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.

Exploration of the shared pathways and common biomarker in adamantinomatous craniopharyngioma and type 2 diabetes using integrated bioinformatics analysis.

Craniopharyngiomas are rare tumors of the central nervous system that typically present with symptoms such as headache and visual impairment, and those reflecting endocrine abnormalities, which seriously affect the quality of life of patients. Patients with craniopharyngiomas are at higher cardiometabolic risk, defined as conditions favoring the development of type 2 diabetes and cardiovascular disease. However, the underlying common pathogenic mechanisms of craniopharyngiomas and type 2 diabetes are not clear. Especially due to the difficulty of conducting in vitro or in vivo experiments on craniopharyngioma, we thought the common pathway analysis between craniopharyngioma and type 2 diabetes based on bioinformatics is a powerful and feasible method. In the present study, using public datasets (GSE94349, GSE68015, GSE38642 and GSE41762) obtained from the GEO database, the gene expression associated with adamantinomatous craniopharyngioma, a subtype of craniopharyngioma, and type 2 diabetes were analyzed using a bioinformatic approach. We found 11 hub genes using a protein-protein interaction network analysis. Of these, seven (DKK1, MMP12, KRT14, PLAU, WNT5B, IKBKB, and FGF19) were also identified by least absolute shrinkage and selection operator analysis. Finally, single-gene validation and receptor operating characteristic analysis revealed that four of these genes (MMP12, PLAU, KRT14, and DKK1) may be involved in the common pathogenetic mechanism of adamantinomatous craniopharyngioma and type 2 diabetes. In addition, we have characterized the differences in immune cell infiltration that characterize these two diseases, providing a reference for further research.

Multiomics integration-based immunological characterizations of adamantinomatous craniopharyngioma in relation to keratinization.

Although adamantinomatous craniopharyngioma (ACP) is a tumour with low histological malignancy, there are very few therapeutic options other than surgery. ACP has high histological complexity, and the unique features of the immunological microenvironment within ACP remain elusive. Further elucidation of the tumour microenvironment is particularly important to expand our knowledge of potential therapeutic targets. Here, we performed integrative analysis of 58,081 nuclei through single-nucleus RNA sequencing and spatial transcriptomics on ACP specimens to characterize the features and intercellular network within the microenvironment. The ACP environment is highly immunosuppressive with low levels of T-cell infiltration/cytotoxicity. Moreover, tumour-associated macrophages (TAMs), which originate from distinct sources, highly infiltrate the microenvironment. Using spatial transcriptomic data, we observed one kind of non-microglial derived TAM that highly expressed GPNMB close to the terminally differentiated epithelial cell characterized by RHCG, and this colocalization was verified by asmFISH. We also found the positive correlation of infiltration between these two cell types in datasets with larger cohort. According to intercellular communication analysis, we report a regulatory network that could facilitate the keratinization of RHCG+ epithelial cells, eventually causing tumour progression. Our findings provide a comprehensive analysis of the ACP immune microenvironment and reveal a potential therapeutic strategy base on interfering with these two types of cells.

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.

Identification of core genes of craniopharyngioma angiogenesis based on single-cell nuclear transcriptome sequencing.

This study aimed to explore the core genes of craniopharyngioma angiogenesis for targeted vascular therapy based on single-cell nuclear transcriptome sequencing. For single-cell nuclear transcriptome sequencing, we collected six samples from the tumor center and adjacent hypothalamic tumor tissues from three patients with craniopharyngioma, as well as four normal brain tissues based on Gene Expression Omnibus. We screened genes with differential up-regulation between vascular endothelial cells of craniopharyngioma and those of normal brain tissues, performed GO and KEGG analysis, constructed the protein-protein interaction network, and selected key genes verified using immunofluorescence. After data cleaning and quality control, 623 craniopharyngioma endothelial cells and 439 healthy brain endothelial cells were obtained. Compared with normal brain endothelial cells, craniopharyngioma endothelial cells were screened for 394 differentially up-expressed genes (DEGs). GO and KEGG results showed that DEGs probably modulated endothelial cells, adherens junction, focal adhesion, migration, actin cytoskeleton, and invasion via the PI3K-AKT, Rap1, Ras, Wnt, and Hippo pathways. The core genes screened were CTNNB1, PTK2, ITGB1, STAT3, FYN, HIF1A, VCL, SMAD3, PECAM1, FOS, and CDH5. This study obtained possible anti-angiogenic genes in craniopharyngioma. Our results shed novel insights into molecular mechanisms and craniopharyngioma treatment.

