Clinical application of combination [11C]C-methionine and [13N]N-ammonia PET/CT in recurrent functional pituitary adenomas with negative MRI or [18F]F-FDG PET/CT.

BACKGROUND: We assessed the value of positron emission tomography/computed tomography (PET/CT) with [13N]N-ammonia ([13N]N-NH3) and [11C]C-methionine ([11C]C-MET) for the evaluation and management of recurrent secreting pituitary adenoma, which could not be detected by magnetic resonance imaging (MRI) or fluorine-18 fluorodeoxyglucose ([18F]F-FDG) PET. METHODS: Nine consecutive patients with biochemical and clinical evidence of active recurrent tumor not detected by MRI and [18F]F-FDG PET were enrolled in this study. All of the patients underwent [13N]N-NH3 and [11C]C-MET PET/CT, after which the pattern of tracer uptake was studied, the tumor position was located, and a clinical decision was made. RESULTS: In general, [11C]C-MET had a higher uptake in pituitary adenomas (PAs) than that in pituitary tissues, while [13N]N-NH3 had a higher uptake in pituitary tissue than in pituitary adenomas. Increased [11C]C-MET uptake was observed in all nine PAs and three pituitary tissues, while all pituitary tissues and only one pituitary adenoma showed increased [13N]N-NH3 uptake. Four patients had concordant imaging and surgical findings indicative of biochemical remission without hypopituitarism after treatment. Radiotherapy was adopted in two patients, medication in another two, and follow-up observation in one case. CONCLUSION: Combined [11C]C-MET and [13N]N-NH3 PET/CT is effective in the differentiation of PAs from pituitary tissue in recurrent functional PAs with negative MRI or [18F]F-FDG PET. These results provide a valuable reference for further disease management.

Correlation between tumor invasion and somatostatin receptor subtypes in acromegaly.

OBJECTIVE: The low expression of somatostatin receptor (SSTR) subtypes in somatotropinoma is associated with a poor response to somatostatin analogs (SSAs). However, the correlation between SSTRs and tumor invasion has not yet been clarified. Therefore, the authors aimed to investigate the relationship between SSTRs and tumor invasion, as well as the correlation between tumor invasiveness and pharmacological response to SSAs. METHODS: A total of 102 patients with acromegaly who underwent surgery between December 2016 and December 2021 at the largest pituitary tumor surgery center in southern China were included in this retrospective study. Patients were divided into the noninvasive tumor group (Knosp grades 0-2 and Hardy-Wilson grade I or II) and invasive group (either Knosp grade 3 or 4 or Hardy-Wilson grade III or IV). The positive response to SSAs was defined by the following criteria after at least 3 months of SSA treatment: 1) ≥ 50% reduction or age- and sex-adjusted normal range of insulin-like growth factor-1 (IGF-1) level; 2) ≥ 80% reduction in or normal range of growth hormone (GH) level; or 3) > 20% reduction in tumor volume. The reference for the normal range of age- and sex-adjusted serum IGF-1 levels was derived from a survey of 2791 healthy adults (1339 males and 1452 females) in China. Demographics and clinical characteristics including tumor size, biochemical assessment, expression levels of SSTRs, and response to preoperative SSAs were compared between the invasive group and noninvasive group. Receiver operating characteristic (ROC) curve analysis was performed to assess the association between SSTR2 and tumor invasion. RESULTS: Compared with the noninvasive group, the invasive group presented with a larger tumor size (9.99 ± 10.41 cm3 vs 3.50 ± 4.02 cm3, p < 0.001), relatively lower SSTR2 expression (p < 0.001), and poorer response to SSAs (36.4% vs 91.7%, p < 0.001). In addition, there was a significant negative correlation between SSTR2 mRNA level and tumor size (r = -0.214, p = 0.031). However, there were no statistically significant differences in the expression of SSTR1, SSTR3, and SSTR5 between the groups. ROC analysis revealed that the low SSTR2 mRNA level was closely associated with tumor invasion (area under the curve 0.805, p < 0.0001). CONCLUSIONS: Tumor invasion is negatively correlated with SSTR2 level but is not associated with other SSTR subtypes. Patients with invasive tumors have a poorer response to SSA therapy, which may be due to the low level of SSTR2 expression. Therefore, SSTR2 could be considered as a routine investigative marker for aiding management of postoperative residual tumors.

