Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk

Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

U tủy thượng thận ở trẻ em - kiều gen và kiểu hình

Pheochromocytomas (PCC) và Pragangliomas (PLG) là những khối u thần kinh – nội tiết. Khối u tiết catecholamine xuất phát từ tủy thượng thận được gọi là Pheochromocytoma. Khối u có nguồn gốc ngoài thượng thận, có thể tiết catecholamine hoặc không có chức năng, bắt nguồn từ các hạch thần kinh giao cảm hoặc phó giao cảm được gọi là Paraganglioma. Vì biểu hiện lâm sàng của hai nhóm bệnh PCC và PLG có tiết catecholamine tương tự nhau, phương pháp điều trị như nhau, nên trên lâm sàng thuật ngữ PCC (u tủy thượng thận) được dùng để chỉ cả 2 loại khối u. U tủy thượng thận là một bệnh lý hiếm gặp ở trẻ em, ước tính tần suất gặp ở 1 trong 50.000 – 100.000 trẻ. Bệnh có thể xuất hiện đơn độc nhưng cũng có thể kèm theo trong một số hội chứng von Hippel – Lindau, bệnh u xơ thần kinh type 1 (NF1) hay hội chứng Pheochromocytoma – Paragangliomas di truyền. Ở trẻ em, khoảng 60% - 80% nguyên nhân u tủy thượng thận là do di truyền. Tăng huyết áp ác tính là một triệu chứng thường gặp và có thể gây những biến chứng nặng nề. Chúng tôi báo cáo 2 trường hợp trẻ nữ vào viện vì đau đầu dữ dội, nôn, đau bụng và co giật. Trẻ được phát hiện tình trạng cao huyết áp kèm theo có khối u ổ bụng. Chẩn đoán xác định của 2 bệnh nhân là u tủy thượng thận. Trong đó, một bệnh nhân tìm thấy nguyên nhân gây bệnh là do đột biết gen succinate dehydrogenase complex iron sulfur subunit B (SDHB).

Management of Multiple Head and Neck Paragangliomas With Assistance of a 3-D Model

Introduction: Extirpation of multiple head and neck paragangliomas carries challenge due to close anatomic relationships with critical neurovascular bundles. Objectives: This study aims to assess whether the application of 3-D models can assist with surgical planning and treatment of these paragangliomas, decrease surgically related morbidity and mortality. Methods: Fourteen patients undergoing surgical resection of multiple head and neck paragangliomas were enrolled in this study. A preoperative 3-D model was created based on radiologic data, and relevant critical anatomic relationships were preoperatively assessed and intraoperatively validated. Results: All 14 patients presented with multiple head and neck paragangliomas, including bilateral carotid body tumors (CBT, n = 9), concurrent CBT with glomus jugulare tumors (GJT, n = 4), and multiple vagal paragangliomas (n = 1). Ten patients underwent genomic analysis and all harbored succinate dehydrogenase complex subunit D (SDHD) mutations. Under guidance of the 3-D model, the internal carotid artery (ICA) was circumferentially encased by tumor on 5 of the operated sides, in 4 (80%) of which the tumor was successfully dissected out from the ICA, whereas ICA reconstruction was required on one side (20%). Following removal of CBT, anterior rerouting of the facial nerve was avoided in 3 (75%) of 4 patients during the extirpation of GJT with assistance of a 3-D model. Two patients developed permanent postoperative vocal cord paralysis. There was no vessel rupture or mortality in this study cohort. Conclusion: The 3-D model is beneficial for establishment of a preoperative strategy, as well as planning and guiding the intraoperative procedure for resection of multiple head and neck paragangliomas.

The emerging clinical relevance of genomic profiling in neuroendocrine tumours

Background Neuroendocrine tumours (NETs) arise from hormone-producing or nervous system cells and can develop from anywhere in the body. They have heterogeneous origins from skin to gastrointestinal track and a complicated histology. Thus, there is an inevitable need for genomic profiling to determine the exact genetics of each tumour for prognosis and treatment strategies to overcome the disease’s complexity. For this purpose, next-generation-sequencing (NGS) is the most reliable methodology for both germ-line and somatic studies to make a clinical diagnosis. In this study, we analyse liquid biopsies, formalin fixed paraffin embedded (FFPE) tissues, and peripheral blood samples for their ability to provide information for actionability. Methods A customized multi-gene panel comprised of Succinate Dehydrogenase Complex Iron Sulfur Subunit B (SDHB), Succinate Dehydrogenase Complex Subunit C (SDHC), Cell Division Cycle 73(CDC73), Calcium Sensing Receptor (CASR), Platelet Derived Growth Factor Receptor Alpha (PDGFRA), Succinate Dehydrogenase Complex Flavoprotein Subunit A (SDHA), Ret Proto-Oncogene (RET), Succinate Dehydrogenase Complex Assembly Factor 2(SDHAF2), Menin 1(MEN1), Succinate Dehydrogenase Complex Subunit D (SDHD), MYC Associated Factor X (MAX) and Protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha (PRKAR1A) genes was constructed to assess multiple specimen types including: 3 liquid biopsies, 6 FFPE tissues, and 26 peripheral blood samples from 35 unique NET patients. Quality-control and bioinformatics analyses were performed using QCI-Analyze and QCI-Interpret. Results The three liquid biopsies and the 6 FFPE tissue samples were evaluated for somatic mutations; while the 26 peripheral blood samples were analysed using the germ-line pipeline. Five (55.6%) of the nine patients that were studied for somatic changes carried actionable mutations related to therapy sensitivities. Through the germ-line studies, we observed a 50% positivity rate for disease predisposition with 16 variants classified according to ACMG (American College of Medical Genetics) Standards and Guidelines. Conclusions Genomic profiling medicine is an emerging area of clinical oncology and has become crucial for disease and patient management by providing a precision approach; this is especially true for rare diseases including rare cancers such as NETs. Notably, this study emphasized the relevance of multiple distinctive biological sample types for use in the genetic testing of cancers to help with the choice of therapy to maximize the likelihood of a positive clinical outcome.