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.

Acquired hypothalamic obesity: A clinical overview and update.

Hypothalamic obesity (HO) is a rare and complex disorder that confers substantial morbidity and excess mortality. HO is a unique subtype of obesity characterized by impairment in the key brain pathways that regulate energy intake and expenditure, autonomic nervous system function, and peripheral hormonal signalling. HO often occurs in the context of hypothalamic syndrome, a constellation of symptoms that follow from disruption of hypothalamic functions, for example, temperature regulation, sleep-wake circadian control, and energy balance. Genetic forms of HO, including the monogenic obesity syndromes, often impact central leptin-melanocortin pathways. Acquired forms of HO occur as a result of tumours impacting the hypothalamus, such as craniopharyngioma, surgery or radiation to treat those tumours, or other forms of hypothalamic damage, such as brain injury impacting the region. Risk for severe obesity following hypothalamic injury is increased with larger extent of hypothalamic damage or lesions that contain the medial and posterior hypothalamic nuclei that support melanocortin signalling pathways. Structural damage in these hypothalamic nuclei often leads to hyperphagia, central insulin and leptin resistance, decreased sympathetic activity, low energy expenditure, and increased energy storage in adipose tissue, the collective effect of which is rapid weight gain. Individuals with hyperphagia are perpetually hungry. They do not experience fullness at the end of a meal, nor do they feel satiated after meals, leading them to consume larger and more frequent meals. To date, most efforts to treat HO have been disappointing and met with limited, if any, long-term success. However, new treatments based on the distinct pathophysiology of disturbed energy homeostasis in acquired HO may hold promise for the future.

Unraveling the complexity of the senescence-associated secretory phenotype in adamantinomatous craniopharyngioma using multimodal machine learning analysis.

BACKGROUND: Cellular senescence can have positive and negative effects on the body, including aiding in damage repair and facilitating tumor growth. Adamantinomatous craniopharyngioma (ACP), the most common pediatric sellar/suprasellar brain tumor, poses significant treatment challenges. Recent studies suggest that senescent cells in ACP tumors may contribute to tumor growth and invasion by releasing a senesecence-associated secretory phenotype. However, a detailed analysis of these characteristics has yet to be completed. METHODS: We analyzed primary tissue samples from ACP patients using single-cell, single-nuclei, and spatial RNA sequencing. We performed various analyses, including gene expression clustering, inferred senescence cells from gene expression, and conducted cytokine signaling inference. We utilized LASSO to select essential gene expression pathways associated with senescence. Finally, we validated our findings through immunostaining. RESULTS: We observed significant diversity in gene expression and tissue structure. Key factors such as NFKB, RELA, and SP1 are essential in regulating gene expression, while senescence markers are present throughout the tissue. SPP1 is the most significant cytokine signaling network among ACP cells, while the Wnt signaling pathway predominantly occurs between epithelial and glial cells. Our research has identified links between senescence-associated features and pathways, such as PI3K/Akt/mTOR, MYC, FZD, and Hedgehog, with increased P53 expression associated with senescence in these cells. CONCLUSIONS: A complex interplay between cellular senescence, cytokine signaling, and gene expression pathways underlies ACP development. Further research is crucial to understand how these elements interact to create novel therapeutic approaches for patients with ACP.

