Landscape of Nuclear Medicine in China and Its Progress on Theranostics.

Nuclear medicine in China started in 1956 and, with the rapid development of the economy and continuous breakthroughs in precision medicine, has made significant progress in recent years. Almost 13,000 staff members in nearly 1,200 hospitals serve more than 3.9 million patients each year. Over the past decade, the radiopharmaceutical industry has developed rapidly, with the initial formation of a complete industrial chain of production of various radiopharmaceuticals for both clinical use and basic research. Advanced equipment such as PET/CT scanners is being manufactured domestically and even installed abroad. Recently, research into screening and synthesizing new target probes and their translation into the clinic has gained more attention, with various new tracers with potential clinical value being thoroughly studied. Simultaneously, 68Ga- and 177Lu-labeled tumor-targeted probes and others have been implemented for theranostics in an increasing number of hospitals and would be helped by approval from the National Medical Products Administration. Over the next 10-20 y, with the launch of the Mid- and Long-Term Development Plan for Medical Isotopes (2021-2035) by the Chinese government, there is great potential for nuclear medicine in China. With the rise in independent innovation in manufacturing, the shortage of radiopharmaceuticals will be effectively curtailed. We anticipate that the scale of nuclear medicine will at least double by 2035, covering all high-grade hospitals and leading to the aim of "one county, one department" in China.

Fibroblast Activation Protein Inhibitor Tracers and Their Preclinical, Translational, and Clinical Status in China.

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.

Melanin-Targeting Radiotracers and Their Preclinical, Translational, and Clinical Status: From Past to Future.

Melanin is one of the representative biomarkers of malignant melanoma and a potential target for diagnosis and therapy. With advancements in chemistry and radiolabeling technologies, promising strides have been made to synthesize radiolabeled melanin-binding molecules for various applications. We present an overview of melanin-targeted radiolabeled molecules and compare their features reported in preclinical studies. Clinical practice and trials are also discussed to elaborate on the safety and validity of the probes, and expanded applications beyond melanoma are reviewed. Melanin-targeted imaging holds potential value in the diagnosis, staging, and prognostic assessment of melanoma and other applications. Melanin-targeted radionuclide therapy possesses immense potential but requires more clinical validation. Furthermore, an intriguing avenue for future research involves expanding the application scope of melanin-targeted probes and exploring their value.

Recent Advances in Radiotracers Targeting Novel Cancer-Specific Biomarkers in China: A Brief Overview.

Radiopharmaceuticals play a critical role in nuclear medicine, providing novel tools for specifically delivering radioisotopes for the diagnosis and treatment of cancers. As the starting point for developing radiopharmaceuticals, cancer-specific biomarkers are important and receive worldwide attention. This field in China is currently experiencing a rapid expansion, with multiple radiotracers targeting novel targets being developed and translated into clinical studies. This review provides a brief overview of the exploration of novel imaging targets, preclinical evaluation of their targeting ligands, and translational research in China from 2020 to 2023, for detecting cancer, guiding targeted therapy, and visualizing the immune microenvironment. We believe that China will play an even more important role in the development of nuclear medicine in the world in the future.

Spatiotemporal Concurrent PARP Inhibitor Sensitization Based on Radiation-Responsive Nanovesicles for Lung Cancer Chemoradiotherapy.

