Publications by authors named "Ashley Grossman"

371 Publications

Middle ear neuroendocrine tumours: Insight into their pathogenesis, diagnosis and management.

J Neuroendocrinol 2021 Aug 13;33(9):e13031. Epub 2021 Aug 13.

ENETS Centre of Excellence, Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK.

Recent advances in the diagnosis of neuroendocrine tumours (NETs) have led to the identification of NETs in unusual locations. NETs originating in the middle ear have been reported in a number of case reports with differing terminologies, where they were variously referred to as middle ear adenomas or middle ear carcinoids. In this report, we describe two cases of middle ear NETs with locally advanced disease and with distant metastases, respectively. The embryological origin, pathogenesis and histopathological characteristics, including immunohistochemical markers, are discussed aiming to clarify the terminology of these tumours. Functional imaging modalities (eg, Ga-DOTATATE positron emission tomography/computed tomography/magnetic resonance imaging) play a pivotal role in the diagnosis, staging and determining the optimal systemic therapy in managing NETs of the middle ear. In addition, surgical, local and systemic therapeutic modalities are discussed, including the management option of long-acting somatostatin analogue therapy and targeted radionuclide therapy for somatostatin receptor-positive well-differentiated middle ear NETs.
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http://dx.doi.org/10.1111/jne.13031DOI Listing
August 2021

Metastatic Medullary Thyroid Cancer: The Role of 68Gallium-DOTA-Somatostatin Analogue PET/CT and Peptide Receptor Radionuclide Therapy.

J Clin Endocrinol Metab 2021 Aug 11. Epub 2021 Aug 11.

Neuroendocrine tumour unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK.

Context: Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors.

Objective: Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) PET/CT in patients with metastatic MTC, and to determine their eligibility for peptide receptor radionuclide therapy (PRRT).

Methods: We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at five centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS).

Results: Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/ 68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95%CI 8-25) and a median OS of 63 months (95%CI 21-not reached). Of the entire cohort, the median OS was 323 months (95%CI 152-not reached). Predictors of poorer overall survival included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity and age ≥60 years.

Conclusions: The prevalence of high tumour avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients.
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http://dx.doi.org/10.1210/clinem/dgab588DOI Listing
August 2021

MANAGEMENT OF ENDOCRINE DISEASE: Dysnatraemia in COVID-19: prevalence, prognostic impact, pathophysiology, and management.

Eur J Endocrinol 2021 Sep 6;185(4):R103-R111. Epub 2021 Sep 6.

First Department of Propaedeutic and Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece.

This review examines the prevalence, aetiology, pathophysiology, prognostic value, and investigation of dysnatraemia in hospitalised COVID-19 patients, taking into account all relevant studies published in PubMed and Cochrane Library studies until March 2021. Hyponatraemia is commonly observed in patients with bacterial pneumonia and is an independent predictor for excess mortality and morbidity. However, it remains unknown whether this association applies to coronavirus disease-2019 (COVID-19). Several studies reported a 20-35% prevalence for hyponatraemia and 2-5% for hypernatraemia in patients admitted with COVID-19. In addition, hyponatraemia on admission was a risk factor for progression to severe disease, being associated with an increased likelihood for the need for invasive mechanical ventilation, with an odds ratio (OR) of 1.83-3.30. Hyponatraemia seems to be an independent risk factor for mortality, with an OR of 1.40-1.50 compared to normonatraemia, while hypernatraemia is related to even worse outcomes than hyponatraemia. Furthermore, preliminary data show an inverse association between serum sodium and interleukin-6 levels, suggesting that hyponatraemia might be used as a surrogate marker for the risk of a cytokine storm and the need for treatment with interleukin antagonists. In conclusion, dysnatraemia is common and carries a poor prognosis in COVID-19 patients, indicating that it may play a future role in risk stratification and individualising therapy.
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http://dx.doi.org/10.1530/EJE-21-0281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428074PMC
September 2021

Mechanisms of Central Hypogonadism.

Int J Mol Sci 2021 Jul 30;22(15). Epub 2021 Jul 30.

Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK.

Reproductive function depends upon an operational hypothalamo-pituitary-gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy.
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http://dx.doi.org/10.3390/ijms22158217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348115PMC
July 2021

Can COVID-19 immunisation cause subacute thyroiditis?

Clin Endocrinol (Oxf) 2021 Jul 17. Epub 2021 Jul 17.

Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK.

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http://dx.doi.org/10.1111/cen.14555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444846PMC
July 2021

Management of children and young people with idiopathic pituitary stalk thickening, central diabetes insipidus, or both: a national clinical practice consensus guideline.

Lancet Child Adolesc Health 2021 09 30;5(9):662-676. Epub 2021 Jun 30.

London Centre for Paediatric Endocrinology and Diabetes, Great Ormond Street Hospital and University College London Hospitals, London, UK; Section of Molecular Basis of Rare Disease, Genetics and Genomic Medicine Programme, Great Ormond Street Hospital Institute of Child Health, University College London, London, UK.

