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Purpose: This study evaluated the performance of multiparametric magnetic resonance imaging (MRI)–based fusion radiomics models (MMFRs) to predict telomerase reverse transcriptase (TERT) promoter mutation status and progression-free survival (PFS) in glioblastoma patients. Methods: We retrospectively analysed 208 glioblastoma patients from two hospitals. Quantitative imaging features were extracted from each patient's T1-weighted, T1-weighted contrast-enhanced, and T2-weighted preoperative images. Using a coarse-to-fine feature selection strategy, four radiomics signature models were constructed based on the three MRI sequences and their combination for TERT promoter mutation status and PFS; model performance was subsequently evaluated. Subgroup analyses were performed by the radiomics signature of TERT promoter mutation status and PFS to distinguish patients who could benefit from prolonged temozolomide chemotherapy cycles. Results: TERT promoter mutation status was best predicted by MMFR, with an area under the curve (AUC) of 0.816 and 0.812 for the training and internal validation sets, respectively. The external test set also achieved stable and optimal prediction results (AUC, 0.823). MMFR better predicted patient PFS compared with the single-sequence radiomics signature in the test set (C-index, 0.643 vs 0.561 vs 0.620 vs 0.628). Subgroup analyses showed that more than six cycles of postoperative temozolomide chemotherapy were associated with improved PFS for patients in class 2 (high TERT promoter mutation and high survival rates; HR, 0.222; 95% CI, 0.054 − 0.923; p = 0.025). Conclusion: MMFR is an effective method to predict TERT promoter mutations and PFS in patients with glioblastoma. Moreover, subgroup analysis could differentiate patients who may benefit from prolonged TMZ chemotherapy cycles. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the value of intra- and peritumoral deep learning (DL) features based on multi-parametric magnetic resonance imaging (MRI) for identifying telomerase reverse transcriptase (TERT) promoter mutation in glioblastoma (GBM). Methods: In this study, we included 229 patients with GBM who underwent preoperative MRI in two hospitals between November 2016 and September 2022. We used four 2D Convolutional Neural Networks (GoogLeNet, DenseNet121, VGG16, and MobileNetV3-Large) to extract intra- and peritumoral DL features. The Mann–Whitney U test, Pearson correlation analysis, least absolute shrinkage and selection operator, and logistic regression analysis were used for feature selection and construction of DL radiomics (DLR) signatures in different regions. These multi-parametric and multi-region signatures were combined to identify TERT promoter mutation. The area under the receiver operating characteristic curve (AUC) was used to evaluate the effects of the signatures. Results: The signatures based on the DL features from the peritumoral regions with expansion distances of 2 mm, 8 mm, and 10 mm using the GoogLeNet architecture correlated with the optimal AUC values (test set:.823,.753, and.768) in the T2-weighted, T1-weighted contrast-enhanced, and T1-weighted images. Using the stacking fusion method, DLR with multi-parameter and multi-region fusion achieved the best discrimination with AUC values of.948 and.902 in the training and test sets, respectively. Conclusions: The radiomics model based on the fusion of multi-parameter MRI intra- and peritumoral DLR signatures may help to identify TERT promoter mutation in patients with GBM. [ABSTRACT FROM AUTHOR]

Purpose: Both I- and I-labeled meta-iodobenzylguanidine (MIBG) have been widely used in the clinic for targeted imaging of the norepinephrine transporter (NET). The human NET (hNET) gene has been imaged successfully with I-MIBG positron emission tomography (PET) at time points of >24 h post-injection (p.i.). F-labeled MIBG analogs may be ideal to image hNET expression at time points of <8 h p.i. We developed improved methods for the synthesis of known MIBG analogs, [F]MFBG and [F]PFBG and evaluated them in hNET reporter gene-transduced C6 rat glioma cells and xenografts. Methods: [F]MFBG and [F]PFBG were synthesized manually using a three-step synthetic scheme. Wild-type and hNET reporter gene-transduced C6 rat glioma cells and xenografts were used to comparatively evaluate the F-labeled analogs with [I]/[I]MIBG. Results: The fluorination efficacy on benzonitrile was predominantly determined by the position of the trimethylammonium group. The para-isomer afforded higher yields (75 ± 7 %) than meta-isomer (21 ± 5 %). The reaction of [F]fluorobenzylamine with 1H-pyrazole-1-carboximidamide was more efficient than with 2-methyl-2-thiopseudourea. The overall radiochemical yields (decay-corrected) were 11 ± 2 % ( n = 12) for [F]MFBG and 41 ± 12 % ( n = 5) for [F]PFBG, respectively. The specific uptakes of [F]MFBG and [F]PFBG were similar in C6-hNET