Occult SMARCA4-Deficient Undifferentiated Carcinoma Unmasked by 68Ga-FAPI-46 PET/CT.

ABSTRACT: SMARCA4-deficient undifferentiated tumors (SMARCA4-dUT) are rare and aggressive neoplasms commonly found in male smokers and portend a poor prognosis. In this case, we reported 18F-FDG and 68Ga-FAPI-46 PET/CT findings in an occult SMARCA4-dUT located in the left pulmonary hilum along with mediastinal lymph node metastases. 68Ga-FAPI-46 PET/CT showed superiority over 18F-FDG for detecting SMARCA4-dUT lesions. This case highlighted that 68Ga-FAPI-46 PET/CT may be a promising imaging modality in the evaluation of SMARCA4-dUT, particularly for detecting the occult SMARCA4-dUT arising in uncommon sites.

Borneol-modified docetaxel plus tetrandrine micelles for treatment of drug-resistant brain glioma.

OBJECTIVE: Glioma is the most common and deadly primary malignant tumor in adults. Treatment outcomes are ungratified due to the presence of blood-brain barrier (BBB), glioma stem cells (GSCs) and multidrug resistance (MDR). Docetaxel (DTX) is considered as a potential drug for the treatment of brain tumor, but its effectiveness is limited by its low bioavailability and drug resistance. Tetrandrine (TET) reverses the resistance of tumor cells to chemotherapy drugs. Borneol (BO) modified in micelles has been shown to promote DTX plus TET to cross the BBB, allowing the drug to better act on tumors. Therefore, we constructed BO-modified DTX plus TET micelles to inhibit chemotherapeutic drug resistance. SIGNIFICANCE: Provide a new treatment method for drug-resistant brain gliomas. METHODS: In this study, BO-modified DTX plus TET micelles were prepared by thin film dispersion method, their physicochemical properties were characterized. Its targeting ability was investigated. The therapeutic effect on GSCs was investigated by in vivo and in vitro experiments. RESULTS: The BO-modified DTX plus TET micelles were successfully constructed by thin film dispersion method, and the micelles showed good stability. The results showed that targeting micelles increased bEnd.3 uptake and helped drugs cross the BBB in vitro. And we also found that targeting micelles could inhibit cell proliferation, promote cell apoptosis and inhibit the expression of drug-resistant protein, thus provide a new treatment method for GSCs in vitro and in vivo. CONCLUSIONS: BO-modified DTX plus TET micelles may provide a new treatment method for drug-resistant brain gliomas.

Fibroblast Activation Protein-Targeted PET/CT with 18F-Fibroblast Activation Protein Inhibitor-74 for Evaluation of Gastrointestinal Cancer: Comparison with 18F-FDG PET/CT.

Fibroblast activation protein is overexpressed in the stroma of several cancer types. 18F-fibroblast activation protein inhibitor (FAPI)-74 is a PET tracer with high selectivity for fibroblast activation protein and has shown high accumulation in human tumors in clinical studies. However, the use of 18F-FAPI-74 for PET imaging of gastrointestinal cancer has not been systematically investigated. Herein, we investigated the diagnostic accuracy of 18F-FAPI-74 (18F-LNC1005) PET/CT in gastric, liver, and pancreatic cancers and compared the results with those of 18F-FDG PET/CT. Methods: This prospective study analyzed patients with confirmed gastric, liver, or pancreatic malignancies who underwent concurrent 18F-FDG and 18F-FAPI-74 PET/CT between June 2022 and December 2022. PET/CT findings were confirmed by histopathology or radiographic follow-up. 18F-FDG and 18F-FAPI-74 uptake and tumor-to-background ratios were compared using the Wilcoxon signed-rank test. The McNemar test was used to compare the diagnostic accuracy of the 2 scans. Results: Our cohort consisted of 112 patients: 49 with gastric cancer, 39 with liver cancer, and 24 with pancreatic cancer. Among them, 69 patients underwent PET/CT for initial staging and 43 for recurrence detection. Regarding lesion-based diagnostic accuracy, 18F-FAPI-74 PET/CT showed higher sensitivity than did 18F-FDG in the detection of primary tumors (gastric cancer, 88% [22/25] vs. 60% [15/25], P = 0.016; liver cancer, 100% [22/22] vs. 82% [18/22], P = 0.125; pancreatic cancer, 100% [22/22] vs. 86% [19/22], P = 0.250), local recurrence (92% [23/25] vs. 56% [14/25]; P = 0.021), involved lymph nodes (71% [41/58] vs. 40% [23/58]; P < 0.001), and bone and visceral metastases (98% [350/358] vs. 47% [168/358]; P < 0.001). Compared with 18F-FDG, 18F-FAPI-74 PET/CT upstaged 17 patients' TNM staging among all treatment-naïve patients (17/69, 25%) and changed the clinical management of 4 patients (4/43, 9%) in whom recurrence or metastases were detected. Conclusion: 18F-FAPI-74 PET/CT is superior to 18F-FDG PET/CT in detecting primary tumors, local recurrence, lymph node involvement, and bone and visceral metastases in gastric, pancreatic, and liver cancers, with higher uptake in most primary and metastatic lesions.

