Sympathetic Tissue Research Articles

Preoperative Epidural Infusion for Blood Pressure Control in Phaeochromocytoma

The 2004 World Health Organization (WHO) classification of endocrine tumours defines phaeochromocytoma as a catecholamine-producing intra-adrenal tumour arising from the chromaffin cells. The most important functional characteristics of the adrenal and extra-adrenal sympathetic tissue derived tumours is the production of various types of catecholamines and the related clinical attributes [1]. Preoperative blood pressure control in phaeochromocytoma is an uphill task using multiple medications leading to post operative hypotension. It is well known that complete prevention of perioperative hypertension and tachycardia cannot be achieved by any dose or combination of drugs. Epidural anesthesia is often used for pain control in open resection of these tumours; one of its side effects is hypotension [2]. We describe here a case of phaeochromocytoma in whom perioperative blood pressure control was achieved with the help of epidural drugs instead of systemic antihypertensive medications.

Student Competition (Knowledge Generation) ID 1985154

Background Exercising after spinal cord injury (SCI) is necessary to prevent or reduce secondary complications such as obesity, cardiovascular disease, or type II diabetes. The effects of SCI on muscle and autonomic functions determine type, duration, and intensity of exercise capacity. Although SCI exercise guidelines exist, achieving these recommendations requires a comprehensive understanding of how muscle and autonomic function affect a person’s exercise capability. Therefore, we reviewed the effect of SCI level on muscle and sympathetic function during exercise for those living with SCI to better develop strategies to achieve these guidelines. Methods A literature review of exercise, muscle control and SCI was performed to identify muscles innervated by each level and how key sympathetic tissues and organs required for exercise are affected by SCI. We identified spinal levels responsible for increasing heart rate, cardiovascular smooth muscle contraction, inducing sweat and activating adrenal glands since these are essential in maintaining high intensity and long duration exercise. We translated the information into a comprehensive user-friendly poster. Results A comprehensive graphical poster was developed for those living with SCI to understand and identify how their level of SCI affects their muscle and sympathetic function needed for optimal exercise and to meet exercise guidelines. Conclusions This infographic fills a void since this type of ‘person-centred’ information is lacking in the SCI and exercise field. The knowledge acquired through this infographic could further guide training practices and exercise modifications to increase exercise capacity and quality of life for those living with SCI.

THE GREAT PRETENDER: COULD A PHEOCHROMOCYTOMA MANIFEST ITSELF AS A SEIZURE?

Objective: Seizures are defined as transient occurrence of signs or symptoms due to the abnormally excessive or synchronous neuronal activity in the cerebral cortex. Pheochromocytomas and paragangliomas (PPGL) are chromaffin cell tumors arising from the adrenal medulla in 80–85% of patients and from extra-adrenal sympathetic tissue in 10–20% of patients. PPGL has been referred to as ‘‘the great mimic’’ disease. We present a patient with pheochromocytoma possibly disguised as seizures. Design and method: A 44 years old woman was referred to University Clinic of Endocrinology by radiologist. Two years earlier she had syncopal crises . She complained of headache, heart palpitation and malaise, heart palpitations and fatigue during exertion and sense of panic. The maximal self-measured blood pressure was 160/100 mmHg, the pulse is 90-100 beats per min. Abdominal US: a hyperechoic change, 76x65mm was seen, then described in the right lobe of the liver. The following year she had two commotional crises of consciousness and spasms of the extremities . She had a non-specific slowing of FC on EEG on the right for 1-2 seconds. MSCT abdomenal : in the right adrenal gland, a mass 144 x 90mm, with clear borders, pressing into the liver and pushing the right kidney,. The 24h urine was collected, which confirmed a norepinephrine secreting pheochromocytoma. We administered long acting alpha blocking agent preoperatively. The complete surgical excision of the right adrenal mass was done, pathohistological diagnosis: Pheochromocytoma. The last EEG after sleep deprivation performed 2 months postoperatively was described as normal. The patient had no headache or seizure. Results: PPGLs have a notable ability of boosting NE levels systemically and hypertension, the most common sign of PPGL could facilitate the permeability of blood brain barrier to NE. Studies showed NE could play its anticonvulsant property at an appropriate concentration but has a proconvulsant effect in either too high or too low concentrations . Conclusions: The definite pathogenetic mechanisms explaining how PPGL can cause seizures are far from being clearly understood, though “the great pretender” should be considered as a possible etiological factor of seizures.

