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Interventional vs surgical procedures in localized/nonmetastatic insulinomas (ablation vs surgery). 局部/非转移性胰岛素瘤的介入与手术治疗(消融与手术)。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-05-02 Print Date: 2023-06-01 DOI: 10.1530/ERC-22-0362
Alaa Sada, Travis J McKenzie, Adrian Vella, Michael J Levy, Thorvardur R Halfdanarson

Localized insulinoma is an uncommon entity that can result in substantial morbidity due to the associated hypoglycemia. Recent studies have suggested an increase in the incidence of insulinoma in recent decades that may possibly be secondary to increased awareness, incidental diagnoses, and better diagnostic methods. Diagnosing and localizing insulinoma within the pancreas can be challenging, but advances in nuclear imaging may improve diagnostic accuracy. Delays in diagnosis are common, but once a localized insulinoma is diagnosed and appropriately treated, the long-term prognosis is excellent. Surgical resection is considered the standard of care management option for localized insulinoma, but tumor ablation with endoscopic ultrasound guidance has also been shown to be an effective and safe method for therapy.

局限性胰岛素瘤是一种不常见的疾病,可因相关低血糖而导致严重的发病率。最近的研究表明,近几十年来胰岛素瘤的发病率有所增加,这可能是由于意识的提高、偶然诊断和更好的诊断方法所致。胰腺内胰岛素瘤的诊断和定位可能具有挑战性,但核成像的进步可能会提高诊断的准确性。诊断延误很常见,但一旦诊断出局部胰岛素瘤并进行适当治疗,长期预后良好。手术切除被认为是局部胰岛素瘤的标准护理管理选择,但内镜超声引导下的肿瘤消融也被证明是一种有效和安全的治疗方法。
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引用次数: 1
Deiodinases in thyroid tumorigenesis. 甲状腺肿瘤发生中的脱碘酶。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-05-01 DOI: 10.1530/ERC-23-0015
Maria Angela De Stefano, Tommaso Porcelli, Martin Schlumberger, Domenico Salvatore

The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells. Differentiated thyroid cancers overexpress the TH-inactivating type 3 deiodinase (D3), likely to reduce the TH signaling within the tumor. Strikingly, recent evidence suggests that during the late stage of thyroid tumorigenesis, D2 expression raises and this, together with a reduction in D3 expression levels, increases TH intracellular signaling in dedifferentiated thyroid cancers. These findings call into question the different functions of TH in the various stages of thyroid cancers.

三种脱碘酶硒酶是细胞内甲状腺激素(TH)水平的关键调节因子。两种促甲状腺素脱碘酶(1型脱碘酶和2型脱碘酶(D2))通常在滤泡甲状腺细胞中表达,并参与促甲状腺素的产生。在甲状腺肿瘤发生过程中,脱碘酶表达谱发生变化,使细胞内TH水平适应癌细胞的不同需要。分化型甲状腺癌过表达灭活TH的3型脱碘酶(D3),可能降低肿瘤内的TH信号。引人注目的是,最近的证据表明,在甲状腺肿瘤发生的晚期,D2表达升高,这与D3表达水平的降低一起,增加了去分化甲状腺癌中TH细胞内信号传导。这些发现对甲状腺素在甲状腺癌不同阶段的不同功能提出了质疑。
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引用次数: 0
Type 2 deiodinase is expressed in anaplastic thyroid carcinoma and its inhibition causes cell senescence. 2型脱碘酶在间变性甲状腺癌中表达,其抑制可导致细胞衰老。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-05-01 DOI: 10.1530/ERC-23-0016
Maria Angela De Stefano, Tommaso Porcelli, Raffaele Ambrosio, Cristina Luongo, Maddalena Raia, Martin Schlumberger, Domenico Salvatore

