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We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs., Competing Interests: Declaration of interests DT has received personal honoraria for lectures and consulting and support for meeting attendance from Advanced Accelerator Applications and Novartis. CL-L has received personal honoraria for lectures and support for meeting attendance from Ipsen. SN has received research grant to their institution from German Research Foundation. LA has received personal honoraria for lectures from Servier and Ipsen. ALE has received fees for consulting from WL Gore and fees for participation on an advisory board from Artivion. ML has received research grants to their institution from Arbor, Bristol Myers Squibb, Accuray, Biohaven, and Urogen; honoraria for research consulting from VBI Vaccines, InCephalo Therapeutics, Merck, Pyramid Bio, Insightec, Biohaven, Sanianoia, Hemispherian, Novocure, Noxxon, InCando, Century Therapeutics, and CraniUs; honoraria for non-research consulting from Stryker; is a shareholder of Egret Therapeutics; holds patents for the combination of immunotherapy and local chemotherapy to treat malignancies (10864180) and focused radiation to augment immune-based strategies against cancer (9132281); and is a member of the data and safety monitoring board of Cellularity. ELP has received fees for participation on an advisory board from Vysioneer. RTC has received personal honoraria for lectures from Novartis, support for meeting attendance from Ipsen, and serves as a board member for the Society for Endocrinology clinical committee and the UK and Ireland Neuroendocrine Tumour Society clinical committee. JKL has received honoraria for lectures from and is a consultant for Stryker. ERM has received fees for consulting and personal honoraria for lectures from MSD. NN has received an intramural research grant from the National Institutes of Health. NP-T has received research grants to their institution from Innervate, Clarity pharma; fees for consulting from Progenics, Lantheus, and Innervate Lifesciences. NP-T is a member of the data and safety monitoring board of Progenics and Lantheus, and serves as a board member for Society of Nuclear Medicine and Molecular Imaging. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Head & Neck Paragangliomas have been historically relying on surgery mostly, with worsened quality of life and major sequelae. Conventional external radiation therapy seems to offer an equivalent control rate with a low toxicity profile. The aim of this study was to assess the safety and efficiency of intensity-modulated radiation therapy in Head & Neck paragangliomas., Methods: This is a retrospective monocentric study conducted in a referral center, including all patients treated with IMRT, whether as an exclusive or post-operative treatment for a tympanic and jugular, carotid, or vagal paraganglioma. Data collection was performed through the manuscript and computerized medical files, including consultation, operative, imaging, pathological analyses, delineation, and treatment planning reports. Success was defined as the complete or partial regression or stabilization without progression, or relapse in accordance with the RECIST criteria. Acute toxicities and long-term sequelae were assessed., Results: Our cohort included 39 patients included between 2011 and 2021: 18 patients treated for a TJ PG (45.9%), 11 patients for a carotid PG (28.4%), and 9 for a vagal PG (23.1%). Twenty-nine patients had IMRT as an exclusive treatment (74.4%), whereas 10 patients had a post-operative complementary treatment (25.6%). Median follow-up in our cohort was 2318 days (average = 2200 days, 237-5690, sd = 1281.9). Among 39 patients, 37 were successfully controlled with IMRT (94.8%), and the toxicity profile was low without any major toxicity., Conclusion: IMRT seems an ideal treatment, whether exclusive or post-operative for Head & Neck paragangliomas., Level of Evidence: 3 Laryngoscope, 133:607-614, 2023., (© 2022 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the '3PAs' syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

