中文摘要

 第一部分 儿童及青少年造釉型颅咽管瘤患者术后血脂异常及重组人生长激素替代疗效观察和长期随访评价

背景：颅咽管瘤（Craniopharyngiomas, CPs）起源于垂体胚胎发育过程中残余的上皮细胞，是一种罕见的先天性颅内良性肿瘤。其在组织学上主要分为造釉型颅咽管瘤（Adamantinomatous Craniopharyngioma, ACP）和乳头型颅咽管瘤（Papillary Craniopharyngioma, PCP）。儿童青少年起病的CPs多以造釉型为主，此病理类型侵袭性及复发性更强。CPs主要位于鞍区及鞍旁区，与垂体、下丘脑等颅内重要组织结构相邻，肿瘤压迫、手术和放射治疗可能影响下丘脑-垂体功能及长期生活质量，其在儿童及青少年时期接受治疗的长期存活者中表现尤为明显。然而，儿童及青少年CPs术后相关研究缺乏其疗效的长期随访数据。此外，CPs术后下丘脑性肥胖和高脂血症的高发病率日益引起人们的关注。除手术造成的下丘脑和垂体损伤外，垂体激素的缺乏和生活方式的改变也是导致肥胖发生的重要因素。肥胖和血脂代谢异常与心血管疾病（Cardiovascular Diseases, CVDs）的高风险相关，对CPs血脂代谢异常更深入研究可能揭示其肥胖的根源。然而，少量研究探讨儿童颅咽管瘤患者的血脂状况，但研究结果不尽一致。且重组人生长激素（Recombinant Human Growth Hormone, rhGH）替代治疗对儿童颅咽管瘤患者血脂的影响尚不清楚。

目的：通过比较儿童及青少年CPs术后血脂水平与健康对照组的差异，并评估rhGH替代治疗对儿童及青少年CPs血脂水平的影响。此外，评价儿童及青少年CPs术后长期随访的生存结果及影响生存结果的相关临床因素，同时评估其治疗相关副反应。

方法：本研究为回顾性、单中心队列研究，纳入2009年至2020年间于北京协和医院就诊的造釉型颅咽管瘤术后儿童和青少年患者。通过1：2倾向配比健康人群比较两组的患者基线水平、血脂水平及垂体激素水平。并对接受rhGH替代治疗至少1年且治疗前后有完整血脂数据的患者与未接受rhGH替代治疗的患者血脂水平进行比较。通过查阅患者的病历资料，以收集其临床信息、影像学资料以及治疗信息。分析全组患者的总生存时间（Overall Survival, OS）、疾病特异生存时间（Disease - specific Survival, DSS）及无进展生存时间（Progression - free Survival, PFS）。同时分析影响生存结果的相关临床因素，并评估全组患者的治疗相关副反应。

结果：CPs患者总胆固醇（Total Cholesterol, TC）水平（5.17 mmol/L vs 3.77 mmol/L）、甘油三酯（Triglyceride, TG）水平（1.51 mmol/L vs 0.73 mmol/L）和低密度脂蛋白胆固醇（Low - density Lipoprotein Cholesterol, LDL - C）水平（3.14 mmol/L vs 2.10 mmol/L）均高于健康对照组，而高密度脂蛋白胆固醇（High - density Lipoprotein Cholesterol, HDL - C）水平（1.06 mmol/L vs 1.39 mmol/L）则低于健康对照组（P < 0.001）。肥胖患者与非肥胖患者的血脂水平无显著差异。在使用rhGH替代治疗后，TC水平比基线降低了0.90 mmol/L（P = 0.002），LDL - C水平比基线降低了0.73 mmol/L（P = 0.010）。尽管基线LDL - C水平较高，但与未接受rhGH替代治疗的患者相比，接受rhGH替代治疗的患者在开始治疗后LDL - C水平降低更多（-0.73 mmol/L，年龄和性别校正后，P = 0.045）。全组5年、10年和15年OS分别为100%、98.3%和94.6%。相应的DSS分别为100%、98.3%和94.6%。全组5年、10年和15年后的PFS分别为85.4%、72.2%和70.1%。单因素分析结果提示：手术切除分级与临床结局明显相关，接受完全肿瘤切除术（Gross Total Resection, GTR）的患者OS、DSS和PFS显著提高（P < 0.001）。而确诊年龄、性别、肿瘤部位、激素替代治疗及手术方式等变量与预后生存之间未发现显著相关性（P > 0.05）。多因素分析发现：手术切除分级仅与PFS结果相关[风险比（Hazard Ratio, HR） = 0.031 (95% CI: 0.006 - 0.163)， P < 0.001]，而不能改善OS或DSS。术后76例（95%）出现一种或多种垂体功能减退。