Multi-omics analysis of adamantinomatous craniopharyngiomas reveals distinct molecular subgroups with prognostic and treatment response significance.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is the commonest pediatric sellar tumor. No effective drug is available and interpatient heterogeneity is prominent. This study aimed to identify distinct molecular subgroups of ACP based on the multi-omics profiles, imaging findings, and histological features, in order to predict the response to anti-inflammatory treatment and immunotherapies. METHODS: Totally 142 Chinese cases diagnosed with craniopharyngiomas were profiled, including 119 ACPs and 23 papillary craniopharyngiomas. Whole-exome sequencing (151 tumors, including recurrent ones), RNA sequencing (84 tumors), and DNA methylome profiling (95 tumors) were performed. Consensus clustering and non-negative matrix factorization were used for subgrouping, and Cox regression were utilized for prognostic evaluation, respectively. RESULTS: Three distinct molecular subgroups were identified: WNT, ImA, and ImB. The WNT subgroup showed higher Wnt/ß-catenin pathway activity, with a greater number of epithelial cells and more predominantly solid tumors. The ImA and ImB subgroups had activated inflammatory and interferon response pathways, with enhanced immune cell infiltration and more predominantly cystic tumors. Mitogen-activated protein kinases (MEK/MAPK) signaling was activated only in ImA samples, while IL-6 and epithelial-mesenchymal transition biomarkers were highly expressed in the ImB group, mostly consisting of children. The degree of astrogliosis was significantly elevated in the ImA group, with severe finger-like protrusions at the invasive front of the tumor. The molecular subgrouping was an independent prognostic factor, with the WNT group having longer event-free survival than ImB (Cox, P = 0.04). ImA/ImB cases were more likely to respond to immune checkpoint blockade (ICB) therapy than the WNT group ( P <0.01). In the preliminary screening of subtyping markers, CD38 was significantly downregulated in WNT compared with ImA and ImB ( P = 0.01). CONCLUSIONS: ACP comprises three molecular subtypes with distinct imaging and histological features. The prognosis of the WNT type is better than that of the ImB group, which is more likely to benefit from the ICB treatment.

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.

The molecular pathogenesis of craniopharyngiomas.

Research from the last 20 years has provided important insights into the molecular pathogenesis of craniopharyngiomas (CPs). Besides the well-known clinical and histological differences between the subtypes of CPs, adamantinomatous (ACP) and papillary (PCP) craniopharyngiomas, other molecular differences have been identified, further elucidating pathways related to the origin and development of such tumors. The present minireview assesses current knowledge on embryogenesis and the genetic, epigenetic, transcriptomic, and signaling pathways involved in the ACP and PCP subtypes, revealing the similarities and differences in their profiles. ACP and PCP subtypes can be identified by the presence of mutations in CTNNB1 and BRAF genes, with prevalence around 60% and 90%, respectively. Therefore, ß-catenin accumulates in the nucleus-cytoplasm of cell clusters in ACPs and, in PCPs, cell immunostaining with specific antibody against the V600E-mutated protein can be seen. Distinct patterns of DNA methylation further differentiate ACPs and PCPs. In addition, research on genetic and epigenetic changes and tumor microenvironment specificities have further clarified the development and progression of the disease. No relevant transcriptional differences in ACPs have emerged between children and adults. In conclusion, ACPs and PCPs present diverse genetic signatures and each subtype is associated with specific signaling pathways. A better understanding of the pathways related to the growth of such tumors is paramount for the development of novel targeted therapeutic agents.

Inhibition of integrated stress response protects against lipid-induced senescence in hypothalamic neural stem cells in adamantinomatous craniopharyngioma.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is a benign tumor with malignant clinical manifestations. ACP adjacent to the hypothalamus often presents with more severe symptoms and higher incidence of hypothalamic dysfunction. However, the mechanism underlying hypothalamic dysfunction remains unclear. METHODS: Immunostaining was performed to determine the nerve damage to the floor of the third ventricle (3VF) adjacent to ACP and to examine the recruitment and senescence of hypothalamic neural stem cells (htNSCs). The accumulation of lipid droplets (LDs) in htNSCs was evaluated via BODIPY staining, oil red O staining, and transmission electron microscopy. In vitro and in vivo assays were used to evaluate the effect of cystic fluid or oxidized low-density lipoprotein and that of oxytocin (OXT) on htNSC senescence and the hypothalamic function. The protein expression levels were analyzed using western blotting. RESULTS: htNSCs with massive LD accumulation were recruited to the damaged 3VF adjacent to ACP. The LDs in htNSCs induced senescence and reduced neuronal differentiation; however, htNSC senescence was effectively prevented by inhibiting either CD36 or integrated stress response (ISR) signaling. Furthermore, OXT pretreatment reduced lipotoxicity via the inhibition of ISR signaling and the repair of the blood-brain barrier. CONCLUSIONS: Reduced LD aggregation or ISR signaling inhibition prevented senescence in htNSCs and identified molecular pathways and potential therapeutic targets that may improve hypothalamic dysfunction in ACP patients.

