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Introduction: The ability of PET/CT imaging to delineate neuroendocrine neoplasms (NENs) and predict prognosis in affected patients is often compromised by substantial uptake heterogeneity. We hereby proposed a hybrid standardized uptake value (SUV) thresholding algorithm to extract volumetric parameters from somatostatin receptor (SSTR) PET/CT imaging and investigate their prognostic performance in patients with 68Ga-DOTATATE-avid stage IV NENs. Methods: For 38 retrospectively enrolled patients, we used either fixed SUV thresholding of normal liver parenchyma (method A), 41% of the SUVmax for each lesion (method B), or a hybrid method (method A for liver metastases; fixed SUV threshold of normal bone for bone metastases; method B for primary tumors and other metastases) to quantify the whole-body SSTR-expressing tumor volume (SRETVwb) and total lesion SSTR expression (TLSREwb). Patient survival was also recorded and analyzed. Results: PET/CT images revealed heterogeneous uptake of 68Ga-DOTATATE at primary and metastatic sites. Progression-free survival (PFS) and overall survival (OS) were negatively correlated with the extent of liver or bone metastases (p < 0.05), but not significantly correlated with tumor grade or 18F-FDG PET/CT positivity. By the hybrid method, PFS was significantly shorter in patients with high SRETVwb, and OS was significantly shorter in those with high SRETVwb and TLSREwb (p < 0.05). However, when derived from method A or method B, neither SRETVwb nor TLSREwb could predict patient outcomes. Conclusion: Compared with other methods used in 68Ga-DOTATATE-avid stage IV NENs, our hybrid SUV thresholding method demonstrated robustness, with greater precision, reliability, and prognostic power. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the influences of age‐matched control and/or age‐specific template on voxel‐wise analysis of brain 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG PET) data in pediatric epilepsy patients. We, retrospectively, included 538 pediatric (196 females; age range of 12 months to 18 years) and 35 adult subjects (18 females; age range of 20–50 years) without any cerebral pathology as pediatric and adult control group, respectively, as well as 109 pediatric patients with drug‐resistant epilepsy (38 females; age range of 13 months to 18 years) as epilepsy group. Statistical parametric mapping (SPM) analysis for 18F‐FDG PET data of each epilepsy patients was performed in four types of procedures, by using age‐matched controls with age‐specific template, age‐matched controls with adult template, adult controls with age‐specific template or adult controls with adult template. The numbers of brain regions affected by artifacts among these four types of SPM analysis procedures were further compared. Any template being adopted, the artifacts were significantly less in SPM analysis procedures using age‐matched controls than those using adult controls in each age range (p <.001 in each comparison), except in the age range of 15–18 (p >.05 in each comparison). No significant difference was found in artifacts, when compared procedures using the identical control group with different templates (p = 1.000 in each comparison). In conclusion, the age stratification for age‐matched control should be divided as many layers as possible for the SPM analysis of brain 18F‐FDG PET images, especially in pediatric patients ≤14‐year‐old, while age‐specific template is not mandatory. [ABSTRACT FROM AUTHOR]

Objective: Prostate-specific membrane antigen (PSMA)-PET/CT imaging has gained increasing clinical importance for the detection and staging of high-risk primary prostate cancer (PCa). However, it is unclear whether the routine practice of prostate biopsy obscures the image finding of PSMA-PET/CT. This study aimed to compare the tumor positivity rate of PSMA-PET/CT performed pre- (PSMA-PET/CTpre) and post-biopsy (PSMA-PET/CTpost) in high-risk PCa patients. Patients and methods: We matched 58 PSMA-PET/CTpost with 58 PSMA-PET/CTpre studies for primary detection of high-risk PCa according to clinical characteristics. Three subgroups of PSMA-PET/CTpost were defined by the intervals after biopsy (≤ 1 week, 1 ~ 2 weeks, and 2 ~ 5 weeks). Tumor positivity rates were determined, and SUVmax of primary tumors were compared separately for the two main groups and the related subgroups. Malignant prostate