Feohromocitom kao potencijalni uzrok napada epilepsije

Epileptic seizures are defined as the transient appearance of signs or symptoms due to excessive or synchronous neuronal activity in the cerebral cortex. Pheochromocytomas and paragangliomas (PPGL) are tumors of chromaffin cells that arise from the medulla of the adrenal gland in 80-85% of patients and from the extra-adrenal sympathetic tissue of the abdomen, pelvis and chest in 10-20% of patients. The clinical picture of PPGL is variable and ranges from the absence of symptoms to severe clinical picture, depending on the biochemical profile. They are most often manifested by paroxysmal hypertension, followed by episodes of severe headache or diaphoresis, while epileptic attacks are rare. Neurological symptoms are present in many patients with PPGL. Also, paroxysmal neurological conditions such as vasodilating headache, intracranial tumors, diencephalic-autonomic epilepsy, hypertensive encephalopathy, focal arterial disease of the brain and anxiety state have been described, which may have similar clinical manifestations with pheochromocytomas. We present a 44-year-old woman, who has been diagnosed with pheochromocytoma as possible etiological basis of epileptic seizures. Pheochromocytoma, with its low incidence and "chameleon" clinical spectrum, should be considered as a potential etiological factor of convulsions.

ODP041 Hearing Loss Reveals Dopamine-secreting Metastatic Paraganglioma

Abstract Background Paragangliomas are neuroendocrine tumors arising from chromaffin cells in extra-adrenal parasympathetic or sympathetic tissues. Frequently they produce catecholamines such as epinephrine and norepinephrine which cause adrenergic symptoms. Rarely, paragangliomas produce only dopamine. These tumors carry a worse prognosis than other types of paragangliomas, especially when associated with loss of SDH-B. Case A 41 year old African American female with developmental delay, allergic rhinitis, OSA, and obesity presented to a primary care clinic for evaluation of hearing loss and left ear pain. Patient was treated for acute otitis media but symptoms failed to resolve. She was referred to audiology where she was found to have a mixed conductive and sensorineural hearing loss on the left. Despite using hearing aids, a year later the patient presented to an ENT clinic with several weeks of worsening left aural fullness and decreased hearing. On otoscopy, a mass was visualized in the middle ear. CT scan identified a lytic lesion at the jugular foramen extending into the middle ear; MR of the inner auditory canal was concerning for a paraganglioma. PET CT revealed widely metastatic disease including FDG avid cervical and supraclavicular lymph nodes, pulmonary nodules, hepatic lesions, and sclerotic lesions in the vertebral column and right humerus. Biopsy of an hepatic lesion confirmed metastatic paraganglioma with loss of SDH-B. Labs were consistent with dopamine excess. A 24 hour urine dopamine was 1020 mcg/24 hour (normal 65-400) with plasma dopamine elevated at 191 pg/mL (normal <30). A 24 hour urine norepinephrine level was mildly elevated at 85 mcg/24 hours (normal 15-80) but plasma norepinephrine and epinephrine were both normal. The patient denied any history of palpitations, flushing, headaches, or chest pain. She was briefly started on doxazosin but this was later discontinued as metanephrines and normetanephrines were not significantly elevated. The tumor was not amenable for surgery. Ultimately after discussion with oncology, the patient opted to proceed with temozolomide and capecitabine chemotherapy. Discussion It is important to recognize differences in treating dopamine secreting paragangliomas compared with other catecholamine producing tumors. Preoperative alpha blockade is not routinely recommended as it may cause hypotension and postoperative cardiovascular collapse. While chemotherapy with Cyclophosphamide–dacarbazine–vincristine has historically been used for metastatic paragangliomas, temozolomide is now showing benefit in cases with SDH-B mutation. Sources cited: Foo, S. H., et al. "Dopamine-secreting phaeochromocytomas and paragangliomas: clinical features and management." Singapore Med J 51.5 (2010): e89-e93. Hadoux, J., Favier, J., Scoazec, J. -Y., et al (2014),SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int. J. Cancer, 135: 2711-2720. https://doi.org/10.1002/ijc.28913. Presentation: No date and time listed

Chronic Diarrhea and Weight Loss in an 18-month-old Boy.