Anaplastic thyroid cancer (ATC) is a rare thyroid tumor that frequently originates from the dedifferentiation of a well-differentiated papillary or follicular thyroid cancer. Type 2 deiodinase (D2), responsible for the activation of the thyroid hormone thyroxine into tri-iodothyronine (T3), is expressed in normal thyroid cells and its expression is strongly downregulated in papillary thyroid cancer. In skin cancer, D2 has been associated with cancer progression, dedifferentiation, and epithelial-mesenchymal transition. Here, we show that D2 is highly expressed in anaplastic compared to papillary thyroid cancer cell lines and that D2-derived T3 is required for ATC cell proliferation. D2 inhibition is associated with G1 growth arrest and induction of cell senescence, together with reduced cell migration and invasive potential. Finally, we found that mutated p5372R(R248W), frequently found in ATC, is able to induce D2 expression in transfected papillary thyroid cancer cells. Our results show that the action of D2 is crucial for ATC proliferation and invasiveness, providing a potential new therapeutic target for the treatment of ATC.

间变性甲状腺癌(ATC)是一种罕见的甲状腺肿瘤,通常起源于分化良好的乳头状或滤泡状甲状腺癌的去分化。2型脱碘酶(D2)负责将甲状腺激素甲状腺素激活为三碘甲状腺原氨酸(T3),在正常甲状腺细胞中表达,在甲状腺乳头状癌中表达强烈下调。在皮肤癌中,D2与癌症进展、去分化和上皮间质转化有关。在这里,我们发现与甲状腺乳头状癌细胞系相比,D2在间变性中高度表达,并且D2衍生的T3是ATC细胞增殖所必需的。D2抑制与G1生长停滞和诱导细胞衰老有关,同时还与细胞迁移和侵袭潜力减少有关。最后,我们发现突变的p5372R(R248W),经常在ATC中发现,能够诱导D2在转染的甲状腺乳头状癌细胞中表达。我们的研究结果表明,D2的作用对ATC的增殖和侵袭至关重要,为ATC的治疗提供了一个潜在的新的治疗靶点。
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引用次数: 0
International symposium on pheochromocytoma: an event of dedicated healthcare professionals and researchers striving for better patient outcomes. 嗜铬细胞瘤国际研讨会:致力于医疗保健专业人员和研究人员争取更好的患者结果的事件。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-05-01 DOI: 10.1530/ERC-23-0030
Karel Pacak, Roderick J Clifton-Bligh

Pheochromocytomas and paragangliomas (PPGLs) are defined as neuroendocrine tumors that produce catecholamines. Many recent advances in their management, localization, treatment, as well as surveillance have significantly improved outcomes for patients with PPGLs or carriers of pathogenic genetic variants linked to the development of these tumors. At present, those advances mainly include the molecular stratification of PPGLs into seven clusters, the 2017 WHO revised definition of these tumors, the presence of specific clinical features pointing toward PPGL, the use of plasma metanephrines and 3-methoxytyramine with specific reference limits to assess the likelihood of having a PPGL (e.g. patients at high and low risk) including age-specific reference limits, nuclear medicine guidelines outlining cluster- and metastatic disease-specific functional (here mainly positron emission tomography and metaiodobenzylguanidine scintigraphy) imaging in the precise diagnostic localization of PPGLs, the guidelines for using radio- vs chemotherapy for patients with metastatic disease, and the international consensus on initial screening and follow-up of asymptomatic germline SDHx pathogenic variant carriers. Furthermore, new collaborative efforts particularly based on multi-institutional and worldwide initiatives are now considered key forces in improving our understanding and knowledge about these tumors and future successful treatments or even preventative interventions.

