Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling.

Craniopharyngiomas (CPs), particularly Adamantinomatous Craniopharyngiomas (ACPs), often exhibit a heightened risk of postoperative recurrence and severe complications of the endocrine and hypothalamic function. The primary objective of this study is to investigate potential novel targeted therapies within the microenvironment of ACP tumors. Cancer-Associated Fibroblasts (CAFs) were identified in the craniopharyngioma microenvironment, notably in regions characterized by cholesterol clefts, wet keratin, ghost cells, and fibrous stroma in ACPs. CAFs, alongside ghost cells, basaloid-like epithelium cells and calcifications, were found to secrete PROS1 and GAS6, which can activate AXL receptors on the surface of tumor epithelium cells, promoting immune suppression and tumor progression in ACPs. Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models.

Lipid nanoparticles for delivering mRNA therapeutics hold immense promise for the treatment of a wide range of lung-associated diseases. However, the lack of effective methodologies capable of identifying the pulmonary delivery profile of chemically distinct lipid libraries poses a significant obstacle to the advancement of mRNA therapeutics. Here we report the implementation of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials. We combinatorially synthesize 180 cationic, degradable lipids which are initially screened in vitro. We then use barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo. The top-performing nanoparticle formulation delivering Cas9-based genetic editors exhibits therapeutic potential for antiangiogenic cancer therapy within a lung tumor model in female mice. These data demonstrate that employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.

Machine learning based on magnetic resonance imaging and clinical parameters helps predict mesenchymal-epithelial transition factor expression in oral tongue squamous cell carcinoma: a pilot study.

OBJECTIVES: This study aimed to develop machine learning models to predict phosphorylated mesenchymal-epithelial transition factor (p-MET) expression in oral tongue squamous cell carcinoma (OTSCC) using magnetic resonance imaging (MRI)-derived texture features and clinical features. METHODS: Thirty-four patients with OTSCC were retrospectively collected. Texture features were derived from preoperative MR images, including T2WI, apparent diffusion coefficient mapping, and contrast-enhanced (ce)-T1WI. Dimension reduction was performed consecutively with reproducibility analysis and an information gain algorithm. Five machine learning methods-AdaBoost, logistic regression (LR), naïve Bayes (NB), random forest (RF), and support vector machine (SVM)-were adopted to create models predicting p-MET expression. Their performance was assessed with fivefold cross-validation. RESULTS: In total, 22 and 12 cases showed low and high p-MET expression, respectively. After dimension reduction, 3 texture features (ADC-Minimum, ce-T1WI-Imc2, and ce-T1WI-DependenceVariance) and 2 clinical features (depth of invasion [DOI] and T-stage) were selected with good reproducibility and best correlation with p-MET expression levels. The RF model yielded the best overall performance, correctly classifying p-MET expression status in 87.5% of OTSCCs with an area under the receiver operating characteristic curve of 0.875. CONCLUSION: Differences in p-MET expression in OTSCCs can be noninvasively reflected in MRI-based texture features and clinical parameters. Machine learning can potentially predict biomarker expression levels, such as MET, in patients with OTSCC.

Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors.

The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, here we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP+ CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR T cells and to anti-PD-1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8+ T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.

PCBP1 protects bladder cancer cells from mitochondria injury and ferroptosis by inducing LACTB mRNA degradation.