Feasibility analysis of ACTH adenoma model in USP8-/- mice.

INTRODUCTION: Patients with adrenocorticotropic hormone (ACTH)-secreting pituitary tumours (35% to 60%) present with somatic mutations in the USP8 gene. USP8 mutations lead to enhanced deubiquitination of the epidermal growth factor receptor (EGFR) and result in an imbalance in EGFR signalling, accompanied by excessive activation of ACTH production and cell growth. USP8 emerged as a novel and exciting candidate gene for Cushing's disease. MATERIAL AND METHODS: In this study, USP8 mutant mouse models (USP8+/- and USP8-/-) were established, their phenotypes were analysed and identified, biochemical indexes were detected, pituitary and adrenal tissue specimens were taken for HE staining and immunohistochemical identification of hormones, and the differences between the 2 groups of mutant mice and wild type mice were analysed and compared. RESULTS: Compared with the control group (wild type), immunofluorescence assay results for USP8+/- mice and USP8-/- mice showed increased pituitary ACTH expression, which was statistically different (p < 0.05), and there were no significant differences in body weight, plasma ACTH, 24-hour urinary free cortisol, and immunohistochemical results. Higher blood glucose in USP8-/- mice than in USP8+/+ mice was observed. The heart rates of USP8-/- mice were higher than those of USP8+/- mice and USP8+/+ mice. HE staining and tissue fibre staining were done, and no significant pathological changes were seen in the 3 groups of pituitary and adrenal tissues. CONCLUSION: USP8 knockout mice have the potential to form an animal model of ACTH adenoma.

Facial Emotion Recognition Using a Novel Fusion of Convolutional Neural Network and Local Binary Pattern in Crime Investigation.

The exploration of facial emotion recognition aims to analyze psychological characteristics of juveniles involved in crimes and promote the application of deep learning to psychological feature extraction. First, the relationship between facial emotion recognition and psychological characteristics is discussed. On this basis, a facial emotion recognition model is constructed by increasing the layers of the convolutional neural network (CNN) and integrating CNN with several neural networks such as VGGNet, AlexNet, and LeNet-5. Second, based on the feature fusion, an optimized Central Local Binary Pattern (CLBP) algorithm is introduced into the CNN to construct a CNN-CLBP algorithm for facial emotion recognition. Finally, the validity analysis is conducted on the algorithm after the preprocessing of face images and the optimization of relevant parameters. Compared with other methods, the CNN-CLBP algorithm has higher accuracy in facial expression recognition, with an average recognition rate of 88.16%. Besides, the recognition accuracy of this algorithm is improved by image preprocessing and parameter optimization, and there is no poor-fitting. Moreover, the CNN-CLBP algorithm can recognize 97% of the happy expressions and surprised expressions, but the misidentification rate of sad expressions is 22.54%. The research result provides data reference and direction for analyzing psychological characteristics of juveniles involved in crimes.

Prevalence and clinical characteristics of Crooke's cell adenomas in 101 patients with T-PIT-positive pituitary adenomas: Case series and literature review.

Purpose: We aimed to perform a retrospective analysis of a rare subtype of corticotroph adenoma, Crooke's cell adenoma, to better understand its clinical features. Methods: We collected T-PIT-positive pituitary adenomas and screened Crooke's cell adenomas from January 2020 to December 2021 in our center. Case reports of such tumors were also collected through a literature search. Clinical data such as biochemical tests, imaging examinations, and pathological data of the above cases were analyzed. Results: A total of 101 T-PIT-positive patients were treated in our center in the last 2 years, and 4 were finally pathologically diagnosed with Crooke's cell adenomas. All of these patients were male with elevated adrenocorticotropic hormone levels, and 50.0% presented with hypercortisolemia, Cushing's syndrome, visual impairment, and headache. The tumor diameter was significantly larger in these 4 patients (37.0 mm) than in the other patients (26.0 mm), and their tumor invasive behavior was more pronounced. Cases reported in the literature were mainly female (72.8%), and the clinical presentation was also dominated by Cushing's syndrome (65.1%) and hormonal dysfunction. Tumors were more common as macroadenomas (33.2 mm) and suprasellar growths (63.8%). The tumor recurrence rate was as high as 55.6%, with 6 cases progressing to pituitary carcinomas and 7.7% of tumor-related deaths. Our further integrated analysis of our center and reported cases revealed that gender, Cushing's syndrome, visual dysfunction, hormonal disorders, and tumor growth characteristics were statistically different in different tumor categories. Conclusion: Crooke's cell adenoma is a tumor subtype with obvious clinical aggressive behavior, and an in-depth analysis of its clinical characteristics may assist in developing a comprehensive treatment plan.