Chronic Diarrhea and Weight Loss in an 18-month-old Boy.

Laparoscopic removal of a large pheochromocytoma-paraganglioma of the Zuckerkandl organ

Paragangliomas represent 15 to 20% of all chromaffin tissue tumors. Most often, paragangliomas are located in the abdominal cavity along the large vessels — in the para-aortic region from the diaphragm to the aortic bifurcation. One of the most common extra-adrenal pheochromocytomas is the Zuckerkandl tumor, originating from the para-aortic accumulation of sympathetic tissue located in the area of the inferior mesenteric artery’s origine or in the zone of the aortic bifurcation itself. Due to the technical difficulty in performing laparoscopic removal of paragangliomas, conversion to laparotomy is frequent and reaches 80%. The article describes a clinical case of a patient suffering from this type of neoplasm, with diagnosis details and treatment by a successful radical laparoscopic intervention with a large chromaffinnoma located in a difficult anatomical zone removal.

ADDED VALUE OF CATECHOLAMINE PHENOTYPING AND GENETIC SCREENING FOR THE CHARACTERIZATION OF PHEOCHROMOCYTOMA: A BELGIAN MULTICENTRE COHORT

Abstract Objective: Pheochromocytomas/paragangliomas (PPGL) are rare neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or from neural-crest derived sympathetic tissue. They secrete catecholamines in varying amounts, which accounts for their symptomatology. Hypertension is the most common sign, found in approximately 95% of patients. Nowadays, biochemical testing remains the simplest and most widely available method to assess PPGL in first intention. Identification of mutations in known susceptibility genes may help further refining tumor characterization and prognosis assessment. The objective of this study was to analyze clinical characteristics of PPGL from Belgium according to their secretory and genetic profiles. Design and method: We retrospectively analyzed a cohort of 120 cases of non-syndromic PPGL diagnosed in 19 Belgian centres. Clinical characteristics were correlated with three catecholamine phenotypes based on urinary metanephrines (noradrenergic, adrenergic and silent) and with the results of genetic screening. Results: Our cohort included a majority of women (59%). The mean age at diagnosis was 47 ± 7 years. We documented the prevalence of pediatric (7.5%), extra-adrenal (13.3%), bilateral (2.9%), multifocal (5.1%), recurrent (8.5%), metastatic (7.6%) and familial (5.9%) cases. While the yield of positive genetic screening was low (15%), the presence of at least one of these criteria was associated with a 4-fold increased prevalence of mutation (30.3 vs 8.5%; p = 0.03). In the subset in whom metanephrines values were available (n = 62), the prevalence of adrenergic, noradrenergic and silent phenotypes was 58%, 34% and 8% respectively. Patients belonging to these three subsets differed by age at diagnosis (51 ± 14; 38 ± 17; 42 ± 13 years; p = 0.009), the proportion of extra-adrenal tumors (2.8%; 9.5%; 40%; p = 0.016), pediatric (2.8%; 19%; 0%; p = 0.074) and familial (0%; 18.8%; 0%; p = 0.041) cases. Finally, an excess of dopamine secretion was associated with a higher prevalence of metastatic disease (25% vs 1.9%; p = 0.005). Conclusions: Secretory phenotypes and genetic profiles deserve to be integrated in the preoperative characterization of PPGL and may help orienting management and follow-up. Simple clinical features are associated with an increased probability of inherited tumor. Identification of an increased dopamine secretion should raise the suspicion of metastatic PPGL.

