Differentiating lung neuroendocrine neoplasms from tumor-like infection using CT in patients with ectopic ACTH syndrome.

OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) are the most frequent cause of ectopic adrenocorticotropic hormone syndrome (EAS); lung infection is common in EAS. An imaging finding of infection in EAS patients can mimic NENs. This retrospective study investigated EAS-associated pulmonary imaging indicators. METHODS: Forty-five pulmonary NENs and 27 tumor-like infections from 59 EAS patients (45 NEN and 14 infection patients) were included. Clinical manifestations, CT features, 18F-FDG, or 68Ga-DOTATATE-PET/CT images and pathological results were collected. RESULTS: High-sensitivity C-reactive protein (p < 0.001) and expectoration occurrence (p = 0.04) were higher, and finger oxygen saturation (p = 0.01) was lower in the infection group than the NENs group. Higher-grade NENs were underrepresented in our cohort. Pulmonary NENs were solitary primary tumors, 80% of which were peripheral tumors. Overlying vessel sign and airway involvement were more frequent in the NENs group (p < 0.001). Multifocal (p = 0.001) and peripheral (p = 0.02) lesions, cavity (p < 0.001), spiculation (p = 0.01), pleural retraction (p < 0.001), connection to pulmonary veins (p = 0.02), and distal atelectasis or inflammatory exudation (p = 0.001) were more frequent in the infection group. The median CT value increment between the non-contrast and arterial phases was significantly higher in NENs lesions (p < 0.001). Receiver operating characteristic curve analysis indicated a moderate predictive ability at 48.3 HU of delta CT value (sensitivity, 95.0%; specificity, 54.1%). CONCLUSION: Chest CT scans are valuable for localizing and characterizing pulmonary lesions in rare EAS, thereby enabling prompt differential diagnosis and treatment. CRITICAL RELEVANCE STATEMENT: Thin-slice CT images are valuable for the localization and identification of pulmonary ectopic adrenocorticotropic hormone syndrome lesions, leading to prompt differential diagnosis and effective treatment. KEY POINTS: Lung tumor-like infections can mimic neuroendocrine neoplasms (NENs) in ectopic adrenocorticotropic hormone syndrome (EAS) patients. NENs are solitary lesions, whereas infections are multiple peripheral pseudotumors each with identifying imaging findings. Typical CT signs aid in localization and creating an appropriate differential diagnosis.

Direct Optical Patterning of Metal-Organic Frameworks via Photoacid-Induced Etching.

Metal-organic frameworks (MOFs) are a class of porous materials constructed from organic linkers and inorganic building blocks. Coordinative competition labilizes some MOFs under harsh chemical conditions because of their weak bonding. However, instability is not always a negative property of a material. In this study, we demonstrated the use of the acidic lability of MOFs for direct optical patterning. The controllable acid release from the photoacid generator at the exposed area causes bond cleavage between the linkers and metal ions/clusters, leading to solubility changes and pattern formation after development. This process avoids redundant steps and possible contamination in traditional photolithography, while maintaining the original properties of patterned MOFs. The preserved porosity and crystallinity promoted the development of MOFs for gas sensors and solid displays.

Synthesis, preclinical evaluation and pilot clinical translation of [68Ga]Ga-PMD22, a novel nanobody PET probe targeting CLDN18.2 of gastrointestinal cancer.

PURPOSE: Claudin18.2 (CLDN18.2) is a novel target for diagnosis and therapy of gastrointestinal cancer. This study aimed to evaluate the safety and feasibility of a novel CLDN18.2-targeted nanobody, PMD22, labeled with gallium-68 ([68Ga]Ga), for detecting CLDN18.2 expression in patients with gastrointestinal cancer using PET/CT imaging. METHODS: [68Ga]Ga-PMD22 was synthesized based on the nanobody, and its cell binding properties were assayed. Preclinical pharmacokinetics were determined in CLDN18.2-positive xenografts using microPET/CT. Effective dosimetry of [68Ga]Ga-PMD22 was evaluated in 5 gastrointestinal cancer patients, and PET/CT imaging of [68Ga]Ga-PMD22 and [18F]FDG were performed head-to-head in 16 gastrointestinal cancer patients. Pathological tissues were obtained for CLDN18.2 immunohistochemical (IHC) staining and comparative analysis with PET/CT findings. RESULTS: Cell binding assay showed that [68Ga]Ga-PMD22 had a higher binding ability to AGSCLDN18.2 and BGC823CLDN18.2 cells than to AGS and BGC823 cells (p < 0.001). MicroPET/CT images showed that [68Ga]Ga-PMD22 rapidly accumulated in AGSCLDN18.2 and BGC823CLDN18.2 tumors, and high contrast tumor to background imaging was clearly observed. In the pilot study, the effective dose of [68Ga]Ga-PMD22 was 1.68E-02 ± 1.45E-02 mSv/MBq, and the CLDN18.2 IHC staining result was highly correlated with the SUVmax/BKGstomach of [68Ga]Ga-PMD22 (rs = 0.848, p < 0.01). CONCLUSION: A novel [68Ga]Ga-labeled nanobody probe targeting CLDN18.2, [68Ga]Ga-PMD22, was established and preliminarily proved to be safe and effective in revealing CLDN18.2-positive gastrointestinal cancer, providing a basis for the clinical translation of the agent. CLINICAL TRIAL REGISTRATION: This study was registered on the ClinicalTrials.gov (NCT05937919).

Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

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.

Hyperuricemia as an independent risk factor for achilles tendon rupture in male: a case-control study.

OBJECTIVE: To study the correlation between achilles tendon rupture (ATR) and hyperuricemia, also verify the known risk factors for ATR. METHODS: A retrospective review of 488 subjects was performed (182 with Achilles tendon rupture, 306 controls with ankle sprains). Demographic variables and risk factors for rupture were tabulated and compared. The baseline data and related indicators were compared, and the risk factors of ATR were analyzed by constructing a binary logistic regression model. RESULTS: Univariate logistic analysis showed that BMI, smoking, and hyperuricemia were risk factors for the development of ATR (OR = 1.65, 95%CI 1.13-2.42, P = 0.01; OR = 1.47, 95%CI 1.00-2.24, P < 0.05; OR = 2.85, 95%CI 1.84-4.42, P < 0.01). Multifactorial analysis showed that BMI ≥ 25 kg/m2, smoking, and hyperuricemia were independent risk factors for the development of ATR (OR = 1.66, 95%CI 1.11-2.49, P = 0.01; OR = 2.15, 95%CI 1.28-3.60, P < 0.01; OR = 3.06, 95%CI 1.92-4.89, P < 0.01). Among the blood biochemical indicators, total cholesterol (TC) and uric acid (UA) were independent risk factors for the occurrence of ATR (OR = 1.54, 95% CI 1.12-2.12, P = 0.01; OR = 1.01, 95% CI 1.01-1.01, P < 0.01). CONCLUSION: Our study confirmed that, as in previous results, higher BMI, smoking, and total cholesterol are risk factors for ATR, Hyperuricemia may contribute to the development of ATR, and adjunctive tests for TC and UA in the blood biochemistry may be helpful in predicting the risk of ATR.

Comparison of novel PSMA-targeting [177Lu]Lu-P17-087 with its albumin binding derivative [177Lu]Lu-P17-088 in metastatic castration-resistant prostate cancer patients: a first-in-human study.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for diagnosis and radioligand therapy (RLT) of prostate cancer. Two novel PSMA-targeting radionuclide therapy agents, [177Lu]Lu-P17-087, and its albumin binder modified derivative, [177Lu]Lu-P17-088, were evaluated in metastatic castration-resistant prostate cancer (mCRPC) patients. The primary endpoint was dosimetry evaluation, the second endpoint was radiation toxicity assessment (CTCAE 5.0) and PSA response (PCWG3). METHODS: Patients with PSMA-positive tumors were enrolled after [68Ga]Ga-PSMA-11 PET/CT scan. Five mCRPC patients received [177Lu]Lu-P17-087 and four other patients received [177Lu]Lu-P17-088 (1.2 GBq/patient). Multiple whole body planar scintigraphy was performed at 1.5, 4, 24, 48, 72, 120 and 168 h after injection and one SPECT/CT imaging was performed at 24 h post-injection for each patient. Dosimetry evaluation was compared in both patient groups. RESULTS: Patients showed no major clinical side-effects under this low dose treatment. As expected [177Lu]Lu-P17-088 with longer blood circulation (due to its albumin binding) exhibited higher effective doses than [177Lu]Lu-P17-087 (0.151 ± 0.036 vs. 0.056 ± 0.019 mGy/MBq, P = 0.001). Similarly, red marrow received 0.119 ± 0.068 and 0.048 ± 0.020 mGy/MBq, while kidney doses were 0.119 ± 0.068 and 0.046 ± 0.022 mGy/MBq, respectively. [177Lu]Lu-P17-087 demonstrated excellent tumor uptake and faster kinetics; while [177Lu]Lu-P17-088 displayed a slower washout and higher average dose (7.75 ± 4.18 vs. 4.72 ± 2.29 mGy/MBq, P = 0.018). After administration of [177Lu]Lu-P17-087 and [177Lu]Lu-P17-088, 3/5 and 3/4 patients showed reducing PSA values, respectively. CONCLUSION: [177Lu]Lu-P17-088 and [177Lu]Lu-P17-087 displayed different pharmacokinetics but excellent PSMA-targeting dose delivery in mCRPC patients. These two agents are promising RLT agents for personalized treatment of mCRPC. Further studies with increased dose and frequency of RLT are warranted to evaluate the potential therapeutic efficacy. TRIAL REGISTRATION: 177Lu-P17-087/177Lu-P17-088 in Patients with Metastatic Castration-resistant Prostate Cancer (NCT05603559, Registered at 25 October, 2022). URL OF REGISTRY: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05603559 .