Multiparametric MRI Features Predict the SYP Gene Expression in Low-Grade Glioma Patients: A Machine Learning-Based Radiomics Analysis.

PURPOSE: Synaptophysin (SYP) gene expression levels correlate with the survival rate of glioma patients. This study aimed to explore the feasibility of applying a multiparametric magnetic resonance imaging (MRI) radiomics model composed of a convolutional neural network to predict the SYP gene expression in patients with glioma. METHOD: Using the TCGA database, we examined 614 patients diagnosed with glioma. First, the relationship between the SYP gene expression level and outcome of survival rate was investigated using partial correlation analysis. Then, 7266 patches were extracted from each of the 108 low-grade glioma patients who had available multiparametric MRI scans, which included preoperative T1-weighted images (T1WI), T2-weighted images (T2WI), and contrast-enhanced T1WI images in the TCIA database. Finally, a radiomics features-based model was built using a convolutional neural network (ConvNet), which can perform autonomous learning classification using a ROC curve, accuracy, recall rate, sensitivity, and specificity as evaluation indicators. RESULTS: The expression level of SYP decreased with the increase in the tumor grade. With regard to grade II, grade III, and general patients, those with higher SYP expression levels had better survival rates. However, the SYP expression level did not show any significant association with the outcome in Level IV patients. CONCLUSION: Our multiparametric MRI radiomics model constructed using ConvNet showed good performance in predicting the SYP gene expression level and prognosis in low-grade glioma patients.

MEG3/MIR-376B-3P/HMGA2 axis is involved in pituitary tumor invasiveness.

OBJECTIVE: To date, long noncoding RNAs (lncRNAs) have proven to function as key regulators in tumorigenesis. Among these lncRNAs, MEG3 displays low levels in various neoplasms and tumor cell lines. However, the regulatory mechanism of MEG3 and MIR-376B-3P, one of the microRNAs from downstream gene clusters of the DLK1-MEG3 locus, remains insufficiently defined. METHODS: The authors used quantitative real-time polymerase chain reaction analysis to analyze whether decreased MEG3 and MIR-376B-3P expression levels were associated with the invasiveness of clinical nonfunctioning pituitary adenomas (CNFPAs) in 30 patients. Furthermore, functional experiments unveiled the pathophysiological role of MEG3, MIR-376B-3P, and HMGA2 in pituitary-derived folliculostellate (PDFS) cell lines. Moreover, dual-luciferase reporter assay, Western blot analysis, and immunofluorescence were applied to reveal the correlations among MEG3, MIR-376B-3P, and HMGA2. RESULTS: MEG3 and MIR-376B-3P were decreased in patients with CNFPA, and their transcriptional levels were highly associated with invasive CNFPAs. Moreover, excessive expression of MEG3 and MIR-376B-3P inhibited tumorigenesis and promoted apoptosis in PDFS cells. Importantly, the authors found that MEG3 acted as an enhancer of MIR-376B-3P expression. Furthermore, as a target gene of MIR-376B-3P, HMGA2 served as an oncogene in pituitary adenoma and could be negatively regulated by MEG3 via enriching MIR-376B-3P. CONCLUSIONS: This study offers a novel mechanism of an MEG3/MIR-376B-3P/HMGA2 regulatory network in CNFPAs, which may become a breakthrough for anticancer treatments.

Common tools for pituitary adenomas research: cell lines and primary cells.

