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.

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.

Subtype-dependent difference of glucose transporter 1 and hexokinase II expression in craniopharyngioma: an immunohistochemical study.

Papillary craniopharyngiomas are characterized by the BRAF V600E mutation. Enhancement of glucose metabolism may be involved in the downstream of the BRAF V600E mutation in many types of tumors. Glucose metabolism was investigated in craniopharyngioma using immunohistochemical analysis. The study included 29 cases of craniopharyngioma (18 adamantinomatous type [ACP], 11 papillary type [PCP]). Immunohistochemical analysis was performed with anti-glucose transporter-1 (GLUT-1), anti-hexokinase-II (HK-II), anti-BRAF V600E, and anti-beta-catenin antibodies. Expressions of GLUT-1 and HK-II were evaluated using a semiquantitative 4-tiered scale as 0, 1+, 2+, 3+, and divided into negative (0 or 1+) or positive (2+ or 3+) group. GLUT-1 expression level was significantly higher in PCPs than ACPs (0, 1+, 2+, 3+ = 2, 12, 4, 0 cases in ACP, respectively, 0, 1+, 2+, 3+ = 0, 2, 5, 4 in PCP, p = 0.001), and most PCPs were classified into positive group (positive rate, 22.2% [4/18] in ACP, 81.8% [9/11] in PCP; p = 0.003). HK-II expression was also conspicuous in PCPs (0, 1+, 2+, 3+ = 7, 9, 2, 0 cases in ACP, 0, 3, 3, 5 in PCP; p = 0.001), and most of them divided into positive group (positive rate, 11.1% [2/18] in ACP, 72.7% [8/11] in PCP; p = 0.001). Expression patterns of BRAF V600E and beta-catenin reflected the clinicopathological subtypes. Both GLUT-1 and HK-II expressions were prominent in PCP. Glucose metabolism might be more enhanced in PCP than ACP. PCP may use the glucose metabolic system downstream of the BRAF V600E mutant protein.

Preoperative BMI Predicts Postoperative Weight Gain in Adult-onset Craniopharyngioma.

CONTEXT: Craniopharyngiomas, while benign, have the highest morbidity of all nonmalignant sellar tumors. Studies on weight and metabolic outcomes in adult-onset craniopharyngioma (AOCP) remain sparse. OBJECTIVE: To examine postsurgical weight and metabolic outcomes in AOCP and to identify any clinical predictors of weight gain. METHODS: Retrospective chart review of patients with AOCP who underwent surgery between January 2014 and May 2019 in a single pituitary center. The study included 45 patients with AOCP with a minimum follow-up of 3 months. Median follow-up time was 26 months (interquartile range [IQR] 10-44). Main outcome measures were the changes in weight/body mass index (BMI), metabolic comorbidities, and pituitary deficiencies between preoperative and last follow-up. RESULTS: Both weight and BMI were higher at last follow-up, with a mean increase of 3.4 kg for weight (P = .015) and 1.15 kg/m2 for BMI (P = .0095). Median % weight change was 2.7% (IQR -1.1%, 8.8%). Obesity rate increased from 37.8% at baseline to 55.6% at last follow-up. One-third of patients had ~15% median weight gain. The prevalence of metabolic comorbidities at last follow-up was not different from baseline. Pituitary deficiencies increased postoperatively, with 58% of patients having ≥3 hormonal deficiencies. Preoperative BMI was inversely associated with postoperative weight gain, which remained significant after adjusting for age, sex, race, tumor, and treatment characteristics. Patients with ≥3 hormonal deficiencies at last follow-up also had higher postoperative weight gain. CONCLUSION: In this AOCP cohort, those with a lower BMI at the preoperative visit had higher postoperative weight gain. Our finding may help physicians better counsel patients and provide anticipatory guidance on postoperative expectations and management.

Revived Attention for Adult Craniopharyngioma.

Craniopharyngioma as a rare tumor originating from cells of rathke's pouch and representing 2-5% of all intracranial tumors is a rare and generally benign neoplasm of the central nervous system with two incidence peaks one in childhood and one after 40 years of age. Data on adult patients is scarce compared to childhood onset tumors, however the burden of disease caused by the tumors and related treatment options is significant. Clinical symptoms range from headaches, visual disability, cranial nerve affection or hypothalamic symptoms (e. g. morbid obesity) to endocrine disorders. Most symptoms are related to tumor mass effect. The current standard of diagnostics is the determination of serum hormone levels and contrast enhanced magnetic resonance imaging often resulting in surgical treatment which holds a key role in all treatment concepts and should follow a hypothalamus sparing path. Radiation therapy may prove beneficial as adjuvant therapeutic option or in recurrent tumor, especially papillary tumors may be targeted using BRAF-600 inhibitors, targeted therapies for adamantinomatous craniopharyngioma have not yet reached a stage of clinical testing. Although prognosis regarding overall survival is favorable, life expectancy may be reduced due to the tumor itself as well as due to treatment effects. An important aspect especially in the adult population is the reduction in quality of life which is comparable to primary malignant brain tumors and metastases, calling for individual patient specific treatment approaches.

