EJNMMI Research最新文献

Background: Terbium-161 (Tb-161) emits internal conversion and Auger electrons, in addition to beta-minus radiation, which might be of added benefit for targeted radionuclide therapy (TRT) compared to Lutetium-177 (Lu-177). We extensively compared Lu-177 and Tb-161 for fibroblast activation protein (FAP)- TRT in a preclinical setting. To study this, FAP-2286 was labeled with Lu-177 and Tb-161 and characterized in vitro on FAP-expressing cells and ex vivo using patient tumor samples. Moreover, in vivo studies (i.e. biodistribution and efficacy) were performed using a clinically representative pancreatic ductal adenocarcinoma (PDAC) mouse model. Biodistribution was performed 1, 4, 24, and 48 h post injection of 5 MBq/500 pmol [¹⁷⁷Lu]Lu-FAP-2286 or [¹⁶¹Tb]Tb-FAP-2286. Subsequently, animals were treated with 4 × 40 MBq/500 pmol [¹⁷⁷Lu]Lu-FAP-2286 or [¹⁶¹Tb]Tb-FAP-2286 and with alternating doses of 2 × 40 MBq/500 pmol of each radiopharmaceutical.

Results: No difference in [¹⁷⁷Lu]Lu-FAP-2286 and [¹⁶¹Tb]Tb-FAP-2286 uptake was observed in the cell models. In vivo studies did not show a survival benefit of 4 × 40 MBq/500 pmol [¹⁷⁷Lu]Lu-FAP-2286 or [¹⁶¹Tb]Tb-FAP-2286, while Kaplan-Meier analyses demonstrated a modest prolonged survival after tandem therapy in mice that first received [¹⁷⁷Lu]Lu-FAP-2286 followed by [¹⁶¹Tb]Tb-FAP-2286. Dosimetry calculations based on autoradiography studies on patient tumor samples showed that even with lower binding, a higher absorbed dose to the tumor can be accomplished with [¹⁶¹Tb]Tb-FAP-2286.

Conclusions: In our in vitro and in vivo studies, [¹⁷⁷Lu]Lu-FAP-2286 and [¹⁶¹Tb]Tb-FAP-2286 demonstrated similar behavior. In the applied PDAC mouse model, FAP-TRT showed limited therapeutic efficacy, most likely due to the limited radiopharmaceutical uptake observed in the tumors. This hampered determination of a potential benefit of either radioisotope for FAP-TRT. Of note, a modest response was observed in the tandem therapy group that first received [¹⁷⁷Lu]Lu-FAP-2286, followed by [¹⁶¹Tb]Tb-FAP-2286.

Background: Nectin-4 is a promising theranostic target for cancers treatment due to its high abundance/expression in different cancer entities such as bladder cancer, breast cancer, and pancreatic cancer This study evaluated the biodistribution and radiation dosimetry of [⁶⁸Ga]Ga-DOTA-Sar¹⁰-Nectin-4 ([⁶⁸Ga]Ga-FZ-NR-1), a novel Nectin-4-targeting PET tracer developed by our team, to assess its safety and support its clinical translation. Eight patients with pathologically confirmed malignancies (breast cancer, pancreatic cancer, or bladder cancer) underwent whole-body (WB) PET/CT scans at 10, 40, and 180 min after the injection of [⁶⁸Ga]Ga-FZ-NR-1. The images were reconstructed using the Ordered Subset Expectation Maximization (OSEM) algorithm with TOF and PSF technology. The brain, salivary, heart, lungs, stomach, spleen, liver, gallbladder, pancreas, kidneys, colon, and prostate in males or uterus in females as target organs were semi-automatically segmented on PET/CT images using the Hermes Internal Radiation Dosimetry (HIRD) software toolkit. Time-activity curves (TACs) were obtained for these organs based on measured activity concentrations. The time-integrated activity coefficients (TIACs) of these target organs were calculated by integrating the TACs. Organ-specific absorbed doses and the total body effective dose were estimated using IDAC-Dose 2.1 software. Meanwhile, bladder dosimetry employed a standard voiding model.

