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Treatment of acromegaly with oral octreotide 用口服奥曲肽治疗肢端肥大症
IF 6.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-01 DOI: 10.1016/j.beem.2024.101888

Acromegaly is a rare disease caused by a growth hormone excess, usually due to a secreting pituitary adenoma. Somatostatin receptor ligands (SRL) are the mainstay of medical therapy for patients with acromegaly who fail to achieve biochemical control post-operatively or are not eligible for surgical treatment. SRLs are typically administered as monthly injections and have shown to be effective in maintaining biochemical and radiological control of acromegaly. However, these injections may cause local adverse events and are associated with increased psychological burden in some patients. Oral octreotide provides a new alternative for patients responding to injectable SRLs. This new formulation has shown to have similar safety and efficacy profiles compared to injectable SRLs and may be a preferable option for some patients with acromegaly. The aim of this review is to provide an overview of the role of oral octreotide in the management of acromegaly.

肢端肥大症是一种罕见疾病,由生长激素过多引起,通常是由于分泌性垂体腺瘤所致。体生长抑素受体配体(SRL)是肢端肥大症患者术后生化控制失败或不符合手术治疗条件时的主要药物疗法。SRL通常每月注射一次,在维持肢端肥大症的生化控制和放射学控制方面效果显著。然而,这些注射剂可能会引起局部不良反应,并增加一些患者的心理负担。口服奥曲肽为对注射SRL有反应的患者提供了新的选择。与注射用SRL相比,这种新制剂具有相似的安全性和疗效,可能是一些肢端肥大症患者的首选。本综述旨在概述口服奥曲肽在肢端肥大症治疗中的作用。
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引用次数: 0
Real-world value of cabergoline in the treatment of acromegaly 卡麦角林治疗肢端肥大症的实际价值
IF 6.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-01 DOI: 10.1016/j.beem.2024.101887

Cabergoline is an ergot derivative long-acting dopamine receptor 2 (DR2) selective agonist administered orally and widely used for the treatment of prolactin-secreting adenomas and Parkinson’s disease. DR2 is expressed in most somatotroph adenomas. In acromegaly, cabergoline is used off-label and its role is limited by the relatively modest efficacy for achieving hormonal remission and thus, it is largely indicated in patients with mild elevation of GH/IGF-I postoperatively. It can be given as monotherapy, usually at a higher weekly dose than usually required to treat prolactinomas, but also as an add-on treatment in patients partially responding to the somatostatin receptor ligands octreotide or lanreotide. IGF-1 normalization with cabergoline can be achieved in about a third of the patients. Low baseline IGF-1 level (below 1.5 x ULN) before cabergoline initiation is a good predictor for remission. Combination treatment with the GH receptor antagonist pegvisomant can also be beneficial. The inexpensive, well-tolerated and convenient oral administration of cabergoline makes it an attractive medical therapy for active acromegaly.

卡麦角林是一种麦角衍生物,是一种长效多巴胺受体 2(DR2)选择性激动剂,口服给药,广泛用于治疗分泌催乳素的腺瘤和帕金森病。在肢端肥大症中,卡麦角林属于标签外用药,其作用受到限制,因为它在实现激素缓解方面的疗效相对较弱,因此主要适用于术后 GH/IGF-I 轻度升高的患者。它可以作为单药治疗,通常每周剂量高于治疗催乳素瘤所需的剂量,也可以作为对体泌素受体配体奥曲肽或兰瑞肽有部分反应的患者的附加治疗。约有三分之一的患者可以通过卡贝戈林实现 IGF-1 正常化。开始使用卡麦角林前,低基线 IGF-1 水平(低于 1.5 x ULN)是病情缓解的良好预测指标。与 GH 受体拮抗剂 pegvisomant 的联合治疗也有益处。卡麦角林价格低廉、耐受性好且口服方便,是治疗活动性肢端肥大症的一种极具吸引力的药物疗法。
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引用次数: 0
Efficacy and safety of radiosurgery in acromegaly 放射外科治疗肢端肥大症的有效性和安全性。
IF 6.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-01 DOI: 10.1016/j.beem.2024.101898

Stereotactic radiosurgery (SRS) more and more frequently plays a crucial role in the treatment of acromegaly. We provide a systematic review of the literature and meta-analysis, according to PRISMA, on SRS for the management of growth hormone (GH)-secreting pituitary adenomas, including several radiosurgical techniques, with the aim of describing efficacy and safety of this treatment. A weighted random effects model was used to calculate pooled outcome estimates. From 346 abstract reviews, 27 retrospective studies were included. Despite the variability in hormonal remission criteria and the heterogeneity between treatment guidelines among included studies, most of them reported an endocrine remission rate between 40% and 60%. Random effects meta-analysis for overall endocrine remission and 5-year probability of remission estimate after SRS were 46% (95% CI: 39–53%) and of 48% (95% CI: 38–57%), respectively. Random effects meta-analysis for new hypopituitarism estimate after SRS was 23% (95% CI: 17–29%). Furthermore, incidence of radiation induced optic neuropathy after SRS ranged between 0% and 6% This meta-analysis confirms and quantifies safety and effectiveness of SRS to achieve endocrine remission after surgical management in acromegaly.