嗜铬细胞瘤和副神经节瘤(PPGLs)被定义为产生儿茶酚胺的神经内分泌肿瘤。最近在其管理、定位、治疗和监测方面的许多进展显著改善了PPGLs患者或与这些肿瘤发展相关的致病基因变异携带者的预后。目前,这些进展主要包括PPGL的分子分层分为7类,2017年WHO修订了这些肿瘤的定义,存在指向PPGL的特定临床特征,使用具有特定参考限值的血浆肾上腺素和3-甲氧基酪胺来评估PPGL的可能性(例如高危和低危患者),包括年龄特异性参考限值。核医学指南概述了聚类和转移性疾病特异性功能成像(主要是正电子发射断层扫描和间氧苄基胍显像)在PPGLs精确诊断定位中的应用,转移性疾病患者使用放化疗的指南,以及对无症状种系SDHx致病变异携带者的初始筛查和随访的国际共识。此外,新的合作努力,特别是基于多机构和全球倡议,现在被认为是提高我们对这些肿瘤和未来成功治疗甚至预防性干预的理解和知识的关键力量。
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引用次数: 0
Vandetanib downregulates type 2 deiodinase in fibro/adipogenic progenitors. 万德替尼下调纤维/脂肪源性祖细胞2型脱碘酶。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-05-01 DOI: 10.1530/ERC-22-0269
Tommaso Porcelli, Raffaele Ambrosio, Maria Angela De Stefano, Cristina Luongo, Daniela Terracciano, Caterina Miro, Monica Dentice, Martin Schlumberger, Domenico Salvatore

Treatment with tyrosine kinase inhibitors (TKIs) has been associated with alterations in circulating thyroid hormone levels, possibly related to perturbations in peripheral thyroid hormone metabolism. In this study, we evaluated the effect of the multi-kinase inhibitor vandetanib on the expression of the three deiodinase selenoenzymes, responsible for the thyroid hormone activation (type 1 and type 2 deiodinases) or for its inactivation (type 3 deiodinase). Here, we show that the multi-kinase inhibitor vandetanib determines a strong cell-specific downregulation of type 2 deiodinase (D2) expression and a significant reduction in D2 enzymatic activity. This occurs in the diffused population of fibro/adipogenic progenitors, which reside in different tissues - including the muscles - and normally express D2. Given the widespread diffusion of mesenchymal cells within the body, our results may explain at least partially the alterations in thyroid hormone levels that occur in vandetanib-treated patients. Our findings represent a step forward into the understanding of the mechanisms by which TKIs induce hypothyroidism and identify a resident cell population in which such an effect takes place.

酪氨酸激酶抑制剂(TKIs)治疗与循环甲状腺激素水平的改变有关,可能与外周甲状腺激素代谢的扰动有关。在这项研究中,我们评估了多激酶抑制剂vandetanib对三种脱碘酶硒酶表达的影响,这三种脱碘酶负责甲状腺激素的激活(1型和2型脱碘酶)或失活(3型脱碘酶)。在这里,我们发现多激酶抑制剂vandetanib决定了2型脱碘酶(D2)表达的强烈细胞特异性下调和D2酶活性的显著降低。这种情况发生在弥漫性纤维/脂肪祖细胞中,它们存在于不同的组织中,包括肌肉,通常表达D2。鉴于间充质细胞在体内的广泛扩散,我们的研究结果至少可以部分解释万德替尼治疗患者甲状腺激素水平的改变。我们的研究结果代表了对TKIs诱导甲状腺功能减退的机制的理解,并确定了发生这种作用的驻留细胞群。
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引用次数: 1
COVID-19 in patients with neuroendocrine neoplasms: 2-year results of the INTENSIVE study. 神经内分泌肿瘤患者的COVID-19: INTENSIVE研究的2年结果
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-04-26 Print Date: 2023-06-01 DOI: 10.1530/ERC-22-0395
Nicola Fazio, Lorenzo Gervaso, Thorvardur R Halfdanarson, Mohamad Sonbol, Rachel A Eiring, Sara Pusceddu, Natalie Prinzi, Benedetta Lombardi Stocchetti, Simona Grozinsky-Glasberg, David J Gross, Thomas Walter, Patrick Robelin, Catherine Lombard-Bohas, Samuele Frassoni, Vincenzo Bagnardi, Lorenzo Antonuzzo, Clotilde Sparano, Sara Massironi, Fabio Gelsomino, Alberto Bongiovanni, Nicoletta Ranallo, Salvatore Tafuto, Maura Rossi, Mauro Cives, Kakil Ibrahim Rasul, Hytham Hamid, Alessandra Chirco, Michela Squadroni, Anna La Salvia, Jorge Hernando, Johannes Hofland, Anna Koumarianou, Sabrina Boselli, Darina Tamayo, Cristina Mazzon, Manila Rubino, Francesca Spada

