The Clinical Significance of Inflammatory Mediators in Predicting Obesity and Progression-Free Survival in Patients with Craniopharyngioma

The Clinical Significance of Inflammatory Mediators in Predicting Obesity and Progression-Free Survival in Patients with Craniopharyngioma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Clinical Significance of Inflammatory Mediators in Predicting Obesity and Progression-Free Survival in Patients with Craniopharyngioma Youchao Xiao, Wentao Wu, Fangzheng Liu, Yanfei Jia, Lu Jin, Ning Qiao, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4272844/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract 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. craniopharyngioma inflammatory mediators leptin obesity progression-free survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction Craniopharyngioma (CP) is a rare malformational tumor mainly located in the sellar area, accounting for 0.5–2.5 new cases per 1 million people per year globally [1]. However, despite low-grade histological malignancy (WHO grade I) and high survival rates[2], survivors often experience obesity and tumor recurrence, which significantly adversely affect their quality of life [3]. The hypothalamus acts as the energy center, linking direct synaptic connections to limbic systems that mediate motivation to eat and process reward[4]. Mechanistically, neurons within hypothalamic nuclei maintain energy homeostasis by responding to nutrient signalling and hormone binding, such as leptin, insulin, ghrelin, and cholecystokinin[5]. Injury to the hypothalamus can disrupt the delicate balance between energy intake and expenditure[4]. Due to the proximity of CP to the hypothalamus and the high probability of hypothalamic damage from the tumor and treatment, hyperphagia and morbid obesity (occurring in up to 50% of cases) in CP have traditionally been attributed to physical hypothalamus damage caused by a combination of tumor invasion and treatments[1]. However, a high proportion of CP patients (more than 50%) with an integrated hypothalamus characterized by no hypothalamic involvement (HI) and a normal floor of the third ventricle develop obesity postoperatively[6], indicating that specific unrevealed mechanisms also contribute to obesity in patients with CP, except for physical damage to the hypothalamus. Two independent studies supported the idea that injecting cyst fluid of CP into the brain of model animals contributes to the pathogenesis of obesity[7, 8], these results help us understand the obesity of CP from the perspective of biofactors in cyst fluid secreted by the tumor. While the cyst fluid is rich in various growth factors and inflammatory mediators, including interleukin (IL)1A, IL1B, IL6, IL10, C-X-C motif chemokine ligand (CXCL) 1, CXCL8, and tumor necrosis factor-alpha (TNF)[9, 10], and these two studies did not reveal which specific substances play a role in promoting obesity. Therefore, the present study first aimed to explore the relationship between the expression levels of these seven inflammatory mediators and weight changes, which will be helpful for subsequent experiments and drug development. Consistent with previous research[11–13], one of our previous studies revealed that hypothalamic resistance to circulation hormones, such as leptin, contributes to obesity[14]. Patients with CP exhibit abnormally elevated preoperative leptin relative to fat mass and fail to suppress food intake or increase energy expenditure effectively, indicating the existence of leptin resistance in patients with CP[14]. Unfortunately, which factors cause hyperleptinemia and leptin resistance in patients with CP is still unknown. Emerging evidence indicates that activated glial cells secrete various cytokines and inflammatory mediators, which could impair the sensitivity of hypothalamic neurons to peripheral metabolic signals, such as leptin and insulin, ultimately resulting in metabolic dysfunction[15, 16]. However, it remains unclear whether inflammatory mediators secreted by tumor cells contribute to leptin resistance characterized by elevated plasma leptin in patients with CP, consequently leading to morbid obesity. Therefore, the present study also exploreed the correlation between the expression levels of inflammatory mediators and plasma leptin concentrations in CP, which could further provide evidence for supporting crass talking among inflammatory mediators, leptin, and the hypothalamus. Although various treatment modalities, including surgery, irradiation, cyst aspiration, and intracystic therapies, have shown efficacy in improving the prognosis of patients with CP[1], reducing the rate of tumor recurrence and improving the ability to predict the prognosis of patients are still urgent problems in clinical practice. Numerous studies have evaluated the value of inflammatory mediators in predicting the prognosis of various tumors, including laryngeal squamous cell carcinoma[17], colorectal cancer[18], and gastric cancer[19]. However, studies on the associations between these seven inflammatory mediators and CP are rare. Thus, the present study also aimed to reveal the associations among these seven inflammatory mediators, clinical characteristics, and progression-free survival in patients with CP. 2 Patients and methods 2.1 Patient selection A single-center cohort study was conducted on patients diagnosed with CP who underwent endoscopic endonasal transsphenoidal surgery at Beijing Tiantan Hospital between January 2019 and March 2022. Patient selection was based on the following criteria: (I) age ≥ 18 years at the time of diagnosis, (II) primary CP without prior history of irradiation or cyst aspiration, (III) confirmed availability of histological diagnosis, (IV) presence of well-preserved tumor tissue for RNA testing and availability of plasma samples for enzyme-linked immunosorbent assay (ELISA) testing, and (V) minimum follow up period of 1-year. All procedures in our study followed the ethical standards of the institutional and national research committees and the Declaration of Helsinki. The institutional review board of Beijing Tiantan Hospital approved this study. Informed consent was obtained from all subjects involved in the study. 2.2 Clinical data and definition The baseline characteristics and demographics were obtained from the hospital medical records. Patients were followed from primary surgery until secondary surgery, administration of radiotherapy, death, or March 2023, whichever came first. Based on preoperative magnetic resonance imaging (MRI), the maximum diameters of the tumor and cyst in each of the three dimensions were defined as tumor size and cyst size, respectively. The tumor volume and cyst volume were approximately calculated using the following formula: volume = 4/3 × π × (a/2 × b/2 × c/2), where a, b, and c represent the maximum diameters of the tumor in each of the three dimensions[20]. A tumor with a cystic component comprising more than 50% of the total volume was classified as a cystic tumor[14, 20]. The extent of resection was assessed based on surgical videos and postoperative MRI and was categorized as gross total resection (GTR, 100% removal), STR (≥95% removal), or partial resection (PR, <95% removal)[21]. The latter two were combined into the non-gross total resection (NTR) group in the statistical analysis. The degree of HI, which included severe hypothalamus involvement (HI) (grade 2), mild HI (grade 1), and no HI (grade 0), was assessed using Puget’s grading system[22]. Based on body mass index (BMI), body weight status was categorized as obesity (BMI ≥ 30 kg/m2), overweight (BMI ≥ 25kg/m2), or normal weight (BMI < 25kg/m2). Consistent with our previous study, postoperative weight changes ≥5% were considered clinically significant[14, 20]. Hormone deficiency was assessed based on principles established in previous research[23]. Progression-free survival (PFS) was defined as the time from primary surgery to recurrence or death, whichever occurred first. 2.3 Assay of inflammatory mediator expression in tumor tissue The tumor specimens of 130 patients with CP and 11 normal pituitary tissue samples were collected during surgical procedures and quickly stored at -80℃. Total RNA was extracted from the samples using Steadypure universal RNA extraction kit (Accurate Biotechnology, Hunan, China, Cat No. AG21017). The primers used for reverse-transcription quantitative polymerase chain reaction (RT-qPCR) amplification are listed in Table 1. SYBR Green qPCR Mix (Biosharp Biotechnology, BL698A) was used to perform qPCR on QuantStudio 5 RealTime PCR System following the manufacturer’s protocol. The housekeeping gene GAPDH was used for normalization. The relative mRNA expression was determined using the 2 − ΔΔCT method and was expressed as log2 (X+1). Each sample was tested in triplicate. 2.4 Measurement of plasma leptin concentration Peripheral blood samples were obtained from patients with CP before tumor surgery. The samples were centrifuged at 3000 rpm for 2 min at 4 °C, and the plasma was collected and stored at -80 ℃ until the ELISA test. The plasma leptin concentration was measured using the ELISA method according to the manufacturer’s protocol (Peprotech, Inc., Cat No. 900-K90). 