EJNMMI Research最新文献

Background: In the present study, we aimed to investigate the role of baseline (B), interim (I) and end-of-treatment (Eot) ¹⁸F-FDG PET/CT in assessing the prognosis of diffuse large B cell lymphoma (DLBCL), so as to identify patients who need intensive treatment at an early stage.

Methods: A total of 127 DLBCL patients (62 men; 65 women; median age 62 years) were retrospectively analyzed in this study. Baseline (n = 127), interim (n = 127, after 3-4 cycles) and end-of-treatment (n = 53, after 6-8 cycles) PET/CT images were re-evaluated; semi-quantitative parameters such as maximum standardized uptake value of lesion-to-liver ratio (SUVmax_(LLR)) and lesion-to-mediastinum ratio (SUVmax_(LMR)), total metabolic tumor volume (TMTV) and total metabolic tumor volume (TLG) were recorded. ΔTLG¹ was the change of interim relative to baseline TLG (I to B), ΔTLG² (Eot to B). ΔSUVmax and ΔTMTV were the same algorithm. The visual Deauville 5-point scale (D-5PS) has been adopted as the major criterion for PET evaluation. Visual analysis (VA) and semi-quantitative parameters were assessed for the ability to predict progression-free survival (PFS) and overall survival (OS) by using Kaplan-Meier method, cox regression and logistic regression analysis. When visual and semi-quantitative analysis are combined, the result is only positive if both are positive.

Results: At a median follow-up of 34 months, the median PFS and OS were 20 and 32 months. The survival curve analysis showed that advanced stage and IPI score with poor prognosis, ΔSUVmax_(LLR)¹ < 89.2%, ΔTMTV¹ < 91.8% and ΔTLG¹ < 98.8%, ΔSUVmax_(LLR)² < 86.4% were significantly related to the shortening of PFS in patient (p < 0.05). ΔSUVmax_(LLR)¹ < 83.2% and ΔTLG¹ < 97.6% were significantly correlated with the shortening of OS in patients (p < 0.05). Visual analysis showed that incomplete metabolic remission at I-PET and Eot-PET increased the risk of progress and death. In terms of predicting recurrence by I-PET, the combination of visual and semi-quantitative parameters showed higher positive predictive value (PPV) and specificity than a single index.

Conclusion: Three to four cycles of R-CHOP treatment may be a time point for early prediction of early recurrence/refractory (R/R) patients and active preemptive treatment. Combined visual analysis with semi-quantitative parameters of ¹⁸F-FDG PET/CT at interim can improve prognostic accuracy and may allow for more precise screening of patients requiring early intensive therapy.

Background: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium.

Results: 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [¹¹C]EAI045 was synthesized using [¹¹C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [¹¹C]CO₂ production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [³H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [¹¹C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [³H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [¹¹C]EAI045.

Conclusions: EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [¹¹C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [¹¹C]EAI045 in vivo or [³H]EAI045 in vitro in H1975 xenografts and cells.

Background: Distribution of mAbs into tumour tissue may occur via different processes contributing differently to the ⁸⁹Zr-mAb uptake on PET. Target-specific binding in tumours is of main interest; however, non-specific irreversible uptake may also be present, which influences quantification. The aim was to investigate the presence of non-specific irreversible uptake in tumour tissue using Patlak linearization on ⁸⁹Zr-immuno-PET data of biopsy-proven target-negative tumours. Data of two studies, including target status obtained from biopsies, were retrospectively analysed, and Patlak linearization provided the net rate of irreversible uptake (K_i).

Results: Two tumours were classified as CD20-negative and two as CD20-positive. Four tumours were classified as CEA-negative and nine as CEA-positive. K_i values of CD20-negative (0.43 µL/g/h and 0.92 µL/g/h) and CEA-negative tumours (mdn = 1.97 µL/g/h, interquartile range (IQR) = 1.50-2.39) were higher than zero. Median K_i values of target-negative tumours were lower than CD20-positive (1.87 µL/g/h and 1.90 µL/g/h) and CEA-positive tumours (mdn = 2.77 µL/g/h, IQR = 2.11-3.65).

Conclusion: Biopsy-proven target-negative tumours showed irreversible uptake of ⁸⁹Zr-mAbs measured in vivo using ⁸⁹Zr-immuno-PET data, which suggests the presence of non-specific irreversible uptake in tumours. Consequently, for ⁸⁹Zr-immuno-PET, even if the target is absent, a tumour-to-plasma ratio always increases over time.

Background: Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis. The diagnostic modalities ultrasound and MRI are often unable to detect all lesions, and a clear correlation between imaging and clinical symptoms is still controversial. Therefore, it was our aim to identify a potential target to image active endometriotic lesions.