结论：CPs的肥胖和非肥胖儿童及青少年的血脂状况均不佳，而rhGH替代治疗可以改善其血脂状况且不增加肿瘤复发的风险。儿童及青少年CPs患者术后可长期生存，GTR是影响术后生存结果的独立因素。术后副反应主要为垂体功能减退。

第二部分 动脉弹性的早期变化与儿童和青少年颅咽管瘤术后脂质异常的相关性研究

背景：颅咽管瘤（Craniopharyngiomas, CPs）是起源于垂体胚胎发育过程中残余上皮细胞的罕见良性肿瘤。由于肿瘤的发生位置及与周围重要组织结构（垂体、视交叉、下丘脑等）相邻，CPs具有手术难度高及术后易复发等特点，导致术后患者脂质异常和心血管事件发生率显著上升。脉搏波速度（Pulse Wave Velocity, PWV）是心血管疾病早期筛查的重要工具。

目的：本研究旨在评估CPs手术后患者脂质异常与PWV之间的关系。为临床早期干预及患者预后改善提供理论依据。

方法：本研究为单中心、横断面队列研究，纳入2023年至2024年间于北京协和医院门诊就诊的41例颅咽管瘤术后儿童和青少年患者（女性18例）。分析其颈动脉PWV及临床生化特征。

结果：PWV与总胆固醇（Total Cholesterol, TC）、低密度脂蛋白胆固醇（Low - density Lipoprotein Cholesterol, LDL - C）、高密度脂蛋白胆固醇（High - density Lipoprotein Cholesterol, HDL - C）水平存在显著相关。即使在调整年龄、性别、体重指数（Body Mass Index, BMI）等因素后，平均收缩期起始脉搏波速度（Beginning of Systole, BS）与TC、LDL - C仍保持显著正相关，与HDL - C仍保持显著负相关。此外，不同类型脂质异常与高PWV之间存在显著风险关联。血脂异常组间内膜-中膜厚度（Intima - media Thickness, IMT）无显著差异。

结论：在儿童和青少年起病的CP患者术后人群中，动脉弹性的早期改变发生在颈动脉IMT增厚之前，这些变化与脂质水平显著相关。超快速PWV技术可能作为一项潜在预测指标，用于加强对CP手术后患者脂质异常风险的识别。

第三部分 儿童青少年起病颅咽管瘤术后重组人生长激素替代治疗患者的血清代谢组学研究

背景：颅咽管瘤（Craniopharyngiomas, CPs）作为影响儿童下丘脑-垂体区的常见肿瘤，约占儿童颅内肿瘤的5 - 10%。虽然其组织学病理为良性，但术后下丘脑—垂体功能障碍发生率高达80 - 95%，其中生长激素缺乏症严重影响儿童青少年患者的生长发育和代谢稳态，导致患者生存及生活质量降低。既往研究发现重组人生长激素（recombinant human growth hormone, rhGH）替代治疗可改善CPs术后儿童及青少年脂质异常，但对其代谢影响机制尚不明确。