Unexplained or idiopathic pituitary stalk thickening or central diabetes insipidus not only harbours rare occult malignancies in 40% of cases but can also reflect benign congenital defects. Between 2014 and 2019, a multidisciplinary, expert national guideline development group in the UK systematically developed a management flowchart and clinical practice guideline to inform specialist care and improve outcomes in children and young people (aged <19 years) with idiopathic pituitary stalk thickening, central diabetes insipidus, or both. All such cases of idiopathic pituitary stalk thickening and central diabetes insipidus require dynamic pituitary function testing, specialist pituitary imaging, measurement of serum β-human chorionic gonadotropin and alpha-fetoprotein concentrations, chest x-ray, abdominal ultrasonography, optometry, and skeletal survey for occult disease. Stalk thickening of 4 mm or more at the optic chiasm, 3 mm or more at pituitary insertion, or both, is potentially pathological, particularly if an endocrinopathy or visual impairment coexists. In this guideline, we define the role of surveillance, cerebrospinal fluid tumour markers, whole-body imaging, indications, timing and risks of stalk biopsy, and criteria for discharge. We encourage a registry of outcomes to validate the systematic approach described in this guideline and research to establish typical paediatric stalk sizes and the possible role of novel biomarkers, imaging techniques, or both, in diagnosis.
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http://dx.doi.org/10.1016/S2352-4642(21)00088-2DOI Listing
September 2021

Personalized management of pheochromocytoma and paraganglioma.

Endocr Rev 2021 Jun 19. Epub 2021 Jun 19.

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, Room 1E-3140, 10 Center Drive MSC-1109, Bethesda, Maryland 20892-1109, US.

Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters depending on underlying genetic alterations. With around 30-35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35-40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver-mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to one of three main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype, and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
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http://dx.doi.org/10.1210/endrev/bnab019DOI Listing
June 2021

A clinical approach to parasellar lesions in the transition age.

J Neuroendocrinol 2021 Jun;33(6):e12995

Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK.

Many reviews have summarised the pathology and management of the parasellar region in adult patients, although an analysis of these aspects in the transition years, from puberty onset to the age of peak bone mass, has been lacking. A comprehensive search of English-language original articles, published from 2000 to 2020, was conducted in the MEDLINE database (December 2019 to March 2020). We selected all studies regarding epidemiology, diagnosis and management of the following parasellar lesions: germinoma, craniopharyngioma, Langerhans cell histiocytosis, optic glioma, hypothalamic hamartoma, tuber cinereum hamartoma, cranial chordoma, Rathke cleft cyst, hypophysitis and hypothalamitis during the transition age from childhood to adulthood. In the present review, we provide an overview of the principal parasellar lesions occurring in the transition age. Symptoms are usually a result of the mass effect of the lesions on nearby structures, as well as anterior pituitary deficits. Diabetes insipidus occurs frequently in these patients. In this age group, pubertal developmental disorders may be more evident compared to other stages of life. Parasellar lesions in the transition age mostly include neoplastic lesions such as germinomas, hamartomas, optic gliomas, craniopharyngiomas Langerhans cell histiocytosis and chordomas, and rarely inflammatory lesions (hypophysitis, hypothalamitis). There are limited data on the management of parasellar lesions in the transition age. Endocrine evaluation is crucial for identifying conditions that require hormonal treatment so that they can be treated early to improve the quality of life of the individual patient in this complex age range. The clinical approach to parasellar lesions involves a multidisciplinary effort.
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http://dx.doi.org/10.1111/jne.12995DOI Listing
June 2021

International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers.

Nat Rev Endocrinol 2021 07 21;17(7):435-444. Epub 2021 May 21.

INSERM, PARCC, Equipe Labellisée par la Ligue contre le Cancer, Paris, France.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.
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http://dx.doi.org/10.1038/s41574-021-00492-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205850PMC
July 2021

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

Mod Pathol 2021 09 21;34(9):1634-1650. Epub 2021 May 21.

Department of Medicine, University Health Network, University of Toronto, Toronto, ON, Canada.

The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.
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http://dx.doi.org/10.1038/s41379-021-00820-yDOI Listing
September 2021

Changing biological behaviour of NETs during the evolution of the disease: progress on progression.

Endocr Relat Cancer 2021 Apr 29;28(5):R121-R140. Epub 2021 Apr 29.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK.

Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.
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http://dx.doi.org/10.1530/ERC-20-0473DOI Listing
April 2021

Early Metabolic Benefits of Switching Hydrocortisone to Modified Release Hydrocortisone in Adult Adrenal Insufficiency.

Front Endocrinol (Lausanne) 2021 11;12:641247. Epub 2021 Mar 11.

Warwickshire Institute for the Study of Diabetes Endocrinology and Metabolism, University Hospitals Coventry and Warwickshire, Clifford Bridge Road, Coventry, United Kingdom.

