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OBJECTIVES: Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom. DESIGN AND PATIENTS: Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated. MEASUREMENTS: Clinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed. RESULTS: Of 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results. CONCLUSIONS: Somatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.
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Neoplasias das Glândulas Suprarrenais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/patologia , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Paraganglioma/patologia , Feocromocitoma/diagnóstico , Estudos RetrospectivosRESUMO
OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) are rare, but strongly heritable tumours. Variants in succinate dehydrogenase (SDH) subunits are identified in approximately 25% of cases. However, clinical and genetic information of patients with SDHC variants are underreported. DESIGN: This retrospective case series collated data from 18 UK Genetics and Endocrinology departments. PATIENTS: Both asymptomatic and disease-affected patients with confirmed SDHC germline variants are included. MEASUREMENTS: Clinical data including tumour type and location, surveillance outcomes and interventions, SDHC genetic variant assessment, interpretation, and tumour risk calculation. RESULTS: We report 91 SDHC cases, 46 probands and 45 non-probands. Fifty-one cases were disease-affected. Median age at genetic diagnosis was 43 years (range: 11-79). Twenty-four SDHC germline variants were identified including six novel variants. Head and neck paraganglioma (HNPGL, n = 30, 65.2%), extra-adrenal paraganglioma (EAPGL, n = 13, 28.2%) and phaeochromocytomas (PCC) (n = 3, 6.5%) were present. One case had multiple PPGLs. Malignant disease was reported in 19.6% (9/46). Eight cases had non-PPGL SDHC-associated tumours, six gastrointestinal stromal tumours (GIST) and two renal cell cancers (RCC). Cumulative tumour risk (95% CI) at age 60 years was 0.94 (CI: 0.79-0.99) in probands, and 0.16 (CI: 0-0.31) in non-probands, respectively. CONCLUSIONS: This study describes the largest cohort of 91 SDHC patients worldwide. We confirm disease-affected SDHC variant cases develop isolated HNPGL disease in nearly 2/3 of patients, EAPGL and PCC in 1/3, with an increased risk of GIST and RCC. One fifth developed malignant disease, requiring comprehensive lifelong tumour screening and surveillance.
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Neoplasias das Glândulas Suprarrenais , Carcinoma de Células Renais , Tumores do Estroma Gastrointestinal , Neoplasias Renais , Paraganglioma , Feocromocitoma , Neoplasias das Glândulas Suprarrenais/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Paraganglioma/genética , Paraganglioma/patologia , Feocromocitoma/genética , Feocromocitoma/patologia , Estudos Retrospectivos , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo , Reino UnidoRESUMO
Temozolomide (TMZ) has been shown as an effective treatment option in aggressive pituitary adenomas and carcinomas. This review analyses the published case series and demonstrates 42 % of patents show a radiological response and 27 % experience stable disease following TMZ. Prolactinomas and corticotroph tumours respond best to TMZ, showing approximately a 50 % response rate, with non-functioning tumours responding only half as frequently. Other factors that may predict the tumour's TMZ response include MGMT and MSH status, but neither is sufficiently robust to determine treatment decisions. TMZ has an accepted role in treating pituitary carcinoma and adenomas if radiation and surgery have failed to control tumour growth. To use TMZ on the basis of anticipated future aggression, as a primary therapy, or in preference to radiotherapy remains controversial.
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Dacarbazina/análogos & derivados , Neoplasias Hipofisárias/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico , Dacarbazina/uso terapêutico , Humanos , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Neoplasias Hipofisárias/enzimologia , Prolactinoma/tratamento farmacológico , Prolactinoma/enzimologia , Temozolomida , Resultado do TratamentoRESUMO
Chest pain with elevated serum troponin is a common clinical presentation and is normally managed as suspected myocardial infarction or acute coronary syndrome (ACS). We report a 49 year old man who presented with central chest pain sweating and breathlessness. He had a significantly elevated serum troponin I level and a subsequent angiogram showed near normal coronary arteries. He was subsequently investigated for fever and found to have a 3cm right sided adrenal mass consistent with a pheochromocytoma. After confirmation and appropriate blockade laparoscopic adrenalectomy was performed. Pheochromocytoma may present as a mimic of acute coronary syndrome but this is often unrecognized and leaves the patient at risk of future pheo crisis events which may be fatal.