Results: For our studies, we employed the preclinical radiotracer [¹¹¹In]In-FnBPA5, which specifically binds to relaxed fibronectin-an extracellular matrix protein with key functions in homeostasis that has been implicated in the pathogenesis of diseases such as cancer and fibrosis. We employed this tracer in biodistribution as well as SPECT/CT studies in mice and conducted immunohistochemical stainings on mouse uterine tissue as well as on patient-derived endometriosis tissue. In biodistribution and SPECT/CT studies using the radiotracer [¹¹¹In]In-FnBPA5, we found that radiotracer uptake in the myometrium varies with the estrous cycle of the mouse, leading to higher uptake of [¹¹¹In]In-FnBPA5 during estrogen-dependent phases, which indicates an increased abundance of relaxed fibronectin when estrogen levels are high. Finally, immunohistochemical analysis of patient samples demonstrated that there is preferential relaxation of fibronectin in the proximity of the endometriotic stroma.

Conclusion: Estrous cycle stages characterized by high estrogen levels result in a higher abundance of relaxed fibronectin in the murine myometrium. This finding together with a first proof-of-concept study employing human endometriosis tissues suggests that relaxed fibronectin could be a potential target for the development of a diagnostic radiotracer targeting endometriotic lesions. With [¹¹¹In]In-FnBPA5, the matching targeting molecule is in preclinical development.

Background: Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer-related deaths in men. Prostate-specific membrane antigen (PSMA) as a target has gained increasing attention. This research aims to investigate and understand how altering size of PEG impacts the in vitro and in vivo behavior and performance of PSMA inhibitors, with a specific focus on their pharmacokinetic characteristics and targeting properties.

Results: Two ⁶⁸Ga-labeled PSMA-targeted radiotracers were developed, namely [⁶⁸Ga]Ga-PP4-WD and [⁶⁸Ga]Ga-PP8-WD, with varying sizes of polyethylene glycol (PEG). [⁶⁸Ga]Ga-PP4-WD and [⁶⁸Ga]Ga-PP8-WD had excellent affinity for PSMA with IC50 being 8.06 ± 0.91, 6.13 ± 0.79 nM, respectively. Both tracers enabled clear visualization of LNCaP tumors in PET images with excellent tumor-to-background contrast. They also revealed highly efficient uptake and internalization into LNCaP cells, increasing over time. The biodistribution studies demonstrated that both radioligands exhibited significant and specific uptake into LNCaP tumors. Furthermore, they were rapidly cleared through the renal pathway, as evidenced by [⁶⁸Ga]Ga-PP4-WD and [⁶⁸Ga]Ga-PP8-WD showing a tenfold and a fivefold less in renal uptake, respectively, compared to [⁶⁸Ga]Ga-Flu-1 in 30 min. Both in vitro and in vivo experiments demonstrated that PEG size significantly impacted tumor-targeting and pharmacokinetic properties.

Conclusions: These radiotracers have demonstrated their effectiveness in significantly reducing kidney uptake while maintaining the absorbed dose in tumors. Both radiotracers exhibited strong binding and internalization characteristics in vitro, displayed high specificity and affinity for PSMA in vivo.

Background: The prevalence of ischemia with non-obstructive coronary artery disease (INOCA) is substantial, but its risk stratification has been suboptimal. Resting SPECT myocardial perfusion imaging (MPI) could provide useful heart information including spherical indices. We aimed to evaluate the prognostic value of spherical indices in individuals with INOCA.

Results: During a median follow-up of 47.2 ± 20.8 months, 49 (17.2%) patients experienced major adverse cardiac events (MACE). Compared to those without MACE, those with MACE had a higher shape index (SI) (0.60 ± 0.07 vs. 0.58 ± 0.06; P = 0.028) and a lower E2 (eccentricity index calculated by the QPS) (0.81 ± 0.05 vs. 0.83 ± 0.04; P = 0.019). MACE event-free survival analysis revealed significant differences in the SI and E2 among all patients (all log-rank P < 0.01). Multivariate Cox analysis showed abnormal SI (HR: 2.73, 95% CI 1.44-5.18, P = 0.002) and E2 (HR: 1.94, 95% CI 1.08-3.48, P = 0.026) were both independent predictors for MACE when they were put into the same model, respectively. The incorporation of the SI into the baseline model demonstrated a significant improvement in the predictive accuracy for MACEs (P = 0.026), whereas E2 did not exhibit a similar improvement (P > 0.05).

Conclusion: For patients with INOCA, spherical indices (especially the SI) were associated with long-term MACE, which could be a preferable indicator for risk stratification and prognostic prediction.