The Emerging Role of the FGF/FGFR Pathway in Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumors (GIST) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. The vast majority are characterized by mutually exclusive activating mutations in KIT or Platelet-derived growth factor alpha (PDGFRA) receptors, or less frequently by succinate dehydrogenase complex (SDH) or NF1 inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 5% of GISTs lack any of such mutations and are called quadruple wild-type (WT) GISTs. Recently, deregulated Fibroblast Growth Factor (FGF)/FGF-receptor (FGFR) signaling emerged as a relevant pathway driving oncogenic activity in different molecular subgroups of GISTs. This review summarizes all the current evidences supporting the key role of the FGF/FGFR pathway activation in GISTs, whereby either activating mutations, oncogenic gene fusions, or autocrine/paracrine signaling have been detected in quadruple WT, SDH-deficient, or KIT-mutant GISTs.

Regional metastatic paraganglioma of the bladder: a rare cause of myocardial infarction, reversible cardiomyopathy and an intracardiac thrombus

Sympathetic paragangliomas are rare neuroendocrine tumours that arise from chromaffin cells and secrete catecholamines. On rare occasions, patients with sympathetic paragangliomas can present with symptoms of congestive heart failure. The optimal treatment is surgical to remove all disease and thereby improve survival as well as restore cardiac function. We report a case of a patient with a regional metastatic bladder paraganglioma and a succinate dehydrogenase complex subunit B gene mutation presenting with cardiomyopathy who had significant improvement in his cardiac function with surgical resection despite further progression of metastatic disease. During his 4-year follow-up period, the patient remains free from heart-failure signs and symptoms.

Neck paraganglioma and follicular lymphoma: a case report

Background Paragangliomas and pheochromocytomas are sympathetic or parasympathetic tumors derived from the paraganglia and the adrenal medulla, respectively. Paragangliomas and pheochromocytomas can be sporadic or familial, the latter frequently being multifocal and possibly due to succinate dehydrogenase complex genes mutations. In addition, 12% of sporadic paragangliomas are related to covered succinate dehydrogenase complex mutations. The importance of identifying succinate dehydrogenase complex mutations is related to the risk for these patients of developing multiple tumors, including non-endocrine ones, showing an aggressive clinical presentation. Case presentation We report the case of a 45-year-old Caucasian man with an indolent mass in his neck. Ultrasound of his neck, magnetic resonance imaging, and 1,4,7,10-tetraazacyclododecane-N(I),N(II),N(III),N(IIII)-tetraacetic acid(D)-Phe(1)-thy(3)-octreotide (68Ga-DOTATOC) positron emission tomography-computed tomography and endocrine work-up were consistent with a carotid body paraganglioma with concomitant nodal enlargement in several body regions, which turned out to be a follicular lymphoma at histology. He was found to carry a germline Succinate dehydrogenase subunit B gene (SDHB) mutation. Conclusion It is crucial to look for a second malignancy in the case of a paraganglioma demonstrating succinate dehydrogenase complex germline mutations.

Quantitative Analysis of CCL5 and ep300 in Periapical Inflammatory Lesions

<p><strong>Objectives. </strong><em>In silico </em>bioinformatical analysis suggested that the expression of two genes, <em>CCL5 </em>(C-C Motif Chemokine Receptor 5) and <em>ep300 </em>(Histone acetyltransferase p300), could be used as potential new biomarkers in differentiation between periapical granulomas and radicular cysts. Thus, we hypothesized that gene expression of <em>CCL5 </em>and <em>ep300 </em>in periapical lesions would classify the lesions as either granuloma or cyst.</p><p><strong>Materials. </strong>Patient samples (n=122) included 46 periapical granulomas, 38 radicular cysts and 38 healthy gingival samples as controls. Real-time PCR analysis of <em>CCL5 </em>and <em>ep300 </em>transcripts was compared to <em>SDHA </em>(Succinate dehydrogenase complex, subunit A) as the reference. Clinical parameters (e.g., intensity of inflammation and lesion size) were measured and correlated with <em>CCL5 </em>and <em>ep300 </em>expression. ROC (Receiver operating characteristic) and logistic regression analyses were used to establish the diagnostic character of ΔCt values.</p><p><strong>Results. </strong>Granulomas and radicular cysts had significantly higher expression of <em>CCL5 </em>and <em>ep300 </em>compared to controls (P&lt;0.05). However, no differences were observed when comparing granulomas and radicular cysts. ROC analyses showed that <em>CCL5 </em>and <em>ep300 </em>have good diagnostic accuracy, but low accuracy for distinguishing between the lesions.</p><p><strong>Conclusions. </strong>This study confirmed that expression of <em>CCL5 </em>and <em>ep300 </em>is relevant for the pathogenesis of periapical inflammatory lesions but cannot be used as a distinctive marker between these lesions.</p>

A rare case of familial middle mediastinal paraganglioma

A 57-year-old lady with a history of familial paraganglioma syndrome type 4 with mutation in the succinate dehydrogenase complex, subunit B gene, had a nonfunctioning middle mediastinal paraganglioma. She also had a pituitary macroadenoma with elevated serum prolactin levels. Surgical excision of the highly vascular mediastinal tumor was performed after preparing the patient preoperatively with alpha blockers and strictly monitoring her blood pressure and blood sugar levels.