2.5 Statistical method s Patients were categorized into high- and low-expression groups according to the median levels of inflammatory mediators. Univariate and multivariate logistic regression analyses were performed to calculate the unadjusted odds ratio (uOR) and the adjusted odds ratio (aOR). The Pearson correlation test was also used to estimate the correlation between inflammatory mediator expression and leptin concentration. Parametric variables were analyzed using Student’s t-test, while nonparametric variables were analyzed using the Mann-Whitney U-test to compare between groups. Categorical variables were compared using Chi-square and Fisher’s exact tests. The Spearman correlation test performed correlation analysis between gene expression, size, and volume (both tumor and cyst). The Kaplan-Meier (K–M) curves and log-rank tests were employed to validate the survival rates between the low- and high-expression groups. A P -value < 0.05 was considered to indicate statistical significance. Furthermore, all the statistical analyses were performed, and the results were visualized using SPSS 24 (SSPS, Inc., Chicago, USA) and GraphPad Prism 9 (GraphPad Software, Inc., La Jolla, CA, USA). 3 Results 3.1 Patient characteristics Fig.1 visually illustrates the patient selection process, while Table 2 summarizes patient characteristics. This study included 130 participants (71 males and 59 females) with a mean age of 43.92±12.52 years. Histological analysis confirmed 98 cases of adamantinomatous craniopharyngioma (ACP) and 32 cases of papillary craniopharyngioma (PCP). The mean duration of follow-up was 22.67±9.29 months. Calcification was observed in 61.5% of the cohort (n=80). Preoperative hydrocephalus and preoperative visual field damage were present in 26.2% (n=34) and 17.7% (n=23) of patients, respectively. Regarding preoperative body weight, 60 patients had normal weight, 56 were overweight, and 14 were obese. Gonadotropic hormone deficiency (n=34, 26.2%) and antidiuretic hormone deficiency (n=32, 24.6%) were the two most common preoperative hormone deficiencies in patients with CP. The incidence of other hormone deficiencies, including growth hormone deficiency (n=19, 14.6%), thyroid-stimulating hormone deficiency (n=16, 12.3%), and adrenocorticotropic hormone deficiency (n=12, 9.2%), was less than 15%. On preoperative MRI, severe HI (grade 2) was observed in approximately half of the patients (n=64, 49.2%), while mild HI (grade 1) and no HI (grade 0) were observed in 36.9% (n=48), and 14.6% (n=19) of patients, respectively. The mean tumor size was 3.1±0.97 cm, and the mean tumor volume was 13.01±11.82 cm3. Moreover, the mean size and mean volume of the cysts were 2.02±1.05 cm and 5.86±8.62 cm3, respectively. Among the 130 cases, 76 tumors were identified as cystic tumors. Finally, GTR was achieved in 120 patients (92.3%), and NTR was achieved in 10 patients (7.7%). 3.2 Association between inflammatory mediators, weight gain, new-onset obesity, and leptin concentration According to the univariate logistic regression analysis, significant weight gain (weight change ≥5%) was associated with higher expression of CXCL1 (Fig.2a, unadjusted odds ratio (uOR) = 2.12, 95% confidence interval (CI), 1.05-4.28, P =0.036). New-onset postoperative obesity was associated with high expressions of CXCL1 (Fig.2c, uOR = 3.67, 95% CI, 1.11-12.15, P =0.034) and TNF (Fig.2c, uOR = 2.92, 95% CI, 1.04-9.02, P =0.045).Multivariate logistic regression analysis adjusted for age, gender, HI, and preoperative body mass index (BMI) was conducted to explore the independent relationships among inflammatory mediators, significant weight gain, and new-onset obesity. The results revealed that high expressions of CXCL1 (Fig.2b, adjusted odds ratio (aOR) = 2.21, 95% CI, 1.02-4.77, P =0.044) and CXCL8 (Fig.2b, aOR = 2.43, 95% CI, 1.08-5.51, P =0.032) were independent risk factors for significant weight gain, while high expression levels of CXCL1 (Fig.2d, aOR = 4.58, 95% CI, 1.21-17.26, P =0.025) and TNF (Fig.2d, aOR = 3.83, 95% CI, 1.10-13.31, P =0.035) were found to be independent risk factors for new-onset postoperative obesity. Leptin, a cytokine secreted by fat cells that regulates energy balance, is abnormally elevated relative to the degree of obesity in patients with CP[14]. However, the underlying mechanisms of leptin elevation and resistance in CP remain uncertain. Therefore, we attempted to explain this abnormal elevation by investigating the relationship between the inflammatory mediators and plasma leptin. The mean plasma leptin concentration was 29.18±25.56 ng/ml, ranging from 0.5 ng/ml to 131.3 ng/ml. The plasma leptin concentration was positively correlated with expressions of CXCL1 (Fig.3a, r=0.185, P =0.036), CXCL8 (Fig.3b, r=0.204, P =0.020), and IL10 (Fig.3f, r=0.227, P =0.009), while it did not show a significant correlation with the expression levels of IL1A ( P =0.208), IL1B ( P =0.680), IL6 ( P =0.790), and TNF ( P =0.809). 3.3 Inflammatory mediators associate with clinical characteristics and progression-free survival The mRNA expression levels of these seven inflammatory mediators were significantly higher in CP tumor tissue than in normal pituitary tissue (Fig.4, and all P <0.05, Mann Whitney U-test). Table 3 depicts the associations between inflammatory meditator expression and clinicopathologic parameters. Compared with the PCP subtype, the ACP subtype exhibited lower levels of CXCL1, CXCL8, IL1A, and IL1B (all P <0.05) but higher levels of IL10 ( P =0.027). Tumors with calcification exhibited lower CXCL1, CXCL8, IL1A, and IL1B (all P <0.01) than those without calcification. Furthermore, severe HI was associated with higher levels of CXCL1 ( P =0.013) and CXCL8 ( P =0.043). Moreover, higher IL6 expression and lower TNF expression were associated with preoperative hydrocephalus. Cystic tumors exhibited higher expression of IL1B, IL6, IL10, and TNF (all P <0.05) than non-cystic tumors. Furthermore, no significant associations were detected between inflammatory meditators expression and other characteristics, including age, sex, preoperative visual field damage, and preoperative obesity. In terms of tumor size and tumor volume, tumor size was positively correlated with levels of CXCL1 (r=0.17, P =0.048), CXCL8 (r=0.18, P =0.037), and IL6 (r=0.27, P =0.009). Tumor volume was positively correlated with levels of CXCL8 (r=0.18, P =0.037) and IL6 (r=0.28, P =0.004). In contrast, TNF expression negatively correlated with tumor size (r= -0.18, P =0.040) and tumor volume (r= -0.18, P =0.040). In terms of cyst size and cyst volume, IL6 expression was positively correlated with cyst size (r=0.22, P =0.013) and cyst volume (r=0.25, P =0.005), and IL10 expression was also positively correlated with the cyst size (r=0.24, P =0.006) and cyst volume (r=0.26, P =0.002). To determine the prognostic value of inflammatory mediators in patients with CP, we dichotomized the cohort into two groups (high and low expression groups) based on the median expression of each gene, and the details are shown in Fig.5. The K–M curves revealed that poor PFS was associated with high CXCL1 ( hazard ratio (HR)=2.33, 95% CI, 1.06-5.11, P =0.041), CXCL8 (HR=2.30, 95% CI, 1.06-4.97, P =0.037), IL1A (HR=2.56, 95% CI, 1.19-5.53, P =0.021), IL6 (HR=2.30, 95% CI, 1.05-5.03, P =0.044), and TNF (HR=2.19, 95% CI, 1.02-4.74, P =0.033) expression. However, no significant association was observed between poor PFS and the expression of IL1B ( P =0.602) or IL10 ( P =0.486). 4 Discussion Craniopharyngioma (CP), classified as a histologically nonmalignant intracerebral tumor (WHO grade I), typically exhibits favourable 5- and 10-year survival rates[2, 24]. However, the management of CP presents significant challenges due to its high recurrence rate and long-term morbidities, such as morbid obesity[25]. Recent studies have established that inflammatory mediators are tightly associated with tumor recurrence and obesity[26, 27], while these associations have not been thoroughly explored in CP. Therefore, we examined the expression profiles of inflammatory mediators in CP and investigated the potential associations between inflammatory mediators and clinical outcomes to identify targets for rational therapy. 