Identifying Genes Involved in Paraganglioma Genesis

The paraganglion system is composed of a collection of chromaffin cells that is distributed throughout the body. Embryonically, chromaffin cells arise from the neuroectodermal tissue of the neural crest and are thought to migrate along the innervating nerves or vasculature towards their primordial location to form the paraganglia. The largest paraganglion is the adrenal medulla, an important neuroendocrine organ, which is the body’s main source of catecholamines (adrenalin, noradrenalin and dopamine). The adrenal medulla receives input from the sympathetic nervous system through preganglionic fibers upon which it releases its secretions directly into the blood. Besides this adrenal station there are many extra‐adrenal paraganglia that are distributed along the body axis and located in the proximity of ganglia of the sympathetic chain or in association with cranial nerves and blood vessels

Refractive changes following surgery for correction of esotropia

Purpose: To evaluate changes in refraction and corneal curvature following surgery for correction of acquired esotropia. Methods: 42 eyes of 21 patients with acquired moderate angle esotropia without any other form of strabismus were prospectively enrolled and submitted to a complete ophthalmological examination followed by recess/resect procedure in a single eye. Data from the fellow eye were selected as control. Ophthalmological assessment was carried out preoperatively, 1 month after surgery and 6 months after surgery, where astigmatism was compared using vector analysis and the polar value concept. Results: The eyes submitted to surgery revealed a significant (p<0.05) decrease in spherical equivalent, from 3.28 ± 1.98 diopters to 3.05 ± 1.95 diopters. Refraction data disclosed a significant increase in the 90° component of net astigmatism, from 0.458 ± 0.594 diopters to 1.002 ± 0.718 diopters, which was also observed in keratometric readings:1.083 ± 0.560 diopters to 1.690 ± 0.591 diopters. Surgically induced astigmatism, assessed using refraction data was 0.63 ± 0.27 diopters at an average axis of 92.30 ± 14.91 degrees, and 0.71 ± 0.27 diopters at an average axis of 94.45 ± 15.69 degrees as obtained by keratometric readings. This is visually demonstrated by the corneal topography difference map. Conclusions: There is a statistically significant and clinically relevant increase in with-the-rule astigmatism in esotropic patients submitted to monocular recess/resect surgery. This change is stable at a 6 month follow-up and is associated with a decrease in mean spherical equivalent.Objetivo: Estudar o comportamento da refração e da curvatura corneana em pacientes com esotropia essencial submetidos à cirurgia monocular para correção do estrabismo. Métodos: Estudo prospectivo em que 42 olhos de 21 pacientes com esotropia essencial de ângulo moderado, sem quaisquer outros estrabismos associados, foram selecionados e submetidos ao exame oftalmológico completo e à cirurgia monocular. O olho contralateral serviu como grupo controle. Foram feitas avaliações de pré-operatório, pós-operatório de 1 mês e pós-operatório de 6 meses. O astigmatismo pré-operatório foi confrontado com os astigmatismos pós-operatórios por análise vetorial e cálculo do valor polar. Resultados: Obtivemos, nos olhos operados, redução significante (p<0,05) na médio do equivalente esférico, de 3,28 ±1,98 dioptrias para 3,05 ± 1,95 dioptrias. Na refração houve um aumento significante da média do componente a 90° do astigmatismo, de 0,458 ± 0,594 dioptrias para 1,002 ± 0,718 dioptrias, também observado na ceratometria: 1,083 ± 0,560 dioptrias para 1,690 ± 0,591 dioptrias. A média do astigmatismo induzido pela cirurgia, na refração, foi de 0,63 ± 0,27 dioptrias a um eixo médio de 92,30 ± 14,91 graus e de 0,71 ± 0,27 dioptrias a um eixo médio de 94,45 ± 15,69 graus na ceratometria, evidenciáveis graficamente pelo mapa diferencial da topografia corneana. Conclusões: Observa-se aumento estatisticamente significante e clinicamente relevante do astigmatismo a-favor-da-regra em pacientes esotrópicos submetidos ao retrocesso/ressecção monocular. Essa mudança é estável ao longo do tempo e é acompanhada de diminuição significante do equivalente esférico.Faculdade de Medicina da Universidade de São Paulo Hospital das Clínicas Departamento de OftalmologiaSanta Casa de São Paulo Departamento de OftalmologiaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de OftalmologiaUNIFESP, EPM, Depto. de OftalmologiaSciEL

