The clinical significance of inflammatory mediators in predicting obesity and progression-free survival in patients with adult-onset Craniopharyngioma.

BACKGROUND: Craniopharyngioma (CP) is a rare malformational tumor characterized by high rates of recurrence and morbid obesity. However, the role of inflammatory mediators in obesity and the prognosis of patients with CP remains unknown. Therefore, the present study aimed to analyze associations of inflammatory mediators with weight-related outcomes and the prognosis of patients with CP. METHODS: A total of 130 consecutive patients with CP were included in this study. The expression levels of seven inflammatory mediators and the plasma leptin concentration were investigated. Clinical parameters, weight changes, new-onset obesity, and progression-free survival (PFS) were recorded. The relationships between inflammatory mediators, clinicopathologic parameters, weight-related outcomes, and PFS were explored. RESULTS: Compared with those in normal pituitary tissue, the expressions of inflammatory mediators in tumor tissue were higher. Higher expression levels of CXCL1 and CXCL8 were identified as independent risk factors for significant weight gain, and CXCL1 and TNF were identified as independent risk factors for new-onset postoperative obesity. Poor PFS was associated with higher expression levels of CXCL1, CXCL8, IL1A, IL6, and TNF. CONCLUSION: The present study revealed that inflammatory mediators are associated with morbid obesity in patients with CP. Inflammatory mediators may be the critical bridge between elevated leptin and weight-related outcomes. Additionally, PFS was associated with the expression of inflammatory mediators. Further research is needed to elucidate the underlying mechanisms of inflammatory mediators and their potential as targets for novel therapies for CP.

Gut microbiota composition and metabolic characteristics in patients with Craniopharyngioma.

BACKGROUND: Emerging evidence suggests that the gut microbiota is associated with various intracranial neoplastic diseases. It has been observed that alterations in the gut microbiota are present in gliomas, meningiomas, and pituitary neuroendocrine tumors (Pit-NETs). However, the correlation between gut microbiota and craniopharyngioma (CP), a rare embryonic malformation tumor in the sellar region, has not been previously mentioned. Consequently, this study aimed to investigate the gut microbiota composition and metabolic patterns in CP patients, with the goal of identifying potential therapeutic approaches. METHODS: We enrolled 15 medication-free and non-operated patients with CP and 15 healthy controls (HCs), conducting sequential metagenomic and metabolomic analyses on fecal samples to investigate changes in the gut microbiota of CP patients. RESULTS: The composition of gut microbiota in patients with CP compared to HCs show significant discrepancies at both the genus and species levels. The CP group exhibits greater species diversity. And the metabolic patterns between the two groups vary markedly. CONCLUSIONS: The gut microbiota composition and metabolic patterns in patients with CP differ significantly from the healthy population, presenting potential new therapeutic opportunities.

Acetazolamide Alleviate Cerebral Edema Induced by Ischemic Stroke Through Inhibiting the Expression of AQP4 mRNA.

OBJECTIVE: We want to investigate the effect of aquaporin-4 (AQP4) on cerebral edema induced by ischemic stroke in rats and explore whether inhibiting the expression of AQP4 through acetazolamide (AZA) could attenuate brain edema and protect cerebral function. METHODS: The Sprague Dawley (SD) rats were randomly divided into four groups: sham + saline group, sham + AZA group, AZA intervention group, and nonintervention group. Each group was divided into five subgroups according to the time of cerebral ischemia (6 h, 1 day, 3 days, 5 days, and 7 days). The model of cerebral infarction in rats was adopted by means of the bilateral carotid arteries ligation (2-VO) method. The rats in intervention group were given intraperitoneal injection of AZA (35 mg/kg/day). Hematoxylin-eosin staining was performed for pathological analysis of the infarcted area. The brain water content was calculated to evaluate the degree of brain edema. The messenger RNA (mRNA) and protein expressions of AQP4 in the brain were measured by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. RESULTS: Significant cerebral pathological damages were found in ischemic stroke rats. The brain water content, protein, and mRNA expression of AQP4 of the intervention and nonintervention groups were markedly higher than those of the sham groups. By contrast, AZA administration reduced the brain water content, whereas improved cerebral dysfunction was induced by ischemic stroke. Moreover, AZA obviously reduced the protein and mRNA expression of AQP4 after ischemic stroke in rats' brains. CONCLUSIONS: The expression of AQP4 was closely related to cerebral edema induced by ischemic stroke. Decreasing the expression of AQP4 mRNA by AZA administration can effectively relieve cerebral edema and decrease cerebral pathological damage.