cells, but 4-fold less than that of [I]/[I]MIBG. However, in vivo [F]MFBG accumulation in C6-hNET tumors was 1.6-fold higher than that of [F]PFBG at 1 h p.i., whereas their uptakes were similar at 4 h. Despite [F]MFBG having a 2.8-fold lower affinity to hNET and approximately 4-fold lower cell uptake in vitro compared to [I]/[I]MIBG, PET imaging demonstrated that [F]MFBG was able to visualize C6-hNET xenografts better than [I]MIBG. Biodistribution studies showed [F]MFBG and I-MIBG had a similar tumor accumulation, which was lower than that of no-carrier-added [I]MIBG, but [F]MFBG showed a significantly more rapid body clearance and lower uptake in most non-targeting organs. Conclusion: [F]MFBG and [F]PFBG were synthesized in reasonable radiochemical yields under milder conditions. [F]MFBG is a better PET ligand to image hNET expression in vivo at 1-4 h p.i. than both [F]PFBG and [I]/[I]MIBG. [ABSTRACT FROM AUTHOR]

Blood-brain barrier (BBB) obstructing brain drug delivery severely hampers the therapeutic efficacy towards glioma. An efficient brain delivery strategy is of paramount importance for the treatment of glioma. Inspired by brain targeting exosome, biomimetic BBB penetrated hybrid (pHybrid) nanovesicles, engineered by membrane fusion between blood exosome and tLyp-1 peptide modified liposome, is explored for brain targeting drug delivery. Transferrin receptor (TfR) on pHybrid nanovesicles facilitates the BBB transcytosis into brain parenchyma, and eventually endocytosed by glioma cells and diffusion to extra-vascular tumor tissues under the guidance of tLyp-1 peptide. pHybrid nanovesicles co-loaded with salvianolic acid B (SAB) and cryptotanshinone (CPT), which is constructed by membrane hybridization of blood exosome loaded with SAB and tLyp-1 modified liposome loaded with CPT, are explored for cytotoxic and anti-angiogenetic therapy towards glioma. Upon accumulation at tumor site, the loaded CPT and SAB shows synergistic effects towards glioma from cytotoxicity on cancer cells and anti-angiogenesis on tumor, respectively. Overall, this study provides a biomimetic nanoplatform for increased BBB transcytosis into brain parenchyma, which serves as a prospective strategy for delivering therapeutic agents against glioma through synergistic mechanisms. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction Chemokine receptor-4 (CXCR4, fusin, CD184) is expressed on several tissues involved in immune regulation and is upregulated in many diseases including malignant gliomas. A radiolabeled small molecule that readily crosses the blood–brain barrier can aid in identifying CXCR4-expressing gliomas and monitoring CXCR4-targeted therapy. In the current work, we have synthesized and evaluated an [ 18 F]-labeled small molecule based on a pyrimidine–pyridine amine for its ability to target CXCR4. Experimental The nonradioactive standards and the nitro precursor used in this study were prepared using established methods. An HPLC method was developed to separate the nitro-precursor from the nonradioactive standard and radioactive product. The nitro-precursor was radiolabeled with 18 F under inert, anhydrous conditions using the [ 18 F]-kryptofix 2.2.2 complex to form the desired N-(4-(((6-[ 18 F]fluoropyridin-2-yl)amino)methyl)benzyl)pyrimidin-2-amine ([ 18 F]-3). The purified radiolabeled compound was used in serum stability, partition coefficient, cellular uptake, and in vivo cancer targeting studies. Results [ 18 F]-3 was synthesized in 4–10% decay-corrected yield (to start of synthesis). [ 18 F]- 3 (t R ≈ 27 min) was separated from the precursor (t R ≈ 30 min) using a pentafluorophenyl column with an isocratic solvent system. [ 18 F]- 3 displayed acceptable serum stability over 2 h. The amount of [ 18 F]- 3 bound to the plasma proteins was determined to be > 97%. The partition coefficient (LogD 7.4 ) is 1.4 ± 0.5. Competitive in vitro inhibition indicated 3 does not inhibit uptake of 67 Ga-pentixafor. Cell culture media incubation and ex vivo urine analysis indicate rapid metabolism of [ 18 F]- 3 into hydrophilic metabolites. Thus, in vitro uptake of [ 18 F]- 3 in CXCR4 overexpressing U87 cells (U87 CXCR4) and U87 WT indicated no specific binding. In vivo studies in mice bearing U87 CXCR4 and U87 WT tumors on the left and right shoulders were carried out using [ 18 F]- 3 and 68 Ga-pentixafor on consecutive days. The CXCR4 positive tumor was clearly visualized in the PET study using 68 Ga-pentixafor, but not with [ 18 F]- 3 . Conclusions We have successfully synthesized both a radiolabeled analog to previously reported CXCR4-targeting molecules and a nitro precursor. Our in vitro and in vivo studies indicate that [ 18 F]- 3 is rapidly metabolized and, therefore, does not target CXCR4-expressing tumors. Optimization of the structure to improve the in vivo (and in vitro ) stability, binding, and solubility could lead to an appropriate CXCR4-targeted radiodiagnositic molecule. [ABSTRACT FROM AUTHOR]