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

我们对神经内分泌肿瘤(NENs)和分子证实的严重急性呼吸系统综合征冠状病毒2型阳性患者进行了一项回顾性/前瞻性全球研究。INTENSIVE研究的85名患者的初步结果已于2021年公布。现在,我们正在报告两年的分析。在此,我们报告了2020年6月1日至2022年5月31日期间连续入选的患者的数据。在118个联系的中心中,25个是主动招募的,19个在数据截止时主动招募,共招募了280名患者。2020年,47.5%的患者出现严重急性呼吸系统综合征冠状病毒2型阳性,2021年为35.1%,2022年为17.4%。新冠肺炎诊断的中位年龄为60岁。分化良好的肿瘤、无功能、转移期和胃肠胰(GEP)原发部位代表了大多数NEN。新冠肺炎占总数的22.8%,其中61.3%需要住院治疗;11名患者(3.9%)需要亚重症监护室或重症监护室治疗,14名患者死亡(5%),其中11例(3.9%)与新冠肺炎直接相关。糖尿病和新冠肺炎诊断年龄>70岁与新冠肺炎死亡率显著相关,而胸部原发部位与新冠肺炎发病率显著相关。与2020年相比,2022年住院人数和肺炎人数均大幅下降。在我们最大的新冠肺炎NEN患者系列中,无论新冠肺炎如何,NEN人群与一般NEN患者群体相似。然而,对于新冠肺炎发病率和死亡率的增加,应仔细考虑年龄较大、非GEP原发部位和糖尿病。通过将我们的结果与新冠肺炎登记的其他癌症患者中的NEN患者进行整合,可以获得相关信息。
{"title":"COVID-19 in patients with neuroendocrine neoplasms: 2-year results of the INTENSIVE study.","authors":"Nicola Fazio,&nbsp;Lorenzo Gervaso,&nbsp;Thorvardur R Halfdanarson,&nbsp;Mohamad Sonbol,&nbsp;Rachel A Eiring,&nbsp;Sara Pusceddu,&nbsp;Natalie Prinzi,&nbsp;Benedetta Lombardi Stocchetti,&nbsp;Simona Grozinsky-Glasberg,&nbsp;David J Gross,&nbsp;Thomas Walter,&nbsp;Patrick Robelin,&nbsp;Catherine Lombard-Bohas,&nbsp;Samuele Frassoni,&nbsp;Vincenzo Bagnardi,&nbsp;Lorenzo Antonuzzo,&nbsp;Clotilde Sparano,&nbsp;Sara Massironi,&nbsp;Fabio Gelsomino,&nbsp;Alberto Bongiovanni,&nbsp;Nicoletta Ranallo,&nbsp;Salvatore Tafuto,&nbsp;Maura Rossi,&nbsp;Mauro Cives,&nbsp;Kakil Ibrahim Rasul,&nbsp;Hytham Hamid,&nbsp;Alessandra Chirco,&nbsp;Michela Squadroni,&nbsp;Anna La Salvia,&nbsp;Jorge Hernando,&nbsp;Johannes Hofland,&nbsp;Anna Koumarianou,&nbsp;Sabrina Boselli,&nbsp;Darina Tamayo,&nbsp;Cristina Mazzon,&nbsp;Manila Rubino,&nbsp;Francesca Spada","doi":"10.1530/ERC-22-0395","DOIUrl":"10.1530/ERC-22-0395","url":null,"abstract":"<p><p>We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.</p>","PeriodicalId":11654,"journal":{"name":"Endocrine-related cancer","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2023-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9476828","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
Diffuse sclerosing variant papillary thyroid carcinoma has worse survival than classic papillary thyroid carcinoma: a meta-analysis. 弥漫性硬化变异性甲状腺乳头状癌的生存率比典型甲状腺乳头状癌差:一项荟萃分析。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-04-26 Print Date: 2023-06-01 DOI: 10.1530/ERC-22-0348
Henry Crayton, Katherine Wu, David Leong, Nazim Bhimani, Matti Gild, Anthony Glover

Diffuse sclerosing variant (DSV) of papillary thyroid carcinomais a rare form of thyroid cancer that demonstrates more aggressive histopathology than classical papillary thyroid carcinoma (c-PTC); however, if this leads to worse survival is debated. Many DSVs are driven by fusion events which are of recent clinical importance due to the advent of targeted RET inhibitors. A systematic search and meta-analysis of the literature was performed to compare outcomes of disease-specific mortality (DSM), metastatic and recurrent disease and the incidence of fusion events between DSV and c-PTC to July 2022. The Newcastle-Ottawa Quality Assessment studies was used to assess quality. An odds ratio (OR) was utilised to measure outcomes with 95% CIs. The Preferred Reporting Items for Systematic Reviews and Meta-analysis guideline was followed. Seventeen studies were included with 874 DSV patients compared to 76,013 c-PTC patients. DSV patients had worse DSM (OR=2.50, 95% CI 1.39-4.51) and presented with a higher rate of metastatic lymph nodes (OR = 5.85, 95% CI 2.73-12.53) and more distant metastases (OR = 3.83, 95% CI 2.17-6.77). DSV patients had higher odds of recurrent disease (OR = 3.23, 95% CI 2.00-5.23) and overall distant metastasis (OR = 2.70, 95% CI 1.74-4.17). Rates of RET fusion alterations for DSV ranged from 25 to 83%. DSV has a worse prognosis than c-PTC with higher rates of recurrent disease and distant metastasis. The high prevalence of RET fusions offers the potential to improve outcomes for patients with DSV.

甲状腺乳头状癌的弥漫性硬化变异体(DSV)是一种罕见的甲状腺癌症,其组织病理学表现比经典的甲状腺乳头状瘤(c-PTC)更具侵袭性;然而,这是否会导致更糟糕的生存还有待商榷。许多DSV是由融合事件驱动的,由于靶向RET抑制剂的出现,融合事件最近在临床上具有重要意义。对文献进行了系统检索和荟萃分析,以比较截至2022年7月DSV和c-PTC之间疾病特异性死亡率(DSM)、转移性和复发性疾病的结果以及融合事件的发生率。纽卡斯尔-渥太华质量评估研究用于评估质量。比值比(OR)用于测量95%CI的结果。遵循系统评价和荟萃分析的首选报告项目指南。17项研究包括874名DSV患者,而76013名c-PTC患者。DSV患者的DSM更差(OR=2.50,95%CI 1.39-4.51),淋巴结转移率更高(OR=5.85,95%CI 2.73-12.53),远处转移率更大(OR=3.83,95%CI 2.17-6.77)25%至83%。DSV的预后比c-PTC差,复发率和远处转移率较高。RET融合的高患病率为改善DSV患者的预后提供了潜力。
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引用次数: 0
Distortion in transmission of pathogenic SDHB- and SDHD-mutated alleles from parent to offspring. 致病性SDHB和sdhd突变等位基因从亲代到后代的传播扭曲。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-04-06 Print Date: 2023-05-01 DOI: 10.1530/ERC-22-0233
Dahlia F Davidoff, Eugénie S Lim, Diana E Benn, Yuvanaa Subramaniam, Eleanor Dorman, John R Burgess, Scott A Akker, Roderick J Clifton-Bligh

Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs's cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew's Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.

