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Cushing syndrome from an ACTH-producing pheochromocytoma or paraganglioma: structured review of 94 cases 由分泌促肾上腺皮质激素的嗜铬细胞瘤或副神经节瘤引发的库欣综合征:94 个病例的结构性回顾
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-09-01 DOI: 10.1530/erc-24-0029
David Kishlyansky, Alexander A Leung, Janice Pasieka, Amita Mahajan, Gregory Kline

Adrenocorticotropic hormone-producing pheochromocytoma/paraganglioma are rare neuroendocrine tumours that co-secrete excess catecholamines and adrenocorticotropic hormone, resulting in Cushing syndrome. This review aims to summarize important patient characteristics, investigations, and outcomes in all cases reported in the English literature. A literature search was conducted to identify all English-language case reports and case-series describing adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas. Relevant characteristics were systematically recorded. Cases that did not provide definitive evidence of an ACTH-producing pheochromocytoma/paraganglioma were excluded. Our search strategy identified 93 published cases that met the inclusion criteria. We additionally reported one patient for a total of 94 cases. Details related to patient characteristics, laboratory data, and outcomes were commonly underreported. The median age was 47 years and females accounted for 72% of cases. A cushingoid appearance was reported in 82% and hypertension in 86%. Infections were reported in 23% of patients. Urinary metanephrines were elevated at least 3-fold above normal in 74%. ACTH levels were high in 88% and inappropriately normal in 12%. The median 24-hour urinary cortisol was 21-fold the upper limit of normal. Adrenalectomy was performed in nearly all patients with 88% achieving cure of both catecholamine and glucocorticoid excess. A total of 11 patients died. Metastases were uncommon (6%). Adrenocorticotropic hormone-producing pheochromocytoma/paraganglioma is associated with considerable morbidity and mortality. It should be considered in the diagnostic workup of all patients with ectopic Cushing Syndrome. Surgical cure is achieved in most patients and infections are the leading cause of peri-operative mortality.

促肾上腺皮质激素分泌性嗜铬细胞瘤/副神经节瘤是一种罕见的神经内分泌肿瘤,可同时分泌过量儿茶酚胺和促肾上腺皮质激素,导致库欣综合征。本综述旨在总结英文文献中报道的所有病例的重要患者特征、检查和结果。我们进行了文献检索,以确定所有描述产生促肾上腺皮质激素的嗜铬细胞瘤/副神经节瘤的英文病例报告和病例系列。对相关特征进行了系统记录。未提供产生促肾上腺皮质激素的嗜铬细胞瘤/副神经节瘤确凿证据的病例被排除在外。我们的搜索策略发现了 93 例符合纳入标准的已发表病例。我们还报告了一名患者,共计 94 例。与患者特征、实验室数据和预后相关的细节通常报告不足。中位年龄为 47 岁,女性占 72%。82%的病例表现为库欣样,86%的病例表现为高血压。23%的患者出现感染。74%的患者尿中的甲肾上腺素比正常值至少高出3倍。88%的患者促肾上腺皮质激素水平偏高,12%的患者水平不正常。24 小时尿皮质醇中位数是正常值上限的 21 倍。几乎所有患者都接受了肾上腺切除术,88%的患者治愈了儿茶酚胺和糖皮质激素过多症。共有 11 名患者死亡。转移并不常见(6%)。产生促肾上腺皮质激素的嗜铬细胞瘤/副神经节瘤与相当高的发病率和死亡率有关。所有异位库欣综合征患者在诊断时都应考虑到这一疾病。大多数患者可通过手术治愈,而感染是围手术期死亡的主要原因。
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引用次数: 0
GPNMB promotes tumor growth and is a biomarker for lymphangioleiomyomatosis GPNMB 促进肿瘤生长,是淋巴管瘤病的生物标记物
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-04-01 DOI: 10.1530/erc-23-0312
Erin Gibbons, Manisha Taya, Huixing Wu, Samia H Lopa, Joel Moss, Elizabeth P. Henske, Francis X. Mccormack, Stephen R Hammes

Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in-vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in-vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls, and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