The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes

Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry

The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes

Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry

A non-catecholamine-producing sympathetic paraganglioma of the spermatic cord: the importance of performing candidate gene mutation analysis

textabstractBackground: Catecholamine-producing tumours are called pheochromocytomas when they are located in the adrenal gland and sympathetic paragangliomas when they are located elsewhere in the abdomen. Rarely these tumours do not produce catecholamines and even more rarely they arise in the spermatic cord. Over the past decade, systematic mutation analysis of apparently sporadic cases of pheochromocytomas and paragangliomas has elucidated the frequent presence of germ line mutations in one of five candidate genes, including RET, VHL, SDHB, SDHC, and SDHD. Clinical history and methods: We describe a 45-year-old man with a non catecholamine-producing paraganglioma of the spermatic cord. We performed SDHB immunohistochemistry and performed mutation analysis of the SDHB, SDHC, and SDHD genes. Results: There was no staining of tumour cells with SDHB immunohistochemistry, indicative of an SDH mutation. Mutation analysis demonstrated a germ line SDHD mutation (p.Val147Met). Conclusions: Systematic mutation analysis is required in paraganglioma patients for the detection of germ line mutations. This should be preceded by SDHB immunohistochemistry to limit the number of genes to be tested

Bariatric surgery: evidence-based practical recommendations

[Resumen] La obesidad mórbida es, habitualmente, refractaria a los tratamientos convencionales, por lo que la modificación de hábitos dietéticos y de actividad física y/o el uso de fármacos consiguen pérdidas de peso parciales con habitual recuperación posterior. La cirugía bariátrica constituye una opción terapéutica para los casos de obesidad con elevado índice de masa corporal (IMC) asociada a comorbilidades, con buenos resultados a corto y largo plazo. El Grupo de Trabajo sobre Obesidad de la Sociedad Española de Endocrinología y Nutrición (GOSEEN) ha elaborado un documento con recomendaciones prácticas basadas en la evidencia para el tratamiento quirúrgico de la obesidad. La revisión se estructura en 3 partes. En la primera se definen los conceptos de obesidad y comorbilidades asociadas, los tratamientos médicos y sus resultados, las indicaciones y contraindicaciones para el tratamiento quirúrgico con los criterios de selección de los pacientes, el manejo pre y perioperatorio y la valoración de grupos especiales, como adolescentes y personas de edad avanzada. En la segunda parte se describen las distintas técnicas quirúrgicas, las vías de acceso y los resultados comparativos, las complicaciones tanto a corto como a largo plazo, la repercusión de la pérdida ponderal sobre las comorbilidades y los criterios para evaluar la efectividad de la cirugía. En la tercera parte se desarrolla el seguimiento postoperatorio, el control dietético en fases tempranas y más tardías tras la cirugía, y el calendario de control médico y analítico con la suplementación de los distintos macro y micronutrientes en función de la técnica quirúrgica empleada. Se incluye un apartado final sobre gestación y cirugía bariátrica, así como tablas y gráficos complementarios al texto desarrollado. La cirugía bariátrica sigue siendo un tratamiento discutido para la obesidad, pero los resultados en la corrección del exceso ponderal con mejoría en las patologías asociadas y en la calidad de vida confirman que puede ser el tratamiento de elección en pacientes seleccionados, con la técnica quirúrgica apropiada y con un correcto control pre y postoperatorio.[Abstract] Morbid obesity is usually refractory to conventional treatments. Consequently, weight that is lost by modifying diet and exercise and/or the use of drugs is usually later regained. Bariatric surgery constitutes a therapeutic option in obese patients with a high body mass index associated with comorbidities and achieves good results in both the short and the long term. The Obesity Working Group of the Spanish Society of Endocrinology and Nutrition has produced a document with practical, evidencebased recommendations for the surgical treatment of obesity. The review is structured in three parts. The first part defines the concepts of obesity and associated comorbidities, medical treatments, their results, and the indications and contraindications for surgical treatment, as well as the criteria for patient selection, pre- and perisurgical management, and assessment of special groups such as adolescents and the elderly. The second part discusses the different surgical techniques, approaches and comparative results, short- and long-term complications, the repercussions of weight loss on comorbidities, and the criteria for assessing the effectiveness of surgery. The third part discusses postsurgical follow-up, dietary control in the early and subsequent stages after surgery and the schedule for medical and laboratory follow-up, together with the different macro- and micronutrient supplements that should be used depending on the surgical technique employed. A final section is included on pregnancy and bariatric surgery, as well as tables and figures that complement the text. Although bariatric surgery continues to be a questionable treatment for obesity, the results correcting excess weight, with improvements in associated comorbidities and in quality of life, confirm that this option could be the treatment of choice in selected patients when the appropriate surgical technique and correct preand postoperative follow-up are employed

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe