Model systems in SDHx-related pheochromocytoma/paraganglioma

Pheochromocytoma (PHEO) and paraganglioma (PGL) (together PPGL) are tumors with poor outcomes that arise from neuroendocrine cells in the adrenal gland, and sympathetic and parasympathetic ganglia outside the adrenal gland, respectively. Many follow germline mutations in genes coding for subunits of succinate dehydrogenase (SDH), a tetrameric enzyme in the tricarboxylic acid (TCA) cycle that both converts succinate to fumarate and participates in electron transport. Germline SDH subunit B (SDHB) mutations have a high metastatic potential. Herein, we review the spectrum of model organisms that have contributed hugely to our understanding of SDH dysfunction. In Saccharomyces cerevisiae (yeast), succinate accumulation inhibits alpha-ketoglutarate-dependent dioxygenase enzymes leading to DNA demethylation. In the worm Caenorhabditis elegans, mutated SDH creates developmental abnormalities, metabolic rewiring, an energy deficit and oxygen hypersensitivity (the latter is also found in Drosophila melanogaster). In the zebrafish Danio rerio, sdhb mutants display a shorter lifespan with defective energy metabolism. Recently, SDHB-deficient pheochromocytoma has been cultivated in xenografts and has generated cell lines, which can be traced back to a heterozygous SDHB-deficient rat. We propose that a combination of such models can be efficiently and effectively used in both pathophysiological studies and drug-screening projects in order to find novel strategies in PPGL treatment.

Screening for cancer of the colon and rectum A review on incidence, mortality, cost and benefit

Key words: Cardioneuroablation, Atrioventricular block, Syncope, Arrhythmia According to clinical guidelines a symptomatic atrioventricular block (AV block) is treated with a pacemaker. For young individuals such a therapy can be difficult due to possible long term complications such as infections, lead disruptions and pacemaker induced cardiomyopathy. We describe a twenty year old man with recurrent syncopes due to intermittent parasympathetic caused AV block of grade 2. The patient underwent cardioneuroablation where parasympathetic ganglia in the right atrium were ablated. After the procedure the PR interval normalized. This procedure has never been performed in Iceland before and there is a limited amount of case reports in the literature.

Equid herpesvirus-1 Distribution in Equine Lymphoid and Neural Tissues 70 Days Post Infection

Equid herpesvirus-1 (EHV-1) causes respiratory disease, abortion and myeloencephalopathy in horses worldwide. As member of the Alphaherpesvirinae, latency is key to EHV-1 epidemiology. EHV-1 latent infection has been detected in the trigeminal ganglion (TG), respiratory associated lymphoid tissue (RALT) and peripheral blood mononuclear cells (PBMC) but additional locations are likely. The aim of this study was to investigate the distribution of viral DNA throughout the equine body. Twenty-five horses divided into three groups were experimentally infected via intranasal instillation with one of three EHV-1 viruses and euthanized on Day 70, post infection. During necropsy, TG, various sympathetic/parasympathetic ganglia of head, neck, thorax and abdomen, spinal cord dorsal root ganglia, RALT, mesenteric lymph nodes, spleen and PBMC of each horse were collected. Genomic viral loads and L-(late) gene transcriptional activity in each tissue and PBMC were measured using qPCR. In addition, immunohistochemistry (IHC) was applied on neural parenchyma tissue sections. EHV-1 DNA was detected in many neural and lymphoid tissue sections, but not in PBMC. L-gene transcriptional activity was not detected in any sample, and translational activity was not apparent on IHC. Tissue tropism differed between the Ab4 wild type and the two mutant viruses.

Pancreas Optical Clearing and 3-D Microscopy in Health and Diabetes

Although first described over a hundred years ago, tissue optical clearing is undergoing renewed interest due to numerous advances in optical clearing methods, microscopy systems, and three-dimensional (3-D) image analysis programs. These advances are advantageous for intact mouse tissues or pieces of human tissues because samples sized several millimeters can be studied. Optical clearing methods are particularly useful for studies of the neuroanatomy of the central and peripheral nervous systems and tissue vasculature or lymphatic system. Using examples from solvent- and aqueous-based optical clearing methods, the mouse and human pancreatic structures and networks will be reviewed in 3-D for neuro-insular complexes, parasympathetic ganglia, and adipocyte infiltration as well as lymphatics in diabetes. Optical clearing with multiplex immunofluorescence microscopy provides new opportunities to examine the role of the nervous and circulatory systems in pancreatic and islet functions by defining their neurovascular anatomy in health and diabetes.