淋巴管瘤病(LAM)是一种罕见的进行性囊性肺病,几乎只影响女性患者。囊肿是由两个结节性硬化症(TSC)基因之一发生突变的平滑肌瘤引起的肺部破坏区域。此外,生物标记物不足也阻碍了对疾病进展的监测。因此,我们需要新的治疗方案和生物标志物。LAM细胞表达黑色素细胞标志物,包括糖蛋白非转移性黑色素瘤蛋白B(GPNMB)。GPNMB在LAM中的功能目前尚不清楚;然而,GPNMB在肿瘤细胞和良性细胞上的独特细胞表面表达使其成为潜在的治疗靶点,其细胞外外延的持续释放表明其有可能成为血清生物标志物。在这里,我们证实 GPNMB 的表达依赖于 mTORC1 信号转导,并且 GPNMB 在体外调节 TSC2 基因缺失肿瘤细胞的侵袭。此外,我们还证明了 GPNMB 可促进体内 TSC2 基因缺失异种移植瘤的生长,而异种移植瘤的生长需要外结构域的释放。我们还证明,GPNMB的外结构域会被蛋白酶ADAM10和17从TSC2-null细胞的细胞表面释放出来,并确定了GPNMB上的蛋白酶靶序列。最后,我们证明了在 LAM 患者血清中,GPNMB 外结构域的含量高于健康对照组,而且外结构域的含量会随着 mTORC1 的抑制而降低,从而使其成为一种潜在的 LAM 生物标志物。
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引用次数: 0
Importance of 3β-hydroxysteroid dehydrogenases and their clinical use in prostate cancer 3β- 羟基类固醇脱氢酶的重要性及其在前列腺癌中的临床应用
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-04-01 DOI: 10.1530/erc-24-0023
Masaki Shiota, Satoshi Endo, Shigehiro Tsukahara, Tokiyosh Tanegashima, Satoshi Kobayashi, Takashi Matsumoto, Masatoshi Eto

Androgen receptor signaling is crucial for the development of treatment resistance in prostate cancer. Among steroidogenic enzymes, 3β-hydroxysteroid dehydrogenases (3βHSDs) play critical roles in extragonadal androgen synthesis, especially 3βHSD1. Increased expression of 3βHSDs is observed in castration-resistant prostate cancer tumors compared with primary prostate tumors, indicating their involvement in castration resistance. Recent studies link 3βHSD1 to resistance to androgen receptor signaling inhibitors. The regulation of 3βHSD1 expression involves various factors, including transcription factors, microenvironmental influences, and post-transcriptional modifications. Additionally, the clinical significance of HSD3B1 genotypes, particularly the rs1047303 variant has been extensively studied. The impact of HSD3B1 genotypes on treatment outcomes varies according to the therapy administered, suggesting the potential of HSD3B1 genotyping for personalized medicine. Targeting 3βHSDs may be a promising strategy for prostate cancer management. Overall, understanding the roles of 3βHSDs and their genetic variations may enable the development and optimization of novel treatments for prostate cancer.

雄激素受体信号转导对前列腺癌耐药性的形成至关重要。在类固醇生成酶中,3β-羟基类固醇脱氢酶(3βHSDs)在对角线外雄激素合成中起着关键作用,尤其是 3βHSD1。 与原发性前列腺肿瘤相比,在阉割耐药前列腺肿瘤中观察到 3βHSDs 表达增加,表明它们参与了阉割耐药。最近的研究表明,3βHSD1 与雄激素受体信号抑制剂的耐药性有关。3βHSD1 的表达调控涉及多种因素,包括转录因子、微环境影响和转录后修饰。此外,有关 HSD3B1 基因型,尤其是 rs1047303 变体的临床意义的研究也非常广泛。HSD3B1基因型对治疗结果的影响因治疗方法而异,这表明HSD3B1基因分型具有个性化医疗的潜力。以 3βHSDs 为靶点可能是一种很有前景的前列腺癌治疗策略。总之,了解 3βHSDs 的作用及其基因变异有助于开发和优化前列腺癌的新疗法。
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引用次数: 0
Neuropilin-2 and soluble neuropilin-2 in neuroendocrine neoplasms 神经内分泌肿瘤中的神经肽-2 和可溶性神经肽-2
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-04-01 DOI: 10.1530/erc-24-0052
Laura Gerard, Céline Patte, Laurence Chardon, Valerie Hervieu, Léa Payen, Marion Allio, Claire Marx, Hugo Clermidy, Alice Durand, Patrick Mehlen, Julien Bollard, Gilles Poncet, Colette Roche, Benjamin Gibert, Thomas Walter