嗜铬细胞瘤和副神经节瘤是高度可遗传的肿瘤;与种系突变相关的一半是由克雷布斯循环酶基因突变引起的,包括琥珀酸脱氢酶(SDH)。SDH等位基因的遗传被认为是孟德尔遗传(每个亲本的概率为50%)。以1:1的比例偏离亲本等位基因的传递被称为传递比畸变(TRD)。我们试图评估TRD是否发生在SDHB致病性变体(PV)的传播中。这项研究由澳大利亚皇家北岸医院的发现队列中的41个家庭和英国圣巴塞洛缪医院的验证队列中的四十一个家庭进行。纳入标准为临床诊断的SDHB PV和至少两代可用的谱系。对575名参与者的TRD进行了精确二项测试。SDHB PV的传播率在发现队列中为0.59(P=0.005),在验证队列中为0.67(P<0.001),在联合队列中为0.62(P<0.001。未观察到母体效应。在校正了潜在的混杂因素后,TRD仍然显著:0.67(P<0.001),不包括家庭规模数据不完整的家庭;0.58(P<0.001)。在来自英国13个家庭的81名患者队列中,SDHD PVs的TRD也很明显。SDHB和SDHD PVs的TRD原因尚不清楚,但我们假设在早期胚胎发生过程中选择了生存优势。SDHB和SDHD的TRD的存在对生殖咨询和杂合子状态的进一步研究有意义。
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引用次数: 0
Progress and challenges in experimental models for pheochromocytoma and paraganglioma. 嗜铬细胞瘤和副神经节瘤实验模型的进展和挑战。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-04-04 Print Date: 2023-05-01 DOI: 10.1530/ERC-22-0405
Arthur S Tischler, Judith Favier

Experimental models for pheochromocytoma and paraganglioma are needed for basic pathobiology research and for preclinical testing of drugs to improve treatment of patients with these tumors, especially patients with metastatic disease. The paucity of models reflects the rarity of the tumors, their slow growth, and their genetic complexity. While there are no human cell line or xenograft models that faithfully recapitulate the genotype or phenotype of these tumors, the past decade has shown progress in development and utilization of animal models, including a mouse and a rat model for SDH-deficient pheochromocytoma associated with germline Sdhb mutations. There are also innovative approaches to preclinical testing of potential treatments in primary cultures of human tumors. Challenges with these primary cultures include how to account for heterogeneous cell populations that will vary depending on the initial tumor dissociation and how to distinguish drug effects on neoplastic vs normal cells. The feasible duration for maintaining cultures must also be balanced against time required to reliably assess drug efficacy. Considerations potentially important for all in vitro studies include species differences, phenotype drift, changes that occur in the transition from tissue to cell culture, and the O2 concentration in which cultures are maintained.

嗜铬细胞瘤和副神经节瘤的实验模型是基础病理生物学研究和药物临床前测试所必需的,以改善这些肿瘤患者,特别是转移性疾病患者的治疗。模型的缺乏反映了肿瘤的罕见性、生长缓慢和遗传复杂性。虽然没有人细胞系或异种移植物模型能够忠实地再现这些肿瘤的基因型或表型,但过去十年在动物模型的开发和利用方面取得了进展,包括与种系Sdhb突变相关的SDH缺陷型嗜铬细胞瘤的小鼠和大鼠模型。在人类肿瘤的原代培养中,也有创新的方法来进行潜在治疗的临床前测试。这些原代培养的挑战包括如何解释异质性细胞群,这些细胞群将根据最初的肿瘤解离而变化,以及如何区分药物对肿瘤细胞和正常细胞的影响。维持培养物的可行持续时间也必须与可靠评估药物疗效所需的时间相平衡。对所有体外研究可能重要的考虑因素包括物种差异、表型漂移、从组织到细胞培养的过渡过程中发生的变化,以及维持培养的O2浓度。
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引用次数: 0
COL12A1 as a prognostic biomarker links immunotherapy response in breast cancer. COL12A1作为预后生物标志物与乳腺癌免疫治疗反应相关
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-04-03 Print Date: 2023-05-01 DOI: 10.1530/ERC-23-0012
Yuanliang Yan, Qiuju Liang, Yuanhong Liu, Shangjun Zhou, Zhijie Xu