Adult craniopharyngioma concomitant with unruptured intracranial aneurysms: incidence, risk factors, and treatment strategies.

OBJECTIVE: Concomitant unruptured intracranial aneurysms (UIAs) in patients with craniopharyngioma (CP) pose a challenge for surgical management. This study presents the largest known single-institution case series to investigate the incidence of UIA in CP patients, with the aim of exploring the potential risk factors for the occurrence of UIA in CP patients and proposing treatment strategies. METHODS: The authors retrospectively reviewed the records of 289 adult CP patients treated in their department between January 2020 and August 2022. Routine CT angiography (CTA) was performed preoperatively in all cases. Logistic regression analysis was used to identify the risk factors for the occurrence of aneurysms. Aneurysms with the following characteristics were considered to have a high risk of intraoperative rupture and required treatment before tumor resection: 1) preliminary assessment of a high inherent risk of rupture (risk of rupture in their natural progression); and 2) location close to the tumor, irregular shape, and/or growth toward the tumor, even if the preliminary assessment indicated a low inherent risk of rupture. RESULTS: Twenty-three of 289 CP patients (7.96%, 95% CI 5.36-11.6) were diagnosed with both CP and UIA (CP-UIA). Hypertension (OR 4.148, 95% CI 1.654-10.398; p = 0.002), estrogen deficiency (OR 3.097, 95% CI 1.241-7.731; p = 0.015), and suprasellar tumor (OR 4.316, 95% CI 1.596-11.67; p = 0.004) were independent risk factors for intracranial aneurysms (IAs) in CP patients. Among the 23 CP-UIA patients, 6 (26.1%) with a high risk of aneurysm rupture underwent endovascular treatment (EVT) before tumor resection. Seventeen (73.9%) patients with a low risk of rupture underwent tumor resection only. CONCLUSIONS: The incidence rate of IA in patients with CP was higher than that in the general population. Routine preoperative CTA is advised for adult CP patients. Patients with papillary CP exhibited a higher proportion of CP-UIAs. Older age, hypertension, estrogen deficiency, and suprasellar tumor were independent risk factors for the occurrence of IAs in CP patients. IAs in CP patients are predominantly located in the C6 and C7 segments of the internal carotid artery and are often suitable for EVT. When treating CP-UIAs, tumor-related symptoms, risk of aneurysm rupture, the spatial relationship between the tumor and IA, and the approach for tumor resection should be considered.

Effects of Craniotomy and Endoscopic Endonasal Transsphenoidal Surgery on Bodyweight in Adult-Onset Craniopharyngioma: A Single-Center Retrospective Study.

Craniopharyngioma (CP) is a histologically benign tumor with high mortality and morbidity. Although surgical treatment is essential in managing CP, the best surgical approach is debated. A retrospective cohort of 117 patients with adult-onset CP (AOCP) treated between 2018 and 2020 in Beijing Tiantan Hospital was identified and examined. The effects of traditional craniotomy (TC) and endoscopic endonasal transsphenoidal surgery (EETS) on the extent of surgical resection, hypothalamic involvement (HI), postoperative endocrine function, and postoperative weight were compared in the cohort. The cohort comprised 43 males and 74 females, divided into the TC (n = 59) and EETS (n = 58) groups. The EETS group possessed a higher rate of gross total resection (GTR) (adjusted odds ratio (aOR) = 4.08, p = 0.029) and improved HI (aOR = 2.58, p = 0.041) than the TC group. Worse postoperative HI was only observed in the TC group (5 patients). The EETS was associated with fewer adverse hormonal outcomes, including posterior pituitary dysfunction (aOR = 0.386, p = 0.040) and hypopituitarism (aOR = 0.384, p = 0.031). Additionally, multivariate logistic regression analysis confirmed that EETS was related to fewer cases of weight gain >5% (aOR = 0.376, p = 0.034), significant weight change (aOR = 0.379, p = 0.022), and postoperative obesity (aOR = 0.259, p = 0.032). Compared to TC, EETS shows advantages in accomplishing GTR, hypothalamus protection, postoperative endocrine function reservation, and postoperative weight control. These data suggest that the EETS deserves more application in managing patients with AOCP.