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.

Integrative analyses identify HIF-1α as a potential protective role with immune cell infiltration in adamantinomatous craniopharyngioma.

Craniopharyngiomas (CPs) are histologically benign tumors located in the sellar-suprasellar region. Although the transcriptome development in recent years have deepened our knowledge to the tumorigenesis process of adamantinomatous craniopharyngioma (ACP), the peritumoral immune infiltration of tumor is still not well understood. In this study, weighted gene coexpression network analysis (WGCNA) was applied to identify different gene modules based on clinical characteristics and gene expression, and then, the protein-protein interaction (PPI) network with the Cytohubba plug-in were performed to screen pivotal genes. In addition, immune cell infiltration (ICI) analysis was used to evaluate the immune microenvironment of ACP patients. In total, 8,568 differential expression genes were identified based on our datasets and two microarray profiles from the public database. The functional enrichment analysis revealed that upregulated genes were mainly enriched in immune-related pathways while downregulated genes were shown in the hormone and transduction of signaling pathways. The WGCNA investigated the most relevant modules, and 1,858 hub genes was detected, from which the PPI network identified 14 pivotal genes, and the Hypoxia-inducible factor 1-alpha (HIF-1α) pathway including four critical genes may be involved in the development of ACP. Moreover, naïve CD4+ and CD8+ T cells were decreased while specific subtypes of T cells were significantly increased in ACP patients according to ICI analysis. Validation by immunofluorescence staining revealed a higher expression of HIF-1α in ACP (ACP vs. control) and adult-subtype (adult vs. children), suggesting a possible state of immune system activation. Notably, children with low HIF-1α scores were related to the hypothalamus involvement and hydrocephalus symptoms. In this study, we successfully identified HIF-1α as a key role in the tumorigenesis and development of ACP through comprehensive integrated analyses and systematically investigated the potential relationship with immune cells in ACP. The results may provide valuable resources for understanding the underlying mechanisms of ACP and strengthen HIF-1α as a potential immunotherapeutic target in clinical application.

Adamantinomatous craniopharyngioma cyst fluid can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of ß-amyloid.

INTRODUCTION: The mechanism by which adamantinomatous craniopharyngioma (ACP) damages the hypothalamus is still unclear. Cyst fluid rich in lipids and inflammatory factors is a characteristic pathological manifestation of ACP and may play a very important role in hypothalamic injury caused by tumors. OBJECTIVE: The objective of this study was to construct a reliable animal model of ACP cyst fluid-induced hypothalamic injury and explore the specific mechanism of hypothalamic injury caused by cyst fluid. METHODS: An animal model was established by injecting human ACP cyst fluid into the bilateral hypothalamus of mice. ScRNA-seq was performed on the mice hypothalamus and on an ACP sample to obtain a complete gene expression profile for analysis. Data verification was performed through pathological means. RESULTS: ACP cystic fluid caused growth retardation and an increased obesity index in mice, affected the expression of the Npy, Fgfr2, Rnpc3, Sst, and Pcsk1n genes that regulate growth and energy metabolism in hypothalamic neurons, and enhanced the cellular interaction of Agrp-Mc3r. ACP cystic fluid significantly caused inflammatory activation of hypothalamic microglia. The cellular interaction of CD74-APP is significantly strengthened between inflammatory activated microglia and hypothalamic neurons. Beta-amyloid, a marker of neurodegenerative diseases, was deposited in the ACP tumor tissues and in the hypothalamus of mice injected with ACP cyst fluid. CONCLUSION: In this study, a novel animal model of ACP cystic fluid-hypothalamic injury was established. For the first time, it was found that ACP cystic fluid can trigger inflammatory activation of microglia to damage the hypothalamus, which may be related to the upregulation of the CD74-APP interaction and deposition of ß-amyloid, implying that there may be a similar mechanism between ACP cystic fluid damage to the hypothalamus and neurodegenerative diseases.