4.1 Inflammatory mediators ， leptin ， and weight-related outcomes In recent decades, the high incidence of obesity (up to 50%) in patients with CP was widely accepted to be a consequence of physical hypothalamic damage caused by the combination of tumor invasion and treatment[28–30]. Two independent studies revealing cyst fluid contributes to obesity turned us to the obesogenic effect of inflammatory mediators riched in cyst fluid[7, 8]. The present study is the first to explore the associations between expression levels of inflammatory mediators and weight-related outcomes, including significant weight gain and new-onset obesity, in patients with CP. The result showed that higher expression levels of CXCL1 (aOR=2.21, P =0.044) and CXCL8 (aOR=2.43, P =0.032) were independently associated with significant weight gain, and higher expression levels of CXCL1 (aOR=4.58, P =0.025) and TNF (aOR=3.83, P =0.035) were independently associated with new-onset obesity postoperatively. Leakage of these inflammatory mediators causes severe chemical meningitis[31] and can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of β-amyloid[8]. In addition, cyst fluid contributes to tumor cells’ lipid metabolism disorder, which is closely associated with inflammation of the hypothalamus[31, 32]. Further evidence supports that hypothalamic inflammation can induce obesity in model animals fed a high-fat diet[33]. The hypothalamus acts as the energy center and regulates energy balance through the leptin-melanocortin pathway[34]. For example, leptin binds to the receptors of hypothalamic neurons to increase metabolism and decrease food intake[35]. Physiological dysfunctions of the hypothalamus, such as insensitivity to leptin, could lead to energy imbalance [4, 13, 36–39]. Hypothalamic inflammation has been implicated in the development of obesity[15, 27], and this inflammation results in the activation of the NF-κB pathway, overexpression of suppressor of cytokine signalling 3 (SOCS3, a potential mediator of central leptin resistance), and the subsequent development of leptin resistance[35, 40]. In the present study, we found a positive correlation between leptin concentration and levels of CXCL1 (r=0.185, P =0.036), CXCL8 (r=0.204, P =0.020), and IL10 (r=0.227, P =0.009). These results provide preliminary data accounting for the role of inflammatory mediators in leptin elevation and obesity, and we hypothesize that CP tumor cells may induce hypothalamic leptin resistance and subsequent obesity via expressing high inflammatory mediators. Further research focusing on revealing the underlying mechanism of leptin resistance induced by inflammatory mediators in CP will facilitate the design of drugs to block the pathways associated with impaired metabolism and ameliorate obesity. 4.2 Inflammatory mediators, tumorigenesis, and pathogenesis of cysts Differences, including age distribution, incidence rate, pathological behavior, and, most notably, the context of tumorigenesis, exist between the two subgroups of CP, namely PCP and ACP [41]. The senescence-associated secretory phenotype (SASP) means specific cell clusters undergo senescence and secrete growth factors and cytokines, and the SASP has been observed in ACPs and is associated with tumor cell growth [1]. Although the SASP phenomenon has not been observed or well characterized in PCP, the BRAF-v600e (somatic BRAF-v600e mutations primarily drive PCP) is regarded as a senescence inducer[42]. Previous studies have demonstrated that cyst fluid and solid components of CP exhibit high levels of inflammatory mediators[10]. Consistent with these findings, our study also revealed significantly higher expression of inflammatory mediators in CP than in normal pituitary tissue (Fig.2, all P <0.05). Furthermore, we reported that PCP exhibited higher expression of several inflammatory mediators, including CXCL1, CXCL8, IL1A, IL1B, and IL10, compared to ACP (Table 3). In a previous study, the IL6 high expression group with gastric cancer exhibited tumors with a higher diameter[19], our results also indicated a positive correlation of tumor size and volume with the expression levels of CXCL1, CXCL8, and IL6, while a negative correlation was observed with TNF expression (Table 3). Therefore, these findings indicate that inflammatory mediators associated with clinical parameters play an essential role in tumorigenesis in CP subtypes (ACP and PCP), even in the absence of the SASP phenomenon. The primary treatment methods for CP currently involve GTR or STR combined with radiotherapy. Nevertheless, radical surgery can lead to treatment-related damage due to the invasiveness of CP and its proximity to adjacent neural tissue, such as the hypothalamus, pituitary stalk, and optic chiasma. Reducing the mass effect of cyst fluid or solid components has become an option for temporary tumor control and delaying vision deterioration with the expectation of achieving further GTR[43]. Therefore, gaining a better understanding of cyst pathogenesis and developing more effective treatments to limit the volume of cysts are crucial. Carbonic anhydrase IX, an enzyme that causes fluid production, was revealed to be associated with the formation and size of cysts in CP[44], but the specific regulatory mechanisms of this enzyme have yet to be fully elucidated. One study demonstrated the essential role of the inflammatory response in generating cysts with highly elevated levels of inflammatory mediators[45]. The efficacy of intracystic IFN-alpha treatment has been shown to shrink cysts by reducing inflammation-mediated responses, further supporting the causal role of inflammatory mediators in cyst pathogenesis[46]. However, previous studies exploring the correlation between expression levels of inflammatory mediators, cyst size, and cyst volume have been limited by the small sample sizes (ranging from 5 to 15). Hence, the present study enrolled 130 patients (the largest known case series) and verified the higher expression of inflammatory mediators in cystic tumors and their positive correlation with cyst size and cyst volume (Table 3). These results provide further evidence supporting the potential application of anti-inflammation therapies for controlling cyst volume. 4.4 Predictive factors of prognosis in patients with CP Previous analyses have investigated the associations between patients’ CP prognosis and clinical parameters, including the number of surgical interventions, histological type, degree of HI and obesity, neuroendocrine deficiencies[1], surgical approach[47], and calcification[48]. Although these clinical factors related to prognosis provide excellent value for guiding treatment decisions, they do not fully elucidate the etiology and pathogenesis of patients with CP, thereby limiting the development of precise biomarker-based therapies. In the era of personalized medicine, biomarkers hold promise for predicting recurrence and guiding targeted therapies in patients with CP. Therefore, numerous studies have attempted to identify biomarkers to improve prognosis prediction and develop novel targeted therapies. We previously identified integrin α6 as a biomarker associated with adverse overall survival of CP[49]. Furthermore, a study conducted by Zou et al.[50] identified 10 hub genes for potential application in early diagnosis and therapy for ACP. Several studies have also identified the associations between the prognosis of CP and many biomarkers, including B7-H3[51], β-catenin[52], and growth hormone receptors [53]. Moreover, another study identified four inflammatory mediators (CXCL6, CXCL10, CXCL11, and CXCL13) as hub genes with great value for targeted therapy in CP[54]. Our results revealed that high expression levels of inflammatory mediators, including CXCL1, CXCL8, IL1A, IL6, and TNF, were associated with shorter PFS in patients with CP (Fig.5), further validating the potential value of anti-inflammation therapies in CP. Identifying prognostic biomarkers in patients with CP enables the identification of patients at high risk of recurrence and provides insights into targeted therapies based on these biomarkers. 5 Conclusion Our study demonstrated elevated expression levels of inflammatory mediators in CP, with a particularly prominent presence in the PCP subtype. The associations of inflammatory mediators with clinical parameters indicate their potential role in the pathogenesis of tumors and cysts. In addition, inflammatory mediators were independently associated with significant weight gain and new-onset postoperative obesity. Moreover, the expression of inflammatory mediators exhibited significant prognostic value in patients with CP. Therefore, investigating therapeutic strategies targeting these inflammatory mediators holds promise for improving the prognosis of patients with CP and reducing complications, particularly leptin resistance and subsequent morbid obesity. Further studies are warranted to explore the potential of targeting inflammatory mediators as a means to optimize CP management and enhance patient outcomes. Declarations Acknowledgement: The authors thank all members of the Department of Neurosurgery, Beijing Tiantan Hospital, and Capital Medical University. They provided so much advice for this study and backed our work. Statement of Ethics: All procedures in our study followed the ethical standards of the institutional and national research committees and the Declaration of Helsinki. The institutional review board of Beijing Tiantan Hospital approved this study (KY-2021-041-02). Informed consent was obtained from all subjects involved in the study. Conflict of Interest Statement: The authors have no conflicts of interest to declare. Funding Sources: This study is supported by the Beijing Municipal Science and Technology Commission (Grant No. Z191100006619087) and the Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (XMLX202108). The funder had no role in the design, data collection, data analysis, and reporting of this study. Author Contributions: YX, WW, and FL contributed to the conception of the study, formal analysis, manuscript preparation, and writing, SG contributed to academic instruction, funding acquisition, and manuscript reviewing, LJ and YJ contributed to data extraction, data curation, NQ, SR, KC, and LC contributed to statistical methods and constructive discussions. All authors have read and agreed to the published version of the manuscript. Data Availability Statement: Data are not publicly available due to ethical reasons. Further inquiries can be directed to Youchao Xiao and Wentao Wu. References Müller HL, Merchant TE, Warmuth-Metz M, Martinez-Barbera JP, Puget S. Craniopharyngioma. Nat Rev Dis Prim. 2019,5:1–19. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021,23:1231–51. Eveslage M, Calaminus G, Warmuth-Metz M, Kortmann RD, Pohl F, Timmermann B, et al. 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Puget S, Garnett M, Wray A, Grill J, Habrand J-L, Bodaert N, et al. Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg. 2007,106 1 Suppl:3–12. Karavitaki N, Brufani C, Warner JT, Adams CBT, Richards P, Ansorge O, et al. Craniopharyngiomas in children and adults: Systematic analysis of 121 cases with long-term follow-up. Clin Endocrinol (Oxf). 2005,62:397–409. Pereira AM, Schmid EM, Schutte PJ, Voormolen JHC, Biermasz NR, Van Thiel SW, et al. High prevalence of long-term cardiovascular, neurological and psychosocial morbidity after treatment for craniopharyngioma. Clin Endocrinol (Oxf). 2005,62:197–204. Duan D, Wehbeh L, Mukherjee D, Hamrahian AH, Rodriguez FJ, Gujar S, et al. Preoperative BMI Predicts Postoperative Weight Gain in Adult-onset Craniopharyngioma. J Clin Endocrinol Metab. 2021,106:1603–17. Ray I, Michael A, Meira LB, Ellis PE. The Role of Cytokines in Epithelial–Mesenchymal Transition in Gynaecological Cancers: A Systematic Review. Cells. 2023,12:1–37. Sonnefeld L, Rohmann N, Geisler C, Laudes M. Is human obesity an inflammatory disease of the hypothalamus? Eur J Endocrinol. 2023,188:37–45. Van Iersel L, Brokke KE, Adan RAH, Bulthuis LCM, Van Den Akker ELT, Van Santen HM. Pathophysiology and individualized treatment of hypothalamic obesity following craniopharyngioma and other suprasellar tumors: A systematic review. Endocr Rev. 2019,40:193–235. Van Gompel JJ, Nippoldt TB, Higgins DM, Meyer FB. Magnetic resonance imaging-graded hypothalamic compression in surgically treated adult craniopharyngiomas determining postoperative obesity. Neurosurg Focus. 2010,28:E3. Park SW, Jung HW, Lee YA, Shin CH, Yang SW, Cheon J-E, et al. Tumor origin and growth pattern at diagnosis and surgical hypothalamic damage predict obesity in pediatric craniopharyngioma. J Neurooncol. 2013,113:417–24. Dalvi PS, Chalmers JA, Luo V, Han D-Y, Wellhauser L, Liu Y, et al. High fat induces acute and chronic inflammation in the hypothalamus: effect of high-fat diet, palmitate and TNF-α on appetite-regulating NPY neurons. Int J Obes (Lond). 2017,41:149–58. Wang C-H, Qi S-T, Fan J, Pan J, Peng J-X, Nie J, et al. Identification of tumor stem-like cells in admanatimomatous craniopharyngioma and determination of these cells’ pathological significance. J Neurosurg. 2019,:1–11. Ullah R, Rauf N, Nabi G, Yi S, Yu-Dong Z, Fu J. Mechanistic insight into high-fat diet-induced metabolic inflammation in the arcuate nucleus of the hypothalamus. Biomed Pharmacother. 2021,142:112012. Koves IH, Roth C. Genetic and Syndromic Causes of Obesity and its Management. Indian J Pediatr. 2018,85:478–85. Kwon O, Kim KW, Kim MS. Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci. 2016,73:1457–77. Patel L, Cooper CD, Quinton ND, Butler GE, Gill MS, Jefferson IG, et al. Serum leptin and leptin binding activity in children and adolescents with hypothalamic dysfunction. J Pediatr Endocrinol Metab. 2002,15:963–71. Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE, et al. Octreotide therapy of pediatric hypothalamic obesity: A double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2003,88:2586–92. Shaikh MG, Grundy RG, Kirk JMW. Hyperleptinaemia rather than fasting hyperinsulinaemia is associated with obesity following hypothalamic damage in children. Eur J Endocrinol. 2008,159:791–7. Guran T, Turan S, Bereket A, Akcay T, Unluguzel G, Bas F, et al. The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children. Eur J Pediatr. 2009,168:1043–8. Kievit P, Howard JK, Badman MK, Balthasar N, Coppari R, Mori H, et al. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab. 2006,4:123–32. Zoicas F, Schöfl C. Craniopharyngioma in adults. Front Endocrinol (Lausanne). 2012,3 MAR:1–8. Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, et al. Oncogenic Braf Induces Melanocyte Senescence and Melanoma in Mice. Cancer Cell. 2009,15:294–303. Garnett MR, Puget S, Grill J, Sainte-Rose C. Craniopharyngioma. Orphanet J Rare Dis. 2007,2:1–7. Proescholdt M, Merrill M, Stoerr EM, Lohmeier A, Dietmaier W, Brawanski A. Expression of carbonic anhydrase IX in craniopharyngiomas: Laboratory investigation. J Neurosurg. 2011,115:796–801. Whelan R, Prince E, Gilani A, Hankinson T. The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment. J Clin Med. 2020,9:519. Bartels U, Laperriere N, Bouffet E, Drake J. Intracystic therapies for cystic craniopharyngioma in childhood. Front Endocrinol (Lausanne). 2012,3 MAR:1–8. KL W, WW P, ML H, MT W. Comparing surgical approaches for craniopharyngioma resection among adults and children: a meta-analysis and systematic review. World Neurosurg. 2023,:143747. Cheng J, Shao Q, Pan Z, You J. Analysis and Long-Term Follow-Up of the Surgical Treatment of Children With Craniopharyngioma. J Craniofac Surg. 2016,27:763–6. Jia Y, Wu W, Xiao Y, Cai K, Gui S, Li Q, et al. Integrin α 6 Indicates a Poor Prognosis of Craniopharyngioma through Bioinformatic Analysis and Experimental Validation. J Oncol. 2022,2022. Zou YF, Zhang SY, Li LW, Jing K, Xia L, Sun CX, et al. Hub genes for early diagnosis and therapy of adamantinomatous craniopharyngioma. Med (United States). 2022,101:E30278. Chen C, Wang Y, Zhong K, Jiang C, Wang L, Yuan Z, et al. Frequent B7-H3 overexpression in craniopharyngioma. Biochem Biophys Res Commun. 2019,514:379–85. Li Z, Xu J, Huang S, You C. Aberrant membranous expression of β-catenin predicts poor prognosis in patients with craniopharyngioma. Ann Diagn Pathol. 2015,19:403–8. Ogawa Y, Watanabe M, Tominaga T. Prognostic factors of craniopharyngioma with special reference to autocrine/paracrine signaling: underestimated implication of growth hormone receptor. Acta Neurochir (Wien). 2015,157:1731–40. Lin D, Zhao W, Yang J, Wang H, Zhang H. Integrative Analysis of Biomarkers and Mechanisms in Adamantinomatous Craniopharyngioma. Front Genet. 2022,13 March:1–13. Tables Tables 1, 2, and 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table2.docx Table3.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 May, 2024 Reviews received at journal 22 May, 2024 Reviews received at journal 13 May, 2024 Reviewers agreed at journal 29 Apr, 2024 Reviewers agreed at journal 24 Apr, 2024 Reviewers invited by journal 24 Apr, 2024 Editor assigned by journal 24 Apr, 2024 Submission checks completed at journal 16 Apr, 2024 First submitted to journal 15 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4272844","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":298809190,"identity":"1ba7b8d2-0a48-41ce-818f-00fc4d2fdbda","order_by":0,"name":"Youchao Xiao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYJACZhDBxsDA+ICBQUIGJsrYQIQWZgOgFh7itYB0SQAJwloMjvcYfi6osUnsYz98rOpGjQUPA/vhp5t5GGxkNxxgfvYAm5YzZ4ylZxxLM2bjSUu7nXMM6DCeNLPbPAxpxhsOsJkbYNNyI8eMmYftsBwbQ47Z7Rw2oBYJHjaglsOJGw7wgJ2KXcu/wzxs/G/MinP+wbX8x6+Ftw1oiwSQkdsG13IApxbJM8eKpXn7gH6ReJYsndsHVA/0y805BsnGMw+zmWHTwne8eeNnnm82ifP7kw9+zvlWJ8fPfvjZjTcVdrJ9x5ufYdOicABdhA3iYAZEfKEB+Qbs4qNgFIyCUTAKEAAAHP1WMTS7c94AAAAASUVORK5CYII=","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":true,"prefix":"","firstName":"Youchao","middleName":"","lastName":"Xiao","suffix":""},{"id":298809191,"identity":"db13468a-8b33-4e83-874d-0fb3172a696f","order_by":1,"name":"Wentao Wu","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wentao","middleName":"","lastName":"Wu","suffix":""},{"id":298809192,"identity":"81db864e-afb8-4f26-9188-27ffad5c737d","order_by":2,"name":"Fangzheng Liu","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fangzheng","middleName":"","lastName":"Liu","suffix":""},{"id":298809193,"identity":"38ec2ca6-7aa9-41ac-854e-dfa34d1d4f7b","order_by":3,"name":"Yanfei Jia","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yanfei","middleName":"","lastName":"Jia","suffix":""},{"id":298809199,"identity":"7d81d89d-a6a8-4556-8026-d4388b845e4d","order_by":4,"name":"Lu Jin","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lu","middleName":"","lastName":"Jin","suffix":""},{"id":298809200,"identity":"b5904b14-1af1-41b2-b938-5f07091998cd","order_by":5,"name":"Ning Qiao","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ning","middleName":"","lastName":"Qiao","suffix":""},{"id":298809201,"identity":"bbcec720-231c-4822-be9a-5f65590051c3","order_by":6,"name":"Kefan Cai","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kefan","middleName":"","lastName":"Cai","suffix":""},{"id":298809203,"identity":"be1a68ab-5d4a-44d8-8ede-349e3bbe0f9a","order_by":7,"name":"Siming Ru","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Siming","middleName":"","lastName":"Ru","suffix":""},{"id":298809205,"identity":"4032057d-9fc9-4f94-b98c-24a5b5339793","order_by":8,"name":"Lei Cao","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Cao","suffix":""},{"id":298809207,"identity":"4af092cc-fecc-4273-bba1-74698ab658ee","order_by":9,"name":"Songbai Gui","email":"","orcid":"","institution":"Beijing Tian Tan Hospital","correspondingAuthor":false,"prefix":"","firstName":"Songbai","middleName":"","lastName":"Gui","suffix":""}],"badges":[],"createdAt":"2024-04-16 03:24:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4272844/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4272844/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56140130,"identity":"bc530482-5e72-429d-ade2-0cb56d0628d7","added_by":"auto","created_at":"2024-05-09 04:04:41","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":220540,"visible":true,"origin":"","legend":"\u003cp\u003eThe flowchart of patient selection\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/0baf9f9379f4ee4cff1924a4.png"},{"id":56140172,"identity":"48df2749-8125-4fb4-a61c-9ca01795d5e1","added_by":"auto","created_at":"2024-05-09 04:08:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":560625,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate logistic analysis for (a) significant weight gain and (c) new-onset obesity. Multivariate logistic analysis for (b) significant weight gain and (d) new-onset obesity. Clinical parameters, including age, sex, histopathologic subtype, calcification, hypothalamus involvement, the extent of surgical resection, and preoperative body mass index, were adjusted for in the multivariate logistic analysis. uOR, unadjusted odds ratio. aOR, adjusted odds ratio.