Clinical Significance of Plasma Leptin and Its Receptors mRNA Expression in Craniopharyngiomas: A Prospective Study.

Craniopharyngioma (CP) is a benign tumor with a high rate of obesity and frequent recurrence. Moreover, the role of leptin/leptin receptors axis in obesity and the prognosis of CP is still unknown. Plasma leptin concentration and mRNA expression of leptin receptors were assessed in patients with CP. Moreover, the association between leptin/leptin receptors axis, weight-related outcomes, and progression-free survival (PFS) were explored in CP patients. Leptin receptors overexpressed in CP tumor tissue were compared to normal brain tissue (p < 0.05); compared to healthy controls, the concentration of leptin was elevated in CP with or without matched age, sex, and body mass index (BMI) (p < 0.05). The high plasma leptin level was an independent risk predictor for significant weight gain (adjusted odds ratio (aOR) = 2.29, and p = 0.030) and new-onset obesity (aOR = 6.64, and p = 0.016). High plasma leptin level (adjusted hazard ratio (aHR) = 3.74, and p = 0.011) and leptin receptor (LEPR) mRNA expression (aHR = 3.12, and p = 0.045) were independent risk factors for poor PFS in CP. Inappropriately elevated leptin relative to BMI and its failure to inhibit further weight gain indicate the existence of leptin resistance in patients with CP. Leptin and LEPR were independent predictors for PFS of patients with CP. The leptin/leptin receptors axis may be a potential therapeutic target for obesity in patients with CP.

A Full View of Papillary Craniopharyngioma Based on Expanded Endonasal Approach: A Comprehensive Clinical Characterization of 101 Cases.

OBJECTIVE: The enlarged endonasal approach (EEA) has emerged as the preferred surgical procedure for removing craniopharyngiomas, due to its advantages of direct visualization and reduction of blind corners. However, owing to a low incidence of papillary CPs (PCPs) compared to adamantinomatous CPs (ACPs), a full view of PCP based on the EEA approach is limited. In this paper, the authors present the largest series to date analyzing the clinical characteristics based on the EEA approach for PCPs. METHODS: A retrospective review was conducted on 101 PCPs patients who underwent endoscopic endonasal surgery (EEA) and whose condition was confirmed via postoperative pathology. The PCPs were classified into three types based on MRI data and intraoperative findings from EEA: suprasellar/intra-suprasellar (3V floor intact) type (Type I), suprasellar/intra-suprasellar (3V floor invasive) type (Type II), and intra-third ventricle type (Type III). The general characteristics of the three types of tumors were summarized, and postoperative follow-up was conducted to record detailed information on changes in vision, endocrine replacement, tumor recurrence, and quality of life. RESULTS: Out of the 101 cases, 36 (36.64%) were classified as type I, 52 (51.49%) as type II, and 13 (12.87%) as type III. The mean age of type III patients was 40.46 ± 14.15 years old, younger than the other two types (p = 0.021). Headache (84.62%) and memory decline (61.54%) were prominent features in patients with type III (p = 0.029). Visual impairment was more common in type II (80.77%, p = 0.01). Gross total resection (GTR) was achieved in 91 patients (90.10%). There were no significant differences in GTR rates among the three types of tumors. There were significant differences in quality of life among the three types of PCP (p = 0.004), and type III presented with the highest rate of good postoperative quality of life (92.31%) based on the KPS score. Thirteen (12.87%) tumors recurred within a mean follow-up time of 38 (range, 8-63) months. Type II PCPs (OR 5.826, 95%CI 1.185-28.652, p = 0.030) and relapsed patients (OR 4.485, 95%CI 1.229-16.374, p = 0.023) were confirmed as independent risk factors for tumor recurrence. CONCLUSIONS: Most of the PCPs including intra-third ventricle PCPs can be safely and effectively removed through neuroendoscopy with EEA. Suprasellar/intra-suprasellar (third cerebral ventricle floor-invasive) type PCPs may have a worse postoperative quality of life compared to the other two types, and it may be a strong predictor of tumor recurrence.