Robotic Adrenalectomy for Pheochromocytoma in a Patient with Fontan Physiology

PHEOCHROMOCYTOMAS ARE rare neuroendocrine tumors that arise from both chromaffin cells in the adrenal medulla and sympathetic ganglion, or nonchromaffin cells in the parasympathetic ganglion. 1 Zhao B Zhou Y Zhao Y et al. Co-occurrence of pheochromocytoma-paraganglioma and cyanotic congenital heart disease: A case report and literature review. Front Endocrinol (Lausanne). 2018; 9: 165 Crossref PubMed Scopus (6) Google Scholar Pheochromocytomas arising from sympathetic tissue more commonly secrete catecholamines than those arising outside sympathetic tissue. 2 Lenders JW Eisenhofer G Mannelli M et al. Phaeochromocytoma. Lancet. 2005; 366: 665-675 Abstract Full Text Full Text PDF PubMed Scopus (1195) Google Scholar A strong association exists between cyanotic congenital heart disease and pheochromocytomas, with a higher- than- normal incidence seen in patients with cyanotic congenital heart disease (incidence reported as high as 2.5%) versus the normal hypertensive population prevalence of 0.2% to 0.6%. 1 Zhao B Zhou Y Zhao Y et al. Co-occurrence of pheochromocytoma-paraganglioma and cyanotic congenital heart disease: A case report and literature review. Front Endocrinol (Lausanne). 2018; 9: 165 Crossref PubMed Scopus (6) Google Scholar ,3 Lenders JW Duh QY Eisenhofer G et al. Pheochromocytoma and paraganglioma: An endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014; 99: 1915-1942 Crossref PubMed Scopus (1195) Google Scholar Chronic hypoxia has been speculated as a likely pathogenic mechanism related to abnormal activation of the hypoxic pathways located within the chromaffin cells. 4 Opotowsky AR Moko LE Ginns J et al. Pheochromocytoma and paraganglioma in cyanotic congenital heart disease. J Clin Endocrinol Metab. 2015; 100: 1325-1334 Crossref PubMed Scopus (43) Google Scholar , 5 Jochmanova I Yang C Zhuang Z et al. Hypoxia-inducible factor signaling in pheochromocytoma: Turning the rudder in the right direction. J Natl Cancer Inst. 2013; 105: 1270-1283 Crossref PubMed Scopus (111) Google Scholar , 6 Favier J. Pheochromocytomas: The (pseudo)-hypoxia hypothesis. Best Practice Res Clin Endocrinol Metab. 2010; 24: 957-968 Crossref PubMed Scopus (76) Google Scholar Although Fontan is intended to mitigate cyanosis, patients may be exposed to cyanosis before Fontan repair, and patients with failing Fontan physiology may become cyanotic due to fenestration, baffle leaks, and veno-venous collateral circulation. 7 Eagle SS Daves SM. The adult with Fontan physiology: Systematic approach to perioperative management for noncardiac surgery. J Cardiothorac Vasc Anesth. 2011; 25: 320-334 Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Further, excess catecholamines secreted by the pheochromocytoma can mimic and induce heart failure and arrhythmias in all patients, particularly those with Fontan physiology.

Glucagon-Like Peptide-1 Receptor Controls Exocytosis in Chromaffin Cells by Increasing Full Fusion Events

Glucagon-like peptide-1 receptor (GLP-1R) agonists’ ability to increase insulin secretion and promote satiety have led to their development for the treatment of type 2 diabetes and obesity; while these beneficial effects have been attributed to receptors in the pancreas and hypothalamus, the function and importance of extra-pancreatic GLP-1Rs in other organ systems is not well understood despite the possibilities for targeting these receptors for other indications. We have analysed the contribution of GLP-1R to the secretory responses of adrenal medulla, a key player in stress responses. Exendin-4 (Ex-4), a synthetic analogue of GLP-1, increased the synthesis and the release of catecholamines (CA) by increasing cAMP production, without the participation of EPAC (Exchange Proteins Activated by cAMP). Ex-4 increased CA synthesis by promoting the activation of tyrosine hydroxylase (TH), and moreover increased the quantum size of exocytotic events by switching exocytosis from partial to full fusion. Our results give a strong support to the role of GLP-1 in the fine control of glycaemia and blood pressure by sympathetic tissues.

1196Transvascular pace-capture of aorticorenal ganglia provides a testable procedural endpoint for transcatheter renal artery denervation and identifies a novel therapeutic ablation target for denervation

Abstract Background Transcatheter renal denervation procedures often produces incomplete renal denervation and inconsistent antihypertensive effect. The lack of an intraprocedural method for renal sympathetic nerve function assessment has precluded a rational and physiologically based approach to ensure adequate denervation has been achieved at the time of the procedure. Purpose To demonstrate that it is possible to localise aorticorenal ganglia via transvascular pacing to provide: 1) a testable procedural endpoint for transcatheter renal denervation and, 2) a novel ablation target for renal denervation. Methods High frequency pacing in the inferior vena cava and aorta, invasive blood pressure measurements and renal angiography was performed in sheep (N=19) to identify ARG pace-capture sites by concurrent hypertensive and renal vasoconstrictive responses. Group A (N=5) underwent ink injection labelling at the ARG pace-capture site for histological verification; Group B (N=6) received unilateral irrigated radiofrequency ablation of ARG pace-capture sites and assessment of renal innervation at 1week post-procedure; and Group C (N=8) had ARG pacing performed prior to and 2–3 weeks after unilateral transcatheter microwave renal denervation. Results ARG pace-capture responses were observed at paired discrete sites in the posterior IVC and anterolateral aorta approximately 40mm above the ipsilateral renal artery. Pacing elicited a mean arterial blood pressure change of 22.2 [IQR 15.5–34.3] mmHg, p<0.001, together with ipsilateral renal vasoconstriction with main renal artery calibre change of −0.42mm [IQR −0.64mm to −0.24mm] measured with quantitative coronary analysis (QCA), p<0.0001, and branch renal artery median pixel density index change −10.4% [IQR −22.7% to −3.0%], p=0.003. Contralateral renal arterial vasoconstriction was not observed consistently at either the main or branch renal artery level. Sympathetic ganglionic tissue was observed at ARG pace-capture sites, and ganglion ablation caused significant ipsilateral renal denervation with a median hilar functional sympathetic nerve area reduction of 51% [IQR 24%–52%], p=0.043, and renal cortical norepinephrine reduction of 54% [IQR 36%–59%], p=0.043. Circumferential renal denervation resulted in immediate and sustained abolition of ARP pacing induced renal vasoconstriction and significant ipsilateral renal denervation. Conclusion Localisation of ARG using transvascular pacing is feasible with pace-capture demonstrated by concurrent hypertensive and ipsilateral renal arterial vasoconstrictive responses. Abolition of ARG pacing induced renal arterial vasoconstriction may indicate successful renal sympathetic denervation, providing a physiological procedural endpoint to guide transcatheter renal denervation. Additionally, ablation of ARG could provide an alternative or adjunctive method for renal denervation. Acknowledgement/Funding University of Sydney; Western Sydney Local health District; National Health and Medical Research Council of Australia; National Heart Foundation (Au)

Superior Cervical Ganglion: Axonal Passage and Inputs

Axons of the rostral middle (MCG) and inferior (ICG) cervical ganglion were reported to bypass the superior cervical ganglion (SCG). However, the distribution of these neurons has not been determined. Meanwhile, it has been inconsistent with the distribution of the preganglionic neurons of the SCG. To examine the above issues, we recently injected wheat germ agglutinin- horseradish peroxidase (WGA-HRP) into the entire or partial (rostral or caudal) SCG of the rat (Anatomical Record, 301:1906-1916, 2018). By preparing complete whole-mounts of the sympathetic tissues and sections of the brainstem and spinal cord, we labeled neurons that are distributed evenly in the MCG (left: 258 ＞ right: 121) ICG (left: 848, right: 681) and CST (up to 770). It is found specifically a novel cervical ganglion and termed it as the ＂pre-middle cervical ganglion＂ (pMCG) that is located rostral to the MSG and sends axons (left: 120 ＞ right: 82) to bypass the SCG. In addition to the preganglionic neurons in the cervical (C1-C4) and thoracic (T1-T4) segments, we also labeled neurons (233) that extend dendrites into the vestibular nuclear complex and locate in the intermediate reticular nuclei (96%) and perifacial zone (4%) of the brainstem ranging from Bregma -10.0 to -11.0 mm, mainly in -10.80 mm. With tracer injection into the rostral or caudal SCG, we labeled neurons correspondingly in the brainstem, C1-C2 or T1-T2. These data indicated that many neurons in pMCG, MCG and ICG run rostrally within the CST to project to their peripheral targets rather than segmentally via the closest rami. For their close anatomical location, neurons in pMCG and MCG may have similar or complementary function. Numerous neurons in the CST and caudal cervical ganglia provide bypass axons via SCG may imply special function that is useful for electroceuticals. The newly identified preganglionic neurons located in the rostral brainstem may be involved in the vestibulo-autonomic interaction for their extending dendrites into the vestibular nuclear complex that has been known to form an interaction pathway with the vagal complex.

(401) Visualising and Treating Pain in Children

Background: Pain is one of the most under diagnosed, under treated medical problems, particularly in children.1,2 Ten percent of hospitalized children show features of chronic pain.2 Chronic pain conservative estimates 20% to 35% of children and adolescents affected worldwide.2 Pain costs has been extrapolated to $19.5 billion USA annually.2, 3 Problem: Current diagnostic methods rely on self-reports and caregivers perception. Young children can be challenging if they are non-verbal or have developmental disabilities and depends on his or her intellectual and social development.4 Emergency primary care physicians report a need for pain assessment procedures in children and youth. 5 Results: The law of pain; the origin of all pain is inflammation and the inflammatory response.6 Using four FDA approved devices combined can augment clinical palpation. Data comparisons are made between a painful and non-painful point, a display shows differential amounts: Pain Pressure Thresholds Tolerances “PPT's”, Temperature, Sympathetic Skin Response and Tissue Sounds.7 When inflammation is gone, treatment outcomes software shows no more difference between comparison points. Gamification will enhance patient engagement improving outcomes.8 Sensors can be worn, air cells apply intermittent pneumatic compression massage therapy, squeezes edema to regions with normal lymphatic drainage.9 Disease detection once relied on physician's palpation skills to evaluate the soft tissues for signs of inflammation heat (calor), pain (dolor), redness (rubor), and swelling (tumor), fluor (secretion). Biosensors could supplement palpation for musculoskeletal pain, the most common single type of chronic pain; chronic low back pain is the most prevalent. 10 Conclusion: If pain were assessed with the same zeal as other vital signs are, it would have a much better chance of being treated properly. We need to train doctors and nurses to treat pain as a vital sign. 11 JCAHO regulations regard pain as “the fifth vital sign”, this approach provides Based Medicine/Practices (EBM/EBP).

Reabilitação intra-hospitalar após transplante cardíaco

A insuficiência cardíaca (IC) é uma síndrome complexa caracterizada por alterações neuro-humorais, dispneia, miopatia periférica e redução da expectativa de vida. O transplante cardíaco (TxC) é a última terapia para pacientes com IC. Entretanto, após o TxC as alterações periféricas contribuem para a intolerância ao exercício. A reabilitação cardíaca (RC) é uma intervenção complexa e promove a melhora da capacidade ao exercício, possibilitando retorno mais rápido às atividades diárias. Também promove a melhora da função endotelial, da hemodinâmica, da atividade nervosa simpática, do consumo de oxigênio e da perfusão tecidual, promovendo a redução da mortalidade e da necessidade de hospitalização. A RC intra-hospitalar deve ser iniciada precocemente para evitar os efeitos deletérios do repouso, bem como promover a independência funcional nas atividades diárias. A prescrição do exercício deve levar em conta o fato de que no coração denervado a resposta ao esforço é diferente e deve ser baseada na escala de Borg. Independente do método de prescrição de atividade física pós-transplante, esta pode diminuir e até mesmo reverter as alterações fisiológicas em pacientes após TxC.