The implementation of chemoradiation combinations has gained great momentum in clinical practices. However, the full utility of this paradigm is often restricted by the discordant tempos of action of chemotherapy and radiotherapy. Here, a gold nanoparticle-based radiation-responsive nanovesicle system loaded with cisplatin and veliparib, denoted as CV-Au NVs, is developed to augment the concurrent chemoradiation effect in a spatiotemporally controllable manner of drug release. Upon irradiation, the in situ generation of •OH induces the oxidation of polyphenylene sulfide from being hydrophobic to hydrophilic, resulting in the disintegration of the nanovesicles and the rapid release of the entrapped cisplatin and veliparib (the poly ADP-ribose polymerase (PARP) inhibitor). Cisplatin-induced DNA damage and the impairment of the DNA repair mechanism mediated by veliparib synergistically elicit potent pro-apoptotic effects. In vivo studies suggest that one-dose injection of the CV-Au NVs and one-time X-ray irradiation paradigm effectively inhibit tumor growth in the A549 lung cancer model. This study provides new insight into designing nanomedicine platforms in chemoradiation therapy from a vantage point of synergizing both chemotherapy and radiation therapy in a spatiotemporally concurrent manner.

Interplay between lipid dysregulation and ferroptosis in chondrocytes and the targeted therapy effect of metformin on osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide; the role of lipid dysregulation in OA and mechanisms underlying targeted therapy effect of lipid-lowering metformin on OA remains poorly defined. OBJECTIVES: To investigate the effects of lipid dysregulation on OA progression and to explore lipid dysregulation-targeting OA treatment of metformin. METHODS: RNA-Seq data, biochemical, and histochemical assays in human and murine OA cartilage as well as primary chondrocytes were utilized to determine lipid dysregulation. Effects of metformin, a potent lipid-lowering medication, on ACSL4 expression and chondrocyte metabolism were determined. Further molecular experiments, including RT-qPCR, western blotting, flow cytometry, and immunofluorescence staining, were performed to investigate underlying mechanisms. Mice with intra-articular injection of metformin were utilized to determine the effects on ACLT-induced OA progression. RESULTS: ACSL4 and 4-HNE expressions were elevated in human and ACLT-induced mouse OA cartilage and IL-1ß-treated chondrocytes (P < 0.05). Ferrostatin-1 largely rescued IL-1ß-induced MDA, lipid peroxidation, and ferroptotic mitochondrial morphology (P < 0.05). Metformin decreased the levels of OA-related genes (P < 0.05) and increased the levels of p-AMPK and p-ACC in IL-1ß-treated chondrocytes. Intra-articular injection of metformin alleviated ACLT-induced OA lesions in mice, and reverted the percentage of chondrocytes positive for MMP13, Col2a1, ACSL4 and 4-HNE in ACLT mice (P < 0.05). Ferroptotic chondrocytes promoted the recruitment and chemotaxis of RAW264.7 cells via CCL2, which was blocked by metformin in vitro (P < 0.05). CONCLUSION: We establish a critical role of polyunsaturated fatty acids metabolic process in OA cartilage degradation and define metformin as a potential OA treatment. Metformin reshapes lipid availability and ameliorates chondrocyte ferroptosis sensitivity via the AMPK/ACC pathway. In the future, gene-edited animals and extensive omics technologies will be utilized to reveal detailed lipids' involvement in cartilage lesions.

The role of lipid metabolism in osteoporosis: Clinical implication and cellular mechanism.

In recent years, researchers have become focused on the relationship between lipids and bone metabolism balance. Moreover, many diseases related to lipid metabolism disorders, such as nonalcoholic fatty liver disease, atherosclerosis, obesity, and menopause, are associated with osteoporotic phenotypes. It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass. Furthermore, similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models. Abnormal lipid metabolism (such as increased oxidized lipids and elevated plasma cholesterol) affects bone microenvironment homeostasis via cross-organ communication, promoting differentiation of mesenchymal stem cells to adipocytes, and inhibiting commitment towards osteoblasts. Moreover, disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cytokines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts. Conclusively, this review addresses the possible link between lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism balance. We also summarize the possible approaches and prospects of intervening lipid metabolism for osteoporosis treatment.

Comparison of diagnostic efficacy between 99mTc-methylene diphosphate SPECT/CT and MRI for bone and joint infections: a multicenter retrospective analysis.