235Anatomic guided ablation of the right ganglionated plexus is enough for cardiac autonomic denervation in patients with significant bradyarrhythmias

Background In patients with significant bradyarrhytmias, cardiac denervation is an alternative therapeutic approach. Previous reports proposed different methods (as high frequency ednocardial stimulation of ganglionated plexus and specific atrial electrogram identification) and targets (right and left atrial ganglionated plexus) for adequate denervation. There is no consensus on the best way to perform these procedures, in spite the right atrial ganglia plexus (GP) ablation seeming to be the most contributive to its success. Purpose To assess the results of a purely anatomic approach for ablation of just the right atrial plexus in patients with severe vagal bradyarrhytmias. Methods We enrolled patients referred for ablation of cardiac parasympathetic ganglia, with or without atrial fibrillation ablation. We performed eletroanatomic mapping of the right and left atria and used an irrigated tip catheter for ablation, aiming at the anterior right GP at the right pulmonary veins antrum along with ablation at the superior vena cava junction and the inferior right GP at the posterior aspect of the right inferior pulmonary vein along with ablation of the right aspect of the interatrial septum, between the posterior wall and coronary sinus ostium (Figure 1). We assessed the PW and Wenckenback cycle lengths (CL) pre and post procedure in patients with sinus arrest or AV block, respectively, and the patients had new 24h holter readings at least 30 days from the index procedure. Results We enrolled 12 patients: 9 males (75%), median age of 49,5 years (IQR 36-61,75). All patients had structurally normal hearts. 7 patients had only ablation of the parasympathetic ganglia and 5 patients had simultaneous pulmonary vein isolation for previously documented atrial fibrillation. 7 patients (58,3%) had sinus bradycardia (2 patients had sinus arrest with pauses of 8 and 13 seconds), 2 patients with cardioinhibitory syncope (with pauses of 23 and 28 seconds) and 3 patients had transient high degree AV block. The ablation procedure led to a median sinus rate acceleration of 15 bpm (IQR 3-29), a median decrease of 320 ms in PW (IQR 23,75-609,5) in patients with sinus arrest and a decrease of 80 ms in wenckenback CL (IQR 60-200) in patients with AV block. With a median follow up of 133,50 days (IQR 36-61,75), no patient had recurrence of symptoms or conduction disturbances. Conclusions In selected patients with severe functional paroxysmal bradyarrhytmias, cardiac denervation using an ablation strategy purely based on anatomic aspects and targeting only the right GP, seems to be an effective therapeutic approach. Abstract Figure 1: Abl of right ganglionated plex

Neurogenic Bladder Dysfunction in Cancer Patients after Operations on the Pelvic Organs

The review is devoted to the generalization and analysis of domestic and foreign works describing the mechanism of development of neurogenic dysfunction of the bladder after surgery on the pelvic organs in cancer patients. All modern authors agree that the cause of these disorders is trauma of the pelvic nerves and interruption of the reflex arc. Unfortunately, when removing malignant tumors of the pelvic organs, urological complications are difficult and often impossible to avoid. This is due to the complex neuroanatomy of the bladder, its proximity to the rectum, the uterus, as well as the volume and radicality of cancer operations. The article shows that if the parasympathetic ganglia are damaged, there is a violation of the evacuation function of the bladder and a weakening or absence of the urge to urinate. If the sympathetic nervous system is damaged in isolation, on the contrary, an increase in the detrusor tone, intravesical pressure and a decrease in the capacity of the bladder is observed, which is in conditions of low bladder sphincter tone causes imperative urges, frequent urination and incontinence. Prior radiation therapy also affects the development of urological complications. Postradiated soft tissue changes, ischemia, fibrosis lead to great technical difficulties during surgery. In addition, factors that are important in the development of pelvic disorders in this category of patients include urinary system diseases and metabolic – endocrine disorders in case history.

Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.

SDHB mutated paraganglioma imitating thyroid tumor: A case report and review of literature

Paragangliomas of the head and neck are uncommon tumors arising from parasympathetic ganglia. Paragangliomas are mostly asymptomatic and may manifest as palpable mass of neck. The morphologic features are non-specific and comparable to the other neuroendocrine tumors. Most of hereditary cases are associated with alterations in genes of succinate dehydrogenase (SDH). SDHA and SDHB immunohistochemistry is considered as reliable screening method to detect tumors with genetical alterations. Of note, SDHB mutated paragangliomas have the highest risk of local recurrence, distant metastasis and the development of other tumor phenotypes, which are associated with mutation. Therefore, active surveillance of patients and early surgical treatment are essential. In contrast, SDHB mutated head and neck paragangliomas was considered as completely benign tumors, although, the latest literature describes more controversial cases, which may increase awareness. Here, we present a rare case of 21 years old female with asymptomatic neck paraganglioma, which was unexpectedly diagnosed after pathological and immunohistochemical testing of removed thyroid gland and showed unusual immunohistochemical variation for SDH mutation.

Uncommon spreading of primary malignant paraganglioma in a patient with SDHB mutation

Pheochromocytomas (PHEOs) or paragangliomas (PGLs) are rare neuroendocrine tumors arising from adrenal medulla or from chromaffin cells outside the adrenal gland including parasympathetic ganglia, respectively.Here we describe a case of a 56-year-old man evaluated for left hip pain. The anatomical and functional imaging showed a pelvic tumor spreading through the foramen obturatum to the proximal part of the left hip, histologicaly confirmed as PGL. On biochemical evaluation elevated plasma catecholamine and metanephrine levels were found. The diagnosis of metastatic PGL was done based on additional lesions found in bones, liver, and retroperitoneal lymphatic nodes. Treatment with systemic cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy was initiated and with a substantial decrease in tumor burden. Spreading of PGL (PHEO) through the foramen obturatum infiltrating the left hip is very uncommon and has not been described previously.