Superior Identification of Metastatic Lesions by 68 Ga-FAPI-46 to 18 F-FDG PET/CT in a Case of SMARCA4-Deficient Undifferentiated Carcinoma of Stomach.

ABSTRACT: SMARCA4-deficient undifferentiated carcinoma is a new clinical entity characterized by SMARCA4 inactivation and has a dismal prognosis because of rapid growth. In this case, we reported 18 F-FDG and 68 Ga-FAPI-46 PET/CT imaging findings in a patient with SMARCA4-deficient undifferentiated carcinoma of stomach. 68 Ga-FAPI-46 PET/CT showed much higher tumor-to-background contrast of primary tumor and revealed more metastatic lesions than 18 F-FDG PET/CT. This case demonstrated the superiority of 68 Ga-FAPI PET/CT over 18 F-FDG for identifying both primary and metastatic lesions in SMARCA4-deficient undifferentiated carcinoma. This observation may add the information on the benefit of FAPI PET in oncology imaging.

Evaluation of FAPI PET imaging in gastric cancer: a systematic review and meta-analysis.

Purpose: Recent studies suggest that 68Ga-FAPI PET/CT demonstrated superiority over 18F-FDG PET/CT in the evaluation of various cancer types, especially in gastric cancer (GC). By comprehensively reviewing and analysing the differences between 68Ga-FAPI and 18F-FDG in GC, some evidence is provided to foster the broader clinical application of FAPI PET imaging. Methods: In this review, studies published up to July 3, 2023, that employed radionuclide labelled FAPI as a diagnostic radiotracer for PET in GC were analysed. These studies were sourced from both the PubMed and Web of Science databases. Our statistical analysis involved a bivariate meta-analysis of the diagnostic data and a meta-analysis of the quantitative metrics. These were performed using R language. Results: The meta-analysis included 14 studies, with 527 patients, of which 358 were diagnosed with GC. Overall, 68Ga-FAPI showed higher pooled sensitivity (0.84 [95% CI 0.67-0.94] vs. 0.46 [95% CI 0.32-0.60]), specificity (0.91 [95% CI 0.76-0.98] vs. 0.88 [95% CI 0.74-0.96]) and area under the curve (AUC) (0.92 [95% CI 0.77-0.98] vs. 0.52 [95% CI 0.38-0.86]) than 18F-FDG. The evidence showed superior pooled sensitivities of 68Ga-FAPI PET over 18F-FDG for primary tumours, local recurrence, lymph node metastases, distant metastases, and peritoneal metastases. Furthermore, 68Ga-FAPI PET provided higher maximum standardized uptake value (SUVmax) and tumour-to-background ratios (TBR). For bone metastases, while 68Ga-FAPI PET demonstrated slightly lower patient-based pooled sensitivity (0.93 vs. 1.00), it significantly outperformed 18F-FDG in the lesion-based analysis (0.95 vs. 0.65). However, SUVmax (mean difference [MD] 1.79 [95% CI -3.87-7.45]) and TBR (MD 5.01 [95% CI -0.78-10.80]) of bone metastases showed no significant difference between 68Ga-FAPI PET/CT and 18F-FDG PET/CT. Conclusion: Compared with 18F-FDG, 68Ga-FAPI PET imaging showed improved diagnostic accuracy in the evaluation of GC. It can be effectively applied to the early diagnosis, initial staging, and detection of recurrence/metastases of GC. 68Ga-FAPI may have the potential of replacing 18F-FDG in GC in future applications.

Increased 68 Ga-FAPI Uptake in Benign Metastasizing Leiomyoma.

ABSTRACT: Benign metastasizing leiomyomas (BMLs) are benign disseminated extrauterine tumors in patients with prior history of uterine leiomyomas and may occur years after hysterectomy. In this case, we presented 18 F-FDG and 68 Ga-FAPI PET/CT findings in a 37-year-old woman with benign leiomyoma metastasizing to lung and pelvis. The metastatic lesions demonstrated faint 18 F-FDG but elevated 68 Ga-FAPI activity, indicating the low level of glucose metabolism but excessive accumulation of activated fibroblasts in the BMLs. This case demonstrated that 68 Ga-FAPI PET/CT may be potentially useful in the evaluation of BMLs.