Background: Pheochromocytomas and paragangliomas can induce severe cardiovascular manifestations such as Takotsubo-like cardiomyopathy. What the perioperative outcomes are of patients presenting with pheochromocytomas/paragangliomas preceded by Takotsubo-like cardiomyopathy remains an unresolved question., Methods: From 2006 to 2019, all patients who underwent surgery for pheochromocytomas/paragangliomas preceded by Takotsubo-like cardiomyopathy were included from 3 high-volume centers, with specific attention to perioperative hemodynamic instability and postoperative outcomes., Results: Overall, 37 patients were included, with a median age of 45 years. Patients were operated on 2 months (1-4) after a Takotsubo-like cardiomyopathy episode; 33 (89%) had a laparoscopic approach. All those who underwent surgery presented in a hemodynamically stable situation. All except 1 of the pheochromocytomas/paragangliomas patients had at least 1 antihypertensive treatment at the time of surgery. The median preoperative systolic blood pressure in the Takotsubo-like cardiomyopathy group was 120 mm Hg (95-132). Overall, 27/34 (79%) of patients required vasoactive drugs during surgery with nicardipine (n = 22), esmolol (n = 12), and/or norepinephrine (n = 8). No patient presented a catecholamine-induced life-threatening complication such as hypertensive crisis, cardiac arrhythmias, pulmonary edema, cardiac ischemia, or Takotsubo-like cardiomyopathy in the perioperative period. Severe morbi-mortality was nil. The systematic review identified 5 studies including 38 pheochromocytomas/paragangliomas patients with at least 1 episode of acute heart failure considered as Takotsubo-like cardiomyopathy before surgery, of which 28 patients had delayed surgery with 1 postoperative death., Conclusion: Hemodynamically stabilized patients with pheochromocytomas/paragangliomas preceded by Takotsubo-like cardiomyopathy can be safely scheduled for an elective pheochromocytomas/paragangliomas surgery, with similar intra and postoperative outcomes as those without Takotsubo-like cardiomyopathy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Therapies for metastatic SDHB-dependent pheochromocytoma and paraganglioma (PPGL) are limited and poorly efficient. New targeted therapies and identification of early non-invasive biomarkers of response are thus urgently needed for these patients. We characterized an in vivo allograft model of spontaneously immortalized murine chromaffin cells (imCC) with inactivation of the Sdhb gene by dynamic contrast-enhanced MRI (DCE-MRI) and 18FDG-PET. We evaluated the response to several therapies: IACS-010759 (mitochondrial respiratory chain complex I inhibitor), sunitinib (tyrosine kinase inhibitor with anti-angiogenic activity), talazoparib (poly ADP ribose polymerase (PARP) inhibitor) combined or not to temozolomide (alkylating agent), pharmacological inhibitors of HIF2a (PT2385 and PT2977 (belzutifan)) and molecular inactivation of HIF2a (imCC Sdhb-/- shHIF2a). Multimodal imaging was performed, including magnetic resonance spectroscopy (1H-MRS) to monitor the level of succinate in vivo. The allografted model of Sdhb-/- imCC reflected SDHB-deficient tumors, with increased angiogenesis and a particular avidity for 18FDG. After 14 days of treatment, IACS-010759, sunitinib and talazoparib at high doses allowed a significant reduction of the tumor volumes. In contrast to the tumor growth inhibition observed in Sdhb-/- shHIF2a imCC tumors, pharmacological inhibitors of HIF2a (PT2385 and belzutifan) showed no antitumor action in this model, alone or in combination with sunitinib. 1H-MRS, but not DCE-MRI, enabled the monitoring response to sunitinib, which was the best treatment in this study, promoting a decrease in succinate levels detected in vivo. This study paves the way for new therapeutic options and reveals a potential new early biomarker of response to treatment in SDHB-dependent PPGL.