立体定向放射外科(SRS)在渐冻人症的治疗中发挥着越来越重要的作用。我们根据PRISMA对SRS治疗分泌生长激素(GH)的垂体腺瘤的文献进行了系统性回顾和荟萃分析,包括几种放射外科技术,目的是描述这种治疗方法的有效性和安全性。该研究采用加权随机效应模型计算汇总结果估计值。从346篇摘要综述中,共纳入了27篇回顾性研究。尽管荷尔蒙缓解标准存在差异,纳入研究的治疗指南之间也存在异质性,但大多数研究报告的内分泌缓解率在40%至60%之间。随机效应荟萃分析显示,总体内分泌缓解率和SRS后5年缓解概率估计值分别为46%(95% CI:39-53%)和48%(95% CI:38-57%)。随机效应荟萃分析显示,SRS术后新发垂体功能减退症的概率为23%(95% CI:17-29%)。此外,SRS 后辐射诱发视神经病变的发生率介于 0% 和 6% 之间。这项荟萃分析证实并量化了 SRS 在肢端肥大症手术治疗后实现内分泌缓解的安全性和有效性。
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引用次数: 0
Treatment of acromegaly with the nonpeptide, highly selective somatostatin receptor type 2 agonist paltusotine 用非肽类高选择性体生长抑素受体 2 型激动剂帕妥索坦治疗肢端肥大症
IF 6.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-01 DOI: 10.1016/j.beem.2024.101906

Injectable first-generation somatostatin receptor ligands (fg-SRLs) are the standard of care of medical treatment for acromegaly. While fg-SRLs control acromegaly in up to 50 % of patients, they may lead to bothersome injection pain and site reactions. Paltusotine is an investigational, highly selective somatostatin receptor subtype 2 agonist, which is administered orally once a day. To date, phase 2 and 3 clinical trials suggest paltusotine treatment can achieve biochemical and symptom control in acromegaly, with a safety profile comparable to those of the fg-SRLs. Since paltusotine is a once-daily oral drug, it may represent a future treatment option for addressing patient preference or improving quality of life.

注射用第一代体生长抑素受体配体(fg-SRLs)是治疗肢端肥大症的标准药物。虽然fg-SRLs能控制多达50%的患者的肢端肥大症,但它们可能会导致令人烦恼的注射疼痛和注射部位反应。帕托索汀是一种正在研究的高选择性体生长抑素受体亚型2激动剂,每天口服一次。迄今为止,2 期和 3 期临床试验表明,帕妥索坦治疗可控制肢端肥大症的生化和症状,其安全性与 fg-SRLs 相当。由于帕妥索坦是一种每日口服一次的药物,因此它可能是未来解决患者偏好或改善生活质量的一种治疗选择。
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引用次数: 0
Predictors of biochemical response to somatostatin receptor ligands in acromegaly 预测肢端肥大症患者对体生长抑素受体配体的生化反应
IF 6.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-01 DOI: 10.1016/j.beem.2024.101893

Although predictors of response to first-generation somatostatin receptor ligands (fg-SRLs), and to a lesser extent to pasireotide, have been studied in acromegaly for many years, their use is still not recommended in clinical guidelines. Is there insufficient evidence to use them? Numerous biomarkers including various clinical, functional, radiological and molecular markers have been identified. The first ones are applicable pre-surgery, while the molecular predictors are utilized for patients not cured after surgery. In this regard, factors predicting a good response to fg-SRLs are specifically: low basal GH, a low GH nadir in the acute octreotide test, T2 MRI hypointensity, a densely granulated pattern, high immunohistochemistry staining for somatostatin receptor 2 (SSTR2), and E-cadherin. However, there is still a lack of consensus regarding which of these biomarkers is more useful or how to integrate them into clinical practice. With classical statistical methods, it is complex to define reliable and generalizable cut-off values for a single biomarker. The potential solution to the limitations of traditional methods involves combining systems biology with artificial intelligence, which is currently providing answers to such long-standing questions that may eventually be finally included into the clinical guidelines and make personalized medicine a reality. The aim of this review is to describe the current knowledge of the main fg-SRLs and pasireotide response predictors, discuss their current usefulness, and point to future directions in the research of this field.