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Síndrome Coronariana Aguda/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/cirurgia , Feocromocitoma/diagnóstico , Feocromocitoma/cirurgia , Troponina I/sangue , Síndrome Coronariana Aguda/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Adrenalectomia/métodos , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Angiografia por Tomografia Computadorizada/métodos , Angiografia Coronária/métodos , Diagnóstico Diferencial , Dispneia/diagnóstico , Dispneia/etiologia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/diagnóstico por imagem , Medição de Risco , Resultado do TratamentoRESUMO
SUMMARY: We report a rare case of posterior reversible encephalopathy syndrome (PRES), precipitated by ectopic Cushing's syndrome, in a patient with a metastatic pancreatic neuroendocrine tumour. A 55-year-old female presented as a hypertensive emergency with seizures and severe biochemical disturbance, including alkalosis, hypokalaemia and hyperglycaemia. MRI showed vasogenic oedema in the parieto-occipital region, consistent with a diagnosis of PRES. She had a significantly raised serum cortisol (>6000 nmol/L) which did not suppress with dexamethasone. Plasma adrenocorticotropic hormone (ACTH) concentrations were neither suppressed nor raised but were consistently within the normal reference range. The unexpected finding of a normal ACTH may be explained by either tumour secretion of unmeasured ACTH-related peptides, immunoassay antibody interference or episodic ACTH secretion. PRES is usually reversible with prompt and appropriate treatment. Hypercortisolism associated PRES is rare and may be associated with a worse outcome. LEARNING POINTS: PRES secondary to ectopic Cushing's syndrome is very rare. PRES in this context may indicate a worse prognosis. In ectopic Cushing's syndrome, if the serum ACTH level is normal, consider testing for ACTH-related peptides or interfering antibodies. Further research is required to establish the best treatment approach and to improve patients' outcomes.
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Pancreatic neuroendocrine tumours can have varied and complex presentations. Whilst hormone hypersecretion often induces characteristic clinical syndromes, non-specific symptoms may arise due to localized tumour effects. Malignant invasion of local vasculature is an increasingly recognized complication of these neoplasms and can be associated with significant morbidity. Herein, we present the case of a 47-year-old male with a recurrence of a pancreatic neuroendocrine tumour who presented with unusual upper gastrointestinal bleeding. The tumour had recurred within the superior mesenteric vein, replacing the vessel and invading its branches. This resulted in porto-mesenteric hypertension and the formation of bleeding mesenteric varices. The patient subsequently developed progressive metabolic disturbances and was diagnosed with ectopic Cushing's syndrome, despite his primary tumour having been non-functional. This case demonstrates not only a rare pattern of tumour recurrence but also the potential for pancreatic neuroendocrine tumours to de-differentiate and change from non-functional to hormone secreting, a phenomenon which may complicate diagnosis and management.
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Obesity is an ever growing pandemic and a prevalent problem among men of reproductive age that can both cause and exacerbate male-factor infertility by means of endocrine abnormalities, associated comorbidities, and direct effects on the precision and throughput of spermatogenesis. Robust epidemiologic, clinical, genetic, epigenetic, and preclinical data support these findings. Clinical studies on the impact of medically induced weight loss on serum testosterone concentrations and spermatogenesis is promising but may show differential and unsustainable results. In contrast, literature has demonstrated that weight loss after bariatric surgery is correlated with an increase in serum testosterone concentrations that is superior than that obtained with only lifestyle modifications, supporting a further metabolic benefit from surgery that may be specific to the male reproductive system. The data on sperm and semen parameters is controversial to date. Emerging evidence in the burgeoning field of genetics and epigenetics has demonstrated that paternal obesity can affect offspring metabolic and reproductive phenotypes by means of epigenetic reprogramming of spermatogonial stem cells. Understanding the impact of this reprogramming is critical to a comprehensive view of the impact of obesity on subsequent generations. Furthermore, conveying the potential impact of these lifestyle changes on future progeny can serve as a powerful tool for obese men to modify their behavior. Healthcare professionals treating male infertility and obesity need to adapt their practice to assimilate these new findings to better counsel men about the importance of paternal preconception health and the impact of novel non-medical therapeutic interventions. Herein, we summarize the pathophysiology of obesity on the male reproductive system and emerging evidence regarding the potential role of bariatric surgery as treatment of male obesity-associated gonadal dysfunction.
