EJNMMI Research最新文献

Background: Targeted alpha therapy (TAT) with ²²⁵Ac has shown promising results in metastatic castration-resistant prostate cancer (mCRPC) patients pre-treated with [¹⁷⁷Lu]Lu-PSMA radioligand therapy (RLT). A combination treatment regimen adding ¹⁷⁷Lu to decreased ²²⁵Ac activities may improve toxicity profile while maintaining sufficient anti-tumor effect. We therefore evaluated clinical and image-based response parameters in patients treated with ²²⁵Ac-/¹⁷⁷Lu-PSMA combination therapies (ALCT).

Results: Complete response (RECIP-CR), partial response (RECIP-PR), stable disease (RECIP-SD), progressive disease (RECIP-PD) according to RECIP 1.0 was observed in 0/25 (0%), 12/25 (48%), 9/25 (36%) and 4/25 (16%) patients, respectively. Response by RECIP + PSA was observed in 14/25 (56%) patients and progression by RECIP + PSA in 8/25 (32%) patients. Interrater reliability for visual RECIP was substantial (κ = 0.757, p < 0.001), while agreement between visual and quantitative RECIP was almost fully congruent (κ = 0.879, p < 0.001). OS did not significantly vary among the four different therapy regimens (p > 0.05). When grouping patients with declining / stable PSA as responders, these patients showed no significant difference in overall survival compared to patients with progressive PSA after ALCT (p = 0.312). Similarly, there was no significant difference in median overall survival between patients without RECIP-progression (RECIP-PR + RECIP-SD) and patients with RECIP-progression (RECIP-PD) (p > 0.05), but when applying the composite classification, RECIP + PSA responders survived significantly longer compared to patients with RECIP + PSA progression (p = 0.049).

Conclusions: ALCT is a promising therapeutic regimen that may prolong survival in patients who progress during [¹⁷⁷Lu]Lu-PSMA RLT. Our results motivate to further investigate the use of RECIP + PSA as tool for response assessment and for overall survival prediction in mCRPC under ALCT.

Background: Hypertrophic Cardiomyopathy (HCM), a genetic disorder with diverse phenotypes, is associated with risks of heart failure and sudden cardiac death. While the condition involves multiple pathological pathways, including myocardial inflammation, increased workload, myocyte disarray, apoptosis, and fibrosis, the role of molecular imaging via PET-CT remains unexplored in this context. This study aimed to investigate the relationship between myocardial metabolism and perfusion using PET-CT in patients with non-obstructive HCM (NOHCM).

Results: Myocardial perfusion and metabolism were assessed using PET-CT with [¹³N]NH3 and 2-[¹⁸F]FDG uptake, respectively, in 30 NOHCM patients. Baseline measurements included maximal myocardial wall thickness (MMWT), left atrial volume (LAV), NT-proBNP levels, and the sudden cardiac death (SCD) risk score. Increased 2-[¹⁸F]FDG uptake (Target to Background Ratio - TBR ≥ 1.1) was detected in 53% of patients, with an average TBR of 1.4 ± 0.5. The inflammatory pattern involved 11.8 ± 17.2% of the left ventricle (LV) and correlated with MMWT (rho = 0.49, p = 0.009), LAV (rho = 0.39, p = 0.04), and NT-proBNP levels (rho = 0.63, p = 0.003). The maximum TBR within the LV correlated with MMWT (rho = 0.53, p = 0.004), NT-proBNP (rho = 0.70,p = 0.0008), and the SCD risk score (rho = 0.38,p = 0.04). Additionally, the fibrotic (scar) pattern, involving 10.3 ± 10.2% of the LV, correlated with the SCD score (rho = 0.38,p = 0.04).

Conclusion: In patients with NOHCM, PET-CT imaging provides valuable insights into myocardial metabolism and fibrosis, which are closely associated with myocardial hypertrophy, left ventricular dysfunction, and the risk of sudden cardiac death.

Background: This meta-analysis evaluates the diagnostic and staging accuracy of [¹⁸F]F-FES PET/CT, its ability to detect estrogen receptor (ER) positivity, and its effectiveness in predicting response to endocrine therapy in ER-positive (ER+) breast cancer. A systematic search of PubMed, Embase (OVID), and Web of Science databases was conducted for studies published between 2013 and June 2024. Studies involving ER + breast cancer patients who underwent [¹⁸F]F-FES PET/CT were included. We analyzed the diagnostic accuracy, ER detection capability, and predictive ability for endocrine therapy response.