Neuropilin-2 (NRP2), a transmembrane non-tyrosine kinase receptor, has been described as a potential critical player in the tumourigenesis of several solid cancers, and particularly in neuroendocrine neoplasms (NEN). A soluble form of NRP2 (sNRP2) has been previously described and corresponds to a truncated splice isoform. Its prognostic value has never been studied in NEN. NRP2 expression was studied by immunochemistry on tissue microarrays (n=437) and on circulating tumour cells (CTC, n=5 patients with neuroendocrine carcinoma, NEC). We described the levels of sNRP2 in 229 patients with NEN using the ELISA method to identify the factors associated with sNRP2 levels and to evaluate its prognostic role; 90 blood donors represented the healthy control group. NRP2 was found in 97% of neuroendocrine tumours (396/410) and in 74% of NEC (20/27). NRP2 was also expressed in CTC of all the studied patients. The receiver operating characteristic (ROC) analysis showed that sNRP2 had a weak capacity to discriminate between NEN patients and healthy controls [area under curve (AUC)=0.601, p=0.053]. Abnormal sNRP2 levels were associated with inflammatory syndrome, bone and peritoneal metastases, and abnormal chromogranin A levels. Patients with high sNRP2 levels (sNRP2Q3-Q4) had significantly poorer overall survival in multivariate analysis (HR 0.16, 95%CI [0.04-0.67], p=0.015). In conclusion, the present study found that sNRP2 and NRP2 could represent a new prognostic biomarker and a therapeutic target, respectively, particularly in aggressive NEN.

Neuropilin-2 (NRP2)是一种跨膜非酪氨酸激酶受体,已被描述为几种实体癌,特别是神经内分泌肿瘤(NEN)肿瘤发生过程中的潜在关键角色。以前曾描述过一种可溶性的 NRP2(sNRP2),它对应于一种截短的剪接异构体。在 NEN 中,从未对其预后价值进行过研究。我们通过免疫化学方法研究了组织芯片(n=437)和循环肿瘤细胞(CTC,n=5 名神经内分泌癌患者,NEC)中 NRP2 的表达。我们使用 ELISA 方法描述了 229 名 NEN 患者的 sNRP2 水平,以确定与 sNRP2 水平相关的因素并评估其预后作用;90 名献血者代表健康对照组。在97%的神经内分泌肿瘤(396/410)和74%的NEC(20/27)中发现了NRP2。所有研究对象的 CTC 中也表达了 NRP2。接收器操作特征(ROC)分析表明,sNRP2区分NEN患者和健康对照组的能力较弱[曲线下面积(AUC)=0.601,P=0.053]。sNRP2水平异常与炎症综合征、骨和腹膜转移以及嗜铬粒蛋白A水平异常有关。在多变量分析中,sNRP2水平高(sNRP2Q3-Q4)的患者总生存率明显较低(HR 0.16,95%CI [0.04-0.67],p=0.015)。总之,本研究发现,sNRP2 和 NRP2 可分别代表一种新的预后生物标志物和治疗靶点,尤其是在侵袭性 NEN 中。
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引用次数: 0
Genetic disorders and insulinoma/glucagonoma 遗传性疾病和胰岛素瘤/胰高血糖素瘤
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-03-01 DOI: 10.1530/erc-23-0245
Francesca Marini, Francesca Giusti, Maria Luisa Brandi

Insulinoma and glucagonoma are two rare functioning neoplasms of the neuroendocrine cells of the pancreas, respectively characterized by an uncontrolled over-secretion of insulin or glucagon, responsible for the development of the hypoglycemic syndrome and the glucagonoma syndrome. They prevalently arise as sporadic tumors; only about 10% of cases develop in the context of rare inherited tumor syndromes, such as Multiple Endocrine Neoplasia Type 1 (MEN1), Neurofibromatosis type 1 (NF1), and Tuberous Sclerosis Complex (TSC), being the result of an autosomal dominant germline heterozygous loss-of-function mutation in a tumor suppressor gene. Here, we reviewed the main epidemiological and clinical aspects of insulinoma and glucagonoma in the context of genetic syndromes.