Inhibitory Impact Of Cinobufagin In Triple-Negative Breast Cancer Metastasis: Involvements Of Macrophage Reprogramming Through Upregulated MME and Inactivated FAK/STAT3 Signaling.

BACKGROUND: Cinobufagin (CBG), a key bioactive component in cinobufacini, exhibits antitumor properties. This study explores CBG's impact on triple-negative breast cancer (TNBC) metastasis and elucidates the underpinning mechanism. METHODS: Murine xenograft and orthotopic metastatic TNBC models were generated and treated with CBG. The burden of metastatic tumor in the mouse lung, the epithelial to mesenchymal transition (EMT) markers, and macrophage polarization markers within the tumors were examined. The phenotype of tumor-associated macrophages (TAMs) and mobility of TNBCs in vitro in a macrophage-TNBC cell coculture system were analyzed. Physiological targets of CBG were identified by bioinformatics analyses. RESULTS: CBG treatment significantly alleviated lung tumor burden and EMT activity. It triggered an M2-to-M1 shift in TAMs, resulting in decreased TNBC cell migration, invasion, and EMT in vitro. CBG upregulated membrane metalloendopeptidase (MME) expression, suppressing FAK and STAT3 phosphorylation. Silencing of MME, either in mice or TAMs, counteracted CBG effects, reinstating M2 TAM predominance and enhancing TNBC cell metastasis. Cotreatment with Defactinib, a FAK antagonist, reversed M2 TAM polarization and TNBC cell metastasis. Notably, MME silencing in TNBC cells had no impact on CBG-suppressed malignant properties, indicating MME's indirect involvement in TNBC cell behavior through TAM mediation. CONCLUSION: This study unveils CBG's ability to enhance MME expression, deactivate FAK/STAT3 signaling, and inhibit TNBC metastasis by suppressing M2-skewed macrophages.

Synthesis, preclinical, and initial clinical evaluation of integrin αVß3 and gastrin-releasing peptide receptor (GRPR) dual-targeting radiotracer [68Ga]Ga-RGD-RM26-03.

Integrin receptor αvß3 and gastrin-releasing peptide receptor (GRPR) expression of tumors could be detected using PET imaging with radiolabeled Arg-Gly-Asp (RGD) and the antagonistic bombesin analog RM26, respectively. The purpose of this study was to investigate the dual receptor-targeting property of the heterodimer RGD-RM26-03 (denoted as LNC1015), demonstrate the tumor diagnostic value of [68Ga]Ga-LNC1015 in preclinical experiments, and evaluate its preliminary clinical feasibility. METHODS: LNC1015 was designed and synthesized by linking cyclic RGD and the RM26 peptide. Preclinical pharmacokinetics were detected in a PC3 xenograft model using microPET and biodistribution studies. The clinical feasibility of [68Ga]Ga-LNC1015 PET/CT was performed in patients with breast cancer, and the results were compared with those of 18F-fluorodeoxyglucose (FDG). RESULTS: [68Ga]Ga-LNC1015 had good stability in saline for at least 2 h, and favorable binding affinity and specificity were demonstrated in vitro and in vivo. The tumor uptake and retention of [68Ga]Ga-LNC1015 during PET imaging were improved compared with its monomeric counterparts [68Ga]Ga-RGD and [68Ga]Ga-RM26 at all the time points examined. In our initial clinical studies, the tumor uptake and tumor-to-background ratio (TBR) of primary and metastatic lesions in [68Ga]Ga-LNC1015 PET/CT were significantly higher than those in [18F]FDG PET/CT, resulting in high lesion detection rate and tumor delineation. CONCLUSION: The dual targeting radiotracer [68Ga]Ga-LNC1015 showed significantly improved tumor uptake and retention, as well as lower liver uptake than [68Ga]Ga-RGD and [68Ga]Ga-RM26 monomer. The first-in-human study showed high TBRs in patients, suggesting favorable pharmacokinetics and high clinical feasibility for PET/CT imaging of cancer.