Results: [⁶⁸Ga]Ga-FZ-NR-1 was cleared rapidly, primarily via the urinary system. The highest organ absorbed doses per injected activity unit were observed in the kidneys (2.24 × 10⁻¹ mGy/MBq) and bladder wall (1.24 × 10⁻¹ mGy/MBq). Other notable organs were the salivary glands, with an absorbed dose of approximately 2.54 × 10⁻² mGy/MBq. The estimated total body effective dose per injected activity unit was approximately 2.00 × 10⁻² mSv/MBq. Preliminary clinical imaging showed high tracer uptake in breast, pancreatic, and bladder cancer lesions, highlighting its promising diagnostic potential for detecting Nectin-4-expressing tumors.

Conclusion: This human dosimetry assessment of [⁶⁸Ga]Ga-FZ-NR-1 showed a total body effective dose of approximately 2.00 × 10⁻² mSv/MBq, similar to other ⁶⁸Gallium-labeled tracers. Organ absorbed doses were well within the accepted limits, suggesting a favorable radiation risk profile for clinical application as a PET imaging agent targeting Nectin-4. Initial clinical imaging results demonstrates that [⁶⁸Ga]Ga-FZ-NR-1 provides clear visualization of both primary tumors and metastases with high Nectin-4 expression levels.

Background: Spatial filters are required to suppress the statistical noise of SPECT images but with an unavoidable smoothing effect that further decreases the SUV and contrast. This study assesses a deep-learning noise reduction (DLNR) algorithm, previously developed to further reduce bone SPECT recording time on a high-speed whole-body 360° CZT-camera, when used instead of, rather than in addition to, the conventional spatial filters (CSF) recommended for this camera.

Results: The SUVmax of bone lesions (114 definite arthritis or metastasis lesions) and the resolution recovery coefficients of small and medium phantom spheres, were higher for DLNR than CSF or the combination of CSF plus DLNR (CSF-DLNR) (all p < 0.001), whereas the relative noises were lower for DLNR or CSF-DLNR, as compared with CSF (p < 0.001). Consequently, contrast-to-noise ratio (CNR) was dramatically higher for DLNR, as compared with CSF, and also CSF-DLNR, especially for small- and medium-sized structures. Compared with CSF, DLNR provided an almost two-fold CNR increase for the sphere and lesions in the range of one cm³. This dramatic CNR improvement was still documented when DLNR was compared with the median, kernel, Butterworth, or Gaussian filters used alone and set to provide an equivalent image noise reduction to DLNR on the phantom.

Conclusion: When used alone, this DLNR algorithm enhances the contrast-to-noise ratio and quantification of bone lesions, especially those of small or medium sizes. It outperforms conventional spatial filters and provides remarkable image quality for routine analysis of bone SPECT from the high-speed whole-body 360° CZT camera. However, further research and validation studies are still necessary before a widespread adoption in clinical practice.

Key points: Question: How does a deep-learning noise reduction algorithm, previously developed to further reduce bone SPECT recording times on a high-speed whole-body 360° CZT-camera, work when used instead of, rather than in addition to, the conventional spatial filters recommended for this camera. Pertinent findings: When used alone, this deep-learning noise reduction algorithm provides a high level of image denoising and better preserves the activities of small- to medium-sized bone structures and lesions than conventional spatial filters do, leading to a dramatic increase in the corresponding contrast-to-noise ratios.

Implications for patient care: Such a deep-learning noise reduction algorithm could be used not only to reduce SPECT recording time when added to conventional spatial filters, but also to improve image quality and resolution when used alone.

Trial registration: clinicaltrials.gov, NCT06782438, Registered 27 February 2025, https://clinicaltrials.gov/search?id=NCT06782438 .