Results: Out of 189 studies initially identified, 21 met the inclusion criteria. For diagnosis and staging compared to [¹⁸F]F-FDG PET (10 studies), [¹⁸F]F-FES PET/CT demonstrated a sensitivity of 0.75 (95% CI: 0.62-0.85) and a false positive rate (FPR) of 0.27 (95% CI: 0.09-0.50). For ER detection (7 studies), sensitivity was 0.86 (95% CI: 0.71-0.94) with an FPR of 0.45 (95% CI: 0.19-0.73). For predicting response to endocrine therapy (12 studies), [¹⁸F]F-FES PET/CT showed a sensitivity of 0.79 (95% CI: 0.62-0.89) and an FPR of 0.58 (95% CI: 0.42-0.72).

Conclusions: [¹⁸F]F-FES PET/CT is valuable for diagnosing and staging ER + breast cancer, assessing ER status, and predicting response to endocrine therapy. Its implementation can improve treatment planning and patient outcomes in breast cancer management.

Background: Niemann-Pick disease type C (NP-C) is a rare genetic lysosomal lipid storage disorder characterized by progressive neurological impairment. Early diagnosis is critical for initiating treatment with miglustat, which can decelerate disease progression. In this study, we evaluated a cohort of 22 NP-C patients who underwent MRI, [¹⁸F]FDG PET, and clinical assessment at baseline. We performed a cross-sectional and longitudinal imaging study evaluating the role of [¹⁸F]FDG PET as an adjunct diagnostic tool for NP-C alongside MRI, the current neuroimaging standard.

Results: Group-level MRI analysis identified significant cerebellar and thalamic atrophy (d = 1.56, p < 0.0001 and d = 1.09, p < 0.001, respectively), with less pronounced involvement of the frontal lobe and hippocampus, which aligned with existing neuropathological understanding and guidelines. Conversely, [¹⁸F]FDG PET imaging revealed extensive hypometabolism in the cerebellum, thalamus, and cingulate cortex (d = 1.42, p < 0.0001), and moderate hypometabolism in broad frontotemporal areas. [¹⁸F]FDG PET provided higher effect sizes across all brain regions, including regions without apparent atrophy, which suggests that it may be more sensitive than MRI for detecting NP-C neurodegenerative changes. Single-subject visual assessment of individual PET images further validated the clinical utility of [¹⁸F]FDG PET, with significant hypometabolism observed in the cerebellum, thalamus and anterior and posterior cingulate reported by physicians in 17/22 patients. Both hypometabolism and atrophy in the cerebellum were associated with ataxia, (more strongly indicated by [¹⁸F]FDG PET, p < 0.0001 vs. MRI, p = 0.07). Medial temporal lobe atrophy was associated with cognitive impairment (p < 0.05), and frontal hypometabolism was slightly related to behavioural impairment (p < 0.07). Longitudinal [¹⁸F]FDG PET analysis revealed progressive subcortical, cortical and cerebellar hypometabolism, which was most pronounced in the cerebellum (-12% per year, p < 0.001). Patients treated with miglustat showed a trend towards attenuated cerebellar hypometabolism progression compared to untreated patients (p = 0.10).

Conclusions: Our findings delineate a discernible hypometabolism pattern specific to NP-C that distinguishes it from other neurodegenerative conditions, thus suggesting that [¹⁸F]FDG PET might be a promising tool for NP-C diagnosis and to study disease progression.

Trial registration: XUNTA 2015/140. Registered 21 April 2015.

Background: Understanding the mechanisms driving specific and nonspecific tissue uptake of antibodies can inform protein engineering strategies that maximize therapeutic efficacy in target tissues while minimizing off-target tissue toxicities. While in vitro cell assays are typically used to study these internalization mechanisms, there are few methods readily available to evaluate these pathways in vivo. Single photon emission computed tomography (SPECT) imaging with a non-residualizing radiohalogen probe can measure total levels of intact antibody, and a residualizing radiometal-chelate probe, in combination with a non-residualizing probe, can measure catabolized antibody associated with receptor-mediated and nonspecific internalization processes. Here, we describe a SPECT imaging study in human epidermal growth factor receptor 2 (HER2)-expressing tumor-bearing mice aimed at measuring whole body disposition kinetics of tumor-targeting trastuzumab (anti-HER2) and non-targeting (anti-gD) antibodies. Mice received these molecules labeled with either a non-residualizing prosthetic group ([¹²⁵I]SIB) or with a residualizing radiometal-chelate (¹¹¹In-DOTA).