Correlations between the expression of molecules in the TGF-ß signaling pathway and clinical factors in adamantinomatous craniopharyngiomas.

Objective: To investigate the clinical and pathological factors associated with preoperative hypothalamus invasion and postoperative outcomes of adamantinomatous craniopharyngiomas (ACPs) after the expanded endonasal approach (EEA) resection. Methods: Ninety-three specimens of ACPs, consisting of 71 primary and 22 recurrent tumors, were investigated for the expression of TGF-ß1, SMAD2, SMAD3, and ß-catenin by immunohistochemistry staining. The clinical information of relevant patients, including the extent of resection, hypothalamus invasion, endocrinopathy, complications, and prognosis, was reviewed. The relationships between the expression of these immunopathological markers and clinical factors were analyzed. Results: Endocrinological dysfunctions were more common in recurrent patients and primary patients with hypothalamus invasion in the comparisons. For recurrent patients, the rate of gross total resection (GTR) was significantly lower than for primary patients (63.6% vs. 90.1%, P = 0.007). According to radiological and intraoperative findings, invasive ACPs (IACPs) included 48 (67.6%) cases in primary tumors. The expression of TGF-ß1 and ß-catenin was significantly higher in recurrent tumors (P = 0.021 and P = 0.018, respectively) and IACPs (P = 0.008 and P = 0.004, respectively). The expression level of TGF-ß1 was associated with hypothalamus involvement (Puget grade, P = 0.05; Vile grade, P = 0.002), postoperative endocrinopathy (P = 0.01), and pituitary stalk preservation (P = 0.008) in primary patients. In addition, the extent of resection, treatment history, hypothalamic invasion, and level of TGF-ß1 expression had significant influences on tumor recurrence/progression after surgery separately. Conclusion: Our study demonstrated the potential role of TGF-ß1 in the regulation of hypothalamus invasion in ACPs and the prediction of prognosis after EEA surgery. The TGF-ß signaling pathway may represent a crucial mechanism in the aggressive behavior and progression of ACPs.

Identification of SAA1 as a prognostic biomarker associated with immune infiltration in glioblastoma.

Glioblastoma (GBM) is the most lethal tumour in the central nervous system (CNS), GBM has a poor prognosis due to treatment tolerance and tumour recurrence; new molecular biomarkers are needed to acquire accurate prognosis and to promote therapeutic strategies. Data from Gene Expression Omnibus (GEO) was analysed to screen differentially expressed genes (DEGs), and 279 DEGs were screened. The protein-protein interaction (PPI) network of DEGs was constructed and visualized, top 10 hub genes were identified by using Cytoscape consequently. The function of DEGs was explored by enrichment analysis, DEGs were enriched in tumour-associated biologic processions and pathways. Gene Expression Profiling Interactive Analysis (GEPIA) database was used to identify prognostic genes; serum amyloid A1 (SAA1) was identified as a critical prognostic gene due to higher SAA1 expression associated with poor overall survival (OS) (HR = 1.5, p < .05) and poor disease-free survival (DFS) (HR = 1.9, p < .01). Dataset from The Chinese Glioma Genome Atlas database validated the prognostic value of SAA1 and reported the relationship between SAA1 expression and clinical characteristics, including age, sex, history of relapse, and the status of IDH. Gene set enrichment analysis (GSEA) identified six SAA1-related pathways; the identification of pathways could provide insight into the therapeutic strategies of GBM. Lastly, the relationship between SAA1 expression and immune infiltration was explored, and the result showed that SAA1 expression negatively correlated with the infiltration level of T cells, and SAA1 expression positively correlated with the infiltration level of Treg cells. The overexpression of SAA1 was associated with poor OS and DFS in GBM, and the expression of the SAA1 gene may affect the infiltration level of immune cells. Therefore, SAA1 could be a promising prognostic biomarker associated with immune infiltration and therapeutic target for GBM.

