欧洲内分泌学会生长激素替代治疗安全性的共识解读——颅咽管瘤术后

2022年, 欧洲内分泌学会更新了《在癌症、颅内肿瘤及垂体瘤幸存者中生长激素替代治疗的安全性:共识声明》, 共包含了15条国际关注的安全性问题和态度声明。在欧洲内分泌学会的支持下, 生长激素研究学会邀请了16个国家涵盖10个专业学会的55位专家组成国际专家小组, 讨论了癌症和颅内肿瘤患者生长激素替代安全性的问题, 并形成国际专家共识。     

老年人颅咽管瘤的诊断及治疗

颅咽管瘤为先天性肿瘤,目前发病学尚有争议,主要有两种理论<'[1-3]>:第一种是胚胎起源理论,颅咽管瘤起源于最初连接Rathke's囊与口腔颅咽管的胚胎釉质原基.第二种是组织化生理论,颅咽管瘤是垂体结节部腺垂体、垂体柄细胞鳞状化生结果.在组织学上颅咽管瘤为良性肿瘤,有些病例则呈恶性病程.     

老年人颅咽管瘤的临床特点

一、研究对象与方法　　我院 1980～ 1997年共收治 798例颅咽管瘤患者 ,其中6 0岁以上者 14例 ,男 9例 ,女 5例 ,年龄 6 0～ 6 8岁 ,平均6 1 8岁 ,病史 3个月至 3年。症状 :视力减退 12例 ,头痛 10例 ,偏盲 8例 ,性欲减退 4例 ,多饮多尿 3例。首发症状 :视力减退 8例 ,头痛 2例 ,多饮多尿、性欲减退、眼睑下垂及精神症状各 1例。体征 :视神经萎缩 11例 ,视野缺损 10例 ,嗜睡、定向力减退各 1例。肿瘤性质 :囊性肿瘤 13例 ,囊实性肿瘤 1例。术前并存症 :冠心病 3例 ,高血压 4例 ,慢性支气管炎、类风湿性关节炎、糖尿病、白内障及脑梗死各 1例…     

颅咽管瘤切除术后高钠血症的预防与处理

回顾性分析58例颅咽管瘤切除术患者的临床资料。结果：术后发生高钠血症15例。肿瘤与第3脑室底（下丘脑）的密切程度术前MRI检查及术前是否应用糖皮质激寨与术后高钠血症的发生有关。认为颅咽管瘤患者术前MRI检查示肿瘤与第3脑室底（下丘脑）关系越密切,术后高钠血症发生几率越大,术前常规应用糖皮质激素对高钠血症有一定预防作用。     

颅咽管瘤的手术治疗策略（附35例报告）

目的总结颅咽管瘤手术治疗的经验与体会。方法回顾性分析经显微神经外科手术治疗的35例颅咽管瘤患者的临床资料。结果肿瘤全切除术32例,部分切除术3例,死亡1例。结论熟悉局部显微解剖并熟练运用显微外科技术是取得手术成功的关键。手术治疗应在保留神经血管功能前提下尽量全切除肿瘤。     

颅咽管瘤中肥胖的机制与影响

颅咽管瘤是一种罕见的良性肿瘤,其鞍区占位效应严重影响下丘脑-垂体-靶腺轴功能.明显的激素分泌异常可直接影响脂代谢,导致下丘脑性肥胖.目前认为,肥胖只是肿瘤的一种相关症状,不参与颅咽管瘤的进展.但近期研究表明,肥胖不仅影响颅咽管瘤的预后,而且针对肥胖的治疗正成为一种新的肿瘤治疗方法.     

颅咽管瘤的显微外科治疗

手术是治疗颅咽管瘤的主要手段，以往所采用的直视下肿瘤切除术有极高的手术死亡率。近10余年来，随着颅底显微外科技术的发展，许多颅咽管瘤可通过显微外科技术治疗，并取得了良好效果。1993年2月至2004年2月，我院经显微外科手术治疗颅咽管瘤97例，有详细资料记录者67例。现报告如下。     