Context: When an SDHx mutation is identified in a patient with a pheochromocytoma (PCC) or a paraganglioma (PGL), predictive genetic testing can detect mutation carriers that would benefit from screening protocols., Objective: To define the tumor detection rate in a large cohort of asymptomatic SDHX mutation carriers., Design and Setting: Retrospective multicentric study in 6 referral centers., Patients: Between 2005 and 2019, 249 asymptomatic SDHx (171 SDHB, 31 SDHC, 47 SDHD) mutation carriers, with at least 1 imaging work-up were enrolled., Results: Initial work-up, including anatomical (98% of subjects [97-100% according to center]) and/or functional imaging (67% [14-90%]) detected 48 tumors in 40 patients. After a negative initial work-up, 124 patients benefited from 1 to 9 subsequent follow-up assessments (mean: 1.9 per patient), with a median follow-up time of 5 (1-13) years. Anatomical (86% [49-100 %]) and/or functional imaging (36% [7-60 %]) identified 10 new tumors (mean size: 16 mm [4-50]) in 10 patients. Altogether, 58 tumors (55 paraganglioma [PGL], including 45 head and neck PGL, 2 pheochromocytoma [PCC], 1 gastrointestinal stromal tumor [GIST]), were detected in 50 patients (22 [13%] SDHB, 1 [3.2%] SDHC, and 27 [57%] SDHD), with a median age of 41 years old [11-86], 76% without catecholamine secretion and 80% during initial imaging work-up., Conclusions: Imaging screening enabled detection of tumors in 20% of asymptomatic SDHx mutation carriers, with a higher detection rate in SDHD (57%) than in SDHB (13%) and SDHC (3%) mutation carriers, arguing for a gene-by-gene approach. Prospective studies using well-defined protocols are needed to obtain strong and useful data., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors arising from the adrenal medulla or extra-adrenal paraganglia. Around 40% of all cases are caused by a germline mutation in a susceptibility gene, half of which being found in an SDHx gene (SDHA, SDHB, SDHC, SDHD or SDHAF2). They encode the four subunits and assembly factor of succinate dehydrogenase (SDH), a mitochondrial enzyme involved both in the tricarboxylic acid cycle and electron transport chain. SDHx mutations lead to the accumulation of succinate, which acts as an oncometabolite by inhibiting iron(II) and alpha-ketoglutarate-dependent dioxygenases thereby regulating the cell's hypoxic response and epigenetic processes. Moreover, SDHx mutations induce cell metabolic reprogramming and redox imbalance. Major discoveries in PPGL pathophysiology have been made since the initial discovery of SDHD gene mutations in 2000, improving the understanding of their biology and patient management. It indeed provides new opportunities for diagnostic tools and innovative therapeutic targets in order to improve the prognosis of patients affected by these rare tumors, in particular in the context of metastatic diseases associated with SDHB mutations. This review first describes an overview of the pathophysiology and then focuses on clinical implications of the epigenetic and metabolic reprogramming of SDH-deficient PPGL.

Purpose: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy ( 1 H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of 1 H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients., Methods: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for 1 H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor., Results: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1 H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%., Conclusions: Detection of succinate using 1 H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs.

Context: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors explained by germline or somatic mutations in about 70% of cases. Patients with SDHB mutations are at high risk of developing metastatic disease, yet no reliable tumor biomarkers are available to predict tumor aggressiveness., Objective: We aimed at identifying long noncoding RNAs (lncRNAs) specific for PPGL molecular groups and metastatic progression., Design and Methods: To analyze the expression of lncRNAs, we used a mining approach of transcriptome data from a well-characterized series of 187 tumor tissues. Clustering consensus analysis was performed to determine a lncRNA-based classification, and informative transcripts were validated in an independent series of 51 PPGLs. The expression of metastasis-related lncRNAs was confirmed by RT-qPCR. Receiver operating characteristic (ROC) curve analysis was used to estimate the predictive accuracy of potential markers., Main Outcome Measure: Univariate/multivariate and metastasis-free survival (MFS) analyses were carried out for the assessment of risk factors and clinical outcomes., Results: Four lncRNA-based subtypes strongly correlated with mRNA expression clusters (chi-square P-values from 1.38 × 10-32 to 1.07 × 10-67). We identified one putative lncRNA (GenBank: BC063866) that accurately discriminates metastatic from benign tumors in patients with SDHx mutations (area under the curve 0.95; P = 4.59 × 10-05). Moreover, this transcript appeared as an independent risk factor associated with