胰岛素瘤和胰高血糖素瘤是两种罕见的胰腺神经内分泌细胞功能性肿瘤,分别以胰岛素或胰高血糖素分泌过多失控为特征,导致低血糖综合征和胰高血糖素瘤综合征的发生。它们主要以散发性肿瘤的形式出现;只有约 10%的病例是在罕见的遗传性肿瘤综合征(如多发性内分泌肿瘤 1 型(MEN1)、神经纤维瘤病 1 型(NF1)和结节性硬化综合征(TSC))的背景下发生的,是肿瘤抑制基因常染色体显性种系杂合功能缺失突变的结果。在此,我们回顾了遗传综合征中胰岛素瘤和胰高血糖素瘤的主要流行病学和临床表现。
{"title":"Genetic disorders and insulinoma/glucagonoma","authors":"Francesca Marini, Francesca Giusti, Maria Luisa Brandi","doi":"10.1530/erc-23-0245","DOIUrl":"https://doi.org/10.1530/erc-23-0245","url":null,"abstract":"<p>Insulinoma and glucagonoma are two rare functioning neoplasms of the neuroendocrine cells of the pancreas, respectively characterized by an uncontrolled over-secretion of insulin or glucagon, responsible for the development of the hypoglycemic syndrome and the glucagonoma syndrome. They prevalently arise as sporadic tumors; only about 10% of cases develop in the context of rare inherited tumor syndromes, such as Multiple Endocrine Neoplasia Type 1 (MEN1), Neurofibromatosis type 1 (NF1), and Tuberous Sclerosis Complex (TSC), being the result of an autosomal dominant germline heterozygous loss-of-function mutation in a tumor suppressor gene. Here, we reviewed the main epidemiological and clinical aspects of insulinoma and glucagonoma in the context of genetic syndromes.</p>","PeriodicalId":11654,"journal":{"name":"Endocrine-related cancer","volume":"45 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140324834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impact of Sex on Treatment Decisions and Outcome in Patients with Neuroendocrine Neoplasms 性别对神经内分泌肿瘤患者治疗决定和治疗结果的影响
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-01 DOI: 10.1530/erc-23-0235
Julia Beck, Alexander Siebenhüner, Damian Wild, Emanuel Christ, Julie Refardt

The influence of sex on neuroendocrine neoplasms (NENs) has been scarcely investigated. Thus, this study aimed to compare tumor characteristics, treatment decisions, and overall survival in patients with NENs, stratified by sex. The retrospective analysis of the SwissNET cohort covered NENs of gastroenteropancreatic, pulmonary, or unknown origin from 07/14 – 09/22. The analysis included 1985 patients (46% female and 54% male). Male patients presented with higher staging at time of diagnosis and with more lymph node- and bone-metastases. Surgery was performed more often in female compared to male patients (73.4% vs. 68.7%, p=0.023). Male patients received peptide receptor nuclide therapy (PRRT) earlier than female patients (7.8 months vs 13.1 months from time of diagnosis, p=0.003). The median overall survival was significantly shorter for male compared to female patients (Male: 18 years, Female: not reached, p<0.001, Hazard Ratio (HR) 1.55 [1.19-2.01], p=0.001). In conclusion, male sex was associated with worse outcome in NEN patients, likely due to more advanced tumor stage at the time of diagnosis. Further investigations are required to understand the underlying mechanisms of these sex differences.

有关性别对神经内分泌肿瘤(NENs)影响的研究很少。因此,本研究旨在比较不同性别神经内分泌肿瘤患者的肿瘤特征、治疗决定和总生存率。对SwissNET队列的回顾性分析涵盖了7/14-09/22期间胃肠胰腺、肺部或不明原因的NEN。该分析包括1985名患者(46%为女性,54%为男性)。男性患者在确诊时的分期更高,淋巴结转移和骨转移也更多。与男性患者相比,女性患者更常接受手术治疗(73.4% 对 68.7%,P=0.023)。男性患者比女性患者更早接受肽受体核素疗法(PRRT)(从确诊时算起7.8个月对13.1个月,P=0.003)。男性患者的中位总生存期明显短于女性患者(男性:18 年,女性:未达到,p<0.001,危险比 (HR) 1.55 [1.19-2.01], p=0.001)。总之,男性性别与 NEN 患者较差的预后有关,这可能是由于诊断时肿瘤分期较晚。要了解这些性别差异的潜在机制,还需要进一步的研究。
{"title":"Impact of Sex on Treatment Decisions and Outcome in Patients with Neuroendocrine Neoplasms","authors":"Julia Beck, Alexander Siebenhüner, Damian Wild, Emanuel Christ, Julie Refardt","doi":"10.1530/erc-23-0235","DOIUrl":"https://doi.org/10.1530/erc-23-0235","url":null,"abstract":"<p>The influence of sex on neuroendocrine neoplasms (NENs) has been scarcely investigated. Thus, this study aimed to compare tumor characteristics, treatment decisions, and overall survival in patients with NENs, stratified by sex. The retrospective analysis of the SwissNET cohort covered NENs of gastroenteropancreatic, pulmonary, or unknown origin from 07/14 – 09/22. The analysis included 1985 patients (46% female and 54% male). Male patients presented with higher staging at time of diagnosis and with more lymph node- and bone-metastases. Surgery was performed more often in female compared to male patients (73.4% vs. 68.7%, p=0.023). Male patients received peptide receptor nuclide therapy (PRRT) earlier than female patients (7.8 months vs 13.1 months from time of diagnosis, p=0.003). The median overall survival was significantly shorter for male compared to female patients (Male: 18 years, Female: not reached, p&lt;0.001, Hazard Ratio (HR) 1.55 [1.19-2.01], p=0.001). In conclusion, male sex was associated with worse outcome in NEN patients, likely due to more advanced tumor stage at the time of diagnosis. Further investigations are required to understand the underlying mechanisms of these sex differences.</p>","PeriodicalId":11654,"journal":{"name":"Endocrine-related cancer","volume":"21 1","pages":""},"PeriodicalIF":3.9,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138824197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Beyond the 3 P’s: Adrenal involvement in MEN1 超越 3 P:MEN1 的肾上腺受累
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-12-01 DOI: 10.1530/erc-23-0162
Uriel Clemente-Gutierrez, Carolina R.c. Pieterman, Michael S. Lui, Thomas Szabo Yamashita, Andrés Tame-Elorduy, Bernice L. Huang, Aditya S. Shirali, Derek J. Erstad, Jeffrey E. Lee, Sarah B. Fisher, Paul H. Graham, Elizabeth G. Grubbs, Steven G Waguespack, Chaan S. Ng, Nancy Perrier

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients’ clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47±11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional workup (diagnoses: pheochromocytoma [n=2], adrenocorticotropic hormone–dependent hypercortisolism [n=2], hyperandrogenism [n=1], hyperaldosteronism [n=1]); surgery was indicated for 5 (83.3%; n=12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and 2 with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion’s growth rate and size. A baseline hormonal workup is recommended, and no further biochemical workup is suggested when the initial assessment shows nonfunctioning lesions.