tissues from 20 of these patients were examined by immunohistochemical analysis of PSMA. In addition, the values of PSMA-PET/CTpre and PSMA-PET/CTpost in assessing seminal vesicle invasion (SVI) were evaluated in patients who underwent radical prostatectomy. Results: All the primary tumors were positive on PSMA-PET/CTpost and PSMA-PET/CTpre imaging, resulting in a patient-based positivity rates of 100% (58/58) in both groups. All examined IHC results (20/20) confirmed the high-level expression of PSMA. SUVmax of primary tumors did not differ between the two main groups (16.1, IQR 9.8–26.6 vs. 16.5, IQR 11.0–26.7, p > 0.05). Subgroup analysis of PSMA-PET/CTpost (≤ 1 week, 1 ~ 2 weeks, and 2 ~ 5 weeks) also showed no significant difference in tumor SUVmax (15.8, IQR 9.5–22.2; 17.8, IQR 9.8–29.2; and 15.4, IQR 10.1–30.3. p > 0.05). PSMA-PET/CTpost and PSMA-PET/CTpre exhibited similar value in SVI detection as well. Conclusions: The tumor positivity rate was consistently high for PSMA-PET/CT pre- and post-biopsy. A prior biopsy does not seem to affect the tumor positivity rate of PSMA-PET/CT in high-risk PCa. [ABSTRACT FROM AUTHOR]

Rationale: The role of oxidative stress metabolism during hepatocellular carcinoma (HCC) formation potentially allows for positron emission tomography (PET) imaging of oxidative stress activity for early and precise HCC detection. However, there is currently limited data available on oxidative-stress-related PET imaging for longitudinal monitoring of the pathophysiological changes during HCC formation. This work aimed to explore PET-based longitudinal monitoring of oxidative stress metabolism and determine the sensitivity of [18F]-5-fluoroaminosuberic acid ([18F]FASu) for assessing pathophysiological processes in diethylnitrosamine (DEN) induced rat HCC. Methods: Genomic and clinical data were obtained from the HCC dataset (n = 383) in The Cancer Genome Atlas (TCGA-LIHC) and Gene Expression Omnibus (GEO) datasets. Wistar rats were administered DEN weekly, either by gavage (i.g.) at doses of 10 mg/kg or 80 mg/kg or by intraperitoneal injection (i.p.) at 80 mg/kg, with continuous modeling over a 12-week period followed by 24 weeks of consecutive feeding. PET/CT imaging was conducted at weeks 8, 15, and 21 by tail vein injections of [18F]FASu and [18F]FDG (~3.7 MBq). Finally, contrast-enhanced CT imaging of the nodules was performed at the designed time point. The rats in each group were sacrificed at multiple time points to perform a correlation analysis between PET imaging findings and histological examinations. Results: Bioinformatics analysis revealed that upregulation expression of SLC7A11 in HCC indicates oxidative stress-altered cellular metabolism and allows early detection of HCC formation. By simulating different levels of oxidative stress in DEN-induced rat HCC, the SUVmax of [18F]FASu PET imaging positively correlated with the expression of CD44 and SLC7A11 (r = 0.7913, P < 0.0001; r = 0.7173, P < 0.0001, respectively), which maintain redox homeostasis in the cells. Compared with 18F-fluorodeoxyglucose ([18F]FDG), [18F]FASu PET imaging demonstrated higher sensitivity for HCC diagnosis and enabled the characterization of pathological changes in DEN-induced rat HCC at an early stage. Conclusions: Our findings regarding the oxidative stress characterization of HCC formation in DEN-induced rat models using [18F]FASu PET imaging demonstrated the exciting potential of oxidative-stress-related PET imaging for monitoring the pathophysiological changes during HCC formation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Rationale: Tissue factor (TF) initiates local blood clotting and infiltration of tumor-associated macrophages, leading to tumor recurrence post-local ablation. Our study addressed inefficient cancer cell killing and immunosuppressive macrophage infiltration after percutaneous ethanol injection (PEI) in hepatocellular carcinoma (HCC). We evaluated the feasibility of 18 F-radiolabeled polypeptide TF-targeted radioligand (tTF) as a PET tracer for assessing tumor response. We also explored the efficacy and safety of 177 Lu-radiolabeled tTF to eradicate residual tumors and tumor-associated macrophages. Methods: TF expression in the locally treated human HCC was assessed. Biodistribution, pharmacokinetics, and TF-targeted specificity of Al 18 F-NOTA-tTF were investigated in Kunming (KM) and/or Hepa1-6 mice. Evaluation of FDG/tTF PET