poor clinical outcome of SDHx carriers (log-rank test P = 2.29 × 10-05)., Conclusion: Our findings extend the spectrum of transcriptional dysregulations in PPGL to lncRNAs and provide a novel biomarker that could be useful to identify potentially metastatic tumors in patients carrying SDHx mutations., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale : Deregulation of metabolism and induction of vascularization are major hallmarks of cancer. Using a new multimodal preclinical imaging instrument, we explored a sequence of events leading to sunitinib-induced resistance in a murine model of paraganglioma (PGL) invalidated for the expression of succinate dehydrogenase subunit B ( Sdhb -/- ). Methods : Two groups of Sdhb -/- tumors bearing mice were treated with sunitinib (6 weeks) or vehicle (3 weeks). Concurrent Positron Emission Tomography (PET) with 2' -deoxy-2'-[ 18 F]fluoro-D-glucose (FDG), Computed Tomography (CT) and Ultrafast Ultrasound Imaging (UUI) imaging sessions were performed once a week and ex vivo samples were analyzed by western blots and histology. Results : PET-CT-UUI enabled to detect a rapid growth of Sdhb -/- tumors with increased glycolysis and vascular development. Sunitinib treatment prevented tumor growth, vessel development and reduced FDG uptake at week 1 and 2 (W1-2). Thereafter, imaging revealed tumor escape from sunitinib treatment: FDG uptake in tumors increased at W3, followed by tumor growth and vessel development at W4-5. Perfused vessels were preferentially distributed in the hypermetabolic regions of the tumors and the perfused volume increased during escape from sunitinib treatment. Finally, initial changes in total lesion glycolysis and maximum vessel length at W1 were predictive of resistance to sunitinib. Conclusion : These results demonstrate an adaptive resistance of Sdhb -/- tumors to six weeks of sunitinib treatment. Early metabolic changes and delayed vessel architecture changes were detectable and predictable in vivo early during anti-angiogenic treatment. Simultaneous metabolic, anatomical and functional imaging can monitor precisely the effects of anti-angiogenic treatment of tumors., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS)., Methods: We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours., Results: In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available., Conclusion: The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale : Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that present variable outcomes. To date, no effective therapies or reliable prognostic markers are available for patients who develop metastatic PPGL (mPPGL). Our aim was to discover robust prognostic markers validated through in vitro models, and define specific therapeutic options according to tumor genomic features. Methods : We analyzed three PPGL miRNome datasets (n=443), validated candidate markers and assessed them in serum samples (n=36) to find a metastatic miRNA signature. An integrative study of miRNome, transcriptome and proteome was performed to find miRNA targets, which were further characterized in vitro . Results : A signature of six miRNAs (miR-21-3p, miR-183-5p, miR-182-5p, miR-96-5p, miR-551b-3p, and miR-202-5p) was associated with metastatic risk and time to progression. A higher expression of five of these miRNAs was also detected in PPGL patients' liquid biopsies compared with controls. The combined expression of miR-21-3p/miR-183-5p showed the best power to predict metastasis (AUC=0.804, P =4.67·10 -18 ), and was found associated in vitro with pro-metastatic features, such as neuroendocrine-mesenchymal transition phenotype, and increased cell migration rate. A pan-cancer multi-omic integrative study correlated miR-21-3p levels with TSC2 expression, mTOR pathway activation, and a predictive signature for mTOR inhibitor-sensitivity in PPGLs and other cancers. Likewise, we demonstrated in vitro a TSC2 repression and an enhanced rapamycin sensitivity upon miR-21-3p expression. Conclusions : Our findings support the assessment of miR-21-3p/miR-183-5p, in tumors and liquid biopsies, as biomarkers for risk stratification to improve the PPGL patients' management. We propose miR-21-3p to select mPPGL patients who may benefit from mTOR inhibitors., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Metastatic pheochromocytoma/paraganglioma (PPGL) represents a major clinical challenge due to limitations in accurate diagnostic tools and effective treatments. Currently, patients classified at high-risk by means of clinical, biochemical and genetic criteria, require a lifelong monitoring, while it remains difficult to determine the metastatic potential of PPGL only on the basis of histopathological features. Thus, tumor molecular markers that improve the risk stratification of these patients are needed. In the past few years, we have witnessed an unprecedented molecular characterization of PPGL, which led to the emergence of promising candidate biomarkers predictive of metastatic behavior. Here, we briefly discuss these breakthroughs and provide some insights for the prospective implementation of molecular markers