Background: Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecological malignancies, primarily due to frequent late-stage diagnosis and the development of resistance to chemotherapy. The aim of this study was to evaluate the expression of tumor-associated targets in a large cohort (n = 179) of various EOC subtypes, represented on two tissue microarrays (TMAs), to support the future development of radionuclide therapies. The study primarily assessed folate receptor-alpha and -beta isoforms (FRα and FRβ), but also somatostatin receptor-2 (SSTR2), prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP), for which established radiopharmaceuticals already exist. Membranous expression of these targets on tumor cells was detected by immunohistochemistry using antibodies validated on xenografts with known target expression and semi-quantitatively evaluated.

Results: Validation of the employed antibodies confirmed specific staining of the respective targets. The TMAs included tumors of high-grade and low-grade serous, endometrioid, clear cell, mucinous and carcinosarcoma. High FRα expression was seen in several EOC histotypes, most frequently in high-grade serous (47%), while it was largely absent in mucinous EOC. The FRβ was expressed only in stromal cells. SSTR2 and PSMA were only present in 8% and 4% of the EOC cases and not associated to a specific subtype. FAP expression on tumor cells was found in 10% of all EOCs, while stromal FAP was seen in 47% of the cases, with the highest prevalence in high-grade serous EOC (42%).

Conclusions: The findings of this study indicate that approved radionuclide therapies targeting SSTR2 or PSMA are unlikely to be suitable for treating EOC. In contrast, the frequent and high expression of FRα in tumor cells and FAP in tumor-associated stromal cells suggests that FRα- and FAP-targeted radiopharmaceuticals hold promise for the treatment of advanced-stage EOC.

Background: Selective internal radiation therapy (SIRT) with yttrium-90 (Y-90) microspheres is an established locoregional treatment for early- to intermediate-stage hepatocellular carcinoma (HCC). While both resin and glass microspheres are widely used, their comparative effectiveness and safety in lobar infusion remain unclear. This study aimed to compare the effectiveness and safety of resin versus glass microspheres in patients with early- to intermediate-stage HCC undergoing lobar Y-90 SIRT.

Results: A retrospective single-center analysis was conducted on 37 consecutive patients with early- to intermediate-stage HCC who underwent lobar Y-90 SIRT (resin: n = 22; glass: n = 15). Baseline characteristics were comparable between the two groups, except for age (glass: 64 ± 6.9 years vs. resin: 69 ± 7.1 years; P = 0.036). Radiation doses to the tumour and non-tumoural liver were comparable between the resin and glass groups (all P > 0.05). Patients treated with resin microspheres showed significantly longer progression-free survival (PFS) (median 9.3 vs. 6.4 months; P = 0.043) and overall survival (OS) (median 16.4 vs. 12.0 months; P = 0.035), and also demonstrated higher overall response rates, compared with those treated with glass microspheres. Univariate Cox regression identified resin microsphere use as a significant predictor of improved PFS and OS, while higher Barcelona Clinic Liver Cancer (BCLC) stage, multifocal disease, and tumour burden ≥ 25% were associated with worse survival (all P < 0.05). Fine-Gray competing risk regression, accounting for post-SIRT treatments as competing events, further confirmed the OS benefit of resin microspheres compared with glass microspheres (subdistribution hazard ratio [SHR] = 0.35; P = 0.011). Subgroup analysis demonstrated that the survival advantage of resin microspheres was particularly evident in patients with a maximum tumour diameter ≥ 5 cm (PFS: hazard ratio [HR] = 0.258, 95% confidence interval [CI]: 0.073-0.914; OS: HR = 0.111, 95% CI: 0.013-0.962). Safety outcomes were comparable between the two groups, with no significant differences in short- to long-term adverse events graded according to the Common Terminology Criteria for Adverse Events version 5.0, or in laboratory changes at 4-month follow-up (all P > 0.05).

Conclusions: In lobar Y-90 SIRT for early-to intermediate-stage HCC, resin microspheres were associated with improved outcomes without increased toxicity compared to glass microspheres, particularly in patients with large tumours. These findings support a potential benefit of resin versus glass microspheres in lobar SIRT and warrant prospective validation in larger cohorts.