Pharmacogenomics of poor drug metabolism in greyhounds: Canine P450 oxidoreductase genetic variation, breed heterogeneity, and functional characterization.

Greyhounds metabolize cytochrome P450 (CYP) 2B11 substrates more slowly than other dog breeds. However, CYP2B11 gene variants associated with decreased CYP2B11 expression do not fully explain reduced CYP2B11 activity in this breed. P450 oxidoreductase (POR) is an essential redox partner for all CYPs. POR protein variants can enhance or repress CYP enzyme function in a CYP isoform and substrate dependent manner. The study objectives were to identify POR protein variants in greyhounds and determine their effect on coexpressed CYP2B11 and CYP2D15 enzyme function. Gene sequencing identified two missense variants (Glu315Gln and Asp570Glu) forming four alleles, POR-H1 (reference), POR-H2 (570Glu), POR-H3 (315Gln, 570Glu) and POR-H4 (315Gln). Out of 68 dog breeds surveyed, POR-H2 was widely distributed across multiple breeds, while POR-H3 was largely restricted to greyhounds and Scottish deerhounds (35% allele frequencies), and POR-H4 was rare. Three-dimensional protein structure modelling indicated significant effects of Glu315Gln (but not Asp570Glu) on protein flexibility through loss of a salt bridge between Glu315 and Arg519. Recombinant POR-H1 (reference) and each POR variant (H2-H4) were expressed alone or with CYP2B11 or CYP2D15 in insect cells. No substantial effects on POR protein expression or enzyme activity (cytochrome c reduction) were observed for any POR variant (versus POR-H1) when expressed alone or with CYP2B11 or CYP2D15. Furthermore, there were no effects on CYP2B11 or CYP2D15 protein expression, or on CYP2D15 enzyme kinetics by any POR variant (versus POR-H1). However, Vmax values for 7-benzyloxyresorufin, propofol and bupropion oxidation by CYP2B11 were significantly reduced by coexpression with POR-H3 (by 34-37%) and POR-H4 (by 65-72%) compared with POR-H1. Km values were unaffected. Our results indicate that the Glu315Gln mutation (common to POR-H3 and POR-H4) reduces CYP2B11 enzyme function without affecting at least one other major canine hepatic P450 (CYP2D15). Additional in vivo studies are warranted to confirm these findings.

Lower-grade gliomas surgery guided by GRPR-targeting PET/NIR dual-modality image probe: a prospective and single-arm clinical trial.

Purpose: Lower-grade gliomas (LGGs) are a group of infiltrative growing glial brain tumors characterized by intricate intratumoral heterogeneity and subtle visual appearance differences from non-tumor tissue, which can lead to errors in pathologic tissue sampling. Although 5-ALA fluorescence has been an essential method for visualizing gliomas during surgery, its effectiveness is limited in the case of LGGs due to low sensitivity. Therefore, we developed a novel PET/NIR dual-modality image probe targeting gastrin-releasing peptide receptor (GRPR) in glioma cells to enhance tumor visualization and improve the accuracy of sampling. Methods: A prospective, non-randomized, single-center feasibility clinical trial (NCT03407781) was conducted in the referral center from October 21, 2016, to August 17, 2018. Consecutive enrollment included patients suspected of having LGGs and considered suitable candidates for surgical removal. Group 1 comprised ten patients who underwent preoperative 68Ga-IRDye800CW-BBN PET/MRI assessment followed by intraoperative fluorescence-guided surgery. Group 2 included 42 patients who underwent IRDye800CW-BBN fluorescence-guided surgery. The primary endpoints were the predictive value of preoperative PET imaging for intraoperative fluorescence and the sensitivity and specificity of fluorescence-guided sampling. Results: Thirty-nine patients were included in the in-depth analysis of endpoints, with 25 (64.1%) exhibiting visible fluorescence, while 14 (35.9%) did not. The preoperative positive PET uptake exhibited a greater accuracy in predicting intraoperative fluorescence compared to MRI enhancement (100% [10/10] vs. 87.2% [34/39]). A total of 125 samples were harvested during surgery. Compared with pathology, subjective fluorescence intensity showed a sensitivity of 88.6% and a specificity of 88.2% in identifying WHO grade III samples. For WHO grade II samples, the sensitivity and specificity of fluorescence were 54.7% and 88.2%, respectively. Conclusion: This study has demonstrated the feasibility of the novel dual-modality imaging technique for integrated pre- and intraoperative targeted imaging via the same molecular receptor in surgeries for LGGs. The PET/NIR dual-modality probe exhibits promise for preoperative surgical planning in fluorescence-guided surgery and provides greater accuracy in guiding tumor sampling compared to 5-ALA in patients with LGGs.