Background: Previous studies have demonstrated that delayed [⁶⁸ Ga]Ga-PSMA PET/CT imaging improves lesion detection compared to early [⁶⁸ Ga]Ga-PSMA PET/CT in patients with prostate cancer. However, the sole use of delayed [⁶⁸ Ga]Ga-PSMA PET/CT has been limited due to the insufficient number of photons obtained with standard PET/CT scanners. The combination of early and delayed [⁶⁸ Ga]Ga-PSMA standard PET/CT may be considered, and it is challenging to incorporate into a high-demand clinical setting. Long field-of-view (LFOV) PET/CT scanners have higher sensitivity compared to standard PET/CT. However, it remains unknown whether the image quality of solitary delayed [⁶⁸ Ga]Ga-PSMA LFOV PET/CT imaging is adequate to satisfy clinical diagnostic requirements. Therefore, the purpose of this study was to evaluate the image quality of delayed [⁶⁸ Ga]Ga-PSMA LFOV PET/CT and examine the feasibility of utilizing delayed [⁶⁸ Ga]Ga-PSMA LFOV PET/CT imaging alone in patients with prostate cancer.

Methods: The study sample consisted of 56 prostate cancer patients who underwent [⁶⁸ Ga]Ga-PSMA-11 LFOV PET/CT scanning between December 2020 and July 2021. All patients were subjected to early LFOV PET/CT imaging at 1-h post-injection as well as delayed LFOV PET/CT imaging at 3-h post-injection using [⁶⁸ Ga]Ga-PSMA-11. The image quality and diagnostic efficiency of solitary delayed [⁶⁸ Ga]Ga-PSMA-11 LFOV PET/CT imaging was analyzed.

Results: The results showed that delayed [⁶⁸ Ga]Ga-PSMA-11 LFOV PET/CT yielded satisfactory image quality that fulfilled clinical diagnostic benchmarks. Compared to early imaging, delayed [⁶⁸ Ga]Ga-PSMA-11 LFOV PET/CT demonstrated heightened lesion SUVmax values (11.0 [2.3-193.6] vs. 7.0 [2.0-124.3], P < 0.001) and superior tumor-to-background ratios (3.3 [0.5-62.2] vs. 1.7 [0.3-30.7], P < 0.001). Additionally, delayed [⁶⁸ Ga]Ga-PSMA-11 LFOV PET/CT detected supplementary lesions in 14 patients (25%) compared to early imaging, resulting in modifications to disease staging and management plans.

Conclusions: In summary, the findings indicate that the image quality of delayed [⁶⁸ Ga]Ga-PSMA-11 LFOV PET/CT is satisfactory for meeting clinical diagnostic prerequisites. The use of solitary delayed [⁶⁸ Ga]Ga-PSMA-11 LFOV PET/CT imaging in prostate cancer simplifies the examination protocol and improves patient compliance, compared to [⁶⁸ Ga]Ga-PSMA-11 standard PET/CT which necessitates both early and delayed imaging.

Background: Peptide receptor radionuclide therapy is effective in treating neuroendocrine tumours, but treatment may be limited by kidney and bone marrow toxicity. In this work, the absorbed dose burden to the bone marrow was estimated using image-based dosimetry and its potential use for predicting treatment-altering toxicity was studied. Peripheral blood samples taken before and after 229 treatments with ¹⁷⁷Lu-DOTATATE in 59 patients were studied. In connection to the treatments, a total of 940 blood sample occasions provided data on white blood cell, neutrophil granulocyte, platelet, erythrocyte and haemoglobin concentrations. SPECT/CT image data were collected at two or three time points after each treatment. Absorbed doses to bone marrow were calculated from the activity concentration in a metastasis-free lumbar vertebra. The rate of delayed and aborted treatments was analysed based on medical records.

Results: The average absorbed dose to the bone marrow was 0.42 Gy (median 0.33 Gy, SD 0.27 Gy) per treatment. Dose-response relationships between white blood cells, neutrophil granulocytes and haemoglobin concentrations were observed, most prominently at 31-45 days after each treatment. The correlations were stronger in patients with skeletal metastases. The rates of haematological toxicity-related delays and aborted treatments were 6% and 12%, respectively. None of the studied bone marrow dosimetric parameters could clearly predict treatment-related toxicity. However, patients with skeletal metastases had higher risk of treatment-altering toxicity (odds ratio = 6.0).

Conclusions: Treatment-altering haematological toxicity in peptide receptor radionuclide therapy is relatively rare and appears difficult to fully predict from post-therapeutic image-based dosimetry. However, for patients with skeletal metastases, the haematological dose-response relationships are stronger. Future studies may focus on this patient group, to further investigate the usefulness of dosimetry in predicting decreases in blood values.