多发性内分泌瘤病 1 型(MEN1)患者经常会发现肾上腺病变(ALs)。然而,MEN1 中的肾上腺病变并没有得到很好的描述,因此其临床处理并不明确。本研究探讨了在 MEN1 中发现的 AL 的发病率和结果。我们对 1990 年至 2021 年期间确诊为 MEN1 的患者进行了回顾性病历审查。AL是通过腹部或胸部成像诊断出来的,分为单侧或双侧、单发或多发结节、弥漫性增大或无弥漫性增大。对可测量的结节病变的大小和随时间的增长情况进行了分析。我们还收集了患者的临床和影像学特征。我们共发现了 382 名 MEN1 患者,其中 89 人(23.3%)患有 ALs。发现时的平均年龄为 47±11.9 岁。我们记录了 101 个可测量的结节性病变(平均大小为 17.5 毫米;范围为 3-123 毫米)。27个结节(26.7%)小于1厘米。79名患者(78.2%)需要观察等待,其中28名患者(35.4%)的病灶正在生长。在进行功能检查的 38 例患者中,有 6 例(15.8%)确诊为功能性病变(诊断:嗜铬细胞瘤 [n=2]、促肾上腺皮质激素依赖性皮质醇增多症 [n=2]、雄激素过多症 [n=1]、醛固酮过多症 [n=1]);5 例(83.3%;n=12 个结节)患者接受了手术治疗,其中 2 例为双侧弥漫性肾上腺增大。两名患者被诊断为肾上腺皮质癌,两名患者被诊断为恶性可能性不确定的肿瘤。AL的放射学或临床进展并不常见。应根据病变的生长速度和大小来怀疑恶性肿瘤。建议进行基线激素检查,如果初步评估显示病变无功能,则不建议进一步进行生化检查。
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引用次数: 0
Hypoxia-associated genetic signature in ovarian steroid cell tumor NOS. 卵巢类固醇细胞肿瘤NOS.缺氧相关基因特征。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-04 Print Date: 2023-11-01 DOI: 10.1530/ERC-23-0179
Angel Chao, Huei-Jean Huang, Chiao-Yun Lin, Chia-Hwa Lee, Chien-Hsing Lin, An-Shine Chao, Chyong-Huey Lai, Ting-Chang Chang, Kai-Yun Wu, Ren-Chin Wu

Steroid cell tumors, not otherwise specified (SCT-NOS), are uncommon ovarian neoplasms accompanied by virilization symptoms due to hyperandrogenism, which are malignant in approximately one-third of the cases. Given the rarity of SCT-NOS, their molecular underpinnings have not yet been studied in depth. In this case series, we performed the first comprehensive analysis of the genetic landscape of this rare ovarian tumor. A detailed clinicopathological description of an index case is also provided. Over a 20-year period, a total of eight patients were seen at our institution. Total nucleic acids (RNA and DNA) were extracted from evaluable formalin-fixed, paraffin-embedded tumor specimens (n = 7) and subjected to TruSight Oncology 500 testing and/or exome sequencing. The results identified pathogenic variants in several hypoxia-related genes - including HIF1A, VHL, SDHB, SRC, IDH2, and FOXO4. As the first comprehensive genetic analysis of SCT-NOS, this study shows that dysregulation in the hypoxia signaling pathway is a key molecular feature of this rare tumor. Clinically, long-term follow-up with periodic measurements of androgen levels should be pursued in all cases since recurrences may occur several years after the initial diagnosis.

类固醇细胞肿瘤(SCT-NOS)是一种罕见的卵巢肿瘤,由于高雄激素血症而伴有男性化症状,约三分之一的病例为恶性。鉴于SCT-NOS的罕见性,其分子基础尚未得到深入研究。在这个病例系列中,我们对这种罕见卵巢肿瘤的遗传景观进行了首次全面分析。还提供了一个索引病例的详细临床病理描述。在20年的时间里,共有8名患者在我们的机构就诊。从可评估的福尔马林固定、石蜡包埋的肿瘤标本(n=7)中提取总核酸(RNA和DNA),并进行TruSight肿瘤学500测试和/或外显子组测序。研究结果在几个缺氧相关基因中发现了致病性变体,包括HIF1A、VHL、SDHB、SRC、IDH2和FOXO4。作为首次对SCT-NOS进行全面的遗传分析,本研究表明缺氧信号通路的失调是这种罕见肿瘤的关键分子特征。临床上,所有病例都应进行长期随访,定期测量雄激素水平,因为在最初诊断后几年可能会复发。
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引用次数: 0
IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer. 转移性前列腺癌症中IGF-1轴随ADT和多烯紫杉醇的变化。
IF 4.1 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-10-04 Print Date: 2023-11-01 DOI: 10.1530/ERC-23-0241
Praful Ravi, Victoria Wang, Raina N Fichorova, Bradley McGregor, Xiao X Wei, Shehzad Basaria, Christopher J Sweeney