Targeted therapies in the medical management of craniopharyngioma.

Craniopharyngioma (CP) is an intracranial benign tumor that behaves aggressively due to its location, infiltration of the surrounding nervous tissue and high capacity for recurrence. Treatment of choice is surgery followed or not by radiotherapy. Recent advances in molecular biology techniques and the better understanding of the genetic alterations of the two histological types of CP have open new therapeutic perspectives with targeted drugs. Adamantinomatous CP (ACP) is associated with activating mutations of the CTNNB1 gene. Such mutations are accompanied by intracellular accumulation of ß-catenin, an oncogenic protein that activates the intracellular Wnt/ ß-catenin signaling pathway, which regulates the transcription of genes involved in cell proliferation. Therefore, the use of molecular therapies directed against the activation of the Wnt/ ß-catenin pathway could be an attractive and promising therapeutic option in the management of ACPs. On the other hand, papillary CP (PCP) is associated with activating mutations in the BRAF gene. This gene encodes a BRAF protein that plays an important role in the intracellular mitogen-activated protein kinase (MAPK) signaling pathway, which also regulates cell proliferation. The use of BRAF inhibitors either in monotherapy or in combination with mitogen-activated protein kinase (MEK) inhibitors has demonstrated therapeutic efficacy in isolated clinical cases of relapsed PCPs. A preliminary report of a recent phase II clinical trial has shown a therapeutic response in 93.7% of patients with BRAF V600E -mutated PCP, with an 85% reduction in tumor size. In the present review we comment on the efficacy and safety of the different drugs being used in patients with PCP.

Craniopharyngioma, Chronotypes and Metabolic Risk Profile.

AIM: To investigate the potential association among Craniopharyngioma (CP), chronotypes and metabolic risk profile. SUBJECTS AND METHODS: The study population included 28 patients (46.4% males; 42.6 ± 15.8 years) and 28 controls, age, gender and BMI matched (46.4% males; 46.5 ± 12.9 years). In this study sample, we evaluated: anthropometric measurements (waist circumference, WC; BMI), plasma glucose, lipid profile, and systolic (SBP) and diastolic (DBP) blood pressure. Morningness-Eveningness was measured with the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ), which included 19 questions about preferred sleep time and daily performance. RESULTS: in both patients and controls grade I obesity was detected in 15 subjects (53.6%), grade II obesity in 13 subjects (46.4%). In the patient group, the mean score of chronotype was 47.8 ± 12.6. In particular, 9 patients (32.1%) exhibited the morning chronotype, 6 (21.4%) the intermediate chronotype and 13 (46.4.%) the evening chronotype. No significant difference was found in gender and age among the chronotype categories. Patients with the evening chronotype had higher blood pressure values and worse metabolic parameters than those with the morning chronotype. In the control group, the mean score of the chronotype was 57.6 ± 9.5. In particular, 16 (57.1%) subjects exhibited the morning chronotype, 10 (35.7%) the intermediate chronotype and only 2 (7.1.%) the evening chronotype. The prevalence of intermediate and evening chronotypes was higher in females than males (p = 0.021), while males have a higher prevalence of the morning chronotype. Subjects with intermediate and evening chronotypes had worse metabolic parameters than those with the morning chronotype. In patients, the chronotype score was inversely correlated to WC, BMI, SBP, DBP, plasma glucose, total cholesterol, triglycerides, LDL cholesterol and positively correlated with HDL cholesterol. No correlation was found between age and chronotype. In controls, the chronotype score was inversely correlated to WC, BMI, plasma glucose, total cholesterol, LDL cholesterol. No correlation was found among chronotype and age, blood pressure, triglycerides, HDL cholesterol. Considering the whole population of the study (patients and controls), at logistic regression the chronotype score was significantly associated with the presence of CP. CONCLUSIONS: for the first time thus far, our study puts the light on the association of the CP with chronotypes and metabolic alterations in this disease, which are the main determinants of the reduced quality of life, higher morbidity and mortality in this setting of patients. This finding suggests that alterations of chronotype might represent an adjunctive risk for CP patients and a possible target for their integrate management.