Results: SPECT imaging data confirmed significant HER2-mediated tumor uptake and catabolism of anti-HER2, evidenced by the high ¹¹¹In-DOTA-anti-HER2 signal over time relative to ¹¹¹In-DOTA-anti-gD and the respective [¹²⁵I]SIB-labeled molecules. [¹²⁵I]SIB-anti-HER2 still showed noticeably higher tumor signal than [¹²⁵I]SIB-anti-gD, demonstrating a meaningful pool of intact anti-HER2 in the interstitial tumor compartment. Spleen showed the greatest catabolism of both mAbs amongst all non-tumor tissues. Compartmental modeling of the SPECT data demonstrated that cell-associated anti-HER2 was primarily receptor-bound, with a peak receptor occupancy of 35% at 13 h post administration of a 10 mg/kg dose, with minimal free and pinocytosed mAb.

Conclusion: Here, we successfully developed an imaging and modeling approach to capture anti-HER2 antibody receptor binding as well as specific and nonspecific internalization over time in vivo. These data and analyses demonstrate the power of SPECT imaging using both non-residualizing and residualizing radioisotopes to better characterize the different biological states (free, bound, and catabolized) of antibodies within interstitial and intracellular compartments. Understanding these distinct antibody internalization mechanisms in tumor and non-tumor tissues enables more informed decisions on dose selection to optimize treatment of tumors with heterogeneous antigen expression while minimizing nonspecific toxicities.

Background: Biocontainment protocols are critical for conducting infectious disease (ID) research, particularly when using small animal models in biosafety level (BSL) 2/3 environments. This study evaluates the impact of poly-methyl methacrylate (PMMA) containment vessels on the performance of preclinical positron emission tomography (PET) systems. We tested containment vessels designed with varying wall thicknesses (3, 6, and 9 mm) to simulate ID imaging facility equipment and protocols. Through the use of multicomponent phantoms and in vivo mouse models of Staphylococcus aureus infection, we assessed key performance metrics including count rate, image quality, activity recovery, and spatial resolution.

Results: The results indicate that the use of PMMA containment causes only minor reductions in imaging performance. The thickest PMMA (9 mm) led to a maximum 6.8% decrease in count rate, which remains well within the acceptable range of variation. Effects on spatial resolution were most noticeable for smaller structures within the phantom study, with a 19.65% difference in full width at half maximum (FWHM) for the thickest walled vessel. In vivo, using infected mice, the containment devices had modest effects on the task of activity concentration to be detected at the infection site, even with the thickest PMMA tube.

Conclusion: These findings suggest that PMMA biocontainment vessels have small but measurable impact on preclinical PET system performance, making them a viable and cost-effective solution for conducting infectious disease imaging under BSL-2/3 conditions. Specifically, the thinnest containment (3 mm) had only minor effects on all tested parameters, suggesting it is well-suited for use in ID enclosures while maintaining accurate qualitative and quantitative assessments. This approach may reduce the burden for fully separate and specialized modifications for BSL-3 imaging facilities, and can be broadly applied to preclinical research involving pathogenic organisms.

Background: Protons, which are considered low-LET (Linear Energy Transfer) radiation, have an average RBE (relative biological effectiveness) of 1.1, with a range from 0.7 to 1.6. Thus, increasing biological effectiveness is of high interest in radiation oncology, and one way to enhance this is by using radiosensitizers. The present work investigates the effectiveness of the proton boron fusion reaction (PBFR) at the cellular level, using the sodium salt of metallacarborane [3,3'-Co(C2B9H11)2]^- (Na[o-COSAN]) as the boron source, aiming to explore the potential of this type of boron clusters as a radiosensitizer for proton therapy. Therefore, the main goal was to test the hypothesis that loading the cells with boron will favour the PBFR at energies close to the Bragg peak. This would enhance the radiation-induced biological effects through the production of alpha-particles.

Results: MDA-MB-231 breast cancer cells were used. Nuclear microscopy assessed [o-COSAN] uptake and distribution in single cells, while biodistribution was studied in tumor-bearing Balb/cSlc-nu/nu mice (MDA-MB-231 xenograft), with boron accumulation in target organs and tumor measured by ICP-OES. The cells were irradiated with a proton beam tuned to reach the PBFR resonance energy of 675 keV at the cell layer. DNA damage was assessed with the g-H2AX assay and cell survival with the clonogenic assay. Beam parameters and dose calibration curves using radiochromic films validated Monte Carlo dosimetry simulations. As expected, we observed higher biological damage in irradiated cells and the presence of [o-COSAN]^- potentiated the damage. These results translate into a lower cellular viability, indicating that DNA damage imposed colonies smaller than their non-irradiated counterparts. This suggests that these damages either took longer time to be repaired or made the cells undergo less efficient survival mechanisms.