Integrin α6 Indicates a Poor Prognosis of Craniopharyngioma through Bioinformatic Analysis and Experimental Validation.

Background: Craniopharyngioma (CP) is a benign slow-growing tumor. It tends to affect children, and the number of patients is on rise. Considering the high morbidity and mortality of CP, it is urgent and pivotal to identify new biomarkers to uncover the etiology and pathogenesis of CP. Methods: The "limma" package was utilized to calculate the data from the Gene Expression Omnibus (GEO) database. Based on differentially expressed genes (DEGs), gene ontology and pathway analysis were deduced from the DAVID web tool. Further, we constructed a protein-protein interaction (PPI) network. Weighted correlation network analysis (WGCNA) was utilized to build a coexpression network. Finally, Western blotting and survival analysis were performed to examine the expression level of important metabolism-related genes. Results: Three hundred and eighty-four DEGs were identified between normal tissues and CPs from the GSE94349 and GSE26966 datasets. The Venn diagram for DEGs and hub genes in the 'turquoise' module revealed four key genes. Finally, the outcome of the survival analysis suggested that Integrin α6 (ITGA6) significantly affected the overall survival time of the patients with CP. Conclusion: IGTA6, as a metabolism-related molecule, was found to be substantially related to the overall survival of patients with CP.

Emerging Roles of miRNA, lncRNA, circRNA, and Their Cross-Talk in Pituitary Adenoma.

Pituitary adenoma (PA) is a common intracranial tumor without specific biomarkers for diagnosis and treatment. Non-coding RNAs (ncRNAs), including microRNAs (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA), regulate a variety of cellular processes, such as cell proliferation, differentiation, and apoptosis. Increasing studies have shown that the dysregulation of ncRNAs, especially the cross-talk between lncRNA/circRNA and miRNA, is related to the pathogenesis, diagnosis, and prognosis of PA. Therefore, ncRNAs can be considered as promising biomarkers for PA. In this review, we summarize the roles of ncRNAs from different specimens (i.e., tissues, biofluids, cells, and exosomes) in multiple subtypes of PA and highlight important advances in understanding the contribution of the cross-talk between ncRNAs (e.g., competing endogenous RNAs) to PA disease.

Immune infiltration in aggressive papillary craniopharyngioma: High infiltration but low action.

Papillary craniopharyngiomas (PCPs) are biologically benign but clinically aggressive lesions hence affect the quality of life. The expression of inflammatory mediators and regulation of the immune microenvironment in PCPs have not been investigated much. In this study, for the first time, we assessed the immune cell infiltration and immune cell signatures in PCPs by analyzing the bulk-RNA sequencing data and immunohistochemical staining. Additionally, we performed qRT-PCR analysis to detect inflammatory mediators interleukin-1α (IL1A) and interleukin-6 (IL6) in different aggressive groups and then developed the IL1A and IL6 prediction models for defining the degree of hypothalamic invasion. Lastly, we defined differentially expressed genes related to invasiveness and implemented enrichment analysis to them. Our results indicated that PCPs are in a state of high immune infiltration but low action with abundant inflammatory cells. High infiltration of neutrophils may lead a low active immune microenvironment. Furthermore, the high expression level of IL1A and IL6 was positively correlated with the invasion of PCP tumors in the hypothalamus. These findings provide new pathological insights into the underlying mechanism of the immune microenvironment in PCP tumors. Moreover, IL1A and IL6 might serve as potential therapeutic targets for PCP tumors, especially to prevent their invasion into the hypothalamus.

Prognostic value of programmed death ligand 1 (PD-L1) in glioblastoma: a systematic review, meta-analysis and validation based on dataset.