Clinical features and prognosis of pediatric infradiaphragmatic craniopharyngioma relative to the tumor inflammatory response.

BACKGROUND: The relationship between clinical responses in pediatric infradiaphragmatic craniopharyngioma (Q-CP) and inflammatory response is still unclear. The objective of this study was to investigate the clinical significance of tumor inflammatory response in pediatric Q-CPs. METHODS: The inflammatory response was evaluated by measuring the number of inflammatory cells in the tumor near adenohypophysis junction. The specimens were classified as mild, moderate, or severe based on the number of inflammatory cells. In addition, the levels of pro-inflammatory cytokines and chemokines in the specimens were measured using a cytokine antibody array. Clinical outcomes were analyzed and compared to the markers of inflammatory response. RESULTS: IL-6 and IL-8 were highly expressed in pediatric Q-CPs, and the transcription level of IL-6 was the highest in the severe group. Most patients (87.3%) had hypopituitarism; the severe inflammation group had an increased incidence of hypopituitarism, which correlated with significantly lower probability of recurrence-free survival and worsened functional status. CONCLUSIONS: Inflammatory response is common in craniopharyngiomas and is closely related to their biological behavior and the patients' clinical prognosis. Further studies of the relationship between craniopharyngiomas and the inflammatory response will enable the discovery of potential therapeutic targets, which will reduce morbidity and result in better outcomes for pediatric Q-CP patients. IMPACT: Pediatric infradiaphragmatic craniopharyngiomas are histologically benign brain tumors that often follow an aggressive clinical course. The inflammatory response in craniopharyngioma is common, which is closely related to the biological behavior and clinical prognosis. Several inflammatory and immune markers have been identified in CP; inflammation is an important role in the pathogenesis of hypopituitarism. The aim was to study the relationship between craniopharyngioma and inflammatory response and find potential therapeutic targets can reduce morbidity and result in better outcomes.

Secondary pituitary hormonal dysfunction patterns: tumor size and subtype matter.

PURPOSE: Patients with sellar masses (SM) frequently have secondary hormonal deficiency (SHD) at initial presentation. While larger SM are more likely to present with SHD, it is unclear whether SHD at presentation is influenced by the type of SM. METHODS: We conducted a retrospective analysis of patients with SM prospectively enrolled in our comprehensive provincial neuropituitary registry between November 2005 and December 2018. SM were subdivided based on size: < 1 cm, 1-1.9 cm, 2-2.9 cm, and > 3 cm. RESULTS: A total of 914 patients met the inclusion criteria, including: 346 nonfunctioning adenomas (NFA), 261 prolactinomas (PRLoma), 51 growth hormone adenomas, 36 adrenocorticotropic adenomas, 93 Rathke's cleft cysts, 70 craniopharyngiomas and 57 meningiomas. The overall rate of SHD at presentation was highest in PRLoma (62.8%) and craniopharyngiomas (64.3%) and lowest in meningiomas (14%). While larger SM were significantly more likely to have SHD, the rate of SHD within each group was significantly different despite similar size (p < 0.001). Of the two largest groups of SM (NFA and PRLoma), NFA had significantly higher odds ratio (3.34, CI 1.89-5.89) of having multiple SHDs when compare with PRLoma, even when corrected for age, gender and size of tumor (p < 0.001). CONCLUSION: Our study shows that the rate and distribution of SHD in SM vary dependent upon the size of the tumor and specific pathology; in particular, NFA are more likely to present with multiple SHDs. Our data will help clinicians in determining adequate hormonal testing strategy for different SM.

Autonomic Dysfunction is Associated with Increased Cardiometabolic Risk in Patients with Childhood-Onset Craniopharyngioma.

Patients with craniopharyngioma are susceptible to autonomic dysfunction as a result of hypothalamic damage. We evaluated indices of heart rate variability (HRV) in patients with childhood-onset craniopharyngioma to investigate autonomic function and its relationship with components of the metabolic syndrome (MetS). This cross-sectional, case-only study included 53 patients (10-30 years of age). We measured the standard deviation of all normal R-R intervals (SDNN) and total power indicating overall HRV, the root-mean square of the difference of successive R-R intervals (RMSSD) and high frequency indicating parasympathetic modulation, and low frequency. These indices were compared according to the presence of the MetS. During the mean 10.8 years of follow-up, 25% of patients were diagnosed with the MetS. Patients with the MetS showed significantly lower levels of SDNN (29.0 vs. 40.6 ms), total power (416.1 vs. 1129.6 ms2), RMSSD (20.1 vs. 34.5 ms), high frequency (94.7 vs. 338.5 ms2), and low frequency (94.5 vs. 289.4 ms2) than those without (p <0.05, for all). Individual components of the MetS including insulin resistance, serum triglycerides levels, and systolic blood pressure were inversely associated with SDNN, total power, RMSSD and high frequency. Higher overall variability and parasympathetic modulation were related to decreased odds ratios for having the MetS (OR 0.91, p=0.029 for SDNN; OR 0.91, p=0.032 for total power). In conclusion, autonomic dysfunction, as evidenced by reduced HRV indices, is associated with increased cardiometabolic risk in patients with childhood-onset craniopharyngioma.