显微手术结合伽玛刀治疗颅咽管瘤的疗效

<正>颅咽管瘤主要临床特点侵袭周围的组织,如视交叉、垂体柄等,故常引起下丘脑-垂体功能紊乱、颅内压增高、视力及视野障碍、尿崩症以及神经和精神症状〔1〕。临床诊断主要依赖于影像学检查,如CT或MRI扫描可明确诊断〔2〕。目前治疗手段主要为手术切除,常用的手术方式为显微切除,但是存在切除不全、术后并发症较高、复发率高等缺点〔3〕,伽马刀借助影像学技术对肿瘤进行定位,并进行精确照射,从而可以提高临床疗     

基因重组人生长激素在儿童中长期应用的安全性

自美国食品药品管理局(FDA)批准将重组人生长激素(rhGH)用于儿童后,20多年来美国已有数十万生长障碍患儿接受了rhGH治疗.由于参加临床试验的患者人数相对较少,一些少见的不良事件(AEs)可能无法发现,因而自1985年起,由Cenentech公司启动了一项开放式、多中心的售后调查,"全国生长协作研究"(NCGS),以监测其rhGH产品的疗效和安全性.自1985年12月至2006年1月1日,累计有54 996例患者(男性65%,女性35%)参加了NCGS,使用rhGH治疗的人年数达195 419,共有900多名医师参与了此项研究.     

Efficacy and safety of recombinant growth hormone treatment in children with growth retardation related to long-term glucocorticosteroid therapy

ObjectiveTo evaluate safety and efficacy of recombinant human growth hormone treatment in children on long-term glucocorticoid therapy.MethodsA 5-year prospective open-label study included children on glucocorticoid therapy with either standard deviation score (SDS) < −2 for height for chronological age (CA) if naïve to growth hormone treatment, or annual growth rate ≥ 0 SDS for CA if currently receiving growth hormone.ResultsNinety-eight patients began treatment, 63 discontinued; 59 were analyzed for safety and 58 for efficacy. There was male predominance (78.0%). Median age was 13.0 years. Median height screening was 136.0 cm (range, 95.1–159.7 cm). Mean SDS for height for CA in the efficacy analysis set was −2.91 ± 1.19 (range, −7.49 to −0.96). Mean growth hormone dose was 0.4, 0.4, 0.4 and 0.3 mg/kg/week at month 0, M12, M24, and M36, respectively. Primary analysis of change in SDS for height for CA from baseline to M36 showed a significant increase of 0.80 ± 1.03. Twenty patients in the safety analysis set had ≥ 1 treatment-emergent adverse event (TEAE) related to study treatment. Two patients experienced serious treatment-related TEAEs: 1 case of poor compliance, and 1 of mild hyperglycemia, both already observed under growth hormone treatment.ConclusionThis study suggests that growth hormone treatment could be effective in increasing height in children on long-term glucocorticoid treatment with a safety profile comparable to that in approved rhGH treatment indications.Clinical trial registrationNCT00163189.     

Efficacy and safety of a new ready-to-use recombinant human growth hormone solution

We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency (GHD) that were paramount to the development of a new recombinant human GH (rh- GH, somatropin), approved as the first 'biosimilar' in Europe. Study 1 consisted of 3 parts performed in 89 children. The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [Somatropin Powder (Sandoz)] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [Somatropin Solution (Sandoz)] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution. Study 2 was performed in 51 children and designed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential; rhGH was given sc at a daily dose of 0.03 mg/kg. Primary [body height, height SD score (HSDS), height velocity, and height velocity (HV) SD score (HVSDS)] and secondary [IGF-I and IGF binding protein 3 (IGFBP-3)] efficacy endpoints and safety parameters were assessed regularly. In study 1, all treatments showed comparable increases in growth. The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was -0.20 cm/yr (95% confidence interval (CI) [-1.34;0.94]) and in mean HVSDS was 0.76 (95% CI [-0.57;2.10]) after 9 months. These very small differences demonstrate comparable therapeutic efficacy between the two treatments. The results of study 2 were consistent with those seen in study 1. Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated. The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations.     