Long-term tadalafil once daily in Chinese men with erectile dysfunction: a 2-year final analysis of a post-marketing, multicenter, randomized, open-label trial.

The long-term safety and effectiveness of once-daily tadalafil is crucial, but limited data are available in Chinese patients with erectile dysfunction (ED). In this post-marketing, multicenter, randomized, open-label trial with 2-year follow-up, 635 ED cases were randomized to receive daily oral tadalafil 2.5 mg or 5 mg for 3 months, of whom 580 continued once-daily tadalafil 5 mg for 21 months. Treatment-emergent adverse events in the 12-month and 24-month period were similar, with the most common being viral upper respiratory tract infection, upper respiratory tract infection, and headache. Significant improvement from baseline in the International Index of Erectile Function-Erectile Function (IIEF-EF) score was detected at month 12 (least squares mean [LSM] change: 7.9, 95% confidence interval [CI]: 7.5-8.4, P < 0.001) and was maintained to month 24 (LSM change: 8.6, 95% CI: 8.1-9.0, P < 0.001). The proportions of patients regaining normal erectile function (IIEF-EF score ≥26) were 43.7% and 48.0% at months 12 and 24, respectively. Global Assessment Questionnaire results showed improved erection function in 97.5% of patients and improved ability to engage in sexual activity in 95.9% of patients at month 12; these values were 96.1% and 95.0% at month 24, respectively. The quality of sexual life score based on the Sexual Life Quality Questionnaire (SLQQ) was increased by 52.2% at month 12 and by 55.3% at month 24 (both P < 0.001). The treatment satisfaction score determined by SLQQ (mean ± standard deviation) was 62.4 ± 21.0 at month 12 versus 65.9 ± 20.2 at month 24. Two-year daily application of tadalafil 5 mg in Chinese men with ED showed a favorable safety profile and durable improvement in sexual performance and satisfaction.

Cannabidiol and cannabidiolic acid: Preliminary in vitro evaluation of metabolism and drug-drug interactions involving canine cytochrome P-450, UDP-glucuronosyltransferase, and P-glycoprotein.

Phytocannabinoid-rich hemp extracts containing cannabidiol (CBD) and cannabidiolic acid (CBDA) are increasingly being used to treat various disorders in dogs. The objectives of this study were to obtain preliminary information regarding the in vitro metabolism of these compounds and their capacity to inhibit canine cytochrome P450 (CYP)-mediated drug metabolism and canine P-glycoprotein-mediated transport. Pure CBD and CBDA, and hemp extracts enriched for CBD and for CBDA were evaluated. Substrate depletion assays using pooled dog liver microsomes showed CYP cofactor-dependent depletion of CBD (but not CBDA) and UDP-glucuronosytransferase cofactor-dependent depletion of CBDA (but not CBD) indicating major roles for CYP and UDP-glucuronosytransferase in the metabolism of these phytocannabinoids, respectively. Further studies using recombinant canine CYPs demonstrated substantial CBD depletion by the major hepatic P450 enzymes CYP1A2 and CYP2C21. These results were confirmed by showing increased CBD depletion by liver microsomes from dogs treated with a known CYP1A2 inducer (ß-naphthoflavone) and with a known CYP2C21 inducer (phenobarbital). Cannabinoid-drug inhibition experiments showed inhibition (IC50 = 4.6-8.1 µM) of tramadol metabolism via CYP2B11-mediated N-demethylation (CBD and CBDA) and CYP2D15-mediated O-demethylation (CBDA only) by dog liver microsomes. CBD and CBDA did not inhibit CYP3A12-mediated midazolam 1'-hydroxylation (IC50 > 10 µM). CBD and CBDA were not substrates or competitive inhibitors of canine P-glycoprotein. Results for cannabinoid-enriched hemp extracts were identical to those for pure cannabinoids. These in vitro studies indicate the potential for cannabinoid-drug interactions involving certain CYPs (but not P-glycoprotein). Confirmatory in vivo studies are warranted.

A phase 1 trial to determine the maximum tolerated dose and patient-specific dosimetry of [177Lu]Lu-LNC1003 in patients with metastatic castration-resistant prostate cancer.