Excellent prognostic value of programmed death ligand 1 (PD-L1) is observed in patients with other cancers; however, the prognostic value of PD-L1 in glioblastoma (GBM) remains unclear. Therefore, this meta-analysis evaluated the prognostic value of PD-L1 in GBM. We performed a systematic search in databases to screen eligible articles. The hazard ratio (HR) and 95% confidence interval (95% CI) were extracted from included articles. This meta-analysis included 15 studies, and the forest plot indicated that increased PD-L1 expression was associated with poorer overall survival (OS) of GBM (HR, 1.16; 95% CI, 1.05-1.27; P = 0.002). Furthermore, stratified analysis confirmed that PD-L1 expression was associated with unfavorable OS at the protein level (HR, 1.30; 95% CI, 1.13-1.48; P< 0.001) and messenger ribonucleic acid (mRNA) level (HR, 1.05; 95% CI, 1.00-1.09; P= 0.041). The analysis of a dataset verified the prognostic value of PD-L1 and revealed an association between PD-L1 mRNA expression and the status of isocitrate dehydrogenase (IDH). In conclusion, increased PD-L1 expression predicts unfavorable OS in GBM and may be a promising prognostic biomarker of GBM.

Bioinformatics analysis of potential core genes for glioblastoma.

BACKGROUND: Glioblastoma (GBM) has a high degree of malignancy, aggressiveness and recurrence rate. However, there are limited options available for the treatment of GBM, and they often result in poor prognosis and unsatisfactory outcomes. MATERIALS AND METHODS: In order to identify potential core genes in GBM that may provide new therapeutic insights, we analyzed three gene chips (GSE2223, GSE4290 and GSE50161) screened from the GEO database. Differentially expressed genes (DEG) from the tissues of GBM and normal brain were screened using GEO2R. To determine the functional annotation and pathway of DEG, Gene Ontology (GO) and KEGG pathway enrichment analysis were conducted using DAVID database. Protein interactions of DEG were visualized using PPI network on Cytoscape software. Next, 10 Hub nodes were screened from the differentially expressed network using MCC algorithm on CytoHubba software and subsequently identified as Hub genes. Finally, the relationship between Hub genes and the prognosis of GBM patients was described using GEPIA2 survival analysis web tool. RESULTS: A total of 37 up-regulated and 187 down-regulated genes were identified through microarray analysis. Amongst the 10 Hub genes selected, SV2B appeared to be the only gene associated with poor prognosis in glioblastoma based on the survival analysis. CONCLUSION: Our study suggests that high expression of SV2B is associated with poor prognosis in GBM patients. Whether SV2B can be used as a new therapeutic target for GBM requires further validation.

A Novel Four-Gene Signature Associated With Immune Checkpoint for Predicting Prognosis in Lower-Grade Glioma.

The overall survival of patients with lower grade glioma (LGG) varies greatly, but the current histopathological classification has limitations in predicting patients' prognosis. Therefore, this study aims to find potential therapeutic target genes and establish a gene signature for predicting the prognosis of LGG. CD44 is a marker of tumor stem cells and has prognostic value in various tumors, but its role in LGG is unclear. By analyzing three glioma datasets from Gene Expression Omnibus (GEO) database, CD44 was upregulated in LGG. We screened 10 CD44-related genes via protein-protein interaction (PPI) network; function enrichment analysis demonstrated that these genes were associated with biological processes and signaling pathways of the tumor; survival analysis showed that four genes (CD44, HYAL2, SPP1, MMP2) were associated with the overall survival (OS) and disease-free survival (DFS)of LGG; a novel four-gene signature was constructed. The prediction model showed good predictive value over 2-, 5-, 8-, and 10-year survival probability in both the development and validation sets. The risk score effectively divided patients into high- and low- risk groups with a distinct outcome. Multivariate analysis confirmed that the risk score and status of IDH were independent prognostic predictors of LGG. Among three LGG subgroups based on the presence of molecular parameters, IDH-mutant gliomas have a favorable OS, especially if combined with 1p/19q codeletion, which further confirmed the distinct biological pattern between three LGG subgroups, and the gene signature is able to divide LGG patients with the same IDH status into high- and low- risk groups. The high-risk group possessed a higher expression of immune checkpoints and was related to the activation of immunosuppressive pathways. Finally, this study provided a convenient tool for predicting patient survival. In summary, the four prognostic genes may be therapeutic targets and prognostic predictors for LGG; this four-gene signature has good prognostic prediction ability and can effectively distinguish high- and low-risk patients. High-risk patients are associated with higher immune checkpoint expression and activation of the immunosuppressive pathway, providing help for screening immunotherapy-sensitive patients.