Objective: There is currently no non-invasive examination that can fully determine the diagnosis of osteomyelitis. SPECT/CT tomographic fusion imaging can provide both local metabolic activity and anatomical information to determine the condition and location. This study evaluates the diagnostic efficacy of 99mTc-MDP SPECT/CT in bone infections, compared to MRI. Methods: In this multicenter retrospective study, 363 patients with suspected bone and joint infections or osteomyelitis were included. Participants underwent 99mTc-MDP SPECT/CT and/or MRI examinations, supplemented by pathogenic bacterial cultures and histopathological analysis. Results: Only SPECT/CT was tested in 169 patients, and only MRI was used in 116. 78 people have implemented both inspections and have detailed information. The diagnostic sensitivity and specificity of SPECT/CT for infection were 96% and 92% respectively, with an accuracy of 96%. For MRI, these figures were 88%, 84%, and 87% respectively. Conclusion: This represents the largest global study to date evaluating osteomyelitis and bone infection diagnosis using 99mTc-MDP SPECT/CT tomographic fusion imaging. The findings indicate that 99mTc-MDP SPECT/CT fusion imaging offers superior diagnostic accuracy compared to MRI. This is particularly evident in cases involving metallic implants and chronic infections. 99mTc-MDP SPECT/CT fusion imaging emerges as a highly suitable non-invasive diagnostic modality, facilitating enhanced clinical follow-up and treatment.

Decomposed FDG PET-based phenotypic heterogeneity predicting clinical prognosis and decision-making in temporal lobe epilepsy patients.

OBJECTIVE: This study utilized a data-driven Bayesian model to automatically identify distinct latent disease factors represented by overlapping glucose metabolism patterns from 18F-Fluorodeoxyglucose PET (18F-FDG PET) to analyze heterogeneity among patients with TLE. METHODS: We employed unsupervised machine learning to estimate latent disease factors from 18F-FDG PET scans, representing whole-brain glucose metabolism patterns in seventy patients with TLE. We estimated the extent to which multiple distinct factors were expressed within each participant and analyzed their relevance to epilepsy burden, including seizure onset, duration, and frequency. Additionally, we established a predictive model for clinical prognosis and decision-making. RESULTS: We identified three latent disease factors: hypometabolism in the unilateral temporal lobe and hippocampus (factor 1), hypometabolism in bilateral prefrontal lobes (factor 2), and hypometabolism in bilateral temporal lobes (factor 3), variably co-expressed within each patient. Factor 3 demonstrated the strongest negative correlation with the age of onset and duration (r = - 0.33, - 0.38 respectively, P < 0.05). The supervised classifier, trained on latent disease factors for predicting patient-specific antiepileptic drug (AED) responses, achieved an area under the curve (AUC) of 0.655. For post-surgical seizure outcomes, the AUC was 0.857, and for clinical decision-making, it was 0.965. CONCLUSIONS: Decomposing 18F-FDG PET-based phenotypic heterogeneity facilitates individual-level predictions relevant to disease monitoring and personalized therapeutic strategies.

Performance Evaluation of the uMI Panorama PET/CT System in Accordance with the National Electrical Manufacturers Association NU 2-2018 Standard.