PURPOSE: This translational study aimed to determine the maximum tolerated dose (MTD), safety, dosimetry, and therapeutic efficacy of 177Lu-PSMA-EB-01 (denoted as [177Lu]Lu-LNC1003) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A total of 13 patients with mCRPC were recruited in this study. A standard 3 + 3 dose escalation protocol was performed. The following dose levels were ultimately evaluated: 1.11, 1.85, and 2.59 GBq/cycle. Patients received [177Lu]Lu-LNC1003 therapy for up to two cycles at a 6-week interval. RESULTS: Patients received fractionated doses of [177Lu]Lu-LNC1003 ranging from 1.11 to 2.59 GBq per cycle. Myelosuppression was dose-limiting at 2.59 GBq, and 1.85 GBq was determined to be the MTD. The total-body effective dose for 177Lu-LNC1003 was 0.35 ± 0.05 mSv/MBq. The salivary glands were found to receive the highest estimated radiation dose, which was calculated to be 3.61 ± 2.83 mSv/MBq. The effective doses of kidneys and red bone marrow were 1.88 ± 0.35 and 0.22 ± 0.04 mSv/MBq, respectively. The tumor mean absorbed doses for bone and lymph node metastases were 8.52 and 9.51 mSv/MBq. Following the first treatment cycle, PSA decline was observed in 1 (33.3%), 4 (66.7%), and 2 (50.0%) patients at dose levels 1 (1.11 GBq), 2 (1.85 GBq), and 3 (2.59 GBq), respectively. Compared with the baseline serum PSA value, 1 (33.3%) at dose level 1 and 4 (66.6%) patients at dose level 2, presented a PSA decline after the second treatment cycle. CONCLUSION: This phase 1 trial revealed that the MTD of [177Lu]Lu-LNC1003 is 1.85 GBq. The treatment with multiple cycles at the dose of 1.11 GBq /cycle and 1.85 GBq /cycle was well tolerated. [177Lu]Lu-LNC1003 has higher tumor effective doses in bone and lymph nodes metastases while the absorbed dose in the red bone marrow should be closely monitored in future treatment studies with higher doses and multiple cycles. The frequency of administration also needs to be further explored to assess the efficacy and side effects of [177Lu]Lu-LNC1003 treatment. TRIAL REGISTRATION: 177Lu-PSMA-EB-01 in patients with metastatic castration-resistant prostate cancer (NCT05613738, Registered 14 November 2022). URL of registry https://classic. CLINICALTRIALS: gov/ct2/show/NCT05613738.

68 Ga-FAPI-04 PET/CT in Assessment of Fibroblast Activation in Keloids : A Prospective Pilot Study.

PURPOSE: Keloids are benign fibroproliferative disorders characterized by the massive proliferation of fibroblasts. Fibroblast activation plays a key role in the invasive growth of keloids. Therefore, a prospective pilot study was conducted to explore the value of 68 Ga-FAPI-04 PET/CT in the assessment of keloids activity. PATIENTS AND METHODS: Twenty-five patients with keloid were enrolled to conduct 68 Ga-FAPI-04 PET/CT. All patients accepted surgery to remove part of the lesions within 1 week. SUV mean and SUV max were measured for semiquantitative analysis and compared with the Vancouver Scar Scale, Laser Speckle Contrast Imaging, pathology, and immunohistochemical stains. RESULTS: A total of 123 lesions were detected in 25 patients, most of which were distributed in the anterior chest wall. The 68 Ga-FAPI-04 uptake was significantly different at different sites ( P < 0.0001). There was uptake heterogeneity within the keloid lesions, and a significant difference was found between the edge and center of some large lesions. The SUV max of 68 Ga-FAPI-04 showed significantly correlation with the Vancouver Scar Scale ( r = 0.565, P < 0.0001) moderately and the Laser Speckle Contrast Imaging parameters mildly. The SUV max of 68 Ga-FAPI-04 had a moderate correlation with FAPI expression ( r = 0.520, P = 0.022). Moreover, collagen, fibroblast activator protein, and Ki-67 expression were found higher at the edges of keloid tissue than in the center. CONCLUSIONS: 68 Ga-FAPI-04 PET/CT can reflect the distribution characteristics of activated fibroblasts in keloid tissue and may provide a novel method for keloid evaluation for further fibroblast-related therapies.

Blend U-Net: Redesigning Skip Connections to Obtain Multiscale Features for Lung CT Images Segmentation.