目的：运用非靶血清代谢组学测序技术，探索rhGH替代治疗对CPs术后儿童及青少年血清代谢物的影响及其作用机制。

方法：选取2023年6月至2024年10月在北京协和医院就诊的儿童及青少年CPs术后且病情稳定的患者。详细采集临床病史资料、生化检查指标并留取患者的血清标本。采用液相色谱-质谱联用技术对血清代谢物进行非靶代谢组学分析，通过主成分分析（Principal Component Analysis, PCA）、偏最小二乘法判别分析（Partial Least Squares Discrimination Analysis, PLS - DA）判断模型对不同分组的区分度。对差异代谢产物进行京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集寻找异常代谢通路。将筛选出的差异代谢物与临床指标进行相关性分析。

结果：本研究共纳入60例患者，其中rhGH治疗组32例，非治疗组28例。两组患者在生长激素（Growth Hormone, GH）、胰岛素样生长因子1（Insulin-like Growth Factor 1, IGF - 1）及IGF - 1标准差分数（Standard Deviation Score, SDS）方面差异具有显著差异性（P ＜ 0.05）。两组间性别、就诊年龄、身高SDS、体重SDS、体重指数（Body Mass Index, BMI）及BMI SDS、空腹胰岛素、空腹血糖、尿酸、脂质异常发生率和肥胖/超重占比均无统计学差异（P ＞ 0.05）。rhGH治疗组各项血脂指标虽有下降趋势，但两组间差异无统计学意义（P ＞ 0.05）。PLS - DA、聚类分析均显示rhGH用药组及非用药组间差异显著（P ＜ 0.05）。rhGH替代治疗主要影响脂质物质，特别是甘油磷酸酯（PC 18:0_18:1）、甘油三酯（TG 16:0_16:0_18:1, TG 16:0_18:2_18:2）及鞘脂类代谢产物（SM 9:1:20/24:1, SM 9:1:20/34:2, SM 9:1:20/36:3, SM 9:1:20/36:2, SM 9:1:20/38:4, SM 9:1;2O/36:4），通路富集分析发现以甘油磷脂代谢途径最为显著。差异代谢物与临床指标相关性分析表明，GH、IGF - 1与多种鞘脂类代谢物显著正相关，而3, 5 - 二碘 - L - 甲状腺原氨酸与IGF - 1呈负相关。

结论：1.儿童青少年CPs术后患者rhGH用药与非用药组间差异显著，以甘油磷脂代谢途径最为显著。

2. rhGH替代治疗主要影响脂质物质，特别是甘油磷酸酯（PC 18:0_18:1）、甘油三酯（TG 16:0_16:0_18:1, TG 16:0_18:2_18:2）及鞘脂类代谢产物（SM 9:1:20/24:1, SM 9:1:20/34:2, SM 9:1:20/36:3, SM 9:1:20/36:2, SM 9:1:20/38:4, SM 9:1;2O/36:4）

Abstract

Part I Observation and long-term follow-up evaluation of postoperative dyslipidemia and recombinant human growth hormone replacement efficacy in children and adolescents with craniopharyngioma

Background: Craniopharyngiomas (CPs), originating from residual epithelial cells during pituitary embryogenesis, represent a rare congenital intracranial benign tumor. Histologically, they primarily manifest as two subtypes: Adamantinomatous Craniopharyngioma (ACP) and Papillary Craniopharyngioma (PCP). Anatomically, CPs predominantly localize to the sellar and parasellar regions, abutting critical neurovascular structures including the pituitary gland and hypothalamus. This anatomical proximity contributes to significant surgical challenges characterized by elevated operative risks and high postoperative recurrence rates, resulting in a paradoxical clinical presentation where these benign tumors exhibit malignant progression patterns despite their histological benignity. Tumor compression, surgery, and radiotherapy may impair hypothalamic-pituitary function and long-term quality of life, particularly in long-term survivors treated during childhood or adolescence. However, there is a lack of long-term follow-up data on outcomes in pediatric and adolescent CP patients post-surgery. Additionally, the high incidence of hypothalamic obesity and dyslipidemia following CP resection has garnered increasing attention. Beyond hypothalamic and pituitary damage caused by surgery, pituitary hormone deficiencies and lifestyle changes are significant contributors to obesity. Obesity and dyslipidemia are linked to an elevated risk of cardiovascular diseases (CVDs), and further investigation into lipid metabolism abnormalities in CPs may elucidate the underlying mechanisms of obesity. However, existing studies on lipid profiles in pediatric CP patients are limited and inconsistent. Furthermore, the impact of recombinant human growth hormone (rhGH) replacement therapy on lipid metabolism in these patients remains unclear.