The uMI Panorama is a novel PET/CT system using silicon photomultiplier and application-specific integrated circuit technologies and providing exceptional spatial and time-of-flight (TOF) resolutions. The objective of this study was to assess the physical performance of the uMI Panorama in accordance with the National Electrical Manufacturers Association (NEMA) NU 2-2018 standard. Methods: Spatial resolution, sensitivity, count rate performance, accuracy, image quality, and TOF resolution were evaluated in accordance with the guidelines outlined in the NEMA NU 2-2018 standard. Energy resolution was determined using the same dataset acquired for the count rate performance evaluation. Images from a Hoffman brain phantom, a mini-Derenzo phantom, and 3 patient studies were evaluated to demonstrate system performance. Results: The transaxial spatial resolution at full width at half maximum was measured as 2.88 mm with a 1-cm offset from the center axial field of view. The sensitivity at the center axial field of view was 20.1 kcps/MBq. At an activity concentration of 73.0 kBq/mL, the peak noise-equivalent count rate (NECR) reached 576 kcps with a scatter fraction of approximately 33.2%. For activity concentrations at or below the peak NECR, the maximum relative count rate error among all slices remained consistently below 3%. When assessed using the NEMA image quality phantom, overall image contrast recovery ranged from 63.2% to 88.4%, whereas background variability ranged from 4.2% to 1.1%. TOF resolution was 189 ps at 5.3 kBq/mL and was consistently lower than 200 ps for activity concentrations at or below the peak NECR. The patient studies demonstrated that scans at 2 min/bed produced images characterized by low noise and high contrast. Clear delineation of nuclei, spinal cords, and other substructures of the brain was observed in the brain PET images. Conclusion: uMI Panorama, the world's first commercial PET system with sub-200-ps TOF resolution, demonstrated fine spatial and fast TOF resolutions, robust count rate performance, and high quantification accuracy across a wide range of activity levels. This advanced technology offers enhanced diagnostic capability for detecting small and low-contrast lesions while showing promising potential under high-count-rate imaging scenarios.

Selective Recovery of Cathode Materials from Spent Lithium-Ion Battery Material with a Near-Room-Temperature Separation.

Effective separation of cathode materials from the current collector is a critical step in recycling a spent lithium-ion battery (LIB). This typically necessitates the decomposition or dissolution of the organic binder, poly(vinylidene fluoride) (PVDF), to achieve efficient recovery of cathode materials. However, this process requires a high decomposition temperature, typically between 400 and 600 °C, and can lead to side reactions, such as current collector oxidation/brittleness, decomposition of cathode materials, and formation of metal fluorides. In this study, we propose that non-thermal plasma (NTP) treatment can be used to achieve an extremely high separation of cathode materials and aluminum current collector at near room temperature. Instead of relying on PVDF decomposition, which requires high temperatures, PVDF can be deactivated by partially breaking down long molecular chains with appropriate NTP conditions. With a total treatment time of around 2000 s and an environmental temperature of approximately 80 °C, minor side reactions can be avoided. The separation rate can reach up to 95.69%, and high-quality cathode materials can be obtained with only 0.02 wt % aluminum impurity content. This research could potentially offer a new approach toward minimizing recycling steps and reducing energy consumption in the recycling of spent LIBs. It could also be extended to the recovery of a broader range of electronic wastes.

Surgical evidence-based comparison of [68Ga]Ga-FAPI-04 PET and MRI-DWI for assisting debulking surgery in ovarian cancer patients.

PURPOSE: Imaging assessment of abdominopelvic tumor burden is crucial for debulking surgery decision in ovarian cancer patients. This study aims to compare the efficiency of [68Ga]Ga-FAPI-04 FAPI PET and MRI-DWI in the preoperative evaluation and its potential impact to debulking surgery decision. METHODS: Thirty-six patients with suspected/confirmed ovarian cancer were enrolled and underwent integrated [68Ga]Ga-FAPI-04 PET/MRI. Nineteen patients (15 stage III-IV and 4 I-II stage) who underwent debulking surgery were involved in the diagnostic efficiency analysis. The images of [68Ga]Ga-FAPI-04 PET and MRI-DWI were visually analyzed respectively. Immunohistochemistry on FAP was performed in metastatic lesions to investigate the radiological missing of [68Ga]Ga-FAPI-04 PET as well as its different performance in primary debulking surgery (PDS) and interval debulking surgery (IDS) patients. Potential imaging impact on management was also studied in 35 confirmed ovarian cancer patients. RESULTS: [68Ga]Ga-FAPI-04 PET displayed higher sensitivity (76.8% vs.59.9%), higher accuracy (84.9% vs. 80.7%), and lower missing rate (23.2% vs. 40.1%) than MRI-DWI in detecting abdominopelvic metastasis. The diagnostic superiority of [68Ga]Ga-FAPI-04 PET is more obvious in PDS patients but diminished in IDS patients. [68Ga]Ga-FAPI-04 PET outperformed MRI-DWI in 70.8% abdominopelvic regions (17/24), which contained seven key regions that impact the resectability and surgical complexity. MRI-DWI hold advantage in the peritoneal surface of the bladder and the central tendon of the diaphragm. Of the contradictory judgments between the two modalities (14.9%), [68Ga]Ga-FAPI-04 PET correctly identified more lesions, particularly in PDS patients (73.8%). In addition, FAP expression was independent of lesion size and decreased in IDS patients. [68Ga]Ga-FAPI-04 PET changed 42% of surgical planning that was previously based on MRI-DWI. CONCLUSION: [68Ga]Ga-FAPI-04 PET is more efficient in assisting debulking surgery in ovarian cancer patients than MRI-DWI. Integrated [68Ga]Ga-FAPI-04 PET/MR imaging is a potential method for planning debulking surgery in ovarian cancer patients.