BACKGROUND: Lung cancer is a pervasive and persistent issue worldwide, with the highest morbidity and mortality among all cancers for many years. In the medical field, computer tomography (CT) images of the lungs are currently recognized as the best way to help doctors detect lung nodules and thus diagnose lung cancer. U-Net is a deep learning network with an encoder-decoder structure, which is extensively employed for medical image segmentation and has derived many improved versions. However, these advancements do not utilize various feature information from all scales, and there is still room for future enhancement. METHODS: In this study, we proposed a new model called Blend U-Net, which incorporates nested structures, redesigned long and short skip connections, and deep supervisions. The nested structures and the long and short skip connections combined characteristic information of different levels from feature maps in all scales, while the deep supervision learning hierarchical representations from all-scale concatenated feature maps. Additionally, we employed a mixed loss function to obtain more accurate results. RESULTS: We evaluated the performance of the Blend U-Net against other architectures on the publicly available Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI) dataset. Moreover, the accuracy of the segmentation was verified by using the dice coefficient. Blend U-Net with a boost of 0.83 points produced the best outcome in a number of baselines. CONCLUSION: Based on the results, our method achieves superior performance in terms of dice coefficient compared to other methods and demonstrates greater proficiency in segmenting lung nodules of varying sizes.

Imaging of Angiogenesis in White Matter Hyperintensities.

Background White matter hyperintensities (WMHs) are areas of increased signal intensity on T2-weighted magnetic resonance imaging (MRI). WMH penumbra may be a potential target for early intervention in WMHs. We explored the relationship between angiogenesis and WMH penumbra in patients with WMHs. Methods and Results Twenty-one patients with confluent WMHs of Fazekas grade ≥2 were included. All the participants underwent 68Ga-NOTA-PRGD2 positron emission tomography/magnetic resonance imaging. WMH penumbra was analyzed with masks created for the WMH and 7 normal-appearing white matter layers; each layer was dilated away from the WMH by 2 mm. Angiogenesis array and ELISA were used to detect the serum levels of angiogenic factors, inflammatory factors, HIF-1 alpha, and S100B. Fourteen patients with increased 68Ga-NOTA-PRGD2 maximum standardized uptake (>0.17) were classified into group 2. Seven patients with maximum standardized uptake ≤0.17 were classified as group 1. WMH volume and serum levels of integrin αvß3, vascular endothelial growth factor receptor 22, and interleukin-1ß tended to be higher in group 2 than in group 1. In group 2, 68Ga-NOTA-PRGD2 uptake was significantly increased at the border between the WMH and normal-appearing white matter than in WMHs (P=0.004). The structure penumbra, defined by fractional anisotropy, was wider in group 2 (8 mm) than in group 1 (2 mm). The cerebral blood flow penumbra was 12 mm in both groups. Angiogenesis showed a correlation with reduced cerebral blood flow and microstructure integrity. Conclusions Our study provides evidence that angiogenesis occurs in the WMH penumbra. Further studies are warranted to verify the effect of angiogenesis on WMH growth.

Dual targeting PET tracer [68Ga]Ga-FAPI-RGD in patients with lung neoplasms: a pilot exploratory study.

Rationale: Early discovery, accurate diagnosis, and staging of lung cancer is essential for patients to receive appropriate treatment. PET/CT has become increasingly recognized as a valuable imaging modality for these patients, but there remains room for improvement in PET tracers. We aimed to evaluate the feasibility of using [68Ga]Ga-FAPI-RGD, a dual-targeting heterodimeric PET tracer that recognizes both fibroblast activation protein (FAP) and integrin αvß3 for detecting lung neoplasms, by comparing it with [18F]FDG and single-targeting tracers [68Ga]Ga-RGD and [68Ga]Ga-FAPI. Methods: This was a pilot exploratory study of patients with suspected lung malignancies. All 51 participants underwent [68Ga]Ga-FAPI-RGD PET/CT, of which: 9 participants received dynamic scans, 44 participants also underwent [18F]FDG PET/CT scan within two weeks, 9 participants underwent [68Ga]Ga-FAPI PET/CT scan and 10 participants underwent [68Ga]Ga-RGD PET/CT scan. The final diagnosis was made based on histopathological analyses and clinical follow-up reports. Results: Among those who underwent dynamic scans, the uptake of pulmonary lesions increased over time. The optimal timepoint for a PET/CT scan was identified to be 2 h post-injection. [68Ga]Ga-FAPI-RGD had a higher detection rate of primary lesions than [18F]FDG (91.4% vs. 77.1%, p < 0.05), higher tumor uptake (SUVmax, 6.9 ± 5.3 vs. 5.3 ± 5.4, p < 0.001) and higher tumor-to-background ratio (10.0 ± 8.4 vs. 9.0 ± 9.1, p < 0.05), demonstrated better accuracy in mediastinal lymph node evaluation (99.7% vs. 90.9%, p < 0.001), and identified more metastases (254 vs. 220). There was also a significant difference between the uptake of [68Ga]Ga-FAPI-RGD and [68Ga]Ga-RGD of primary lesions (SUVmax, 5.8 ± 4.4 vs. 2.3 ± 1.3, p < 0.001). Conclusion: In our small scale cohort study, [68Ga]Ga-FAPI-RGD PET/CT gave a higher primary tumor detection rate, higher tracer uptake, and improved detection of metastases compared with [18F]FDG PET/CT, and [68Ga]Ga-FAPI-RGD also had advantages over [68Ga]Ga-RGD and was non-inferior to [68Ga]Ga-FAPI. We thus provide proof-of-concept for using [68Ga]Ga-FAPI-RGD PET/CT for diagnosing lung cancer. With the stated advantages, the dual-targeting FAPI-RGD should also be explored for therapeutic use in future studies.