Differentiating treatment response from tumor progression is fundamental but challenging for almost all oncological subjects, as the treatment strategy is effective and should be insisted in the former situation, while the therapeutic regimen is invalid and necessitates substitutions in the latter circumstances [1]. However, radiotherapy or immunotherapy may induce pseudo-progression, a transient increase of tumor volume due to tumor cell lysis or immune cell infiltration followed by delayed tumor shrinkage, and is difficult for early clinical and radiological identification [1, 2]. In malignant brain tumors, 10–30% of tumors showed pseudo-progression following radiotherapy, immunotherapy and targeted therapy [3,4,5,6], some of which were not restricted to the recent onset of treatment [7, 8]. In addition, alternative non-neoplastic conditions such as radiation necrosis or inflammation may also mimic neoplasms and warrant appropriate distinction [3]. Response Evaluation Criteria in Solid Tumors (RECIST) and Response Assessment in Neuro­Oncology (RANO) have been proposed [9, 10], yet the performance in distinguishing treatment response from tumor progression remains to be improved [11,12,13,14].

Boramino acids (BAA) are a class of amino acid biosimilars with the boron trifluoride group (–BF₃) to replace the carboxyl group (–COOH) of amino acids, which mimics the corresponding amino acid in biological recognition and transportation [15]. The ¹⁸F-¹⁹F isotope exchange reaction of boron trifluoride moiety allows the molecule to be mildly radiolabeled and can facilitate tumor theranostics through identical chemical structure (the only difference between positron emission tomography [PET] diagnosis and boron neutron capture therapy [BNCT] for treatment is ¹⁸F or ¹⁹F) [15,16,17,18,19,20]. The first-in-human study of this class of PET tracers demonstrated sufficient safety, clean background and high tumor activity in malignant brain tumors [21, 22], validating the concept and potential clinical value of boron amino acids. Subsequently, trifluoroborate boronophenylalanine (BBPA) that replaced the carboxyl group (–COOH) of 4‑boronophenylalanine (BPA) with boron trifluoride group (-BF₃) was synthesized and is recognized as the next generation of boron amino acids thanks to the doubled boron delivery efficiency [23].

This study raised a [¹⁸F]BBPA PET-based approach to differentiate non-neoplastic lesions from proliferating tumors, aiming to provide a non-invasive method to uncover true lesion property. A total of 21 patients were included and underwent [¹⁸F]BBPA PET and contrast-enhanced magnetic resonance imaging (MRI) scans. Both neoplastic and non-neoplastic lesions exhibited elevated [¹⁸F]BBPA radioactivity and cannot be distinguished by traditional parameters. Histograms of the standard uptake value (SUV) within region of interest (ROI) were

Background: [¹⁵O]H₂O PET/CT allows noninvasive quantification of tissue perfusion and can potentially play a future role in the diagnosis and treatment of peripheral artery disease. We aimed to evaluate the reliability of dynamic [¹⁵O]H₂O PET imaging for measuring lower extremity skeletal muscle perfusion. Ten healthy participants underwent same-day test-retest study with six dynamic [¹⁵O]H₂O PET scans of lower legs and feet. Manual volume-of-interests were drawn in skeletal muscles, and PET time activity curves were extracted. K₁ values (mL/min/100 mL) were estimated using a single-tissue compartment model (1TCM), autoradiography (ARG), and parametric imaging with blood input functions obtained from separate heart scans.

Results: Resting perfusion values in the muscle groups of the lower legs ranged from 1.18 to 5.38 mL/min/100 mL (ARG method). In the muscle groups of the feet, perfusion values ranged from 0.41 to 3.41 mL/min/100 mL (ARG method). Test-retest scans demonstrated a strong correlation and good repeatability for skeletal muscle perfusion with an intraclass correlation coefficient (ICC) of 0.88 and 0.87 and a repeatability coefficient of 34% and 53% for lower legs and feet, respectively. An excellent correlation was demonstrated when comparing volume-of-interest-based methods (1TCM and ARG) (lower legs: ICC = 0.96, feet: ICC = 0.99). Parametric images were in excellent agreement with the volume-of-interest-based ARG method (lower legs: ICC = 0.97, feet: ICC = 0.98).

Conclusion: Parametric images and volume-of-interest-based methods demonstrated comparable resting perfusion values in the lower legs and feet of healthy individuals. The largest variation was seen between individuals, whereas a smaller variation was seen between muscle groups. Repeated measurements of resting blood flow yielded a strong overall correlation for all methods.