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/6cd07506e08f342541d1fe55.png"},{"id":56140224,"identity":"b1fb3812-a52c-4058-a788-edcc88704ca1","added_by":"auto","created_at":"2024-05-09 04:09:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":430412,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations between inflammatory mediators expression and plasma leptin concentration.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/f85fae8a6972b811bfb0f0f2.png"},{"id":56140135,"identity":"f065f88c-749d-418e-be2e-e57c2b5567ab","added_by":"auto","created_at":"2024-05-09 04:04:56","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":291907,"visible":true,"origin":"","legend":"\u003cp\u003eThe expressions of inflammation mediators were elevated in the CP tumor tissue compared to normal brain tissue. * means p\u0026lt;0.05, ** means p\u0026lt;0.01, *** means p\u0026lt;0.001.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/8103a26f4c793c62112eca56.png"},{"id":56140193,"identity":"1b0b8716-372c-4f5f-b5e9-57d386d2afc9","added_by":"auto","created_at":"2024-05-09 04:09:13","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":273620,"visible":true,"origin":"","legend":"\u003cp\u003eThe prognostic value of inflammatory mediators expression in CP. The Kaplan–Meier curves indicate that poor PFS was associated with higher CXCL1, CXCL8, IL1A, IL6, and TNF expression. HR, hazard ratio.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/5c184efa7203793acce463cc.png"},{"id":56400389,"identity":"f047b1c2-885f-4690-a1e8-8ac3372b3a10","added_by":"auto","created_at":"2024-05-13 16:27:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2033596,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/a0f7f0c6-237b-41b0-95ea-97e5a7fe85ca.pdf"},{"id":56140110,"identity":"8375b92e-4cff-4473-a83b-81737aafe969","added_by":"auto","created_at":"2024-05-09 04:03:43","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21210,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/0e954b7100759fd159277326.docx"},{"id":56140148,"identity":"ce965e6b-48d6-43d5-97db-c44a76f8b5da","added_by":"auto","created_at":"2024-05-09 04:05:24","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":23019,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/e1e5b823ce8e0232c4ccf513.docx"},{"id":56399596,"identity":"2feca79b-9c4d-4ead-bfc1-151ee1d384e1","added_by":"auto","created_at":"2024-05-13 16:11:06","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":30730,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4272844/v1/5b099e80a09d93b53c000612.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Clinical Significance of Inflammatory Mediators in Predicting Obesity and Progression-Free Survival in Patients with Craniopharyngioma","fulltext":[{"header":"1 Introduction ","content":"\u003cp\u003eCraniopharyngioma (CP) is a rare malformational tumor mainly located in the sellar area, accounting for 0.5–2.5 new cases per 1 million people per year globally\u0026nbsp;[1].\u0026nbsp;However, despite low-grade histological malignancy (WHO grade I) and high survival rates[2], survivors often experience obesity and tumor recurrence, which significantly adversely affect their quality of life\u0026nbsp;[3].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe hypothalamus acts as the energy center, linking direct synaptic connections to limbic systems that mediate motivation to eat and process reward[4]. Mechanistically, neurons within hypothalamic nuclei maintain energy homeostasis by responding to nutrient signalling and hormone binding, such as leptin, insulin, ghrelin, and cholecystokinin[5].\u0026nbsp;Injury to the hypothalamus can disrupt the delicate balance between energy intake and expenditure[4]. Due to the proximity of CP to the hypothalamus and the high probability of hypothalamic damage from the tumor and treatment, hyperphagia and morbid obesity (occurring in up to 50% of cases) in CP have traditionally been attributed to physical hypothalamus damage caused by a combination of tumor invasion and treatments[1].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, a high proportion of CP patients (more than 50%) with an integrated hypothalamus characterized by no hypothalamic involvement (HI) and a normal floor of the third ventricle develop obesity postoperatively[6], indicating that specific unrevealed mechanisms also contribute to obesity in patients with CP, except for physical damage to the hypothalamus. Two independent studies supported the idea that injecting cyst fluid of CP into the brain of model animals contributes to the pathogenesis of obesity[7, 8], these results help us understand the obesity of CP from the\u0026nbsp;perspective\u0026nbsp;of biofactors in cyst fluid secreted by the tumor. While the cyst fluid is rich in various growth factors and inflammatory mediators, including interleukin (IL)1A, IL1B, IL6, IL10, C-X-C motif chemokine ligand (CXCL) 1, CXCL8, and tumor necrosis factor-alpha (TNF)[9, 10], and these two studies did not reveal which specific substances play a role in promoting obesity. Therefore, the present study first aimed to explore the relationship between the expression levels of these seven inflammatory mediators and weight changes, which will be helpful for subsequent experiments and drug development.\u003c/p\u003e\n\u003cp\u003eConsistent with previous research[11–13], one of our previous studies revealed that hypothalamic resistance to circulation hormones, such as leptin, contributes to obesity[14]. Patients with CP exhibit abnormally elevated preoperative leptin relative to fat mass and fail to suppress food intake or increase energy expenditure effectively, indicating the existence of leptin resistance in patients with CP[14]. Unfortunately, which factors cause hyperleptinemia and leptin resistance in patients with CP is still unknown. Emerging evidence indicates that activated glial cells secrete various cytokines and inflammatory mediators, which could impair the sensitivity of hypothalamic neurons to peripheral metabolic signals, such as leptin and insulin, ultimately resulting in metabolic dysfunction[15, 16]. However, it remains unclear whether inflammatory mediators secreted by tumor cells contribute to leptin resistance characterized by elevated plasma leptin in patients with CP, consequently leading to morbid obesity. Therefore, the present study also exploreed the correlation between the expression levels of inflammatory mediators and plasma leptin concentrations in CP, which could further provide evidence for supporting crass talking among inflammatory mediators, leptin, and the hypothalamus.\u003c/p\u003e\n\u003cp\u003eAlthough various treatment modalities, including surgery, irradiation, cyst aspiration, and intracystic therapies, have shown efficacy in improving the prognosis of patients with CP[1], reducing the rate of tumor recurrence and improving the ability to predict the prognosis of patients are still urgent problems in clinical practice. Numerous studies have evaluated the value of inflammatory mediators in predicting the prognosis of various tumors, including laryngeal squamous cell carcinoma[17], colorectal cancer[18], and gastric cancer[19]. However, studies on the associations between these seven inflammatory mediators and CP are rare. Thus, the present study also aimed to reveal the associations among these seven inflammatory mediators, clinical characteristics, and progression-free survival in patients with CP.\u003c/p\u003e"},{"header":"2 Patients and methods","content":"\u003cp\u003e\u003cstrong\u003e2.1 Patient selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA single-center cohort study was conducted on patients diagnosed with CP who underwent endoscopic endonasal transsphenoidal surgery at Beijing Tiantan Hospital between January 2019 and March 2022. Patient selection was based on the following criteria: (I) age ≥ 18 years at the time of diagnosis, (II) primary CP without prior history of irradiation or cyst aspiration, (III) confirmed availability of histological diagnosis, (IV) presence of well-preserved tumor tissue for RNA testing and availability of plasma samples for enzyme-linked immunosorbent assay (ELISA) testing, and (V) minimum follow up period of 1-year.\u0026nbsp;All procedures in our study followed the ethical standards of the institutional and national research committees and the Declaration of Helsinki. The institutional review board of Beijing Tiantan Hospital approved this study. Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Clinical data and definition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics and demographics were obtained from the hospital medical records. Patients were followed from primary surgery until secondary surgery, administration of radiotherapy, death, or March 2023, whichever came first. Based on preoperative magnetic resonance imaging (MRI), the maximum diameters of the tumor and cyst in each of the three dimensions were defined as tumor size and cyst size, respectively. The tumor volume and cyst volume were approximately calculated using the following formula: volume = 4/3 × π × (a/2 × b/2 × c/2), where a, b, and c represent the maximum diameters of the tumor in each of the three dimensions[20]. A tumor with a cystic component comprising more than 50% of the total volume was classified as a cystic tumor[14, 20].\u003c/p\u003e\n\u003cp\u003eThe extent of resection was assessed based on surgical videos and postoperative MRI and was categorized as gross total resection (GTR, 100% removal), STR (≥95% removal), or partial resection (PR, \u0026lt;95% removal)[21]. The latter two were combined into the non-gross total resection (NTR) group in the statistical analysis. The degree of HI, which included severe hypothalamus involvement (HI) (grade 2), mild HI (grade 1), and no HI (grade 0), was assessed using Puget’s grading system[22]. Based on body mass index (BMI), body weight status was categorized as obesity (BMI ≥ 30 kg/m2), overweight (BMI ≥ 25kg/m2), or normal weight (BMI \u0026lt; 25kg/m2). Consistent with our previous study, postoperative weight changes ≥5% were considered clinically significant[14, 20]. Hormone deficiency was assessed based on principles established in previous research[23]. Progression-free survival (PFS) was defined as the time from primary surgery to recurrence or death, whichever occurred first.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Assay of inflammatory mediator expression in tumor tissue\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe tumor specimens of 130 patients with CP and 11 normal pituitary tissue samples were collected during surgical procedures and quickly stored at -80℃. Total RNA was extracted from the samples using Steadypure universal RNA extraction kit (Accurate Biotechnology, Hunan, China, Cat No. AG21017). The primers used for reverse-transcription quantitative polymerase chain reaction (RT-qPCR) amplification are listed in Table 1. SYBR Green qPCR Mix (Biosharp Biotechnology, BL698A) was used to perform qPCR on QuantStudio 5 RealTime PCR System following the manufacturer’s protocol. The housekeeping gene GAPDH was used for normalization. The relative mRNA expression was determined using the 2\u003csup\u003e−\u003c/sup\u003e\u003csup\u003eΔΔCT\u003c/sup\u003e method and was expressed as log2 (X+1). Each sample was tested in triplicate.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4 Measurement of plasma leptin concentration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePeripheral blood samples were obtained from patients with CP before tumor surgery. The samples were centrifuged at 3000 rpm for 2 min at 4 °C, and the plasma was collected and stored at -80 ℃ until the ELISA test. The plasma leptin concentration was measured using the ELISA method according to the manufacturer’s protocol (Peprotech, Inc., Cat No. 900-K90).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5 Statistical method\u003c/strong\u003es\u003c/p\u003e\n\u003cp\u003ePatients were categorized into high- and low-expression groups according to the median levels of inflammatory mediators. Univariate and multivariate logistic regression analyses were performed to calculate the unadjusted odds ratio (uOR) and the adjusted odds ratio (aOR). The Pearson correlation test was also used to estimate the correlation between inflammatory mediator expression and leptin concentration. Parametric variables were analyzed using Student’s t-test, while nonparametric variables were analyzed using the Mann-Whitney U-test to compare between groups. Categorical variables were compared using Chi-square and Fisher’s exact tests. The Spearman correlation test performed correlation analysis between gene expression, size, and volume (both tumor and cyst). The Kaplan-Meier (K–M) curves and log-rank tests were employed to validate the survival rates between the low- and high-expression groups. A \u003cem\u003eP\u003c/em\u003e-value \u0026lt; 0.05 was considered to indicate statistical significance. Furthermore, all the statistical analyses were performed, and the results were visualized using SPSS 24 (SSPS, Inc., Chicago, USA) and GraphPad Prism 9 (GraphPad Software, Inc., La Jolla, CA, USA).\u003c/p\u003e"},{"header":"3 Results","content":"\u003cp\u003e\u003cstrong\u003e3.1 Patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFig.1 visually illustrates the patient selection process, while Table 2 summarizes patient characteristics. This study included 130 participants (71 males and 59 females) with a mean age of 43.92±12.52 years. Histological analysis confirmed 98 cases of adamantinomatous craniopharyngioma (ACP) \u0026nbsp;and 32 cases of papillary craniopharyngioma (PCP). The mean duration of follow-up was 22.67±9.29 months. Calcification was observed in 61.5% of the cohort (n=80). Preoperative hydrocephalus and preoperative visual field damage were present in 26.2% (n=34) and 17.7% (n=23) of patients, respectively. Regarding preoperative body weight, 60 patients had normal weight, 56 were overweight, and 14 were obese. Gonadotropic hormone deficiency (n=34, 26.2%) and antidiuretic hormone deficiency (n=32, 24.6%) were the two most common preoperative hormone deficiencies in patients with CP. The incidence of other hormone deficiencies, including growth hormone deficiency (n=19, 14.6%), thyroid-stimulating hormone deficiency (n=16, 12.3%), and adrenocorticotropic hormone deficiency (n=12, 9.2%), was less than 15%.\u003c/p\u003e\n\u003cp\u003eOn preoperative MRI, severe HI (grade 2) was observed in approximately half of the patients (n=64, 49.2%), while mild HI (grade 1) and no HI (grade 0) were observed in 36.9% (n=48), and 14.6% (n=19) of patients, respectively. The mean tumor size was 3.1±0.97 cm, and the mean tumor volume was 13.01±11.82 cm3. Moreover, the mean size and mean volume of the cysts were 2.02±1.05 cm and 5.86±8.62 cm3, respectively. Among the 130 cases, 76 tumors were identified as cystic tumors. Finally, GTR was achieved in 120 patients (92.3%), and NTR was achieved in 10 patients (7.7%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Association between inflammatory mediators, weight gain, new-onset obesity, and leptin concentration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the univariate logistic regression analysis, significant weight gain (weight change ≥5%) was associated with higher expression of CXCL1 (Fig.2a, unadjusted odds ratio (uOR) = 2.12, 95% confidence interval (CI), 1.05-4.28, \u003cem\u003eP\u003c/em\u003e=0.036). New-onset postoperative obesity was associated with high expressions of CXCL1 (Fig.2c, uOR = 3.67, 95% CI, 1.11-12.15, \u003cem\u003eP\u003c/em\u003e=0.034) and TNF (Fig.2c, uOR = 2.92, 95% CI, 1.04-9.02, \u003cem\u003eP\u003c/em\u003e=0.045).Multivariate logistic regression analysis adjusted for age, gender, HI, and preoperative body mass index (BMI) was conducted to explore the independent relationships among inflammatory mediators, significant weight gain, and new-onset obesity. The results revealed that high expressions of CXCL1 (Fig.2b, adjusted odds ratio (aOR) = 2.21, 95% CI, 1.02-4.77, \u003cem\u003eP\u003c/em\u003e=0.044) and CXCL8 (Fig.2b, aOR = 2.43, 95% CI, 1.08-5.51, \u003cem\u003eP\u003c/em\u003e=0.032) were independent risk factors for significant weight gain, while high expression levels of CXCL1 (Fig.2d, aOR = 4.58, 95% CI, 1.21-17.26, \u003cem\u003eP\u003c/em\u003e=0.025) and TNF (Fig.2d, aOR = 3.83, 95% CI, 1.10-13.31, \u003cem\u003eP\u003c/em\u003e=0.035) were found to be independent risk factors for new-onset postoperative obesity.\u003c/p\u003e\n\u003cp\u003eLeptin, a cytokine secreted by fat cells that regulates energy balance, is abnormally elevated relative to the degree of obesity in patients with CP[14]. However, the underlying mechanisms of leptin elevation and resistance in CP remain uncertain. Therefore, we attempted to explain this abnormal elevation by investigating the relationship between the inflammatory mediators and plasma leptin. The mean plasma leptin concentration was 29.18±25.56 ng/ml, ranging from 0.5 ng/ml to 131.3 ng/ml. The plasma leptin concentration was positively correlated with expressions of CXCL1 (Fig.3a, r=0.185, \u003cem\u003eP\u003c/em\u003e=0.036), CXCL8 (Fig.3b, r=0.204, \u003cem\u003eP\u003c/em\u003e=0.020), and IL10 (Fig.3f, r=0.227, \u003cem\u003eP\u003c/em\u003e=0.009), while it did not show a significant correlation with the expression levels of IL1A (\u003cem\u003eP\u003c/em\u003e=0.208), IL1B (\u003cem\u003eP\u003c/em\u003e=0.680), IL6 (\u003cem\u003eP\u003c/em\u003e=0.790), and TNF (\u003cem\u003eP\u003c/em\u003e=0.809).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Inflammatory mediators associate with clinical characteristics and progression-free survival\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mRNA expression levels of these seven inflammatory mediators were significantly higher in CP tumor tissue than in normal pituitary tissue (Fig.4, and all \u003cem\u003eP\u003c/em\u003e \u0026lt;0.05, Mann Whitney U-test).