尽管对第一代体生长抑素受体配体(fg-SRLs)反应的预测指标,以及对帕司瑞奥肽(pasireotide)反应的预测指标已研究多年,但临床指南仍未推荐使用这些指标。使用它们的证据是否不足?目前已经确定了许多生物标志物,包括各种临床、功能、放射学和分子标志物。前者适用于手术前,而分子预测指标则用于手术后未治愈的患者。在这方面,预测对 fg-SRLs 有良好反应的因素具体包括:基础 GH 低、急性奥曲肽试验中 GH 低谷值、T2 MRI 低密度、致密颗粒形态、体生长激素受体 2(SSTR2)免疫组化染色高和 E-粘连蛋白。然而,对于这些生物标记物中哪一个更有用,或如何将它们与临床实践相结合,目前仍缺乏共识。采用传统的统计方法,为单一生物标志物定义可靠且具有普遍意义的临界值非常复杂。解决传统方法局限性的潜在办法是将系统生物学与人工智能相结合,目前人工智能正在为这些长期存在的问题提供答案,这些答案最终可能被纳入临床指南,使个性化医疗成为现实。本综述旨在描述目前对主要的 fg-SRL 和帕西瑞肽反应预测指标的了解,讨论它们目前的实用性,并指出该领域未来的研究方向。
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引用次数: 0
Current role of pasireotide in the treatment of acromegaly 目前帕西瑞肽在治疗肢端肥大症中的作用
IF 6.1 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-01 DOI: 10.1016/j.beem.2024.101875

“First-generation” somatostatin receptor agonists (SSTRAs) octreotide and lanreotide are the most commonly used first-line pharmacological therapy for patients with acromegaly. A subset of patients respond only partially or not at all to the first-generation SSTRA, necessitating the use of additional pharmacological agents or other modes of therapy. Pasireotide is a “second-generation” SSTRA that has multi-receptor activity. Prospective studies have shown promise in the use of pasireotide in patients with poor response to first-generation SSTRA. Here we elucidate the molecular pathways of resistance to first-generation SSTRA, the mechanism of action, pre-clinical and clinical evidence of the use of pasireotide in patients having incomplete / lack of response to first-generation SSTRA. We also discuss the clinical, pathological, and radiological markers predicting response to pasireotide, and the difference in side-effect profiles of pasireotide, compared to first-generation SSTRA.

"第一代 "体生长抑素受体激动剂(SSTRA)奥曲肽和兰雷奥肽是肢端肥大症患者最常用的一线药物疗法。一部分患者对第一代 SSTRA 仅有部分反应或完全没有反应,因此需要使用其他药物或其他治疗方式。帕西瑞奥肽是一种具有多受体活性的 "第二代 "SSTRA。前瞻性研究显示,帕西瑞奥肽有望用于对第一代SSTRA反应不佳的患者。在此,我们将阐明对第一代 SSTRA 产生耐药性的分子途径、作用机制,以及在对第一代 SSTRA 反应不完全或缺乏反应的患者中使用帕西瑞奥特的临床前和临床证据。我们还讨论了预测帕西瑞奥特反应的临床、病理和放射学指标,以及帕西瑞奥特与第一代SSTRA相比在副作用方面的差异。
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引用次数: 0
“Micromegaly”: Acromegaly with apparently normal GH, an entity on its own? "小儿肢端肥大症肢端肥大症伴有明显正常的 GH,这是一个独立的实体吗?
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-01 DOI: 10.1016/j.beem.2024.101878
Lucio Vilar , Luciana Ansaneli Naves , Manoel Ricardo Alves Martins , Antônio Ribeiro-Oliveira Jr

A small proportion of the patients with acromegaly present with apparently normal basal GH levels and suppressible GH levels despite increased IGF-1 levels, a pattern called micromegaly by some authors. Whether this pattern represents a distinct entity or is just an expression of acromegaly in its early stages is still a matter of debate. Nevertheless, these patients have some peculiar characteristics such as being more likely older and male, mostly harbour microadenomas or small macroadenomas, and have lower IGF-1 and postglucose GH levels. Even though, the frequency and severity of clinical signs and comorbidities are similar to those of patients with classic acromegaly. In conclusion, micromegaly seems to be a distinct clinical entity with a different biological behavior characterized by a low GH output.