imaging, histopathological characteristics, and tumor ablation response was conducted using two incomplete PEI ablation models, with ethanol volumes equivalent to 50% (high-dose (HD) PEI group) or 25% (low-dose (LD) PEI group) of the tumor volume administered. Following PEI, a single dose of 177 Lu-DOTA-tTF was administered on day 1 to assess its efficacy in eradicating residual tumors and immunosuppressive macrophages. Systemic toxicity was evaluated through blood analysis and histological examination of healthy organs. Results: Immunohistochemistry analysis demonstrated elevated TF expression around the ablation margin of residual tissue in human HCC. Radiolabeled tTF exhibited excellent TF-specificity, water solubility, and stability. FDG PET imaging and histological analysis showed tumor recurrence, upregulation of immunosuppressive macrophages, and TF around tumor foci post-treatment in the HD PEI-treated group. Meanwhile, the uptake of 18 F-FDG exhibited a decline, while the uptake of Al 18 F-NOTA-tTF showed an increase in both the HD and LD PEI groups, as observed on day 1 and day 6 post-PEI. These results indicated that increased tTF uptake offers a specific and durable avenue for targeted theranostic applications. Following PEI, 177 Lu-DOTA-tTF therapy demonstrated significant tumor suppression and eradication of immunosuppressive macrophages compared to control groups. Safety assessments indicated no significant toxicity in the main organs of tested animals. Conclusions: Al 18 F-NOTA-tTF is a promising PET tracer for assessing ablated HCC, while 177 Lu-DOTA-tTF provides an effective tool for inhibiting residual tumor growth and immunosuppressive macrophages post-PEI. Significantly, TF-targeting theranostics may help overcome incomplete cancer cell killing and formation of tumor immunosuppressive microenvironment, offering a promising strategy for effective HCC ablation in future clinical practice., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Multiparametric magnetic resonance imaging (mpMRI) is a commonly used method to diagnose pelvic lymph node metastasis (PLNM) in prostate cancer (PCa) patients, but there are few comparative studies on mpMRI and 68 Ga-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in locally advanced PCa (LAPC) patients. Therefore, we designed a retrospective study to compare the diagnostic value of 68 Ga-PSMA PET/CT and mpMRI for PLNM of LAPC., Methods: A retrospective study was performed on 50 patients with LAPC who underwent radical prostatectomy (RP) in Tongji Hospital from 2021 to 2023. All patients underwent PET/CT and mpMRI examination, and were diagnosed as LAPC before surgery, followed by robot-assisted laparoscopic prostatectomy or laparoscopic RP and extended pelvic lymph node dissection (ePLND). Routine postoperative pathological examination was performed. According to the results, the sensitivity, specificity, positive predictive value, and negative predictive value of 68 Ga-PSMA PET/CT and mpMRI for the diagnosis of PLNM of LAPC were compared., Results: Among the 50 patients, the mean age was 65.5±10.3 years, the preoperative total serum prostate-specific antigen (PSA) was 30.7±12.3 ng/mL, and the Gleason score was 7 [7, 8]. The difference in diagnostic efficacy between 68 Ga-PSMA PET/CT and mpMRI in the preoperative diagnosis of PLNM of PCa was determined by postoperative pathological results. Based on the number of patients who developed PLNM, the sensitivity, specificity, positive predictive value, and negative predictive value of 68 Ga-PSMA PET/CT were as follows: 93.75%, 100.00%, 100.00%, 97.14%, and 68.75%, 97.06%, 91.67%, 86.84% for mpMRI, respectively. Based on the number of pelvic metastatic lymph nodes, the sensitivity, specificity, positive predictive value, and negative predictive value of 68 Ga-PSMA PET/CT were 95.24%, 100.00%, 100.00%, 99.48%, and 65.08%, 99.13%, 89.13%, 96.30% for mpMRI, respectively. It turned out that PET/CT was more sensitive than mpMRI in detecting PLNM of PCa, and the difference was statistically significant., Conclusions: 68 Ga-PSMA PET/CT is more sensitive than mpMRI in the detection of PLNM in patients with LAPC. It is a promising method in the diagnosis and preoperative assessment of PLNM in LAPC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-15/coif). The authors have no conflicts of interest to declare., (2024 Translational Andrology and Urology. All rights reserved.)