\u003c/p\u003e\n\u003cp\u003eTable 3 depicts the associations between inflammatory meditator expression and clinicopathologic parameters. Compared with the PCP subtype, the ACP subtype exhibited lower levels of CXCL1, CXCL8, IL1A, and IL1B (all \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05) but higher levels of IL10 (\u003cem\u003eP\u003c/em\u003e=0.027). Tumors with calcification exhibited lower CXCL1, CXCL8, IL1A, and IL1B (all \u003cem\u003eP\u003c/em\u003e\u0026lt;0.01) than those without calcification. Furthermore, severe HI was associated with higher levels of CXCL1 (\u003cem\u003eP\u003c/em\u003e=0.013) and CXCL8 (\u003cem\u003eP\u003c/em\u003e=0.043). Moreover, higher IL6 expression and lower TNF expression were associated with preoperative hydrocephalus. Cystic tumors exhibited higher expression of IL1B, IL6, IL10, and TNF (all \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05) than non-cystic tumors. Furthermore, no significant associations were detected between inflammatory meditators expression and other characteristics, including age, sex, preoperative visual field damage, and preoperative obesity.\u003c/p\u003e\n\u003cp\u003eIn terms of tumor size and tumor volume, tumor size was positively correlated with levels of CXCL1 (r=0.17, \u003cem\u003eP\u003c/em\u003e=0.048), CXCL8 (r=0.18, \u003cem\u003eP\u003c/em\u003e=0.037), and IL6 (r=0.27, \u003cem\u003eP\u003c/em\u003e=0.009). Tumor volume was positively correlated with levels of CXCL8 (r=0.18, \u003cem\u003eP\u003c/em\u003e=0.037) and IL6 (r=0.28, \u003cem\u003eP\u003c/em\u003e=0.004). In contrast, TNF expression negatively correlated with tumor size (r= -0.18, \u003cem\u003eP\u003c/em\u003e=0.040) and tumor volume (r= -0.18, \u003cem\u003eP\u003c/em\u003e=0.040). In terms of cyst size and cyst volume, IL6 expression was positively correlated with cyst size (r=0.22, \u003cem\u003eP\u003c/em\u003e=0.013) and cyst volume (r=0.25, \u003cem\u003eP\u003c/em\u003e=0.005), and IL10 expression was also positively correlated with the cyst size (r=0.24, \u003cem\u003eP\u003c/em\u003e=0.006) and cyst volume (r=0.26, \u003cem\u003eP\u003c/em\u003e=0.002).\u003c/p\u003e\n\u003cp\u003eTo determine the prognostic value of inflammatory mediators in patients with CP, we dichotomized the cohort into two groups (high and low expression groups) based on the median expression of each gene, and the details are shown in Fig.5. The K–M curves revealed that poor PFS was associated with high CXCL1 ( hazard ratio (HR)=2.33, 95% CI, 1.06-5.11, \u003cem\u003eP\u003c/em\u003e=0.041), CXCL8 (HR=2.30, 95% CI, 1.06-4.97, \u003cem\u003eP\u003c/em\u003e=0.037), IL1A (HR=2.56, 95% CI, 1.19-5.53, \u003cem\u003eP\u003c/em\u003e=0.021), IL6 (HR=2.30, 95% CI, 1.05-5.03, \u003cem\u003eP\u003c/em\u003e=0.044), and TNF (HR=2.19, 95% CI, 1.02-4.74, \u003cem\u003eP\u003c/em\u003e=0.033) expression. However, no significant association was observed between poor PFS and the expression of IL1B (\u003cem\u003eP\u003c/em\u003e=0.602) or IL10 (\u003cem\u003eP\u003c/em\u003e=0.486).\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eCraniopharyngioma (CP), classified as a histologically nonmalignant intracerebral tumor (WHO grade I), typically exhibits favourable 5- and 10-year survival rates[2, 24]. However, the management of CP presents significant challenges due to its high recurrence rate and long-term morbidities, such as morbid obesity[25]. Recent studies have established that inflammatory mediators are tightly associated with tumor recurrence and obesity[26, 27], while these associations have not been thoroughly explored in CP. Therefore, we examined the expression profiles of inflammatory mediators in CP and investigated the potential associations between inflammatory mediators and clinical outcomes to identify targets for rational therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.1 Inflammatory mediators\u003c/strong\u003e\u003cstrong\u003e，\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;leptin\u003c/strong\u003e\u003cstrong\u003e，\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;and weight-related outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn recent decades, the high incidence of obesity (up to 50%) in patients with CP was widely accepted to be a consequence of physical hypothalamic damage caused by the combination of tumor invasion and treatment[28–30]. Two independent studies revealing cyst fluid contributes to obesity turned us to the obesogenic effect of inflammatory mediators riched in cyst fluid[7, 8]. The present study is the first to explore the associations between expression levels of inflammatory mediators and weight-related outcomes, including significant weight gain and new-onset obesity, in patients with CP. The result showed that higher expression levels of CXCL1 (aOR=2.21, \u003cem\u003eP\u003c/em\u003e=0.044) and CXCL8 (aOR=2.43, \u003cem\u003eP\u003c/em\u003e=0.032) were independently associated with significant weight gain, and higher expression levels \u0026nbsp;of CXCL1 (aOR=4.58, \u003cem\u003eP\u003c/em\u003e=0.025) and TNF (aOR=3.83, \u003cem\u003eP\u003c/em\u003e=0.035) were independently associated with new-onset obesity postoperatively. Leakage of these inflammatory mediators causes severe chemical meningitis[31] and can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of β-amyloid[8]. In addition, cyst fluid contributes to tumor cells’ lipid metabolism disorder, which is closely associated with inflammation of the hypothalamus[31, 32]. Further evidence supports that hypothalamic inflammation can induce obesity in model animals fed a high-fat diet[33].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe hypothalamus acts as the energy center and regulates energy balance through the leptin-melanocortin pathway[34]. For example, leptin binds to the receptors of hypothalamic neurons to increase metabolism and decrease food intake[35]. Physiological dysfunctions of the hypothalamus, such as insensitivity to leptin, could lead to energy imbalance\u0026nbsp;[4, 13, 36–39].\u0026nbsp;Hypothalamic inflammation has been implicated in the development of obesity[15, 27], and this inflammation results in the activation of the NF-κB pathway, overexpression of suppressor of cytokine signalling 3\u0026nbsp;(SOCS3, a potential mediator of central leptin resistance), and the subsequent development of leptin resistance[35, 40]. In the present study, we found a positive correlation between leptin concentration and levels of CXCL1 (r=0.185, \u003cem\u003eP\u003c/em\u003e=0.036), CXCL8 (r=0.204, \u003cem\u003eP\u003c/em\u003e=0.020), and IL10 (r=0.227, \u003cem\u003eP\u003c/em\u003e=0.009). These results provide preliminary data accounting for the role of inflammatory mediators in leptin elevation and obesity, and we hypothesize that CP tumor cells may induce hypothalamic leptin resistance and subsequent obesity via expressing high inflammatory mediators. Further research focusing on revealing the underlying mechanism of leptin resistance induced by inflammatory mediators in CP will facilitate the design of drugs to block the pathways associated with impaired metabolism and ameliorate obesity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2 Inflammatory mediators, tumorigenesis, and pathogenesis of cysts\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDifferences, including age distribution, incidence rate, pathological behavior, and, most notably, the context of tumorigenesis,\u0026nbsp;exist between the two subgroups of CP, namely PCP and ACP\u0026nbsp;[41]. The senescence-associated secretory phenotype (SASP) means specific cell clusters undergo senescence and secrete growth factors and cytokines, and the SASP has been observed in ACPs and is associated with tumor cell growth\u0026nbsp;[1]. Although the SASP phenomenon has not been observed or well characterized in PCP, the BRAF-v600e (somatic BRAF-v600e mutations primarily drive PCP) is regarded as a senescence inducer[42]. Previous studies have demonstrated that cyst fluid and solid components of CP exhibit high levels of inflammatory mediators[10]. Consistent with these findings, our study also revealed significantly higher expression of inflammatory mediators in CP than in normal pituitary tissue (Fig.2, all \u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Furthermore, we reported that PCP exhibited higher expression of several inflammatory mediators, including CXCL1, CXCL8, IL1A, IL1B, and IL10, compared to ACP (Table 3). In a previous study, the IL6 high expression group with gastric cancer exhibited tumors with a higher diameter[19], our results also indicated a positive correlation of tumor size and volume with the expression levels of CXCL1, CXCL8, and IL6, while a negative correlation was observed with TNF expression (Table 3). Therefore, these findings indicate that inflammatory mediators associated with clinical parameters play an essential role in tumorigenesis in CP subtypes (ACP and PCP), even in the absence of the SASP phenomenon.