一小部分肢端肥大症患者的基础 GH 水平明显正常,尽管 IGF-1 水平升高,但 GH 水平仍可受到抑制,一些学者将这种模式称为微小肢端肥大症。这种模式是代表一个独特的实体,还是只是肢端肥大症早期阶段的一种表现,目前仍有争议。不过,这些患者有一些特殊的特征,如更可能是老年人和男性,大多患有微腺瘤或小的大腺瘤,IGF-1 和糖后 GH 水平较低。尽管如此,其临床症状和合并症的频率和严重程度与典型肢端肥大症患者相似。总之,微小肢端肥大症似乎是一种不同的临床实体,具有不同的生物学行为,其特点是 GH 输出较低。
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引用次数: 0
Genetic diagnosis in acromegaly and gigantism: From research to clinical practice 肢端肥大症和巨人症的基因诊断:从研究到临床实践
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-01 DOI: 10.1016/j.beem.2024.101892
Claudia Ramírez-Rentería (Associate Researcher) , Laura C. Hernández-Ramírez (Associate Researcher)

It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.

通常认为,在所有垂体神经内分泌肿瘤中,只有 5%是由遗传原因引起的。然而,自这一估计被报道以来,导致综合征和非综合征嗜体细胞瘤的多种遗传缺陷已被揭示出来。这种异质性遗传背景导致了 GH 过多的重叠表型。基因检测应该成为治疗渐冻人症和巨人症患者的方法之一,因为基因检测可以完善临床诊断,为针对每位患者的临床治疗提供可能。此外,对高危人群进行基因检测和临床筛查还能在早期及时发现和治疗体细胞营养瘤,从而对疾病的治疗效果产生积极影响。未来的研究应侧重于确定体细胞营养瘤的新基因驱动因素在普通人群中的实际频率,开发最新的疾病特异性多基因面板供临床使用,以及寻找改善全球现代基因检测普及性的策略。
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引用次数: 0
Histopathology of growth hormone-secreting pituitary tumors: State of the art and new perspectives 分泌生长激素的垂体瘤的组织病理学:最新技术和新视角
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-01 DOI: 10.1016/j.beem.2024.101894
Federica Guaraldi (Neuroendocrinologist) , Francesca Ambrosi (Surgical Pathologist) , Costantino Ricci (Surgical Pathologist) , Luisa Di Sciascio (Surgical Pathologist) , Sofia Asioli (Neuropathologist)

Somatotroph (GH) adenomas/PitNETs typically arise from adenohypophysis and are biochemically active, leading to acromegaly and gigantism. More rarely, they present with ectopic origin and do not present overt biochemical or clinical features (silent variants). Histopathological examination should consider the clinical and radiological background, and include multiple steps assessing tumor morphology, pituitary transcription factors (PTFs), hormone secretion, proliferation markers, granulation, and somatostatin receptors (STRs), aimed at depicting as better as possible tumor origin (in case of non-functioning and/or metastatic tumor), and clinical behavior, including response to treatment. GH-secreting tumors are part of the Pit-1 family tumors and can secrete GH only (pure somatotrophs) or co-secrete prolactin (mixed tumors; in this case, various histological subtypes have been identified). Each subtype presents unique radiological, biochemical, and clinical characteristic. Therefore, the integration of biochemical, clinical, radiological, and histopathological elements is fundamental for proper diagnosis and management of pituitary adenomas/PitNETs, to be performed in referral Centers. In more recent times, the importance of genetic and epigenetic evaluation in the characterization of pituitary tumors (i.e., early identification of aggressive variants) has been outlined by some large studies, with the intention of improving targeted treatments.

体液营养(GH)腺瘤/PitNET 通常来自腺嗜酸性粒细胞,具有生化活性,可导致肢端肥大症和巨人症。更罕见的情况是,它们起源于异位,但没有明显的生化或临床特征(沉默变异)。组织病理学检查应考虑临床和放射学背景,包括评估肿瘤形态、垂体转录因子(PTFs)、激素分泌、增殖标记物、肉芽组织和体泌素受体(STRs)的多个步骤,目的是尽可能清楚地描述肿瘤来源(如果是无功能和/或转移性肿瘤)和临床表现,包括对治疗的反应。分泌 GH 的肿瘤是 Pit-1 家族肿瘤的一部分,可以只分泌 GH(纯粹的体液营养瘤),也可以同时分泌催乳素(混合瘤;在这种情况下,已经确定了各种组织学亚型)。每种亚型都具有独特的放射学、生化和临床特征。因此,整合生化、临床、放射学和组织病理学要素是转诊中心对垂体腺瘤/垂体网进行正确诊断和管理的基础。最近,一些大型研究概述了遗传学和表观遗传学评估在垂体瘤特征描述(即早期识别侵袭性变异)中的重要性,目的是改进靶向治疗。
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引用次数: 0
Preface to the Special issue: Diagnosis and treatment of acromegaly, a paradigmatic disease 特刊序言:肢端肥大症的诊断与治疗 肢端肥大症是一种典型的疾病
IF 7.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-05-01 DOI: 10.1016/j.beem.2024.101897
Moisés Mercado
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引用次数: 0
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Best practice & research. Clinical endocrinology & metabolism
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