Fibroblast activation protein (FAP) is highly expressed in many tumor types and constitutes a promising target for tumor-specific delivery of therapeutic radionuclides. [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 is a novel radiopharmaceutical based on a novel bidentate inhibitor of FAP that is excreted more slowly than its monomeric counterparts. Still, the efficacy of radiotherapy is mitigated by cascades of DNA damage repair signaling in tumor cells including those via Poly(ADP-ribose) polymerase (PARP). We hereby aimed to evaluate the efficacy of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 in combination with a PARP inhibitor, Olaparib, in the 4T1 murine triple negative breast cancer (TNBC) model. The therapeutic efficacy was visualized using 18 F-FDG and [ 68 Ga]Ga-FAPI-04 positron emission imaging/computer tomography (PET/CT). Our results demonstrated that Olaparib suppressed BALB/3T3 fibroblasts in vitro and sensitized the efficacy of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 in mice bearing 4T1 tumors via enhancement of DNA damage. Treatment-associated toxicity was tolerable with only mild leukopenia. Therefore, the combination of [ 177 Lu]Lu-DOTAGA.(SA.FAPi) 2 and Olaparib is a feasible treatment against TNBC.

Recently, various immuno-PET tracers based on monoclonal antibodies (mAbs), engineered scaffold proteins, and peptides were developed to target either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), showing promise in assessment of immune checkpoints. We sought to develop an immunotherapeutic agent based PET probe that enables real-time assessment of PD-L1 expression and evaluation of antibody drug biodistribution to select eligible candidates for anti-PD-1/PD-L1 immunotherapies. KN035, a 79.6 kDa size anti-PD-L1 domain antibody under analysis in clinical trials, was used to develop the immuno-PET probe, 89 Zr-Df-KN035. Immuno-PET studies were performed to monitor PD-L1 levels in nude mice bearing LN229 xenografts with positive expression for PD-L1, and to evaluate the whole-body biodistribution in healthy non-human primates (NHPs). LN229 xenografts were markedly visualized from 24 h after injection of 89 Zr-Df-KN035, with elevated accumulation persisting for up to 120 h. Tumor radioactivity was notably reduced in the presence of excess KN035. Mouse ex vivo biodistribution studies performed at 24 and 120 h revealed tumor-to-muscle ratios as high as 5.64 ± 0.65 and 7.70 ± 1.37, respectively. In the NHP model, PET imaging demonstrated low background. The liver and kidney showed moderate accumulation with the highest SUV mean value of 1.15 ± 0.15 and 2.13 ± 0.10 at 72 h, respectively. The spleen, lymph nodes, and salivary glands were also slightly visualized. In conclusion, 89 Zr-Df-KN035, a novel anti-PD-L1 domain antibody-based probe, shows the feasibility of noninvasive in vivo evaluation of PD-L1 expression. This work further provides a template for immunotherapeutic agent based imaging to evaluate human PD-L1 expression and to augment our understanding of therapeutic agent biodistribution, leading to better therapeutic strategies in the future.