\u003c/p\u003e\n\u003cp\u003eThe primary treatment methods for CP currently involve GTR or STR combined with radiotherapy. Nevertheless, radical surgery can lead to treatment-related damage due to the invasiveness of CP and its proximity to adjacent neural tissue, such as the hypothalamus, pituitary stalk, and optic chiasma. Reducing the mass effect of cyst fluid or solid components has become an option for temporary tumor control and delaying vision deterioration with the expectation of achieving further GTR[43]. Therefore, gaining a better understanding of cyst pathogenesis and developing more effective treatments to limit the volume of cysts are crucial. Carbonic anhydrase IX, an enzyme that causes fluid production, was revealed to be associated with the formation and size of cysts in CP[44], but the specific regulatory mechanisms of this enzyme have yet to be fully elucidated. One study demonstrated the essential role of the inflammatory response in generating cysts with highly elevated levels of inflammatory mediators[45]. The efficacy of intracystic IFN-alpha treatment has been shown to shrink cysts by reducing inflammation-mediated responses, further supporting the causal role of inflammatory mediators in cyst pathogenesis[46]. However, previous studies exploring the correlation between expression levels of inflammatory mediators, cyst size, and cyst volume have been limited by the small sample sizes (ranging from 5 to 15). Hence, the present study enrolled 130 patients (the largest known case series) and verified the higher expression of inflammatory mediators in cystic tumors and their positive correlation with cyst size and cyst volume (Table 3). These results provide further evidence supporting the potential application of anti-inflammation therapies for controlling cyst volume.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.4 Predictive factors of prognosis in patients with CP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrevious analyses have investigated the associations between patients’ CP prognosis and clinical parameters, including the number of surgical interventions, histological type, degree of HI and obesity, neuroendocrine deficiencies[1], surgical approach[47], and calcification[48]. Although these clinical factors related to prognosis provide excellent value for guiding treatment decisions, they do not fully elucidate the etiology and pathogenesis of patients with CP, thereby limiting the development of precise biomarker-based therapies.\u003c/p\u003e\n\u003cp\u003eIn the era of personalized medicine, biomarkers hold promise for predicting recurrence and guiding targeted therapies in patients with CP. Therefore, numerous studies have attempted to identify biomarkers to improve prognosis prediction and develop novel targeted therapies. We previously identified integrin α6 as a biomarker associated with adverse overall survival of \u0026nbsp;CP[49]. Furthermore, a study conducted by Zou et al.[50] identified 10 hub genes for potential application in early diagnosis and therapy for ACP. Several studies have also identified the associations between the prognosis of CP and many biomarkers, including B7-H3[51], β-catenin[52], and growth hormone receptors [53]. Moreover, another study identified four inflammatory mediators (CXCL6, CXCL10, CXCL11, and CXCL13) as hub genes with great value for targeted therapy in CP[54]. Our results revealed that high expression levels of inflammatory mediators, including CXCL1, CXCL8, IL1A, IL6, and TNF, were associated with shorter PFS in patients with CP (Fig.5), further validating the potential value of anti-inflammation therapies in CP. Identifying prognostic biomarkers in patients with CP enables the identification of patients at high risk of recurrence and provides insights into targeted therapies based on these biomarkers.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eOur study demonstrated elevated expression levels of inflammatory mediators in CP, with a particularly prominent presence in the PCP subtype. The associations of inflammatory mediators with clinical parameters indicate their potential role in the pathogenesis of tumors and cysts. In addition, inflammatory mediators were independently associated with significant weight gain and new-onset postoperative obesity. Moreover, the expression of inflammatory mediators exhibited significant prognostic value in patients with CP. Therefore, investigating therapeutic strategies targeting these inflammatory mediators holds promise for improving the prognosis of patients with CP and reducing complications, particularly leptin resistance and subsequent morbid obesity. Further studies are warranted to explore the potential of targeting inflammatory mediators as a means to optimize CP management and enhance patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u0026nbsp;\u003c/strong\u003eThe authors thank all members of the Department of Neurosurgery, Beijing Tiantan Hospital, and Capital Medical University.\u0026nbsp;They provided so much advice for this study and backed our work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Ethics:\u0026nbsp;\u003c/strong\u003eAll procedures in our study followed the ethical standards of the institutional and national research committees and the Declaration of Helsinki. The institutional review board of Beijing Tiantan Hospital approved this study (KY-2021-041-02). Informed consent was obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources:\u003c/strong\u003e This study is supported by the Beijing Municipal Science and Technology Commission (Grant No. Z191100006619087) and the Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (XMLX202108). The funder had no role in the design, data collection, data analysis, and reporting of this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eYX, WW, and FL contributed to the conception of the study, formal analysis, manuscript preparation, and writing, SG contributed to academic instruction, funding acquisition, and manuscript reviewing, LJ and YJ contributed to data extraction, data curation, NQ, SR, KC, and LC contributed to statistical methods and constructive discussions. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eData are not publicly available due to ethical reasons. Further inquiries can be directed to Youchao Xiao and Wentao Wu.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eM\u0026uuml;ller HL, Merchant TE, Warmuth-Metz M, Martinez-Barbera JP, Puget S. 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Trends Endocrinol Metab. 2009,20:78\u0026ndash;87.\u003c/li\u003e\n\u003cli\u003eDuan D, Wehbeh L, Mukherjee D, Hamrahian AH, Rodriguez FJ, Gujar S, et al. Preoperative BMI Predicts Postoperative Weight Gain in Adult-onset Craniopharyngioma. J Clin Endocrinol Metab. 2021,106:e1603\u0026ndash;17.\u003c/li\u003e\n\u003cli\u003eTena-Suck ML, Hern\u0026aacute;ndez-Campos ME, Ortiz-Plata A, Salinas-Lara C, Col\u0026iacute;n-Gonz\u0026aacute;lez AL, Santamar\u0026iacute;a A. Intracerebral injection of oil cyst content of human craniopharyngioma (oil machinery fluid) as a toxic model in the rat brain. Acta Histochem. 2014,116:448\u0026ndash;56.\u003c/li\u003e\n\u003cli\u003eAiniwan Y, Chen Y, Mao C, Peng J, Chen S, Wei S, et al. Adamantinomatous craniopharyngioma cyst fluid can trigger inflammatory activation of microglia to damage the hypothalamic neurons by inducing the production of \u0026beta;-amyloid. 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Front Genet. 2022,13 March:1\u0026ndash;13.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1, 2, and 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"craniopharyngioma, inflammatory mediators, leptin, obesity, progression-free survival ","lastPublishedDoi":"10.21203/rs.3.rs-4272844/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4272844/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: 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.\u003c/p\u003e\n\u003cp\u003eMethods: 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 \u0026nbsp;(PFS) were recorded. The relationships between inflammatory mediators, clinicopathologic parameters, weight-related outcomes, and PFS were explored.\u003c/p\u003e\n\u003cp\u003eResults: 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.\u003c/p\u003e\n\u003cp\u003eConclusion: 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.\u003c/p\u003e","manuscriptTitle":"The Clinical Significance of Inflammatory Mediators in Predicting Obesity and Progression-Free Survival in Patients with Craniopharyngioma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-09 02:18:52","doi":"10.21203/rs.3.rs-4272844/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-05-23T13:54:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-22T15:00:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-05-13T19:29:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"09db0b7a-a46a-4aea-ad23-3882b438801c","date":"2024-04-29T19:10:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6cd63024-2b00-4a9c-8b37-269880007b26","date":"2024-04-24T17:47:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-24T13:19:26+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-24T12:59:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-17T03:45:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-04-16T03:23:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fee889dc-9857-43ec-b7b7-73fe860d664f","owner":[],"postedDate":"May 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-06-20T16:16:33+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-09 02:18:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4272844","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4272844","identity":"rs-4272844","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}