The value of 18F-FDG PET/CT in the systemic evaluation of patients with Rosai-Dorfman disease: a retrospective study and literature review.

BACKGROUND: Rosai-Dorfman disease (RDD) is a rare form of non-Langerhans cell histiocytic disease. The aim of this study was to review the characteristics of RDD using 18F-FDG PET/CT and determine its efficacy in the disease management. RESULTS: A total of 28 RDD patients underwent 33 18F-FDG PET/CT scans for systematic assessment and follow-up. The common involved sites included the lymph nodes (17, 60.7%), upper respiratory tract (11, 39.3%), and skin (9, 32.1%). Five patients had more lesions detected in PET/CT images than in CT and/or MRI, including inapparent nodules (n = 5) and bone destruction (n = 3). After thorough treatment evaluation using PET/CT, the treatment strategies of 14 patients (14/16, 87.5%) were changed. Five patients underwent PET/CT twice during follow-up and the SUVs were significantly decreased (15.3 ± 3.4 vs. 4.4 ± 1.0, p = 0.02), which demonstrated disease improvement. CONCLUSIONS: 18F-FDG PET/CT contributed to displaying the holistic characteristics of RDD, in particular during initial assessment, treatment strategy adjustment, or efficacy evaluation, and could compensate for some disadvantages of CT and MRI images.

A prospective head-to-head comparison of [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-11 PET/CT in patients with primary prostate cancer.

PURPOSE: We aimed to compare the diagnostic performance and biodistribution of two similar PET agents, [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-11, in the same group of primary prostate cancer (PCa) patients. METHODS: Fifty patients with untreated, histologically confirmed PCa by needle biopsy were enrolled. Each patient underwent [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-11 PET/CT within a week. In addition to visual analysis, the standardized uptake value (SUV) was measured for semiquantitative comparison and correlation analysis. RESULTS: [68Ga]Ga-P16-093 PET/CT detected more positive tumors than [68Ga]Ga-PSMA-11 PET/CT (202 vs. 190, P = 0.002), both for intraprostatic lesions (48 vs. 41, P = 0.016) and metastatic lesions (154 vs. 149, P = 0.125), especially for intraprostatic lesions in low- and intermediate-risk PCa patients (21/23 vs. 15/23, P = 0.031). Furthermore, [68Ga]Ga-P16-093 PET/CT exhibited a significantly higher SUVmax for most matched tumors (13.7 ± 10.2 vs. 11.4 ± 8.3, P < 0.001). For normal organs, [68Ga]Ga-P16-093 PET/CT showed significantly lower activity in the kidney (SUVmean: 20.1 ± 6.1 vs. 29.3 ± 9.1, P < 0.001) and urinary bladder (SUVmean: 6.5 ± 7.1 vs. 20.9 ± 17.4, P < 0.001), but displayed a higher uptake in the parotid gland (SUVmean: 8.7 ± 2.6 vs. 7.6 ± 2.1, P < 0.001), liver (SUVmean: 7.0 ± 1.9 vs. 3.7 ± 1.3, P < 0.001), and spleen (SUVmean: 8.2 ± 3.0 vs. 5.2 ± 2.2, P < 0.001) than [68Ga]Ga-PSMA-11 PET/CT. CONCLUSION: [68Ga]Ga-P16-093 PET/CT demonstrated higher tumor uptake and better tumor detectability than [68Ga]Ga-PSMA-11 PET/CT, especially in low- and intermediate-risk PCa patients, which indicated that [68Ga]Ga-P16-093 may serve as an alternative agent for detection of PCa. TRIAL REGISTRATION: 68Ga-P16-093 and 68Ga-PSMA-11 PET/CT Imaging in the Same Group of Primary Prostate Cancer Patients (NCT05324332, Registered 12 April 2022, retrospectively registered). URL OF REGISTRY: https://clinicaltrials.gov/ct2/show/NCT05324332 .