Although Poly C Binding Protein 1 (PCBP1) affects cellular ferroptosis and mitochondrial dysfunction, the mechanisms by which PCBP1 regulates bladder cancer (BC) cell functions are unknown. In this study, two BC cell lines (T24 and UMUC3) were treated with different doses of ferroptosis inducer erastin to analyze the effect of PCBP1. Online databases (RPISeq and CatRAPID) were used to predict the possible direct interaction between PCBP1 protein and serine ß-lactamase-like protein (LACTB) mRNA, which was further validated via RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. Mitochondria injury and ferroptosis were evaluated using CCK-8 assay, TUNEL staining, flow cytometry, corresponding kits, and JC-1 staining. In vivo experiments were conducted using tumor xenograft models. Quantitative reverse-transcription polymerase chain reaction was used to detect transcript expression levels, while protein levels were analyzed using western blot and immunohistochemistry. PCBP1 expression was significantly upregulated in BC tissues and cell lines. Also, PCBP1 knockdown increased erastin-mediated ferroptosis in T24 and UMUC3 cells, while PCBP1 overexpression decreased erastin-mediated ferroptosis in T24 and UMUC3 cells. Mechanistic results showed that LACTB mRNA is a novel PCBP1-binding transcript. LACTB upregulation promoted erastin-induced ferroptosis and mitochondrial dysfunction. Furthermore, LACTB overexpression reversed PCBP1-mediated ferroptosis protection, including decreased ROS and enhanced mitochondrial function, which were further alleviated after phosphatidylserine decarboxylase (PISD) overexpression. Moreover, PCBP1 silencing significantly enhanced tumor inhibition effect of sulfasalazine in xenograft mice transplanted with T24 and UMUC3 cells, leading to LACTB upregulation and PISD downregulation. In conclusion, PCBP1 protects BC cells against mitochondria injury and ferroptosis via LACTB/PISD axis.

Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors.

The desmoplastic stroma in solid tumors presents a formidable challenge to immunotherapies that rely on endogenous or adoptively transferred T cells, however, the mechanisms are poorly understood. To define mechanisms involved, we treat established desmoplastic pancreatic tumors with CAR T cells directed to fibroblast activation protein (FAP), an enzyme highly overexpressed on a subset of cancer-associated fibroblasts (CAFs). Depletion of FAP+CAFs results in loss of the structural integrity of desmoplastic matrix. This renders these highly treatment-resistant cancers susceptible to subsequent treatment with a tumor antigen (mesothelin)-targeted CAR and to anti-PD1 antibody therapy. Mechanisms include overcoming stroma-dependent restriction of T cell extravasation and/or perivascular invasion, reversing immune exclusion, relieving T cell suppression, and altering the immune landscape by reducing myeloid cell accumulation and increasing endogenous CD8+ T cell and NK cell infiltration. These data provide strong rationale for combining tumor stroma- and malignant cell-targeted therapies to be tested in clinical trials.

Tumor-Derived Small Extracellular Vesicles Inhibit the Efficacy of CAR T Cells against Solid Tumors.

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable success in the treatment of hematologic malignancies. Unfortunately, it has limited efficacy against solid tumors, even when the targeted antigens are well expressed. A better understanding of the underlying mechanisms of CAR T-cell therapy resistance in solid tumors is necessary to develop strategies to improve efficacy. Here we report that solid tumors release small extracellular vesicles (sEV) that carry both targeted tumor antigens and the immune checkpoint protein PD-L1. These sEVs acted as cell-free functional units to preferentially interact with cognate CAR T cells and efficiently inhibited their proliferation, migration, and function. In syngeneic mouse tumor models, blocking tumor sEV secretion not only boosted the infiltration and antitumor activity of CAR T cells but also improved endogenous antitumor immunity. These results suggest that solid tumors use sEVs as an active defense mechanism to resist CAR T cells and implicate tumor sEVs as a potential therapeutic target to optimize CAR T-cell therapy against solid tumors. SIGNIFICANCE: Small extracellular vesicles secreted by solid tumors inhibit CAR T cells, which provide a molecular explanation for CAR T-cell resistance and suggests that strategies targeting exosome secretion may enhance CAR T-cell efficacy. See related commentary by Ortiz-Espinosa and Srivastava, p. 2637.

Prediction of platinum resistance for advanced high-grade serous ovarian carcinoma using MRI-based radiomics nomogram.