Objective: To compare postoperative lipid profiles in pediatric and adolescent CP patients with those of healthy controls and evaluate the effects of rhGH replacement therapy on lipid levels. Additionally, to assess long-term survival outcomes, identify clinical factors influencing survival, and document treatment-related adverse effects in this population.

Methods: This retrospective, single-center cohort study included pediatric and adolescent CP patients treated at Peking Union Medical College Hospital between 2009 and 2020. Baseline characteristics, lipid profiles, and pituitary hormone levels were compared with a 1:2 propensity score-matched healthy control group. Lipid levels were further analyzed between patients receiving rhGH replacement therapy for ≥ 1 year (with pre- and post-treatment lipid data) and those not receiving rhGH. Clinical, imaging, and treatment data were extracted from medical records. Outcomes included overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). Clinical factors affecting survival and treatment-related adverse effects were analyzed.

Results: CP patients exhibited significantly higher total cholesterol (TC: 5.17 vs. 3.77 mmol/L), triglycerides (TG: 1.51 vs. 0.73 mmol/L), and low-density lipoprotein cholesterol (LDL - C: 3.14 vs. 2.10 mmol/L), and lower high-density lipoprotein cholesterol (HDL - C: 1.06 vs. 1.39 mmol/L) compared to healthy controls (all P < 0.001). No significant differences in lipid profiles were observed between obese and non - obese CP patients. After rhGH therapy, TC decreased by 0.90 mmol/L (P = 0.002) and LDL - C by 0.73 mmol/L (P = 0.010) from baseline. Despite higher baseline LDL - C, rhGH - treated patients showed greater LDL - C reduction compared to non - treated patients (-0.73 mmol/L, age - and sex - adjusted P = 0.045). The 5 -, 10 -, and 15 - year OS rates were 100%, 98.3%, and 94.6%, respectively, with identical DSS rates. The 5 -, 10 -, and 15 -year PFS rates were 85.4%, 72.2%, and 70.1%, respectively. Univariate analysis revealed that extent of resection (gross total resection [GTR]) significantly improved OS, DSS, and PFS (P < 0.001). Age at diagnosis, sex, tumor location, hormone replacement, and surgical approach showed no significant association with survival. Multivariate analysis identified extent of resection as an independent predictor of PFS [HR = 0.031 (95% CI: 0.006 - 0.163), P < 0.001] but not OS or DSS. Postoperative hypopituitarism occurred in 95% (76/80) of patients.

Conclusion: Both obese and non-obese pediatric and adolescent CP patients exhibit unfavorable lipid profiles, which may be ameliorated by rhGH replacement therapy. Long-term survival is achievable post-surgery, with GTR being an independent prognostic factor. Hypopituitarism is the predominant treatment-related adverse effect.

Part II Early changes in arterial elasticity as an indicator for predicting postoperative dyslipidemia in pediatric and adolescents with craniopharyngioma

Background: Craniopharyngiomas (CPs) are rare benign tumors originating from residual epithelial cells during pituitary embryonic development. Due to their location and proximity to vital surrounding structures (such as the pituitary gland, optic chiasm, hypothalamus, etc.), high surgical difficulty and easy postoperative recurrence, the incidence of dyslipidemia and cardiovascular events in CP patients has increased significantly. Pulse wave velocity (PWV) is an important tool for early screening of cardiovascular diseases.

Objective: The purpose of this study was to evaluate the relationship between dyslipidemia and PWV in patients after CPs surgery. To provide theoretical basis for early clinical intervention and improvement of patient prognosis.

Methods: The study was a single-center, cross-sectional cohort study involving 41 children and adolescents (18 females) who underwent craniopharyngioma surgery in the outpatient department of Peking Union Medical College Hospital between 2023 and 2024. Carotid PWV and clinical biochemical characteristics were analyzed.