Abstract B46: MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma

Abstract Neuroblastoma is the most common extra-cranial solid tumor in children and arises from neural crest cells involved in the development of sympathetic nervous tissue. This childhood tumor is characterized by heterogeneity and amplification of the MYCN oncogene is highly associated with aggressive tumors and poor outcome. The aim of this study was to investigate the role of the MYCN-driven miR-17-92 cluster in neuroblastoma pathogenesis. In order to identify putative targets of miR-17-92 we performed in silico prediction analysis and found that miR-17-92 target sites are significantly enriched in the nuclear hormone receptor (NHR) super family, indicating a role for hormonal regulation in neuroblastoma tumorigenesis. Importantly, high expression of several of the NHRs correlated with increased event-free survival of neuroblastoma patients. By using non-MYCN amplified neuroblastoma cells with a tet-regulatable miR-17~92 we could verify a differentially expressed NHR profile in induced compared to uninduced cells. Interestingly, one of the most significantly dowregulated NHRs was the glucocorticoid receptor (GR). Moreover, luciferase reporter assays containing the wildtype or mutated 3'UTR from the gene encoding GR demonstrate that it is a direct target of miR-17~92. Importantly, both MYCN and miR17~92 are able to downregulate GR. We further show that activation of GR signaling by dexamethasone induces differentiation markers and contributes to neural differentiation. Inhibition of MYCN activity and activation of GR signaling induced a significant reduction in tumor growth in a xenograft model of neuroblastoma. Taken together, our findings indicate an important role for miR-17-92 cluster in regulation of NHRs in neuroblastoma biology, with important implications for future therapeutic approaches in patients with MYCN-amplification. Citation Format: Diogo Ribeiro, Ulrica Westermark, Marcus Klarqvist, Jakob Lovén, Marie Arsenian Henriksson. MYCN regulates nuclear hormone receptors and impairs differentiation and survival in neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr B46.

Editorial: Targeting MYCN in Pediatric Cancers.

MYCN is the product of a gene frequently deregulated in childhood tumors that belongs to a small but very famous family of transcription factors whose prototype member is c-MYC. The other member of the family is L-MYC, identified as a gene amplified in a subset of lung cancers. c-MYC is widely expressed in normal tissues, is the most deregulated protooncogene in human cancer, and not surprisingly, it is the subject of intensive investigations in many laboratories worldwide. Clearly, decoding its function in tumorigenesis and finding ways of inhibiting its oncogenic activity would have a very large impact in terms of human health. In contrast to the broad significance of c-MYC, the expression of MYCN is temporally and spatially restricted during embryonal development, being detected mostly in cells of the developing nervous system. This more limited function is also reflected in human pathology, with only a few types of tumors presenting alterations of MYCN. These cancers arise in the nervous system, both central and peripheral, manifesting as medulloblastomas, gliomas, and neuroblastomas. Despite the fact that MYCN-positive tumors are relatively rare, their very aggressive nature and the pediatric setting make therapeutic treatments a clinical challenge.

Mouse models of sepsis elicit spontaneous action potential discharge and enhance intracellular Ca2+ signaling in postganglionic sympathetic neurons

Sepsis is a severe systemic inflammatory disorder that rapidly activates the sympathetic nervous system to enhance catecholamine secretion from postganglionic sympathetic neurons and adrenal chromaffin cells. Although an increase in preganglionic drive to postganglionic sympathetic tissues has been known to contribute to this response for quite some time, only recently was it determined that sepsis also has direct effects on adrenal chromaffin cell Ca2+ signaling and epinephrine release. In the present study, we characterized the direct effects of sepsis on postganglionic sympathetic neuron function. Using the endotoxemia model of sepsis in mice, we found that almost a quarter of postganglionic neurons acquired the ability to fire spontaneous action potentials, which was absent in cells from control mice. Spontaneously firing neurons possessed significantly lower rheobases and fired a greater number of action potentials at twice the rheobase compared to neurons from control mice. Sepsis did not significantly affect voltage-gated Ca2+ currents. However, global Ca2+ signaling was enhanced in postganglionic neurons isolated from 1 to 24h endotoxemic mice. A similar increase in the amplitude of high-K+-stimulated Ca2+ transients was observed during the cecal ligation and puncture model of sepsis. The enhanced excitability and Ca2+ signaling produced during sepsis likely amplify the effect of increased preganglionic drive on norepinephrine release from postganglionic neurons. This is important, as sympathetic neurons are integral to the anti-inflammatory autonomic reflex that is activated during sepsis.

Clinical, biologic, and prognostic differences on the basis of primary tumor site in neuroblastoma: a report from the international neuroblastoma risk group project.