Androgen deprivation therapy (ADT) forms the cornerstone of treatment in locally advanced and metastatic prostate cancer (PCa). Since the growth hormone-insulin-like growth factor (GH-IGF-1) axis has been implicated in prostate tumorigenesis, we aimed to evaluate the association between IGF-1 and its binding proteins on outcomes in men with metastatic PCa treated with ADT, with or without docetaxel (D). We analyzed serum samples for IGF-1 and its family proteins from baseline, 6 months post-randomization, and at the time of progression in men enrolled to receive ADT +/- D in the phase 3 CHAARTED trial. The key outcomes were time to the development of castrate-resistant prostate cancer and overall survival (OS). About 560 patients had samples available for analysis. At 6 months, significant increases in IGF-BP1 (mean Δ+27.4%, P = 0.033), IGF-BP3 (mean Δ+10.3%, P < 0.001), and IGF-BP4 (mean Δ+31.1%, P < 0.001) were seen in the ADT + D group, while the ADT group showed an increase in IGF-BP3 (mean Δ+5.5%, P = 0.015). A higher IGF-1:IGF-BP1 ratio at baseline and after 6 months was associated with improved OS in both the ADT (baseline: hazard ratio (HR) = 0.77, P = 0.026; 6 months: HR = 0.83, P = 0.036) and ADT + D groups (baseline: HR = 0.78, P = 0.04; 6 months: HR = 0.81, P = 0.018). Patients with a log10IGF-1:IGF-BP1 ratio >1.3 at baseline had improved OS when meta-analyzed with data from a prior cohort (HR = 0.71). A higher baseline and 6-month IGF-1:IGF-BP1 ratio was associated with better OS. Further exploration of the IGF-1 axis will be important to assess its role as a predictive biomarker and to target this axis in therapeutic trials.

雄激素剥夺疗法(ADT)是局部晚期和转移性癌症(PCa)治疗的基石。由于生长激素-胰岛素样生长因子(GH-IGF-1)轴与前列腺肿瘤的发生有关,我们旨在评估IGF-1及其结合蛋白对接受ADT、接受或不接受多西他赛(D)治疗的转移性前列腺癌患者预后的影响。我们分析了基线、随机分组后6个月以及在3期CHAARTED试验中接受ADT+/-D的男性进展时的血清样本中IGF-1及其家族蛋白。关键结果是去势耐受性前列腺癌症的发展时间和总生存率(OS)。大约560名患者的样本可供分析。在6个月时,ADT+D组的IGF-BP1(平均Δ+27.4%,P=0.033)、IGF-BP3(平均Δ+10.3%,P<0.001)和IGF-BP4(平均Δ+31.1%,P=0.001)显著增加,而ADT组显示IGF-BP3增加(平均Δ+5.5%,P=0.015)。基线和6个月后IGF-1:IGF-BP1比率较高与两组ADT的OS改善相关(基线:危险比(HR)=0.77,P=0.026;6个月:HR=0.83,P=0.036)和ADT+D组(基线:HR=0.78,P=0.04;6个月,HR=0.81,P=0.018)。当与先前队列的数据进行荟萃分析时,基线时log10IGF-1:IGF-BP1比率>1.3的患者的OS有所改善(HR=0.71)。基线和6个月时IGF-1/IGF-BP1比率越高,OS越好。对IGF-1轴的进一步探索对于评估其作为预测性生物标志物的作用以及在治疗试验中靶向该轴将是重要的。
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引用次数: 0
MicroRNA regulation of the serine synthesis pathway in endocrine-resistant breast cancer cells. 内分泌耐药乳腺癌症细胞丝氨酸合成途径的微小RNA调节。
IF 4.1 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-27 Print Date: 2023-11-01 DOI: 10.1530/ERC-23-0148
Belinda J Petri, Kellianne M Piell, Ali E Wilt, Alexa D Howser, Laura Winkler, Mattie R Whitworth, Bailey L Valdes, Norman L Lehman, Brian F Clem, Carolyn M Klinge