PURPOSE: Pituitary tumor is the common primary brain tumor in humans. For further studying the pathogenesis and new therapeutic targets of pituitary adenoma, cell lines and primary cells are necessary tools. Different from primary cells that have short survival time and hormone secretion maintenance time, cell lines would be endowed with immortal characteristics under the help of gene modification. This review is to explore whether these cell lines still have similar pathophysiological changes in pituitary adenoma cells and methods to prolong the lifespan of pituitary adenoma primary cells. RESULTS: In the cell lines summarized in the review, HP75, PDFS, HPA and GX were derived from human pituitary adenomas. It was found that the cell lines commonly used in articles published between January 2014 and July 2019 were GH3, AtT20, MMQ, GH4C1, HP75 and TtT/GF. Besides, it was glad that many methods had been used to prolong the lifespan and maintain characteristics of pituitary adenoma primary cells. CONCLUSION: The paper reviews most of pituitary adenoma cell lines that have been successfully established since 1968 and the relevant situation of primary culture of pituitary adenoma cells. Obviously, it requires us to make more efforts to obtain human pituitary adenoma cell lines and prolong the lifespan of pituitary adenoma primary cells with maintaining their morphology and ability to secret hormones.

MiR-1299 promotes the synthesis and secretion of prolactin by inhibiting FOXO1 expression in drug-resistant prolactinomas.

Prolactinoma is a clinically common intracranial tumor. When serum prolactin levels are not controlled despite administration of a dopamine agonist, the condition is referred to as drug-resistant prolactinoma. The mechanism underlying persistent prolactin secretion in drug-resistant prolactinoma remains unclear. MicroRNAs play an important role in tumorigenesis and development as well as chemotherapeutic resistance. This study was conducted to investigate the mechanism by which miRNA regulates prolactin secretion in drug-resistant prolactinoma. We first found that miR-1299 was elevated in drug-resistant prolactinoma and inhibited FOXO1 in a targeted manner through miRNA sequencing and luciferase assays. We then confirmed that FOXO1 binds to the promoter of the prolactin gene to inhibit its expression through chromatin immunoprecipitation-quantitative PCR and cytological experiments. Finally, inhibition or overexpression of miR-1299 in primary tumor cells confirmed that drug-resistant prolactinoma promoted prolactin secretion by promoting miR-1299 expression and reducing intracellular FOXO1. These results indicate that FOXO1 and miR-1299 are potential therapeutic targets for drug-resistant prolactinoma as well as other pituitary diseases.

miR-93-5p targets Smad7 to regulate the transforming growth factor-ß1/Smad3 pathway and mediate fibrosis in drug-resistant prolactinoma.

Prolactinoma is a common subtype of pituitary tumors. Dopamine receptor agonists are the preferred treatment for prolactinoma; however, with this therapy, drug resistance often occurs. In our previous work, we found that partial resistant prolactinomas showed increased fibrosis and that the transforming growth factor (TGF)-ß1/Smad3 signaling pathway mediated fibrosis and was involved in drug resistance. Additionally, the success of surgery is known to be heavily influenced by the consistency of the pituitary adenoma. Therefore, in this study, we aimed to clarify the mechanisms of fibrosis in prolactinoma. Using high-throughput sequencing for analysis of microRNAs, we found that miR-93-5p was significantly upregulated in prolactinoma samples with a high degree of fibrosis compared with that in samples without fibrosis. Furthermore, we found that miR-93-5p was negatively correlated with the relative expression of Smad7 and positively correlated with the relative expression of TGF-ß1 in clinical prolactinoma samples. In addition, luciferase reporter assays showed that miR-93-5p could downregulate the Smad7 gene, an important inhibitor of the TGF-ß1/Smad3 signaling pathway, and activate TGF-ß1/Smad3 signaling-mediated fibrosis in a feed-forward loop. Moreover, miR-93-5p could enhance the drug resistance of prolactinoma cells by regulation of TGF-ß1/Smad3-dependent fibrosis. Taken together, our findings demonstrated that miR-93-5p may be a potential therapeutic target for inhibiting fibrosis and reducing drug resistance in prolactinoma cells.

circOMA1-Mediated miR-145-5p Suppresses Tumor Growth of Nonfunctioning Pituitary Adenomas by Targeting TPT1.

