Journal of Nuclear Medicine最新文献

Kirsten rat sarcoma (KRAS) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRAS^G12C oncoprotein-targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the KRAS^G12C mutation in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) patients. Methods: [¹⁸F]PFPMD was synthesized on the basis of AMG510 (sotorasib) by attaching a polyethylene glycol chain to the quinazolinone structure. The binding selectivity and imaging potential of [¹⁸F]PFPMD were verified by cellular uptake, internalization, and blocking (H358: KRAS^G12C mutation; A549: non-KRAS^G12C mutation) studies, as well as by a small-animal PET/CT imaging study on tumor-bearing mice. Five healthy volunteers were enrolled to assess the safety, biodistribution, and dosimetry of [¹⁸F]PFPMD. Subsequently, 14 NSCLC or CRC patients with or without the KRAS^G12C mutation underwent [¹⁸F]PFPMD and [¹⁸F]FDG PET/CT imaging. The SUV_max of tumor uptake of [¹⁸F]PFPMD was measured and compared between patients with and without the KRAS^G12C mutation. Results: [¹⁸F]PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability. The protein-binding assay showed that [¹⁸F]PFPMD selectively binds to the KRAS^G12C protein. [¹⁸F]PFPMD uptake was significantly higher in H358 than in A549 and was decreased by pretreatment with AMG510 (H358 vs. A549: 3.22% ± 0.28% vs. 2.50% ± 0.25%, P < 0.05; block: 2.06% ± 0.13%, P < 0.01). Similar results were observed in tumor-bearing mice on PET imaging (H358 vs. A549: 3.93% ± 0.24% vs. 2.47% ± 0.26% injected dose/g, P < 0.01; block: 2.89% ± 0.29% injected dose/g; P < 0.05). [¹⁸F]PFPMD was safe in humans and was excreted primarily by the gallbladder and intestines. The whole-body effective dose was comparable to that of [¹⁸F]FDG. The accumulation of [¹⁸F]PFPMD in KRAS^G12C mutation tumors was significantly higher than that in non-KRAS^G12C mutation tumors (SUV_max: 3.73 ± 0.58 vs. 2.39 ± 0.22, P < 0.01) in NSCLC and CRC patients. Conclusion: [¹⁸F]PFPMD is a safe and promising PET tracer for noninvasive screening of the KRAS^G12C mutation status in NSCLC and CRC patients.

The development of artificial intelligence (AI) within nuclear imaging involves several ethically fraught components at different stages of the machine learning pipeline, including during data collection, model training and validation, and clinical use. Drawing on the traditional principles of medical and research ethics, and highlighting the need to ensure health justice, the AI task force of the Society of Nuclear Medicine and Molecular Imaging has identified 4 major ethical risks: privacy of data subjects, data quality and model efficacy, fairness toward marginalized populations, and transparency of clinical performance. We provide preliminary recommendations to developers of AI-driven medical devices for mitigating the impact of these risks on patients and populations.

²⁰³Pb is a surrogate imaging match for ²¹²Pb. This elementally matched pair is emerging as a suitable pair for imaging and targeted radionuclide therapy in cancer care. Because of the half-life (51.9 h) and low-energy γ-rays emitted, ²⁰³Pb is suitable for the development of diagnostic radiopharmaceuticals. The aim of this work was to optimize the production and separation of high-specific-activity ²⁰³Pb using electroplated thallium targets. We further investigated the radiochemistry optimization using a suitable chelator, tetraazacyclododecane-1,4,7-triacetic acid (DO3A), and targeting vector, VMT-α-NET (lead-specific chelator conjugated to tyr3-octreotide via a polyethylene glycol linker). Methods: Targets were prepared by electroplating of natural or enriched (²⁰⁵Tl) thallium metal. Scanning electron microscopy was performed to determine the structure and elemental composition of electroplated targets. Targets were irradiated with 24-MeV protons with varying current and beam time to investigate target durability. ²⁰³Pb was purified from the thallium target material using an extraction resin (lead resin) column followed by a second column using a weak cation-exchange resin to elute the lead isotope as [²⁰³Pb]PbCl₂ Inductively coupled plasma mass spectrometry studies were used to further characterize the separation for trace metal contaminants. Radiolabeling efficiency was also investigated for DO3A chelator and VMT-α-NET (a peptide-based targeting conjugate). Results: Electroplated targets were prepared at a high plating density of 76-114 mg/cm² using a plating time of 5 h. A reproducible separation method was established with a final elution in HCl (400 μL, 1 M) suitable for radiolabeling. Greater than 90% recovery yields were achieved, with an average specific activity of 37.7 ± 5.4 GBq/μmol (1.1 ± 0.1 Ci/μmol). Conclusion: An efficient electroplating method was developed to prepare thallium targets suitable for cyclotron irradiation. A simple and fast separation method was developed for routine ²⁰³Pb production with high recovery yields and purity.