Visualization of Intermetastatic Heterogeneity in Mixed Neuroendocrine Carcinoma-Acinar Adenocarcinoma of the Prostate by 68 Ga-PSMA, 68 Ga-FAPI, and 18 F-FDG PET/CT.

ABSTRACT: Mixed neuroendocrine carcinoma-acinar carcinoma is an uncommon histological type of neuroendocrine prostate cancer. It has been rarely reported in de novo prostate malignancies. In this case, we present 68 Ga-PSMA (prostate-specific membrane antigen), 68 Ga-FAPI, and 18 F-FDG PET/CT findings in the de novo form of mixed large-cell neuroendocrine carcinoma-acinar adenocarcinoma of the prostate. Different levels of radiotracer uptake were observed in different metastatic sites on 68 Ga-PSMA, 68 Ga-FAPI, and 18 F-FDG PET/CT. This case demonstrates that the multitracer PET/CT strategy may be used for the noninvasive detection of the intermetastatic heterogeneity in metastatic neuroendocrine prostate cancer.

68 Ga-FAPI Versus 18 F-FDG PET/CT in the Evaluation of Epithelioid Hemangioendothelioma of Bone.

ABSTRACT: Epithelioid hemangioendothelioma (EHE) is a rare type of vascular tumor that may arise in bone. Here we presented a 62-year-old man with suspected bone metastases who underwent PET/CT to detect the primary tumor. He underwent 18 F-FDG and 68 Ga-FAPI PET/CT under the prospective trial NCT04416165. Radiotracer uptake was much higher with 68 Ga-FAPI PET/CT than with 18 F-FDG PET/CT in most of bone lesions. No intense uptake likely presenting the primary tumor was observed. Subsequent bone biopsy confirmed the diagnosis of EHE of bone. This case suggested that 68 Ga-FAPI PET/CT might be a useful tool for evaluation of EHE.

Dynamic Changes of NCR- Type 3 Innate Lymphoid Cells and Their Role in Mice with Bronchopulmonary Dysplasia.

Inflammation is one of the important pathogenesis of bronchopulmonary dysplasia (BPD). Type 3 innate lymphoid cells (ILC3) play a role in a variety of inflammatory lung diseases. In this study, we established the BPD model by injecting lipopolysaccharide into the amniotic cavity of pregnant mice. Here, we investigated the dynamic changes of ILC3 and NKP46- ILC3 population in lung tissues of mice from BPD and the control groups. Results showed that the proportion of ILC3 and NKP46-ILC3 in the BPD group was higher than those of the control group. In addition, the cytokines interleukin-17 (IL-17) and interleukin-22 (IL-22) secreted by ILC3 in this model had also changed that their expression was significantly increased compared with that of the control group. Flow cytometry demonstrated that ILC3 were a rapid source of IL-17. In the anti-CD90 knockdown experiment, we confirmed the alleviation of BPD inflammation in the absence of ILC3. In addition, we injected mice with anti-IL-17 neutralizing antibody, and the results showed that IL-17 could aggravate BPD inflammation. Taken together, ILC3 may play a pro-inflammatory role in BPD by secreting IL-17.

miR-874 ameliorates retinopathy in diabetic rats by NF-κB signaling pathway.

BACKGROUND: Increased activity of the NF-κB signaling pathway boosts the progression of retinopathy in diabetic rats. OBJECTIVES: Using a bioinformatics website, we identified a site where miR-874 binds to the NF-κB p65. Therefore, we speculated that miR-874 might improve retinopathy in diabetic rats by inhibiting the NF-κB signaling pathway. MATERIAL AND METHODS: Ten healthy rats were taken as the control group. Sixty streptozotocin (STZ; 60 mg/kg)-induced diabetes model rats were randomly divided into the model group (injection of normal saline), negative control (NC) agomir group (injection of NC mimic), miR-874 agomir group (injection of miR-874 mimic), miR-874 anti-agomir group (injection of miR-874 inhibitor), EVP4593 group (injection of NF-κB signaling pathway antagonist EVP4593), and miR-874 anti-agomir+EVP4593 group (injection of miR-874 inhibitor and EVP4593). All injections were administered into the caudal vein. RESULTS: miR-874 could target the degradation of p65. Compared with the control group, model rats had reduced miR-874 expression, increased vascular endothelial growth factor (VEGF) and Ang2 protein expression, lowered end-diastolic velocity (EDV) and peak systolic velocity (PSV) of the central retinal artery (CRA) and blood velocity of central retinal vein (CRV) and CRA, heightened plasma viscosity (PV), blood viscosity (BV) and erythrocyte sedimentation rate (ESR) at all shear rates, decreased capillary pericytes (IPCs), increased vascular endothelial cells (VECs), and ascended p65 expression in the retina (all p < 0.05). Thus, it was shown that pathological changes appeared in the retina of diabetic rats. These indices improved in diabetic rats injected with the miR-874 mimic or EVP4593, but deteriorated in those injected with miR-874 inhibitor (all p < 0.05). EVP4593 also could alleviate the aggravation of retinopathy that was caused by miR-874 inhibition in diabetic rats. CONCLUSIONS: miR-874 modulates the NF-κB signaling pathway by targeting the degradation of p65 to further improve the retina of diabetic rats, thus demonstrating the beneficial effect of miR-874 on diabetic retinopathy in rats.

Tissue-Resident Type 2 Innate Lymphoid Cells Arrest Alveolarization in Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a severe complication of the respiratory system associated with preterm birth. Type 2 innate lymphoid cells (ILC2s) play a major role in tissue homeostasis, inflammation, and wound healing. However, the role in BPD remains unclear. The present study showed that ILC2s, interleukin-4 (IL-4), IL-13, and anti-inflammatory (M2) macrophages increased significantly in BPD mice as compared to the control mice. Administration with recombinant mouse IL-33 amplified the above phenomena and aggravated the alveolar structural disorder and functional injury in mice subjected to BPD, and the opposite was true with anti-ST2 antibody. In addition, the depletion of ILC2s in BPD mice with anti-CD90.2 antibody substantially abolished the destructive effect on BPD. In the treatment of BPD with dexamethasone, the number of ILC2s and M2 macrophages and levels of IL-4 and IL-13 decreased with remission as compared to the control group. This study identified a major destructive role of the ILC2s in BPD that could be attenuated as a therapeutic strategy.

[The number of ILC3 and their related cytokines IL-17 and IL-22 increase in lungs of mice with bronchopulmonary dysplasia].

Objective To investigate dynamic changes of type 3 innate lymphoid cells (ILC3) in lungs of mice with bronchopulmonary dysplasia (BPD). Methods Forty newborn C57BL/6 mice were randomized into air group and the hyperoxia group, 20 mice in each group. C57BL/6 newborn mice were delivered by caesarean section on the 19th day of pregnancy and exposed to 850 mL/L O2 for replication of the BPD model. Five mice in each group were sacrificed 1 day, 3, 7, 14 days after they were born for procurement of fresh lung tissues. HE staining was used to observe the pathological changes of lung tissues. ELISA was used to detect the protein content of downstream cytokines interleukin-17 (IL-17), IL-22 and granulocyte-macrophage colony stimulating factor (GM-CSF) in lung homogenate. Flow cytometry was used for measuring the proportion of ILC3 in lymphocytes as well as the proportions of IL-17+ ILC3 and IL-22+ ILC3 in the lung. Results The proportion of ILC3 in lung tissues reached the peak on the 7th day after birth. In contrast with the air group, the proportion of ILC3 in the hyperoxia group was significantly elevated at the same time points. The protein content of IL-17 and IL-22 in the hyperoxia group went up significantly in comparison with those in the air group at the same time points, while the GM-CSF content in the hyperoxia group showed no significant changes. The proportions of IL-17+ILC3 and IL-22+ILC3 in the hyperoxia group significantly increased as compared with those in the air group at the same time points. Conclusion The secretion of IL-17 and IL-22 derived from ILC3 is associated with BPD.

SENP1 has an important role in lung development and influences the differentiation of alveolar type 2 cells.

Post­translational modification via small ubiquitin­like modifier (SUMO) is involved in the regulation of various important cellular processes. SUMO modification can be regulated at the level of conjugation, and can also be reversed by the SUMO­specific proteases (SENPs). However, current studies of the regulation and function of SENP in lung development remain limited. In this study, the expression levels of SENP1 and SUMO1 were assessed during lung development in rats. SUMO1 modification occurred during lung development and changes in SENP1 expression were consistent with the changes in the presence of free SUMO1. In order to investigate the function of SENP1, alveolar type (AT) 2 cells were transfected with SENP1­targeting small interfering RNA, and the proliferation, apoptosis and differentiation function of AT2 cells was subsequently evaluated. Marked upregulation of conjugated SUMO1 was observed following SENP1 inhibition. Furthermore, depletion of SENP1 resulted in increased apoptosis, decreased proliferation and impaired differentiation status of AT2 cells. Thus, the results support that SENP1 is an essential regulator of the balance between SUMOylation and deSUMOylation during lung development, specifically affecting the proliferation and differentiation status of AT2 cells.