CONTEXT: Nonfunctioning pituitary adenomas (NFPAs) are the major cause of hypopituitarism and infertility. However, the pathogenesis of NFPAs remains largely unknown. Previous studies have demonstrated the crucial role of miRNAs in the progression of pituitary adenomas. Increasing evidence has indicated that circular RNAs (circRNAs) might mediate miRNA transcriptional activity, providing new insights to study the pathogenesis of NFPAs. OBJECTIVES: To explore the regulation and activity of the circRNA-miRNA-mRNA axis in the tumorigenesis of NFPAs. DESIGN: The function of miR-145-5p in NFPAs was investigated invitro and invivo. The mechanical details were explored and potential targets of miR-145-5p were identified. Finally, miR-145-5p-associated circRNAs were functionally recognized and confirmed. RESULTS: miR-145-5p was markedly decreased in NFPA samples and correlated negatively with NFPA invasiveness. Overexpression of miR-145-5p suppressed NFPA cell proliferation and invasiveness and promoted apoptosis. Further results confirmed that translationally controlled tumor protein (TPT1) is a target of miR-145-5p and mediated the effect of miR-145-5p. TPT1 and its downstream factors Mcl-1 and Bcl-xL were downregulated, and Bax was upregulated by miR-145-5p. Moreover, circOMA1 (hsa_circRNA_0002316) was demonstrated to sponge miR-145-5p, whose suppression on NFPA cells was abrogated by circOMA1 overexpression. circOMA1 silencing exhibited a similar inhibitory effect with miR-145-5p overexpression by downregulating TPT1. We found that circOMA1 could further upregulate Mcl-1 and Bcl-xL and downregulate Bax. CONCLUSIONS: circOMA1 promotes NFPA progression by acting as the sponge of tumor suppressor miR-145-5p to regulate the TPT1 signaling pathway, revealing a therapeutic target in preventing the tumorigenesis of NFPAs.

Incidence rate and risk factors of early repolarization in patients with growth hormone-secreting pituitary adenoma: a cohort study.

PURPOSE: To investigate the incidence and risk factors for early repolarization (ER) in patients with growth hormone (GH)-secreting pituitary adenomas. METHODS: From August 2014 to August 2016, patients with GH-secreting pituitary adenomas and non-functioning pituitary adenomas admitted to the First Affiliated Hospital, Sun Yat-sen University, were prospectively enrolled. Logistic regression analysis was used to investigate risk factors for ER development. RESULTS: A total of 118 patients with GH-secreting pituitary adenomas (41 with concomitant ER) and 103 patients with non-functioning pituitary adenomas were included. Compared with the non-functioning adenoma group GH and IGF-1 levels, left ventricular mass index (LVMI), and incidence of ER were significantly higher in the GH-secreting pituitary adenoma group (all P<0.05). LVMI was an independent risk factor for ER. Bivariate correlation analysis showed that course of disease, GH, IGF-1, and diabetes were correlated with LVMI. Course of disease and IGF-1 were directly correlated with LVMI. Two-year follow-up of patients who underwent transsphenoidal resection showed that incidence of ER was significantly decreased in patients with normal GH and IGF-1 levels. CONCLUSION: Compared with non-functioning pituitary adenoma patients, patients with GH-secreting pituitary adenomas have a significantly higher incidence of ER. Elevation of serum GH and IGF-1 had positive correlations with cardiac muscle cell hypertrophy and increased LVMI.

MicroRNAs and Target Genes in Pituitary Adenomas.

Pituitary adenomas account for the top three primary intracranial tumors in terms of total incidence rates. The clinical symptoms presented by the disease are often characterized by a series of systemic endocrine disorders, severe occupational lesions, and even some malignant features, and therefore early diagnosis and predicting recurrence would be instructive for clinical treatment of pituitary adenomas. An increasing number of specific microRNA (miRNA) expression signatures have been identified in pituitary, and miRNAs are related with the pituitary tumorigenesis, dysfunction, neurodegeneration, and metastatic non-functioning pituitary carcinoma. Here, this paper reviews the effects of aberrant miRNA expression in human pituitary adenomas and summarizes some corresponding target genes and biological significance over the last 7 years (2010-2017).