Neuroblastoma (NB) is a heterogeneous tumor arising from sympathetic tissues. The impact of primary tumor site in influencing the heterogeneity of NB remains unclear. Children younger than age 21 years diagnosed with NB or ganglioneuroblastoma between 1990 and 2002 and with known primary site were identified from the International Neuroblastoma Risk Group database. Data were compared between sites with respect to clinical and biologic features, as well as event-free survival (EFS) and overall survival (OS). Among 8,369 children, 47% had adrenal tumors. All evaluated clinical and biologic variables differed statistically between primary sites. The features that were > 10% discrepant between sites were stage 4 disease, MYCN amplification, elevated ferritin, elevated lactate dehydrogenase, and segmental chromosomal aberrations, all of which were more frequent in adrenal versus nonadrenal tumors (P < .001). Adrenal tumors were more likely than nonadrenal tumors (adjusted odds ratio, 2.09; 95% CI, 1.67 to 2.63; P < .001) and thoracic tumors were less likely than nonthoracic tumors (adjusted odds ratio, 0.20; 95% CI, 0.11 to 0.39; P < .001) to have MYCN amplification after controlling for age, stage, and histologic grade. EFS and OS differed significantly according to the primary site (P < .001 for both comparisons). After controlling for age, MYCN status, and stage, patients with adrenal tumors had higher risk for events (hazard ratio, 1.13 compared with nonadrenal tumors; 95% CI, 1.03 to 1.23; P = .008), and patients with thoracic tumors had lower risk for events (HR, 0.79 compared with nonthoracic; 95% CI, 0.67 to 0.92; P = .003). Clinical and biologic features show important differences by NB primary site, with adrenal and thoracic sites associated with inferior and superior survival, respectively. Future studies will need to investigate the biologic origin of these differences.

Clinical management of paragangliomas.

Paragangliomas (PGLs) are rare vascular, neuroendocrine tumors of paraganglia, which are associated with either sympathetic tissue in adrenal (pheochromocytomas (PCCs)) and extraadrenal (sympathetic paraganglioma (sPGLs)) locations or parasympathetic tissue of the head and neck paragangliomas (HNPGLs). As HNPGLs are usually benign and most tumors grow slowly, a wait-and-scan policy is often advised. However, their location in the close proximity to cranial nerves and vasculature may result in considerable morbidity due to compression or infiltration of the adjacent structures, necessitating balanced decisions between a wait-and-see policy and active treatment. The main treatment options for HNPGL are surgery and radiotherapy. In contrast to HNPGLs, the majority of sPGL/PCCs produces catecholamines, in advanced cases resulting in typical symptoms and signs such as palpitations, headache, diaphoresis, and hypertension. The state-of-the-art diagnosis and localization of sPGL/PCCs are based on measurement of plasma and/or 24-h urinary excretion of (fractionated) metanephrines and methoxytyramine (MT). sPGL/PCCs can subsequently be localized by anatomical (computed tomography and/or magnetic resonance imaging) and functional imaging studies (123I-metaiodobenzylguanidine-scintigraphy, 111In-pentetreotide scintigraphy, or positron emission tomography with radiolabeled dopamine or dihydroxyphenylalanine). Although most PGL/PCCs are benign, factors such as genetic background, tumor size, tumor location, and high MT levels are associated with higher rates of metastatic disease. Surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. PGL/PCCs have a strong genetic background, with at least one-third of all cases linked with germline mutations in 11 susceptibility genes. As genetic testing becomes more widely available, the diagnosis of PGL/PCCs will be made earlier due to routine screening of at-risk patients. Early detection of a familial PGL allows early detection of potentially malignant PGLs and early surgical treatment, reducing the complication rates of this operation.

Bi-Focal Retroperitoneal Paraganglioma in a Young Patient: A Case Report and Review of the Literature

Extra-adrenal paraganglioma of the retroperitoneum are rare neuroendocrine tumors arising from specialized neural crest cells, intimately associated with sympathetic nervous tissue and distributed along the aorta. Here we present a case of multiple extra-adrenal retroperitoneal paraganglioma in a 16-year-old boy. The clinical presentation, imaging characteristics, and surgical pathologic findings were reported. A comprehensive review of the medical literature concerning multiple extra-adrenal paraganglioma in the pediatric and adult population is also discussed.