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Cirurgia Bariátrica/métodos , Transtornos Gonadais/prevenção & controle , Obesidade/complicações , Transtornos Gonadais/etiologia , Transtornos Gonadais/patologia , Transtornos Gonadais/cirurgia , Humanos , MasculinoRESUMO
Hypophysitis is a rare condition characterised by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy or alternative sella-based pathologies). Hypophysitis can be classified using anatomical, histopathological and aetiological criteria. Non-invasive diagnosis of hypophysitis remains elusive, and the use of currently available serum anti-pituitary antibodies are limited by low sensitivity and specificity. Newer serum markers such as anti-rabphilin 3A are yet to show consistent diagnostic value and are not yet commercially available. Traditionally considered a very rare condition, the recent recognition of IgG4-related disease and hypophysitis as a consequence of use of immune modulatory therapy has resulted in increased understanding of the pathophysiology of hypophysitis. Modern imaging techniques, histological classification and immune profiling are improving the accuracy of the diagnosis of the patient with hypophysitis. The objective of this review is to bring readers up-to-date with current understanding of conditions presenting as hypophysitis, focussing on recent advances and areas for future development. We describe the presenting features, investigation and diagnostic approach of the patient with likely hypophysitis, including existing conventional techniques and those in the research/development arena. Hypophysitis usually results in acute and persistent pituitary hormone deficiency requiring long-term replacement. Management of hypophysitis includes control of the inflammatory pituitary mass using a variety of treatment strategies including surgery and medical therapy. Glucocorticoids remain the mainstay of medical treatment but other immunosuppressive agents (e.g. azathioprine, rituximab) show benefit in some cases, but there is a need for controlled studies to inform practice.
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Hipofisite/diagnóstico , Hipofisite/terapia , Hipofisite Autoimune/diagnóstico , Hipofisite Autoimune/imunologia , Feminino , Glucocorticoides/uso terapêutico , Histiocitose de Células de Langerhans , Humanos , Hipofisite/etiologia , Imunoglobulina G/imunologia , Imunoterapia/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Procedimentos Neurocirúrgicos , Hipófise/imunologia , Hipófise/patologia , Hormônios Adeno-Hipofisários/análise , Hormônios Adeno-Hipofisários/deficiência , Gravidez , Complicações na Gravidez , XantomatoseRESUMO
We describe severe hypokalaemia and hypertension due to a mineralocorticoid effect in a patient with myelodysplastic syndrome taking posaconazole as antifungal prophylaxis. Two distinct mechanisms due to posaconazole are identified: inhibition of 11ß hydroxylase leading to the accumulation of the mineralocorticoid hormone 11-deoxycorticosterone (DOC) and secondly, inhibition of 11ß hydroxysteroid dehydrogenase type 2 (11ßHSD2), as demonstrated by an elevated serum cortisol-to-cortisone ratio. The effects were ameliorated by spironolactone. We also suggest that posaconazole may cause cortisol insufficiency. Patients taking posaconazole should therefore be monitored for hypokalaemia, hypertension and symptoms of hypocortisolaemia, at the onset of treatment and on a monthly basis. Treatment with mineralocorticoid antagonists (spironolactone or eplerenone), supplementation of glucocorticoids (e.g. hydrocortisone) or dose reduction or cessation of posaconazole should all be considered as management strategies. LEARNING POINTS: Combined hypertension and hypokalaemia are suggestive of mineralocorticoid excess; further investigation is appropriate.If serum aldosterone is suppressed, then further investigation to assess for an alternative mineralocorticoid is appropriate, potentially using urine steroid profiling and/or serum steroid panelling.Posaconazole can cause both hypokalaemia and hypertension, and we propose that this is due to two mechanisms - both 11ß hydroxylase inhibition and 11ß HSD2 inhibition.Posaconazole treatment may lead to cortisol insufficiency, which may require treatment; however, in this clinical case, the effect was mild.First-line treatment of this presentation would likely be use of a mineralocorticoid antagonist.Patients taking posaconazole should be monitored for hypertension and hypokalaemia on initiation and monthly thereafter.
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Myocarditis is inflammation of the cardiac muscle. The symptoms, signs and basic investigation findings can mimic that of myocardial infarction. The most common cause is infection (most commonly viral). Cardiovascular magnetic resonance (CMR) is the gold standard non-invasive diagnostic test for potential acute myocarditis as it allows assessment of myocardial oedema and scar. A man aged 25 years was admitted with chest pain, dizziness, headache, palpitations and sweating. His troponin was mildly positive. A CMR was performed which showed mild myocarditis and a right suprarenal mass which was confirmed to be a phaeochromocytoma based on biochemistry and a dedicated imaging workup. Phaeochromocytoma can lead to cardiac involvement in the form of left ventricular dysfunction, or catecholamine-induced myocarditis.