OBJECTIVE: This study aimed to explore the value of a radiomics nomogram to identify platinum resistance and predict the progression-free survival (PFS) of patients with advanced high-grade serous ovarian carcinoma (HGSOC). MATERIALS AND METHODS: In this multicenter retrospective study, 301 patients with advanced HGSOC underwent radiomics features extraction from the whole primary tumor on contrast-enhanced T1WI and T2WI. The radiomics features were selected by the support vector machine-based recursive feature elimination method, and then the radiomics signature was generated. Furthermore, a radiomics nomogram was developed using the radiomics signature and clinical characteristics by multivariable logistic regression. The predictive performance was evaluated using receiver operating characteristic analysis. The net reclassification index (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA) were used to compare the clinical utility and benefits of different models. RESULTS: Five features significantly correlated with platinum resistance were selected to construct the radiomics model. The radiomics nomogram, combining radiomics signatures with three clinical characteristics (FIGO stage, CA-125, and residual tumor), had a higher area under the curve (AUC) compared with the clinical model alone (AUC: 0.799 vs 0.747), with positive NRI and IDI. The net benefit of the radiomics nomogram is typically higher than clinical-only and radiomics-only models. Kaplan-Meier survival analysis showed that the radiomics nomogram-defined high-risk groups had shorter PFS compared with the low-risk groups in patients with advanced HGSOC. CONCLUSIONS: The radiomics nomogram can identify platinum resistance and predict PFS. It helps make the personalized management of advanced HGSOC. KEY POINTS: • The radiomics-based approach has the potential to identify platinum resistance and can help make the personalized management of advanced HGSOC. • The radiomics-clinical nomogram showed improved performance compared with either of them alone for predicting platinum-resistant HGSOC. • The proposed nomogram performed well in predicting the PFS time of patients with low-risk and high-risk HGSOC in both training and testing cohorts.

Improve follicular thyroid carcinoma diagnosis using computer aided diagnosis system on ultrasound images.

Objective: We aim to leverage deep learning to develop a computer aided diagnosis (CAD) system toward helping radiologists in the diagnosis of follicular thyroid carcinoma (FTC) on thyroid ultrasonography. Methods: A dataset of 1159 images, consisting of 351 images from 138 FTC patients and 808 images from 274 benign follicular-pattern nodule patients, was divided into a balanced and unbalanced dataset, and used to train and test the CAD system based on a transfer learning of a residual network. Six radiologists participated in the experiments to verify whether and how much the proposed CAD system helps to improve their performance. Results: On the balanced dataset, the CAD system achieved 0.892 of area under the ROC (AUC). The accuracy, recall, precision, and F1-score of the CAD method were 84.66%, 84.66%, 84.77%, 84.65%, while those of the junior and senior radiologists were 56.82%, 56.82%, 56.95%, 56.62% and 64.20%, 64.20%, 64.35%, 64.11% respectively. With the help of CAD, the metrics of the junior and senior radiologists improved to 62.81%, 62.81%, 62.85%, 62.79% and 73.86%, 73.86%, 74.00%, 73.83%. The results almost repeated on the unbalanced dataset. The results show the proposed CAD approach can not only achieve better performance than radiologists, but also significantly improve the radiologists' diagnosis of FTC. Conclusions: The performances of the CAD system indicate it is a reliable reference for preoperative diagnosis of FTC, and might assist the development of a fast, accessible screening method for FTC.

Monitoring Therapeutic Response to Anti-FAP CAR T Cells Using [18F]AlF-FAPI-74.

PURPOSE: Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T-targeted antigens in tumors and accurate monitoring of response. EXPERIMENTAL DESIGN: We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro, and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer. RESULTS: [18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. We further demonstrated the utility of the tracer to monitor changes in FAP expression following FAP CAR T-cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses. CONCLUSIONS: This noninvasive imaging approach to interrogate the tumor microenvironment represents an innovative pairing of a diagnostic PET probe with solid tumor CAR T-cell therapy and has the potential to serve as a predictive and pharmacodynamic response biomarker for FAP as well as other stroma-targeted therapies. A PET imaging approach targeting FAP expressed on activated fibroblasts of the tumor stroma has the potential to predict and monitor therapeutic response to FAP-targeted CAR T-cell therapy. See related commentary by Weber et al., p. 5241.

A EWSR1-CREM-rearranged gastric mesenchymal tumor accompanied by gastritis cystica profunda and with probable benign behavior: a case report.

Genomic rearrangements involving EWSR1 and the CREB family of transcription factors are increasingly detected in an array of mesenchymal neoplasms, most of which are malignant. Gastritis cystica profunda (GCP) is a rare disease characterized by cystic dilatation of gastric glands into the submucosa and generally regarded as a precursor to tumor. Herein, we report a peculiar case in which an EWSR1-CREM-rearranged gastric mesenchymal tumor was admixed with GCP in a 64-year-old woman. All layers of the gastric wall were invaded, although no lymph node or neural invasion, or tumoral vascular emboli was noted. The mass showed readily distinguishable epithelial and mesenchymal components. The epithelial component consisted mainly of glandular structures with some showing metaplastic growth. The epithelial cells showed focally atypical hyperchromatic nuclei, slightly eosinophilic cytoplasm, and infrequent mitosis. The mesenchymal component consisted of monomorphic, ovoid-shaped cells with scanty cytoplasm, regular nuclei, and rare mitotic figures. Immunohistochemically, the epithelial cells were uniformly positive for cytokeratins, and the mesenchymal neoplasm showed focal positivity for CD10, CD117 and CD56. An EWSR1-CREM fusion was identified with genomic profiling and confirmed with fluorescence in situ hybridization (FISH) in the tumor. Given the low mitotic activity, absence of nodal or distant spread and vascular or neural invasion, and disease-free status at 28-month follow-up, both lesions were likely benign. To our knowledge, this is the first to report an EWSR1-CREM fusion in a gastric mesenchymal tumor with accompanying GCP.

Comprehensive genomic profiling and PD-L1 expression of primary lymphoepithelioma-like carcinoma of the stomach and parotid gland.

BACKGROUND: To investigate the comprehensive genomic profiling and programmed cell death ligand-1 (PD-L1) expression of primary lymphoepithelioma-like carcinoma (LELC) of different anatomical sites in the Chinese population and explore potential therapeutic strategies. METHODS: Capture-based targeted sequencing was performed on tumor tissue samples collected from 35 patients with LELC. Tumor tissues were stained by immunohistochemistry (IHC) for PD-L1. The molecular features of LELC of the stomach/parotid gland and associations between somatic alterations and survival outcomes in LELC of the stomach were explored. RESULTS: All patients with LELC of the stomach/parotid gland were microsatellite-stable with Epstein-Barr virus infection. A total of 215 somatic alterations spanning 126 genes were identified from 18 patients with LELC of the stomach. The most frequently mutated genes included PIK3CA, ARID1A, SMAD4, and KMT2D. In addition, 37 somatic alterations spanning 30 genes were identified from seven patients with LELC of the parotid gland. TP53, GNAS, and BCOR were the most frequently mutated genes. All cases of LELC of the stomach/parotid gland had a low tumor mutational burden (TMB) level, but a high PD-L1 expression level. Compared with LELC of the parotid gland, LELC of the stomach had a significantly higher TMB (1.0 vs. 5.0 mutations/Mb, P=0.0047) and a lower PD-L1 expression level (combined positive score: 90.0 vs. 47.5, P=0.0058). In addition, the presence of alterations in the p53 signaling pathway, homologous recombination pathway, and deoxyribonucleic acid (DNA) damage response pathway predicted unfavorable overall survival in patients with LELC of the stomach. CONCLUSIONS: This study is the first to elucidate the comprehensive genomic profiling of LELC of the stomach in the Chinese population, and the first to demonstrate the molecular features of LELC of the parotid gland. The detection of high PD-L1 expression raises the potential of checkpoint immunotherapy for LELC of the stomach/parotid gland. KEYWORDS: Lymphoepithelioma-like carcinoma of the stomach (LELC of the stomach), lymphoepithelioma-like carcinoma of the parotid gland (LELC of the parotid gland), programmed cell death ligand-1 (PD-L1), genomic profiling, immunotherapy.

Extramedullary Plasmacytoma of the Sinonasal Cavity: Magnetic Resonance Imaging Characteristics With Readout-Segmented Diffusion-Weighted Imaging and Dual-Energy Computed Tomography Features.

PURPOSE: To determine magnetic resonance imaging (MRI) with readout-segmented diffusion-weighted imaging (RESOLVE-DWI) and dual-energy computed tomography (DECT) features of sinonasal extramedullary plasmacytoma (SN-EMP). METHODS: The MRI and/or DECT of 10 patients with SN-EMP confirmed by pathology were retrospectively reviewed. Apparent diffusion coefficient (ADC) values of RESOLVE-DWI were analyzed in 9 patients. The quantitative parameters derived from DECT, including the iodine concentration (IC), effective atomic number, and the slope (k) of spectral attenuation curve, were measured in 3 patients. RESULTS: On conventional MRI, typical lesions were well defined (7 of 9), and isointense to the brain on both T1WI and T2WI (9 of 9). Most lesions presented with marked enhancement on contrast-enhanced T1WI without significant necrosis (8 of 9). Notably, multiple flow-void signals were observed in all lesions (9 of 9). On RESOLVE-DWI, the average ADC value was 0.55 × 10-3 mm2/s, and the normalized ADC value was 0.66 ± 0.04. On DECT, the average values of IC, effective atomic number, and slope (k) was 2.7 mg/mL, 8.62, and 3.8, respectively. CONCLUSIONS: Some typical MRI features (well-defined mass, isointensity to the brain, marked enhancement without obvious cystic changes, multiple flow voids, and a lower ADC value) strongly suggest the diagnosis of SN-EMP. The quantitative parameters derived from RESOLVE-DWI and DECT may provide more information for the diagnosis of SN-EMP.

Grading Trigone Meningiomas Using Conventional Magnetic Resonance Imaging With Susceptibility-Weighted Imaging and Perfusion-Weighted Imaging.

OBJECTIVE: To compare conventional magnetic resonance imaging (MRI), susceptibility-weighted imaging (SWI), and perfusion-weighted imaging (PWI) characteristics in different grades of trigone meningiomas. METHODS: Thirty patients with trigone meningiomas were enrolled in this retrospective study. Conventional MRI was performed in all patients; SWI (17 cases), dynamic contrast-enhanced PWI (10 cases), and dynamic susceptibility contrast PWI (6 cases) were performed. Demographics, conventional MRI features, SWI- and PWI-derived parameters were compared between different grades of trigone meningiomas. RESULTS: On conventional MRI, the irregularity of tumor shape (ρ = 0.497, P = 0.005) and the extent of peritumoral edema (ρ = 0.187, P = 0.022) might help distinguish low-grade and high-grade trigone meningiomas. On multiparametric functional MRI, rTTPmax (1.17 ± 0.06 vs 1.30 ± 0.05, P = 0.048), Kep, Ve, and iAUC demonstrated their potentiality to predict World Health Organization grades I, II, and III trigone meningiomas. CONCLUSIONS: Conventional MRI combined with dynamic susceptibility contrast and dynamic contrast-enhanced can help predict the World Health Organization grade of trigone meningiomas.

Dual-energy CT in differentiating benign sinonasal lesions from malignant ones: comparison with simulated single-energy CT, conventional MRI, and DWI.

OBJECTIVES: To explore the value of dual-energy CT (DECT) for differentiating benign sinonasal lesions from malignant ones, and to compare this finding with simulated single-energy CT (SECT), conventional MRI (cMRI), and diffusion-weighted imaging (DWI). METHODS: Patients with sinonasal lesions (38 benign and 34 malignant) who were confirmed by histopathology underwent DECT, cMRI, and DWI. DECT-derived parameters (iodine concentration (IC), effective atomic number (Eff-Z), 40-180 keV (20-keV interval), virtual non-enhancement (VNC), slope (k), and linear-mixed 0.3 (Mix-0.3)), DECT morphological features, cMRI characteristics, and ADC value of benign and malignant tumors were compared using t test or chi-square test. Receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic performance, and the area under the ROC curve (AUC) was compared using the Z test to select the optimal diagnostic approach. RESULTS: Significantly higher DECT-derived single parameters (IC, Eff-Z, 40 keV, 60 keV, 80 keV, slope (k), Mix-0.3) were found in malignant lesions than those of benign sinonasal lesions (all p < 0.004, Bonferroni correction). Combined quantitative parameters (IC, Eff-Z, 40 keV, 60 keV, 80 keV, slope (k)) can improve the diagnostic efficiency for discriminating these two entities. Combination of DECT quantitative parameters and morphological features can further improve the overall diagnostic performance, with AUC, sensitivity, specificity, and accuracy of 0.935, 96.67%, 90.00%, and 93.52%. Moreover, the AUC of DECT was higher than those of Mix-0.3 (simulated SECT), cMRI, DWI, and cMRI+DWI. CONCLUSIONS: Compared with simulated SECT, cMRI, and DWI, DECT appears to be a more accurate imaging technique for differentiating benign from malignant sinonasal lesions. KEY POINTS: • DE can differentiate benign sinonasal lesions from malignant ones based on DECT-derived qualitative parameters. • DECT appears to be more accurate in the diagnosis of sinonasal lesions when compared with simulated SECT, cMRI, and DWI.

Quantitative dynamic contrast-enhanced MRI and readout segmentation of long variable echo-trains diffusion-weighted imaging in differentiating parotid gland tumors.

PURPOSE: To evaluate the ability of quantitative dynamic contrast-enhanced (DCE)-MRI and readout segmentation of long variable echo-trains diffusion-weighted imaging (RESOLVE-DWI) in differentiating parotid tumors (PTs) with different histological types. METHODS: In this retrospective study, 123 patients with 145 histologically proven PTs who underwent both RESOLVE-DWI and DCE-MRI were enrolled including 51 pleomorphic adenomas (PAs), 52 Warthin's tumors (WTs), 27 other benign neoplasms (OBNs), and 15 malignant tumors (MTs). Quantitative parameters of DCE-MRI (Ktrans, Kep, and Ve) and the apparent diffusion coefficient (ADC) of lesions were calculated and analyzed. Kruskal-Wallis tests with Dunn-Bonferroni correction, logistic regression analyses, and receiver operating characteristic curve were used for statistical analyses. RESULTS: PAs exhibited a lowest Ktrans among these four PTs. WTs demonstrated the highest Kep and lowest Ve values. WTs and MTs showed lower ADCmin values than PAs and OBNs. The combination of Kep and Ve provided 98.1% sensitivity, 85% specificity, and 98.7% accuracy for differentiating WTs from the other three PTs. The ADCmin cutoff value of ≤ 0.826 yielded 80.0% sensitivity, 92.3% specificity, and 90.3% accuracy for the differentiation of MTs from PAs and OBNs. Ktrans with a cutoff value of ≤ 0.185 achieved a sensitivity, specificity, and accuracy of 84.3, 70.4, and 79.5%, respectively, for discriminating PAs from OBNs. CONCLUSION: The combination of quantitative DCE-MRI and RESOLVE-DWI is beneficial for characterizing four histological types of PTs.

Imaging of T-cell Responses in the Context of Cancer Immunotherapy.

Immunotherapy, which promotes the induction of cytotoxic T lymphocytes and enhances their infiltration into and function within tumors, is a rapidly expanding and evolving approach to treating cancer. However, many of the critical denominators for inducing effective anticancer immune responses remain unknown. Efforts are underway to develop comprehensive ex vivo assessments of the immune landscape of patients prior to and during response to immunotherapy. An important complementary approach to these efforts involves the development of noninvasive imaging approaches to detect immune targets, assess delivery of immune-based therapeutics, and evaluate responses to immunotherapy. Herein, we review the merits and limitations of various noninvasive imaging modalities (MRI, PET, and single-photon emission tomography) and discuss candidate targets for cellular and molecular imaging for visualization of T-cell responses at various stages along the cancer-immunity cycle in the context of immunotherapy. We also discuss the potential use of these imaging strategies in monitoring treatment responses and predicting prognosis for patients treated with immunotherapy.

Dual-energy CT in predicting Ki-67 expression in laryngeal squamous cell carcinoma.

PURPOSE: To investigate whether multiple dual-energy computed tomography (DECT) parameters can noninvasively predict the Ki-67 expression (associated with survival and prognosis) in laryngeal squamous cell carcinoma (LSCC). METHODS: Eighty-eight patients with histologically proven LSCC were retrospectively reviewed. Multiple DECT-derived parameters were measured and correlated with Ki-67 expression by Spearman correlation analysis. Comparisons of the DECT-derived parameters between tumors with low- and high-level expression of Ki-67 were made with the t-tests. RESULTS: The iodine concentration (IC), normalized IC (NIC), effective atomic number (Zeff), 40-80 keV, and slope (k) values were positively correlated with Ki-67 expression (all p < 0.05, rho=0.367-0.548). Among all DECT-derived parameters, NIC value had the highest r value in correlation with Ki-67 expression. The IC, NIC, Zeff, 40-80 keV, and slope (k) values were significantly higher in LSCC with high Ki-67 expression than in those with low Ki-67 expression (all p < 0.05). CONCLUSIONS: Multiple DECT-derived parameters (IC, NIC, Zeff, 40-80 keV, and slope (k)) can be used as predictors of survival and prognosis in LSCC, among which the NIC value is the strongest.

Nicotinamide ameliorates energy deficiency and improves retinal function in Cav-1-/- mice.

Caveolin-1(Cav-1) is involved in lipid metabolism and energy homeostasis, which is important for the energetically demanding retina. Although retinal function deficits were noted in Cav-1 knockout (Cav-1-/- ) mice, the underlying causes remain largely unknown. Here, we investigate if the disruption in energy homeostasis presents a potential mechanism for retinal function deficits in Cav-1-/- retina and if it can be ameliorated by nicotinamide (NAM). In this study, NAM was administrated orally for 2 weeks in Cav-1-/- mice before experiments. Oxidative lipidomics was conducted to detect the oxylipin changes, the retinal energy flux was measured by seahorse assay, and the retinal function was assessed by electroretinogram (ERG). Cav-1 deficiency induced the dysregulation of oxidative lipidomics and reduction in energy consumption/production in the retina by decreasing Na+ /K+ -ATPase, oxidative phosphorylation CII, cytochrome c, and oxygen consumption rate (OCR). A decrease in Sirt1 was also detected. Therapeutic administration of NAM significantly increased Sirt1 expression and improved energy deficiency by increasing Na+ /K+ -ATPase, cytochrome c, and OCR. The dysregulation of oxidative lipidomics was partially recovered, and the retinal function was improved as assessed by ERG compared to Cav-1-/- mice. Our study demonstrated the dysregulation of oxidative lipidomics in Cav-1-/- retina and established a link between energy deficiency and retinal function deficits in Cav-1-/- mice. Administration of NAM ameliorated energy deficiency, increased the expression of Sirt1, and improved retinal function, which presents a potential therapeutic strategy for Cav-1 deficiency-induced retinal function deficits.

Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy.

Retinal ischemia/reperfusion injury (RI) is a common cause of irreversible visual impairment and blindness in elderly and critical unmet medical need. While no effective treatment is available for RI, microglial activation and local immune responses in the retina are thought to play important roles in the pathophysiology of neurodegeneration. While survival and activation of microglia depend critically on colony-stimulating factor receptor (CSF-1R) signaling, it remains unclear if targeting the retinal immune microenvironments by CSF-1RAb after RI is sufficient to rescue vision and present a potentially effective therapy. Here we used rodent models of RI and showed that retinal ischemia induced by acute elevation of intraocular pressure triggered an early activation of microglia and macrophages in the retina within 12 h. This was followed by lymphocyte infiltration and increased production of pro-inflammatory cytokines. Intravitreal injection of CSF-1R neutralizing antibody (CSF-1RAb) after RI significantly blocked microglial activation and the subsequent T cell recruitment. This also led to improved retinal ganglion cell survival and function measured by cell quantification and electroretinogram positive scotopic threshold responses, as well as increased visual acuity and contrast sensitivity as assessed by optomotor reflex-based assays, when compared to the isotype-treated control group. Moreover, the administration of CSF-1RAb efficiently attenuated inflammatory responses and activation of human microglia in culture, suggesting a therapeutic target with human relevance. These results, together with the existing clinical safety profiles, support that CSF-1RAb may present a promising therapeutic avenue for RI, a currently untreatable condition, by targeting microglia and the immune microenvironment in the retina to facilitate neural survival and visual function recovery.