of metastatic PPGL in the clinical setting in years to come., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Comprehensive genetic analyses have identified germline SDHB and FH gene mutations as predominant causes of metastatic paraganglioma and pheochromocytoma. However, some suspicious cases remain unexplained. In this study, we performed whole-exome sequencing of a paraganglioma exhibiting an SDHx -like molecular profile in the absence of SDHx or FH mutations and identified a germline mutation in the SLC25A11 gene, which encodes the mitochondrial 2-oxoglutarate/malate carrier. Germline SLC25A11 mutations were identified in six other patients, five of whom had metastatic disease. These mutations were associated with loss of heterozygosity, suggesting that SLC25A11 acts as a tumor-suppressor gene. Pseudohypoxic and hypermethylator phenotypes comparable with those described in SDHx - and FH -related tumors were observed both in tumors with mutated SLC25A11 and in Slc25a11 Δ/Δ immortalized mouse chromaffin knockout cells generated by CRISPR-Cas9 technology. These data show that SLC25A11 is a novel paraganglioma susceptibility gene for which loss of function correlates with metastatic presentation. Significance: A gene encoding a mitochondrial carrier is implicated in a hereditary cancer predisposition syndrome, expanding the role of mitochondrial dysfunction in paraganglioma. Cancer Res; 78(8); 1914-22. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objectives: To systematically review the incidence and factors associated with recurrences or new tumors after apparent complete resection of pheochromocytoma or thoraco-abdomino-pelvic paraganglioma., Design: A systematic review and meta-analysis of published literature was performed., Methods: Pubmed and Embase from 1980 to 2012 were searched for studies published in English on patients with non-metastatic pheochromocytoma or thoraco-abdomino-pelvic paraganglioma, complete tumor resection, postoperative follow-up exceeding 1 month, and recurrence or new tumor documented by pathology, hormonal dosages, or imaging tests. Incidence rates of new events after curative surgery were calculated for each study that had sufficient information and pooled using random-effect meta-analysis., Results: In total, 38 studies were selected from 3518 references, of which 36 reported retrospective cohorts from the USA, Europe, and Asia. Patient follow-up was neither standardized nor exhaustive in the included studies. A clear description of patient retrieval methods was available for nine studies and the follow-up protocol and patient flow for four studies. Only two studies used multivariable methods to assess potential predictors of postoperative events.The overall rate of recurrent disease from 34 studies was 0.98 events/100 person-years (95% confidence interval 0.71, 1.25). Syndromic diseases and paragangliomas were consistently associated with a higher risk of a new event in individual studies and in meta-regression analysis., Conclusions: The risk of recurrent disease after complete resection of pheochromocytoma may be lower than that previously estimated, corresponding to five events for 100 patients followed up for 5 years after complete resection. Risk stratification is required to tailor the follow-up protocol after complete resection of a pheochromocytoma or paraganglioma. Large multicenter studies are needed to this end., (© 2016 European Society of Endocrinology.)

Purpose: Germline mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are found in patients with paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cancers. SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite and which levels, assessed on surgically resected tissue are a highly specific biomarker of SDHx-mutated tumors. The aim of this study was to address the feasibility of detecting succinate in vivo by magnetic resonance spectroscopy., Experimental Design: A pulsed proton magnetic resonance spectroscopy ((1)H-MRS) sequence was developed, optimized, and applied to image nude mice grafted with Sdhb(-/-) or wild-type chromaffin cells. The method was then applied to patients with paraganglioma carrying (n = 5) or not (n = 4) an SDHx gene mutation. Following surgery, succinate was measured using gas chromatography/mass spectrometry, and SDH protein expression was assessed by immunohistochemistry in resected tumors., Results: A succinate peak was observed at 2.44 ppm by (1)H-MRS in all Sdhb(-/-)-derived tumors in mice and in all paragangliomas of patients carrying an SDHx gene mutation, but neither in wild-type mouse tumors nor in patients exempt of SDHx mutation. In one patient, (1)H-MRS results led to the identification of an unsuspected SDHA gene mutation. In another case, it helped define the pathogenicity of a variant of unknown significance in the SDHB gene., Conclusions: Detection of succinate by (1)H-MRS is a highly specific and sensitive hallmark of SDHx mutations. This noninvasive approach is a simple and robust method allowing in vivo detection of the major biomarker of SDHx-mutated tumors., (©2015 American Association for Cancer Research.)

The tricarboxylic acid (TCA) cycle is a central metabolic pathway responsible for supplying reducing potential for oxidative phosphorylation and anabolic substrates for cell growth, repair and proliferation. As such it thought to be essential for cell proliferation and tissue homeostasis. However, since the initial report of an inactivating mutation in the TCA cycle enzyme complex, succinate dehydrogenase (SDH) in paraganglioma (PGL), it has become clear that some cells and tissues are not only able to survive with a truncated TCA cycle, but that they are also able of supporting proliferative phenotype observed in tumours. Here, we show that loss of SDH activity leads to changes in the metabolism of non-essential amino acids. In particular, we demonstrate that pyruvate carboxylase is essential to re-supply the depleted pool of aspartate in SDH-deficient cells. Our results demonstrate that the loss of SDH reduces the metabolic plasticity of cells, suggesting vulnerabilities that can be targeted therapeutically.

Purpose: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (1H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of 1H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients. Methods: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for 1H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor. Results: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%. Conclusions: Detection of succinate using 1H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs. [ABSTRACT FROM AUTHOR]

Paragangliomas and pheochromocytomas are rare neuroendocrine tumours with a very strong genetic component. It is estimated that around 40% of all cases are caused by a germline mutation in one of the 13 predisposing genes identified so far. Half of these inherited cases are intriguingly caused by mutations in genes encoding tricarboxylic acid enzymes, namely SDHA, SDHB, SDHC, SDHD, and SDHAF2 genes, encoding succinate dehydrogenase and its assembly protein, FH encoding fumarate hydratase, and MDH2 encoding malate dehydrogenase. These mutations may also predispose to other type of cancers, such as renal cancer, leiomyomas, or gastro-intestinal stromal tumours. SDH, which is also the complex II of the oxidative respiratory chain, was the first mitochondrial enzyme to be identified having tumour suppressor functions, demonstrating that 80 years after his initial proposal, Otto Warburg may have actually been right when he hypothesized that low mitochondrial respiration was the origin of cancer. This review reports the current view on how such metabolic deficiencies may lead to cancer predisposition and shows that the recent data may lead to the development of innovative therapeutic strategies and establish precision medicine approaches for the management of patients affected by these rare diseases. [ABSTRACT FROM AUTHOR]

Objectives: To systematically review the incidence and factors associated with recurrences or new tumors after apparent complete resection of pheochromocytoma or thoraco-abdomino-pelvic paraganglioma. Design: A systematic review and meta-analysis of published literature was performed. Methods: Pubmed and Embase from 1980 to 2012 were searched for studies published in English on patients with non-metastatic pheochromocytoma or thoraco-abdomino-pelvic paraganglioma, complete tumor resection, postoperative follow-up exceeding 1 month, and recurrence or new tumor documented by pathology, hormonal dosages, or imaging tests. Incidence rates of new events after curative surgery were calculated for each study that had sufficient information and pooled using random-effect meta-analysis. Results: In total, 38 studies were selected from 3518 references, of which 36 reported retrospective cohorts from the USA, Europe, and Asia. Patient follow-up was neither standardized nor exhaustive in the included studies. A clear description of patient retrieval methods was available for nine studies and the follow-up protocol and patient flow for four studies. Only two studies used multivariable methods to assess potential predictors of postoperative events. The overall rate of recurrent disease from 34 studies was 0.98 events/100 person-years (95% confidence interval 0.71, 1.25). Syndromic diseases and paragangliomas were consistently associated with a higher risk of a new event in individual studies and in meta-regression analysis. Conclusions: The risk of recurrent disease after complete resection of pheochromocytoma may be lower than that previously estimated, corresponding to five events for 100 patients followed up for 5 years after complete resection. Risk stratification is required to tailor the follow-up protocol after complete resection of a pheochromocytoma or paraganglioma. Large multicenter studies are needed to this end. [ABSTRACT FROM AUTHOR]