Immunotherapy has shown promising efficacy for breast cancer (BC) patients. Yet the predictive biomarkers for immunotherapy response remain lacking. Based on two GEO datasets, 53 differentially expressed genes associated with durvalumab treatment response were identified. Using least absolute shrinkage and selection operator (LASSO) and univariate Cox regression, four genes (COL12A1, TNN, SCUBE2, and FDCSP) revealed prognostic value in the TCGA BC cohort. COL12A1 outperformed the others, without overlap in its survival curve. Survival analysis by Kaplan-Meier plotter demonstrated that COL12A1 was negatively associated with BC patients' prognosis. A COL12A1-based nomogram was further developed to predict the overall survival in BC patients. The calibration plot revealed an optimal agreement between nomogram prediction and actual observation. Moreover, COL12A1 expression was significantly up-regulated in BC tissues and COL12A1 knockdown impaired the proliferation of MDA-MB-231 and BT549 cells. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment analysis pathway indicated that the function of COL12A1 was related to immunity-related pathways. Immunological analyses illustrated that COL12A1 was correlated with M2 macrophage infiltration and M2 macrophage markers (transforming growth factor beta 1 (TGFB1), interleukin-10, colony stimulating factor 1 receptor (CSF1R) and CD163) in BC. Immunohistochemistry staining further revealed a highly positive relationship of COL12A1 with TGF-β1. The co-incubated models of BC cells and M2 macrophges showed COL12A1 knockdown suppressed M2 macrophage infiltration. Additionally, silencing COL12A1 suppressed TGF-B1 protein expression, and treating with TGFB1 could reverse the inhibitory effects on M2 macrophage infiltration by COL12A1 knockdown. Using immunotherapy datasets, we also found elevated expression of COL12A1 predicted poor response to anti-PD-1/PD-L1 therapy. These results reinforce the current understanding of COL12A1's roles in tumorigenesis and immunotherapy response in BC.

免疫疗法已显示出对癌症(BC)患者有希望的疗效。然而,免疫疗法反应的预测性生物标志物仍然缺乏。基于两个GEO数据集,鉴定了53个与杜伐单抗治疗反应相关的差异表达基因。使用最小绝对收缩和选择算子(LASSO)和单变量Cox回归,四个基因(COL12A1、TNN、SCUBE2和FDCSP)在TCGA BC队列中显示了预后价值。COL12A1的表现优于其他产品,其生存曲线没有重叠。Kaplan-Meier绘图仪的生存分析表明,COL12A1与BC患者的预后呈负相关。进一步开发了基于COL12A1的列线图来预测BC患者的总生存率。校准图显示了诺模图预测和实际观测之间的最佳一致性。此外,COL12A1在BC组织中的表达显著上调,并且COL12A1敲低损害MDA-MB-231和BT549细胞的增殖。基因本体论、京都基因与基因组百科全书和基因集富集分析途径表明,COL12A1的功能与免疫相关途径有关。免疫学分析表明,COL12A1与BC中M2巨噬细胞浸润和M2巨噬细胞标志物(转化生长因子β1(TGFB1)、白细胞介素-10、集落刺激因子1受体(CSF1R)和CD163)相关。免疫组化染色进一步揭示了COL12A1与TGF-β1的高度阳性关系。BC细胞和M2巨噬细胞的共孵育模型显示COL12A1敲低抑制了M2巨噬细胞的浸润。此外,沉默COL12A1抑制TGF-B1蛋白表达,用TGFB1处理可以逆转COL12A1敲低对M2巨噬细胞浸润的抑制作用。使用免疫疗法数据集,我们还发现COL12A1的表达升高预测了对抗PD-1/PD-L1治疗的不良反应。这些结果加强了目前对COL12A1在BC肿瘤发生和免疫治疗反应中的作用的理解。
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引用次数: 1
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Endocrine-related cancer
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