Conclusions: The radiosensitizing effect of [o-COSAN]^- by strategic cellular ¹¹B placement and proton irradiation intensifies the DNA damage, making the nucleus particularly susceptible and thus increasing the destructive capability of alpha-particles, generated in the nuclear fusion reaction, which may lead to increased cell mortality.

Background: Sarcomatoid differentiation is an invasive dedifferentiated feature of tumor and associated with poor prognosis in renal cell carcinoma (RCC) patients. This study aimed to evaluate the utility of ¹⁸F-FDG PET/CT in predicting sarcomatoid differentiation in RCC and its potential prognostic value.

Results: This retrospective study assessed newly diagnosed sarcomatoid differentiation renal cell carcinoma (SDRCC) patients who were staged using ¹⁸F-FDG PET/CT. Patients were categorized into high-grade sarcomatoid differentiation RCC (HG-SDRCC), low-grade sarcomatoid differentiation RCC (LG-SDRCC), and non-sarcomatoid differentiation RCC (non-SDRCC). The maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were compared. Overall survival (OS) and disease-free survival (DFS) were analyzed. SUVmax, MTV, TLG, and SUVmean values were significantly higher in SDRCC compared to non-SDRCC (P < 0.05). Additionally, SUVmax, TLG, and SUVmean were significantly higher in HG-SDRCC compared to non-HG-SDRCC (P < 0.05). ROC curves revealed that SUVmax and SUVmean were effective for distinguishing HG-SDRCC from non-HG-SDRCC. The log-rank test identified SUVmax > 11, MTV > 95, TLG > 500, SUVmean > 5.2, invasion of peripheral tissue and/or organs, and metastasis as risk factors for SDRCC patients. Multivariate Cox proportional hazards model analyses indicated that TLG > 500 was a risk factor for poor DFS, while SUVmax > 11 and SUVmean > 5.2 were risk factors for poor OS.

Conclusions: ¹⁸F-FDG PET/CT can effectively differentiate HG-SDRCC with more aggressive malignancy. The prognostic model developed in this study demonstrates that metabolic parameters, particularly TLG for DFS and SUVmax/SUVmean for OS, serve as more robust predictors of patient outcomes than the degree of sarcomatoid differentiation.

Background: Rheumatoid arthritis (RA) is a common chronic, inflammatory autoimmune disease, and early clinical diagnosis is crucial for its treatment. CXCR4 expression was characterized in arthritic mouse models and joints of RA patients, and [¹⁸ F]AIF-NOTA-QHA-04 specificity was assessed in non-malignant cells with elevated CXCR4 expression. This study explored the application of CXCR4-targeted PET probe [¹⁸ F]AIF-NOTA-QHA-04 in monitoring disease activity and therapeutic efficacy in RA. To this aim, the metabolic characteristics of [¹⁸ F]AIF-NOTA-QHA-04 and correlation of [¹⁸ F]AIF-NOTA-QHA-04 uptake with arthritis severity were evaluated by PET imaging in arthritic mice. [¹⁸ F]AIF-NOTA-QHA-04 potential in evaluating therapeutic efficacy was further investigated in arthritic mice following methotrexate (MTX) and etanercept (ETC) treatment.

Results: CXCR4 expression was significantly increased in the inflamed joints of collagen-induced arthritis (CIA) and collagen-antibody induced arthritic (CAIA) mice, and in synovial tissues of RA patients. [¹⁸ F]AIF-NOTA-QHA-04 showed high specificity for CXCR4, with increased probe uptake in arthritic joints that was strongly correlated with arthritis severity scores. PET imaging revealed that increased uptake of [¹⁸ F]AIF-NOTA-QHA-04 in arthritic joints paralleled disease activity, with uptake decreasing upon remission. Furthermore, [¹⁸ F]AIF-NOTA-QHA-04 PET imaging provided earlier and more sensitive assessments of the efficacy of MTX and ETC compared to traditional methods.

Conclusion: The CXCR4-targeted PET probe [¹⁸ F]AIF-NOTA-QHA-04 is a promising tool for RA diagnosis and monitoring, with high specificity and sensitivity. The potential of this probe as a biomarker for disease activity and therapeutic response underscores its value in personalized medication strategies for the management of RA.