A single-institution prospective pilot clinical trial was performed to demonstrate the feasibility of combining [¹⁷⁷Lu]Lu-PSMA-617 radiopharmaceutical therapy (RPT) with stereotactic body radiotherapy (SBRT) for the treatment of oligometastatic castration-sensitive prostate cancer. Methods: Six patients with 9 prostate-specific membrane antigen (PSMA)-positive oligometastases received 2 cycles of [¹⁷⁷Lu]Lu-PSMA-617 RPT followed by SBRT. After the first intravenous infusion of [¹⁷⁷Lu]Lu-PSMA-617 (7.46 ± 0.15 GBq), patients underwent SPECT/CT at 3.2 ± 0.5, 23.9 ± 0.4, and 87.4 ± 12.0 h. Voxel-based dosimetry was performed with calibration factors (11.7 counts per second/MBq) and recovery coefficients derived from in-house phantom experiments. Lesions were segmented on baseline PSMA PET/CT (50% SUV_max). After a second cycle of [¹⁷⁷Lu]Lu-PSMA-617 (44 ± 3 d; 7.50 ± 0.10 GBq) and an interim PSMA PET/CT scan, SBRT (27 Gy in 3 fractions) was delivered to all PSMA-avid oligometastatic sites, followed by post-PSMA PET/CT. RPT and SBRT voxelwise dose maps were scaled (α/β = 3 Gy; repair half-time, 1.5 h) to calculate the biologically effective dose (BED). Results: All patients completed the combination therapy without complications. No grade 3+ toxicities were noted. The median of the lesion SUV_max as measured on PSMA PET was 16.8 (interquartile range [IQR], 11.6) (baseline), 6.2 (IQR, 2.7) (interim), and 2.9 (IQR, 1.4) (post). PET-derived lesion volumes were 0.4-1.7 cm³ The median lesion-absorbed dose (AD) from the first cycle of [¹⁷⁷Lu]Lu-PSMA-617 RPT (AD_RPT) was 27.7 Gy (range, 8.3-58.2 Gy; corresponding to 3.7 Gy/GBq, range, 1.1-7.7 Gy/GBq), whereas the median lesion AD from SBRT was 28.1 Gy (range, 26.7-28.8 Gy). Spearman rank correlation, ρ, was 0.90 between the baseline lesion PET SUV_max and SPECT SUV_max (P = 0.005), 0.74 (P = 0.046) between the baseline PET SUV_max and the lesion AD_RPT, and -0.81 (P = 0.022) between the lesion AD_RPT and the percent change in PET SUV_max (baseline to interim). The median for the lesion BED from RPT and SBRT was 159 Gy (range, 124-219 Gy). ρ between the BED from RPT and SBRT and the percent change in PET SUV_max (baseline to post) was -0.88 (P = 0.007). Two cycles of [¹⁷⁷Lu]Lu-PSMA-617 RPT contributed approximately 40% to the maximum BED from RPT and SBRT. Conclusion: Lesional dosimetry in patients with oligometastatic castration-sensitive prostate cancer undergoing [¹⁷⁷Lu]Lu-PSMA-617 RPT followed by SBRT is feasible. Combined RPT and SBRT may provide an efficient method to maximize the delivery of meaningful doses to oligometastatic disease while addressing potential microscopic disease reservoirs and limiting the dose exposure to normal tissues.

Since the development of fibroblast activation protein-targeted radiopharmaceuticals, ⁶⁸Ga-fibroblast activation protein inhibitor (FAPI) PET/CT has been found to be suitable for detecting primary and metastatic lesions in many types of tumors. However, there is currently a lack of reliable data regarding the clinical impact of this family of probes. To address this gap, the present study aimed to analyze the clinical impact of ⁶⁸Ga-FAPI PET/CT by examining a large cohort of patients with various tumors. Methods: In total, 226 patients (137 male and 89 female) were included in this retrospective analysis. Pancreatic cancer and head and neck cancers were the most common tumor types in this cohort. TNM stage and oncologic management were initially determined with gold standard imaging, and these results were compared with ⁶⁸Ga-FAPI PET/CT. Changes were classified as major and minor. Results: For 42% of all patients, TNM stage was changed by ⁶⁸Ga-FAPI PET/CT results. Most of these changes resulted in upstaging. A change in clinical management occurred in 117 of 226 patients. Although a major change in management occurred in only 12% of patients, there was a significant improvement in the ability to accurately plan radiation therapy. In general, the highest clinical impact of ⁶⁸Ga-FAPI PET/CT imaging was found in patients with lung cancer, pancreatic cancer, and head and neck tumors. Conclusion: ⁶⁸Ga-FAPI PET/CT is a promising imaging probe that has a significant impact on TNM stage and clinical management. ⁶⁸Ga-FAPI PET/CT promises to be a crucial new technology that will improve on conventional radiologic imaging methods such as contrast-enhanced CT and contrast-enhanced MRI typically acquired for cancer staging.