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Imagem Cinética por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/métodos , Miocardite/diagnóstico por imagem , Feocromocitoma/diagnóstico por imagem , Doença Aguda , Adrenalectomia/métodos , Adulto , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Ecocardiografia/métodos , Humanos , Masculino , Miocardite/complicações , Miocardite/tratamento farmacológico , Feocromocitoma/complicações , Feocromocitoma/cirurgia , Resultado do Tratamento , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/diagnóstico por imagemRESUMO
The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RETE616Q reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.
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Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas Proto-Oncogênicas c-ret/genética , Adulto , Western Blotting , Feminino , Humanos , Masculino , Mutagênese Sítio-Dirigida , Mutação , Linhagem , Proto-Oncogene MasRESUMO
BACKGROUND: Referrals are an important and frequent part of a junior doctor's work. Difficulty with making successful referrals is also very common. Despite this, training in referral skills is not routinely carried out in medical schools. RESULTS: We designed and delivered a 1-h interactive lecture to final year medical students to teach referral skills. The lecture was delivered on six occasions to up to 70 students at each session. 191 students attended and provided evaluation. 68% of students had no previous training in referral skills and 99% felt that referral skills should be included in the undergraduate curriculum. 90% reported that the lecture had improved their understanding of referral techniques and 83 and 80% felt that the lecture had improved their ability and confidence, respectively. CONCLUSIONS: Referral skills can be successfully taught in a large group lecture setting. We recommend that the teaching of referral skills is incorporated into all medical schools' curricula.
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Competência Clínica , Educação Médica/métodos , Encaminhamento e Consulta , Estudantes de Medicina , HumanosRESUMO
Destructive communication is a problem within the NHS; however previous research has focused on bullying. Rude, dismissive and aggressive (RDA) communication between doctors is a more widespread problem and underinvestigated. We conducted a mixed method study combining a survey and focus groups to describe the extent of RDA communication between doctors, its context and subsequent impact. In total, 606 doctors were surveyed across three teaching hospitals in England. Two structured focus groups were held with doctors at one teaching hospital. 31% of doctors described being subject to RDA communication multiple times per week or more often, with junior and registrar doctors affected twice as often as consultants. Rudeness was more commonly experienced from specific specialties: radiology, general surgery, neurosurgery and cardiology. 40% of respondents described that RDA moderately or severely affected their working day. The context for RDA communication was described in five themes: workload, lack of support, patient safety, hierarchy and culture. Impact of RDA communication was described as personal, including emotional distress and substance abuse, and professional, including demotivation. RDA communication between doctors is a widespread and damaging behaviour, occurring in contexts common in healthcare. Recognition of the impact on doctors and potentially patients is key to change.
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Agressão , Atitude do Pessoal de Saúde , Negativismo , Cultura Organizacional , Médicos/psicologia , Médicos/estatística & dados numéricos , Comunicação , Inglaterra , Feminino , Grupos Focais , Hospitais de Ensino , Humanos , Relações Interpessoais , MasculinoRESUMO
BACKGROUND: There is no consensus as to the best method to assess glycemic variability from continuous glucose monitoring (CGM) data. Rate of change has been suggested as a preferred method of assessing glycemic variability, but this assertion has not been validated. METHODS: Forty-eight hours of CGM data were analyzed from 22 subjects (seven controls and 15 with type 1 diabetes) purposively sampled to reflect a range of glycemic variability. SD, mean amplitude of glycemic excursion, continuous overall net glycemic action, SD of rate of change (SDRC), and average absolute rate of change (AARC) were calculated and correlated with a clinical assessment of variability. SDRC and AARC were recalculated following a data smoothing process involving aggregation. RESULTS: SDRC calculated from non-aggregated glucose readings gives a weaker correlation (r = 0.66) with the clinical assessment of variability than the correlations obtained by other indices (r = 0.90-0.96). Following a process of data aggregation, to exclude clinically insignificant fluctuations of blood glucose, we demonstrated that 60 min was the optimal aggregation period. The correlation between clinical assessment of variability and SDRC, 60-min aggregated, is 0.93, which is comparable to correlations shown by other established indices. Similar results are obtained for AARC. CONCLUSIONS: Rate of change calculated after appropriate data aggregation is a valid index of glycemic variability. Optimal data aggregation is achieved by aggregating into 1-h blocks.