Results: A significant correlation exists between PWV and the levels of total cholesterol (TC), low - density lipoprotein cholesterol (LDL - C), and high - density lipoprotein cholesterol (HDL - C). Even after adjusting for age, sex, and body mass index (BMI) factors, the beginning of the systole (BS) maintains a significantly positive correlation with TC and LDL - C and a significantly negative correlation with HDL - C. Moreover, the mean BS exhibits a certain predictive value for dyslipidemia. No significant difference in intima-media thickness (IMT) was witnessed among the dyslipidemia groups.

Conclusion: In the post-operative population of pediatric and adolescent patients with CPs, early alterations in arterial elasticity occur prior to the thickening of the carotid IMT, and these changes are significantly correlated with lipid levels. The ultra - fast PWV technique may function as a potential biomarker for strengthening the identification of the risk of dyslipidemia in patients after CP surgery.

Part III Serum metabolomics study of children and adolescents with craniopharyngioma who received recombinant human growth hormone replacement therapy after surgery

Background: Craniopharyngiomas (CPs), common tumors affecting the hypothalamic-pituitary region in children, account for approximately 5 - 10% of pediatric intracranial tumors. Although histologically benign, postoperative hypothalamic-pituitary dysfunction occurs in 80 - 95% of cases, with growth hormone deficiency (GHD) severely impairing growth, development, and metabolic homeostasis in pediatric and adolescent patients, leading to reduced survival and quality of life. Previous studies suggest that recombinant human growth hormone (rhGH) replacement therapy improves lipid abnormalities in postoperative CPs patients; however, its metabolic mechanisms remain unclear.

Objective: To investigate the effects and mechanisms of rhGH replacement therapy on serum metabolites in postoperative pediatric and adolescent CPs patients using untargeted serum metabolomics.  

Methods: Stable postoperative CPs patients aged ≤ 18 years were recruited from Peking Union Medical College Hospital between June 2023 and October 2024. Clinical history, biochemical parameters, and serum samples were collected. Untargeted metabolomic profiling was performed via liquid chromatography-mass spectrometry (LC - MS). Principal component analysis (PCA) and partial least squares discriminant analysis (PLS - DA) were used to differentiate metabolic profiles between groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified dysregulated metabolic pathways. Correlation analyses linked differential metabolites with clinical indices.  

Results: Sixty patients were enrolled (rhGH-treated group: n = 32; non-treated group: n = 28). Significant differences were observed in growth hormone (GH), insulin-like growth factor-1 (IGF - 1), and IGF - 1 standard deviation scores (SDS) between groups (P < 0.05). No statistical differences were found in sex, age, height SDS, weight SDS, body mass index (BMI), fasting insulin, glucose, uric acid, lipid abnormality rates, or obesity/overweight prevalence (P > 0.05). Lipid profiles showed a downward trend in the rhGH group but lacked statistical significance (P > 0.05). PLS - DA and hierarchical clustering revealed distinct metabolic separation between groups (P < 0.05). rhGH therapy predominantly altered lipid metabolites, including specific glycerophospholipids (PC 18:0_18:1), triglycerides (TG 16:0_16:0_18:1, TG 16:0_18:2_18:2), and sphingolipids (SM 9:1:20/24:1, SM 9:1:20/34:2, SM 9:1:20/36:3, SM 9:1:20/36:2, SM 9:1:20/38:4, SM 9:1;2O/36:4). KEGG enrichment highlighted glycerophospholipid metabolism as the most significantly altered pathway. Correlation analyses demonstrated positive associations between GH/IGF-1 and sphingolipids, while 3, 5 - diiodo - L - thyronine negatively correlated with IGF-1.  

Conclusion: 1. Distinct metabolic differences exist between rhGH - treated and non-treated postoperative CPs patients, with glycerophospholipid metabolism being the most prominently altered pathway. 2. rhGH therapy primarily modulates lipid metabolism, particularly specific glycerophospholipids, triglycerides, and sphingolipids.