Adverse effects of growth hormone replacement therapy in children

Human growth hormone (hGH) replacement therapy has been widely available for clinical purposes for more than fifty years. Starting in 1958, hGH was obtained from cadaveric pituitaries, but in 1985 the association between hGH therapy and Creutzfeldt-Jakob disease was reported. In the same year, the use of recombinant hGH (rhGH) was approved. Side effects of rhGH replacement therapy in children and adolescents include rash and pain at injection site, transient fever, prepubertal gynecomastia, arthralgia, edema, benign intracranial hypertension, insulin resistance, progression of scoliosis, and slipped capital femoral epiphysis. Since GH stimulates cell multiplication, development of neoplasms is a concern. We will review the side effects reported in all rhGH indications.     

Pathophysiology of radiation-induced growth hormone deficiency: Efficacy and safety of GH replacement

Radiation-induced growth hormone deficiency (GHD) is primarily due to hypothalamic damage. GH secretion by the pituitary may be affected either secondary to some degree of quantitative deprivation of hypothalamic input or, if the radiation dose is high enough, by direct pituitary damage. As a consequence, the neurosecretory profile of GH secretion in an irradiated patient remains pulsatile and qualitatively intact. The frequency of pulse generation is unaffected, but the amplitude of the GH pulses is markedly reduced.Over the last 25 years, the final heights achieved by children receiving GH replacement for radiation-induced GHD have improved; these improvements are attributable to refinements in GH dosing schedules, increased use of GnRH analogues for radiation-induced precocious puberty, and a reduced time interval between completion of irradiation and initiation of GH therapy. When retested at the completion of growth, 80–90% of these teenagers are likely to prove severely GH deficient and, therefore, will potentially benefit from GH replacement in adult life. Such long-term GH treatment in patients treated previously for a brain tumor means that critical and continuous surveillance must be devoted to the risk of tumor recurrence and the possibility of second neoplasms.     

Long-term therapy with recombinant human growth hormone (Saizen) in children with idiopathic and organic growth hormone deficiency

In an open-label study, 69 children with organic or idiopathic growth hormone deficiency (GHD) were treated with recombinant human growth hormone (Saizen) for an average of 64.4 mo, with treatment periods as long as 140.9 mo. Auxologic measurements, including height velocity, height standard deviation score, and bone age, were made on a regular basis. The data suggest that long-term treatment with Saizen in children with GHD results in a positive catch-up growth response and proportionate changes in bone age vs height age during treatment. In addition, long-term Saizen therapy was well tolerated, with the majority of adverse events related to common childhood disorders or existing baseline medical conditions and not to study treatment. There were no significant changes in laboratory safety data or vital signs, and no positive antibody tests for Saizen.     

Long-term safety of recombinant human growth hormone in turner syndrome

CONTEXT: Turner syndrome (TS) affects more than 50,000 girls and women in the United States. The National Cooperative Growth Study (NCGS) has collected efficacy and safety data for 5220 TS children treated with recombinant human GH (rhGH) during the last 20 yr. OBJECTIVES: Our objective was to determine frequencies of specific targeted adverse events (AEs) and additional AEs of interest in TS patients. Corresponding safety data in non-TS patients or normal populations were compared for selected AEs. METHODS: Patients may be enrolled at rhGH initiation and followed until discontinuation. Investigators submit AE reports describing any event that is potentially rhGH related or is a targeted event. RESULTS: The Genentech Drug Safety department received 442 AE reports for TS NCGS patients as of June 30, 2006, including 117 serious AEs. Seven deaths occurred; five resulted from aortic dissections/ruptures. The incidence of certain events known to be associated with rhGH (targeted events), including intracranial hypertension, slipped capital femoral epiphysis, scoliosis, and pancreatitis, was increased compared with other non-TS patients in NCGS. There were 10 new-onset malignancies that occurred, including six in patients without known risk factors. Type 1 diabetes also appeared to be increased compared with other NCGS groups. CONCLUSIONS: Children with TS who were treated with rhGH exhibit an increased underlying risk for selected AEs associated with rhGH and for type 1 diabetes, which is likely unrelated to rhGH. The aortic dissection/rupture incidence reflects the higher baseline risk for these events in TS, was consistent with current epidemiological data in smaller TS populations, and is likely unrelated to rhGH. It is not known whether the reported malignancies represent an inherently increased risk in TS patients. Twenty years of experience in 5220 patients indicates no new rhGH-related safety signals in the TS population. The NCGS and similar registries, although focused on the years during rhGH treatment, may also be a window into the natural history of TS in childhood.