Despite the successful combination of therapies improving survival of estrogen receptor α (ER+) breast cancer patients with metastatic disease, mechanisms for acquired endocrine resistance remain to be fully elucidated. The RNA binding protein HNRNPA2B1 (A2B1), a reader of N(6)-methyladenosine (m6A) in transcribed RNA, is upregulated in endocrine-resistant, ER+ LCC9 and LY2 cells compared to parental MCF-7 endocrine-sensitive luminal A breast cancer cells. The miRNA-seq transcriptome of MCF-7 cells overexpressing A2B1 identified the serine metabolic processes pathway. Increased expression of two key enzymes in the serine synthesis pathway (SSP), phosphoserine aminotransferase 1 (PSAT1) and phosphoglycerate dehydrogenase (PHGDH), correlates with poor outcomes in ER+ breast patients who received tamoxifen (TAM). We reported that PSAT1 and PHGDH were higher in LCC9 and LY2 cells compared to MCF-7 cells and their knockdown enhanced TAM sensitivity in these-resistant cells. Here we demonstrate that stable, modest overexpression of A2B1 in MCF-7 cells increased PSAT1 and PHGDH and endocrine resistance. We identified four miRNAs downregulated in MCF-7-A2B1 cells that directly target the PSAT1 3'UTR (miR-145-5p and miR-424-5p), and the PHGDH 3'UTR (miR-34b-5p and miR-876-5p) in dual luciferase assays. Lower expression of miR-145-5p and miR-424-5p in LCC9 and ZR-75-1-4-OHT cells correlated with increased PSAT1 and lower expression of miR-34b-5p and miR-876-5p in LCC9 and ZR-75-1-4-OHT cells correlated with increased PHGDH. Transient transfection of these miRNAs restored endocrine-therapy sensitivity in LCC9 and ZR-75-1-4-OHT cells. Overall, our data suggest a role for decreased A2B1-regulated miRNAs in endocrine resistance and upregulation of the SSP to promote tumor progression in ER+ breast cancer.

尽管雌激素受体α(ER+)乳腺癌转移性疾病患者的治疗组合成功提高了患者的生存率,但获得性内分泌抵抗的机制仍有待完全阐明。RNA结合蛋白HNRNPA2B1(A2B1)是转录RNA中N(6)-甲基腺苷(m6A)的读取器,与亲代MCF-7内分泌敏感的腔a乳腺癌症细胞相比,在内分泌耐受细胞、ER+LCC9和LY2细胞中上调。过表达A2B1的MCF-7细胞的miRNA-seq转录组鉴定了丝氨酸代谢过程途径。丝氨酸合成途径(SSP)中两种关键酶,磷酸丝氨酸氨基转移酶1(PSAT1)和磷酸甘油酸脱氢酶(PHGDH)的表达增加,与接受他莫昔芬(TAM)治疗的ER+乳腺患者的不良预后相关。我们报道,与MCF-7细胞相比,LCC9和LY2细胞中的PSAT1和PHGDH更高,并且它们的敲除增强了这些耐药细胞中的TAM敏感性。在这里,我们证明了MCF-7细胞中A2B1的稳定、适度过表达增加了PSAT1和PHGDH以及内分泌抵抗。我们在MCF-7-A2B1细胞中鉴定了四种下调的miRNA,它们直接靶向PSAT1 3’UTR(miR-145-5p和miR-424-5p)和PHGDH 3’UTR(miR-34b-5p和miR-876-5p)。LCC9和ZR-75-1-4-OHT细胞中miR-145-5p和miR-424-5p的低表达与PSAT1的增加相关,而LCC9、ZR-75-1-4-OHT细胞的miR-34b-5p和miR-876-5p的低表现与PHGDH的增加相关。这些miRNA的瞬时转染恢复了LCC9和ZR-75-1-4-OHT细胞的内分泌治疗敏感性。总体而言,我们的数据表明,A2B1调节的miRNA减少在内分泌抵抗和SSP上调中起作用,以促进ER+乳腺癌症的肿瘤进展。
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Endocrine-related cancer
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