In-depth proteomic profiling captures subtype-specific features of craniopharyngiomas.

Craniopharyngiomas are rare epithelial tumors derived from pituitary gland embryonic tissue. This epithelial tumor can be categorized as an adamantinomatous craniopharyngioma (ACP) or papillary craniopharyngioma (PCP) subtype with histopathological and genetic differences. Genomic and transcriptomic profiles of craniopharyngiomas have been investigated; however, the proteomic profile has yet to be elucidated and added to these profiles. Recent improvements in high-throughput quantitative proteomic approaches have introduced new opportunities for a better understanding of these diseases and the efficient discovery of biomarkers. We aimed to confirm subtype-associated proteomic changes between ACP and PCP specimens. We performed a system-level proteomic study using an integrated approach that combines mass spectrometry-based quantitative proteomic, statistical, and bioinformatics analyses. The bioinformatics analysis showed that differentially expressed proteins between ACP and PCP were significantly involved in mitochondrial organization, fatty acid metabolic processes, exocytosis, the inflammatory response, the cell cycle, RNA splicing, cell migration, and neuron development. Furthermore, using network analysis, we identified hub proteins that were positively correlated with ACP and PCP phenotypes. Our findings improve our understanding of the pathogenesis of craniopharyngiomas and provide novel insights that may ultimately translate to the development of craniopharyngioma subtype-specific therapeutics.

Altered endocannabinoid-dynamics in craniopharyngioma patients and their association with HPA-axis disturbances.

OBJECTIVE: Patients with craniopharyngioma (CP) frequently suffer from morbid obesity. Endocannabinoids (ECs) are involved in weight gain and rewarding behavior but have not been investigated in this context. DESIGN: Cross-sectional single-center study. METHODS: Eighteen patients with CP and 16 age- and sex-matched controls were included. Differences in endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and endocannabinoid-like molecules (oleoyl ethanolamide (OEA), palmitoylethanolamide (PEA), and arachidonic acid (AA) were measured at baseline and following endurance exercise. We further explored ECs-dynamics in relation to markers of HPA-axis activity (ACTH, cortisol, copeptin) and hypothalamic damage. RESULTS: Under resting conditions, independent of differences in BMI, 2-AG levels were more than twice as high in CP patients compared to controls. In contrast, 2-AG and OEA level increased in response to exercise in controls but not in CP patients, while AEA levels decreased in controls. As expected, exercise increased ACTH and copeptin levels in controls only. In a mixed model analysis across time and group, HPA measures did not provide additional information for explaining differences in 2-AG levels. However, AEA levels were negatively influenced by ACTH and copeptin levels, while OEA levels were negatively predicted by copeptin levels only. There were no significant differences in endocannabinoids depending on hypothalamic involvement. CONCLUSION: Patients with CP show signs of a dysregulated endocannabinoid system under resting conditions as well as following exercise in comparison to healthy controls. Increased 2-AG levels under resting conditions and the missing response to physical activity could contribute to the metabolic phenotype of CP patients.

Hypothalamic-Pituitary Outcome after Treatment for Childhood Craniopharyngioma.

Although childhood-onset craniopharyngioma is a low-grade intracranial tumor with excellent prognosis in terms of overall survival, survivors may suffer from devastating consequences caused by hypothalamic damage. Disease- or treatment-related hypothalamic damage leads to disturbed hunger-satiety and thirst feelings, decreased energy expenditure, behavioral problems, disturbances of circadian rhythm, temperature dysregulation, and pituitary dysfunction. These children are at great risk for developing the metabolic syndrome and comorbidities leading to premature mortality. In this chapter, we shall discuss hypothalamic-pituitary morbidity and outcome of childhood-onset craniopharyngioma patients and future perspectives for improvement.