosis) remaining an active area of investigation. In this review, we comprehensively examine the current landscape of ML-based analysis of SPECT imaging with an emphasis on prognostication of coronary artery disease.

Main body: Our systematic search yielded twelve retrospective studies, investigating SPECT-based ML models for prognostic prediction in coronary artery disease patients, with a total sample size of 73,023 individuals. Several of these studies demonstrate the superior prognostic capabilities of ML models over traditional logistic regression (LR) models and total perfusion deficit, especially when incorporating demographic data alongside SPECT imaging. Meta-analysis of 6 studies revealed promising performance of the included ML models, with sensitivity and specificity exceeding 65% for major adverse cardiovascular events and all-cause mortality. Notably, the integration of demographic information with SPECT imaging in ML frameworks shows statistically significant improvements in prognostic performance.

Conclusion: Our review suggests that ML models either independently or in combination with demographic data enhance prognostic prediction in coronary artery disease.

Background: ¹⁸F-Florbetaben amyloid positron emission tomography (PET) scan is crucial for diagnosing Alzheimer's disease, typically involving a 20 min acquisition. However, maintaining such prolonged scans can be challenging in some cases. This study explores the diagnostic impact and feasibility of reducing scan durations by comparing quantitative measures between shortened and standard scans. Additionally, we identified the optimal Centiloid threshold to distinguish between positive and negative amyloid results.

Results: We analyzed 307 PET scans from our memory clinic, each followed up for a minimum of two years. The scans, conducted 90 to 110 min after approximately 300 MBq of ¹⁸F-Florbetaben injection, were categorized into four sets of 5 min durations: 5, 10, 15, and 20 min. Nuclear medicine physicians validated and rated each scan as either amyloid-positive or negative. For quantitative assessments, we employed the standardized uptake value ratio (SUVR) and Centiloid scales, comparing total SUVR and Centiloid values across five subregions (global, frontal, posterior cingulate-precuneus, lateral temporal, and parietal) using Bland-Altman analysis. Receiver operator characteristic (ROC) curves were utilized to develop optimal Centiloid thresholds. Comparing the images at 5, 10, 15, and 20 min images, SUVR and Centiloid values gradually increased with prolonged scan times. The mean SUVR difference between 5 and 20 min was 0.03 for the amyloid-positive and 0.01 for the amyloid-negative groups; Centiloid differences were 4.60 and 2.38, respectively. Additionally, no significant variation was observed in total SUVR and Centiloid values among the durations across all subregions in positive and negative groups (all p > 0.1). ROC analysis indicated that a Centiloid threshold of 21.86 at 5 min provided optimal agreement with visual assessments (AUC = 0.985, sensitivity = 0.950, specificity = 0.972), especially using the global area.

Conclusions: This study demonstrated that 5 min image scans with an optimal threshold of CL = 21.86 exhibited minimal bias in SUVR and Centiloid values compared to longer scans (10, 15, and 20 min). Our findings suggest that shorter scan times are a viable and effective option for brain amyloid PET imaging in clinical settings.