First-in-human validation of enzymolysis clearance strategy for decreasing renal radioactivity using modified [68Ga]Ga-HER2 Affibody.

PURPOSE: Enzymolysis clearance strategy, characterized by releasing the non-reabsorbable radioactive fragment under the specific cleavage of enzymes, is confirmed to be a safe and effective way to reduce the renal radioactivity accumulation in mice. However, the effectiveness of this strategy in humans remains unknown. Human epidermal growth factor receptor 2 (HER2) is overexpressed in various types of tumors, and radiolabeled HER2 Affibody is believed to be an attractive tool for HER2-targeted theranostics. However, its wide application is limited by the high and persistent renal uptake. In this study, we intend to validate the effectiveness of enzymolysis clearance strategy in reducing renal accumulation by using a modified HER2 Affibody. MATERIALS AND METHODS: A new HER2 Affibody ligand, NOTA-MVK-ZHER2:2891, containing a cleavable Met-Val-Lys (MVK) linker was synthesized and labeled with 68Ga. The microPET imaging study was performed in SKOV-3 tumor mice to assess the uptakes of the control ligand and the MVK one in tumors and kidneys. Seven healthy volunteers were included for biodistribution and dosimetric studies with both the control and MVK ligands performed 1 week apart. Urine and blood samples from healthy volunteers were collected for in vivo metabolism study of the two ligands. Four HER2-positive and two HER2-negative patients were recruited for [68Ga]Ga-NOTA-MVK-ZHER2:2891 PET/CT imaging at 2 and 4 h post-injection (p.i.). RESULTS: [68Ga]Ga-NOTA-MVK-ZHER2:2891 was stable both in PBS and in mouse serum. MicroPET images showed that the tumor uptake of [68Ga]Ga-NOTA-MVK-ZHER2:2891 was comparable to that of [68Ga]Ga-NOTA-ZHER2:2891 at all the time points, while the kidney uptake was significantly reduced 40 min p.i. (P < 0.05). The biodistribution study in healthy volunteers showed that the kidney uptake of MVK ligand was significantly lower than that of the control ligand at 1 h p.i. (P < 0.05), with the SUVmean of 34.3 and 45.8, respectively, while the uptakes of the two ligands in the other organs showed negligible difference. The effective doses of the MVK ligand and the control one were 26.1 and 28.7 µSv/MBq, respectively. The enzymolysis fragment of [68Ga]Ga-NOTA-Met-OH was observed in the urine samples of healthy volunteers injected with the MVK ligand, indicating that the enzymolysis clearance strategy worked in humans. The PET/CT study of patients showed that the range of SUVmax of HER2-positive lesions was 9.4-21, while that of HER2-negative lesions was 2.7-6.2, which suggested that the MVK modification did not affect the ability of ZHER2:2891 structure to bind with HER2. CONCLUSION: We for the first time demonstrated that enzymolysis clearance strategy can effectively reduce renal radioactivity accumulation in humans. This strategy is expected to decrease renal radiation dose of peptide and small protein-based radiotracers, especially in the field of radionuclide therapy.