Molecular radionuclide therapy is a relatively novel anticancer treatment option using radiolabeled, tumor-specific vectors. On binding of these vectors to cancer cells, radioactive decay induces DNA damage and other effects, leading to cancer cell death. Treatments, such as with [¹⁷⁷Lu]Lu-octreotate for neuroendocrine tumors and [¹⁷⁷Lu]Lu-PSMA for prostate cancer, are now being implemented into routine clinical practice around the world. Nonetheless, research into the underlying radiobiologic effects of these treatments is essential to further improve them or formulate new ones. The purpose of the European Working Group on the Radiobiology of Molecular Radiotherapy is to promote knowledge, investment, and networking in this area. This report summarizes recent research and insights presented at the second International Workshop on Radiobiology of Molecular Radiotherapy, held in London, U.K., on March 13 and 14, 2023. The symposium was organized by members of the Cancer Research U.K. RadNet City of London and the European Working Group on the Radiobiology of Molecular Radiotherapy.

The prostate-specific membrane antigen (PSMA) inhibitor [¹⁷⁷Lu]Lu-PSMA-617 has been previously demonstrated to be noninferior to docetaxel in achieving a biochemical response in chemotherapy-naïve metastatic castration-resistant prostate cancer patients. Here, we report the final analysis of overall survival (OS) for a phase 2 randomized, controlled trial. Methods: Forty chemotherapy-naïve, PSMA-positive metastatic castration-resistant prostate cancer patients were randomly assigned to [¹⁷⁷Lu]Lu-PSMA-617 (n = 20) or docetaxel (n = 20). Thirty-five patients received treatment per the protocol. Survival analysis was done using Kaplan-Meier curves and the Cox regression model. Results: The mean follow-up duration was 33.4 mo. In intention-to-treat analysis, the median OS for the [¹⁷⁷Lu]Lu-PSMA-617 and docetaxel arms was 15.0 mo (95% CI, 9.5-20.5 mo) and 15.0 mo (95% CI, 8.1-21.9 mo), respectively (P = 0.905). In per-protocol analysis, the median OS was 19.0 mo (95% CI, 12.3-25.7 mo) versus 15.0 mo (95% CI, 8.1-21.9 mo), respectively (P = 0.712). No significant difference in OS was observed between the 2 arms across the analyzed subgroups. Conclusion: Long-term outcomes with [¹⁷⁷Lu]Lu-PSMA-617 administered earlier in the prechemotherapy setting are comparable to those with docetaxel.

Predictive biomarkers of response to human epidermal growth factor receptor 2 (HER2)-directed therapy are essential to inform treatment decisions. The TBCRC026 trial reported that early declines in tumor SUVs corrected for lean body mass (SUL_max) on ¹⁸F-FDG PET/CT predicted a pathologic complete response (pCR) to HER2 therapy with neoadjuvant trastuzumab and pertuzumab (HP) without chemotherapy in estrogen receptor (ER)-negative, HER2-positive breast cancer. We hypothesized that ¹⁸F-FDG PET/CT SUL_max parameters would predict recurrence-free survival (RFS) and overall survival (OS). Methods: Patients with stage II/III ER-negative, HER2-positive breast cancer received neoadjuvant HP (n = 88). pCR after HP alone was 22% (18/83), additional nonstudy neoadjuvant therapy was administered in 28% (25/88), and the majority received adjuvant therapy per physician discretion. ¹⁸F-FDG PET/CT was performed at baseline and at cycle 1, day 15 (C1D15). RFS and OS were summarized using the Kaplan-Meier method and compared between subgroups using logrank tests. Associations between ¹⁸F-FDG PET/CT (≥40% decline in SUL_max between baseline and C1D15, or C1D15 SUL_max ≤ 3) and pCR were evaluated using Cox regressions, where likelihood ratio CIs were reported because of the small numbers of events. Results: Median follow-up was 53.7 mo (83/88 evaluable), with 6 deaths and 14 RFS events. Estimated RFS and OS at 3 y was 84% (95% CI, 76%-92%) and 92% (95% CI, 87%-98%), respectively. A C1D15 SUL_max of 3 or less was associated with improved RFS (hazard ratio [HR], 0.36; 95% CI, 0.11-1.05; P = 0.06) and OS (HR, 0.14; 95% CI, 0.01-0.85; P = 0.03), the latter statistically significant. The association of an SUL_max decline of at least 40% (achieved in 59%) with RFS and OS did not reach statistical significance. pCR was associated with improved RFS (HR, 0.25; 95% CI, 0.01-1.24; P = 0.10) but did not reach statistical significance. Conclusion: For the first time, we report a potential association between a C1D15 SUL_max of 3 or less on ¹⁸F-FDG PET/CT and RFS and OS outcomes in patients with ER-negative, HER2-positive breast cancer receiving neoadjuvant HP alone. If confirmed in future studies, this imaging-based biomarker may facilitate early individualization of therapy.