Avoiding unnecessary biopsy: the combination of PRIMARY score with prostate-specific antigen density for prostate biopsy decision.

BACKGROUND: Avoiding unnecessary biopsies for men with suspected prostate cancer remains a clinical priority. The recently proposed PRIMARY score improves diagnostic accuracy in detecting clinically significant prostate cancer (csPCa). The aim of this study was to determine the best strategy combining PRIMARY score or MRI reporting scores (Prostate Imaging Reporting and Data System [PI-RADS]) with prostate-specific antigen density (PSAD) for prostate biopsy decision making. METHODS: A retrospective analysis of 343 patients who underwent both 68Ga-PSMA PET/CT and MRI before prostate biopsy was performed. PSA was restricted to <20 ng/ml. Different biopsy strategies were developed and compared based on PRIMARY score or PI-RADS with PSAD thresholds. Decision curve analysis (DCA) was plotted to define the optimal biopsy strategy. RESULTS: The prevalence of csPCa was 41.1% (141/343). According to DCA, the strategies of PRIMARY score +PSAD (strategy #1, strategy #2, strategy #6) had a higher net benefit than the strategies of PI-RADS + PSAD at the risk threshold of 8-20%. The best diagnostic strategy was strategy #1 (PRIMARY score 4-5 or PSAD ≥ 0.20), which avoided 38.2% biopsy procedures while missed 9.2% of csPCa cases. From a clinical perspective, strategies with a lower risk of missing csPCa were strategy #2 (PRIMARY score ≥4 or PSAD ≥ 0.15), which avoided 28.6% biopsies while missed 5.7% of csPCa cases, or strategy #6 (PRIMARY score≥3 or PSAD ≥ 0.15), which avoided 20.7% biopsies while missed only 3.5% of csPCa cases. The limitations of the study were the retrospective single-center nature. CONCLUSIONS: The combination of PRIMARY score +PSAD allows individualized decisions to avoid unnecessary biopsy, outperforming the strategies of PI-RADS + PSAD. Further prospective trials are needed to validate these findings.

Calcium-based polymers for suppression of soil acidification by improving acid-buffering capacity and inhibiting nitrification.

Soil acidification is a major threat to agricultural sustainability in tropical and subtropical regions. Biodegradable and environmentally friendly materials, such as calcium lignosulfonate (CaLS), calcium poly(aspartic acid) (PASP-Ca), and calcium poly γ-glutamic acid (γ-PGA-Ca), are known to effectively ameliorate soil acidity. However, their effectiveness in inhibiting soil acidification has not been studied. This study aimed to evaluate the effect of CaLS, PASP-Ca, and γ-PGA-Ca on the resistance of soil toward acidification as directly and indirectly (i.e., via nitrification) caused by the application of HNO3 and urea, respectively. For comparison, Ca(OH)2 and lignin were used as the inorganic and organic controls, respectively. Among the materials, γ-PGA-Ca drove the substantial improvements in the pH buffering capacity (pHBC) of the soil and exhibited the greatest potential in inhibiting HNO3-induced soil acidification via protonation of carboxyl, complexing with Al3+, and cation exchange processes. Under acidification induced by urea, CaLS was the optimal one in inhibiting acidification and increasing exchangeable acidity during incubation. Furthermore, the sharp reduction in the population sizes of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) confirmed the inhibition of nitrification via CaLS application. Therefore, compared to improving soil pHBC, CaLS may play a more important role in suppressing indirect acidification. Overall, γ-PGA-Ca was superior to PASP-Ca and CaLS in enhancing the soil pHBC and the its resistance to acidification induced by HNO3 addition, whereas CaLS was the best at suppressing urea-driven soil acidification by inhibiting nitrification. In conclusion, these results provide a reference for inhibiting soil re-acidification in intensive agricultural systems.

The PRIMARY Score: Diagnostic Performance and Added Value Compared With MRI in Detecting Clinically Significant Prostate Cancer.

PURPOSE: Multiparametric MRI is the current standard for detecting clinically significant prostate cancer (csPCa). However, men with negative or equivocal MRI often undergo unnecessary biopsies due to concerns about false-negative results. The recently proposed 68 Ga-PSMA PET/CT-based PRIMARY score exhibited good diagnostic performance for csPCa. This study aimed to externally validate the performance of the PRIMARY score and evaluate its added diagnostic value to MRI triage in detecting csPCa. PATIENTS AND METHODS: This retrospective cohort study included 431 men who underwent both 68 Ga-PSMA PET/CT and MRI before biopsy. Performance was assessed using the area under the receiver operating characteristic curve and the decision curve analysis. The PRIMARY score + MRI was considered positive for either PRIMARY score 3-5 or Prostate Imaging Reporting and Data System (PI-RADS) 4/5. RESULTS: The prevalence of csPCa was 51.7% (223/431). The area under the receiver operating characteristic curve of the 5-level PRIMARY score for csPCa was significantly higher than that of MRI (0.873 vs 0.786, P < 0.001). For the entire group, sensitivity, specificity, positive predictive value, and negative predictive value of the PRIMARY score were 90.6%, 61.1%, 71.4%, and 85.8%, respectively, which outperformed 87.9%, 49.0%, 64.9%, and 79.1% of PI-RADS on MRI. The PRIAMRY score + MRI improved sensitivity (96.0% vs 87.9%, P < 0.001) and negative predictive value (91.5% vs 79.1%, P < 0.001) without compromising specificity and positive predictive value compared with MRI alone. This combined approach avoided 24.6% (106/431) of unnecessary biopsies, while missing 4.0% (9/223) of csPCa cases. The addition of the PRIMARY score in men with PI-RADS 1-3 showed a net benefit, but not in men with PI-RADS 4/5. CONCLUSIONS: The PRIMARY score was superior to MRI in detecting csPCa, and its added diagnostic value was in men with negative or equivocal MRI results. The PRIMARY score + MRI improved negative predictive value and sensitivity for csPCa compared with MRI alone. Further prospective trials will validate whether men with clinical suspicion of csPCa but negative PRIMARY score + MRI can safely avoid unnecessary biopsies.

Injectable hydrogel with selenium nanoparticles delivery for sustained glutathione peroxidase activation and enhanced osteoarthritis therapeutics.

Reactive oxygen burst in articular chondrocytes is a major contributor to osteoarthritis progression. Although selenium is indispensable role in the antioxidant process, the narrow therapeutic window, delicate toxicity margins, and lack of an efficient delivery system have hindered its translation to clinical applications. Herein, transcriptomic and biochemical analyses revealed that osteoarthritis was associated with selenium metabolic abnormality. A novel injectable hydrogel to deliver selenium nanoparticles (SeNPs) was proposed to intervene selenoprotein expression for osteoarthritis treatment. The hydrogels based on oxidized hyaluronic acid (OHA) cross-linked with hyaluronic acid-adipic acid dihydrazide (HA-ADH) was formulated to load SeNPs through a Schiff base reaction. The hydrogels were further incorporated with SeNPs, which exhibited minimal toxicity, mechanical properties, self-healing capability, and sustained drug release. Encapsulated with SeNPs, the hydrogels facilitated cartilage repair through synergetic effects of scavenging reactive oxygen species (ROS) and depressing apoptosis. Mechanistically, the hydrogel restored redox homeostasis by targeting glutathione peroxidase-1 (GPX1). Therapeutic outcomes of the SeNPs-laden hydrogel were demonstrated in an osteoarthritis rat model created by destabilization of the medial meniscus, including cartilage protection, subchondral bone sclerosis improvement, inflammation attenuation, and pain relief were demonstrated. These results highlight therapeutic potential of OHA/HA-ADH@SeNPs hydrogels, providing fundamental insights into remedying selenium imbalance for osteoarthritis biomaterial development.

Head-to-Head Comparison of 68Ga-PSMA-11 with 68Ga-P137 in Patients with Suspected Prostate Cancer.

P137 is a novel oxalyldiaminopropionic acid-urea-based prostate-specific membrane antigen (PSMA) targeting agent. This study compared the uptake patterns of 68Ga-P137 and the FDA-approved PET tracer 68Ga-PSMA-11 for diagnosing prostate cancer (PCa). Sixteen patients suspected of PCa were scanned by 68Ga-PSMA-11 and 68Ga-P137 PET/CT, respectively, followed by prospective analysis. The tumor-to-background ratio was calculated using normal prostate tissue, blood pool, muscle, and urine as backgrounds. Pathology or follow-up results were used to analyze uptake patterns of benign/malignant lesions and various organs. Thirteen patients were diagnosed with PCa and three with benign prostate diseases (BPD). The number and location of primary lesions, lymph node metastasis (LNM) (n = 25), bone metastasis (n = 30), and liver metastasis (n = 3) detected by the two tracers were identical. Maximum standardized uptake value (SUVmax), tumor/normal prostate ratio, as well as semiquantitative miPSMA-ES and PRIMARY diagnostic scores (P all >0.05) showed similar uptake levels of primary lesions between 68Ga-P137 and 68Ga-PSMA-11. Compared to 68Ga-P137, the SUVmax of 68Ga-PSMA-11 was significantly higher for bone metastasis, LNM, and liver metastasis (14.9 ± 7.2 vs 9.1 ± 4.4, 14.4 ± 5.0 vs 7.5 ± 2.4, 13.9 ± 2.0 vs 8.8 ± 2.4, P all <0.05). One-hour postinjection, SUVmax of the duodenum (9.4 ± 2.1 vs 16.2 ± 6.1), kidney (19.4 ± 4.3 vs 45.6 ± 20.9), and urine (14.1 ± 7.1 vs 42.1 ± 25.9) were significantly lower for 68Ga-P137 than for 68Ga-PSMA-11 (P all <0.05), whereas the radioactivity accumulation of blood pool and muscle (3.9 ± 0.5 vs 1.6 ± 0.4, 1.0 ± 0.1 vs 0.6 ± 0.1, P all <0.05) of 68Ga-P137 was significantly higher than 68Ga-PSMA-11. The uptake level of 68Ga-P137 has no significant difference from that of 68Ga-PSMA-11 in prostate primary lesions, and their imaging performances are visually equivalent for both primary and metastatic lesions, despite a higher blood pool and muscle background and a lower uptake in metastatic lesions. Due to the lower urine excretion of 68Ga-P137, primary prostate lesions near the urine can potentially be displayed clearer than 68Ga-PSMA-11.

First-in-Humans PET Imaging of KRASG12C Mutation Status in Non-Small Cell Lung and Colorectal Cancer Patients Using [18F]PFPMD.

Kirsten rat sarcoma (KRAS) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRASG12C oncoprotein-targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the KRASG12C 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: KRASG12C mutation; A549: non-KRASG12C 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 KRASG12C mutation underwent [18F]PFPMD and [18F]FDG PET/CT imaging. The SUVmax of tumor uptake of [18F]PFPMD was measured and compared between patients with and without the KRASG12C 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 KRASG12C 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 KRASG12C mutation tumors was significantly higher than that in non-KRASG12C mutation tumors (SUVmax: 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 KRASG12C mutation status in NSCLC and CRC patients.