Purpose: To compare metabolic effects of modified release hydrocortisone (MR-HC) with standard hydrocortisone (HC) therapies in adults with Adrenal Insufficiency (AI).

Methods: Adult patients (n = 12) with AI, established on HC therapy, were recruited from Endocrinology clinics at University Hospitals Coventry and Warwickshire (UHCW), UK. Baseline (HC) metabolic assessments included fasting serum HbA1C, lipid and thyroid profiles, accurate measures of body composition (BodPod), and 24-h continuous measures of energy expenditure including Sleeping Metabolic Rate (SMR) using indirect calorimetry within the Human Metabolism Research Unit, UHCW. All participants then switched HC to MR-HC with repeat (MR-HC) metabolic assessments at 3 months. Paired-sample t-tests were used for data comparisons between HC and MR-HC assessments: P-value <0.05 was considered significant.

Results: Following exclusion of 2 participants, analyses were based on 10 participants. Compared with baseline HC data, following 3 months of MR-HC therapy mean fat mass reduced significantly by -3.2 kg (95% CI: -6.0 to -0.4). Mean (SD) baseline HC fat mass vs repeat MR-HC fat mass: 31.9 kg (15.2) vs 28.7 kg (12.8) respectively, P = 0.03. Mean SMR increased significantly by +77 kcal/24 h (95% CI: 10-146). Mean (SD) baseline HC SMR vs repeat MR-HC SMR: 1,517 kcal/24 h (301) vs 1,594 kcal/24 h (344) respectively, P = 0.03. Mean body fat percentage reduced significantly by -3.4% (95% CI: -6.5 to -0.2). Other measures of body composition, energy expenditure, and biochemical analytes were equivalent between HC and MR-HC assessments.

Conclusions: In adults with AI, switching from standard HC to MR-HC associates with early metabolic benefits of reduced fat mass and increased SMR.
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http://dx.doi.org/10.3389/fendo.2021.641247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992002PMC
March 2021

Investigation of the Hypothalamo-pituitary-adrenal (HPA) axis: a contemporary synthesis.

Rev Endocr Metab Disord 2021 06 26;22(2):179-204. Epub 2021 Mar 26.

Department of Endocrinology, Yeditepe University, Medical School, Istanbul, Turkey.

The hypothalamo-pituitary-adrenal (HPA) axis is one of the main components of the stress system. Maintenance of normal physiological events, which include stress responses to internal or external stimuli in the body, depends on appropriate HPA axis function. In the case of severe cortisol deficiency, especially when there is a triggering factor, the patient may develop a life-threatening adrenal crisis which may result in death unless early diagnosis and adequate treatment are carried out. The maintenance of normal physiology and survival depend upon a sufficient level of cortisol in the circulation. Life-long glucocorticoid replacement therapy, in most cases meeting but not exceeding the need of the patient, is essential for normal life expectancy and maintenance of the quality of life. To enable this, the initial step should be the correct diagnosis of adrenal insufficiency (AI) which requires careful evaluation of the HPA axis, a highly dynamic endocrine system. The diagnosis of AI in patients with frank manifestations is not challenging. These patients do not need dynamic tests, and basal cortisol is usually enough to give a correct diagnosis. However, most cases of secondary adrenal insufficiency (SAI) take place in a gray zone when clinical manifestations are mild. In this situation, more complicated methods that can simulate the response of the HPA axis to a major stress are required. Numerous studies in the assessment of HPA axis have been published in the world literature. In this review, the tests used in the diagnosis of secondary AI or in the investigation of suspected HPA axis insufficiency are discussed in detail, and in the light of this, various recommendations are made.
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http://dx.doi.org/10.1007/s11154-020-09611-3DOI Listing
June 2021

Diabetes insipidus secondary to sellar/parasellar lesions.

J Neuroendocrinol 2021 03;33(3):e12954

1st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Diabetes insipidus (DI) is a well-recognised transient or permanent complication following transsphenoidal surgery for pituitary adenomas or other sellar/parasellar lesions. However, data regarding the prevalence of pre-operative DI in sellar/parasellar lesions other than pituitary adenomas are scarce. We systematically reviewed the existing data for defining the prevalence of DI before any treatment in adult patients with sellar/parasellar lesions, excluding pituitary adenomas and metastatic lesions. In total, 646 patients with sellar/parasellar lesions presenting with DI at diagnosis were identified. The most common pathologies of sellar/parasellar lesions presenting with DI at diagnosis were lymphocytic hypophysitis (26.5%), craniopharyngiomas (23.4%), Langerhans's cell histiocytosis (18.9%) and Rathke's cleft cyst (12.7%), accounting for the vast majority (more than 80%) of these lesions. Overall, DI at diagnosis was found in 23.4% of all patients with sellar/parasellar lesions, albeit with a wide range from 10.6% to 76.7%, depending on the nature of the pathology. The highest prevalence of DI was found in less commonly encountered lesions namely germ-cell tumours (76.7%), abscesses (55.4%) and neurosarcoidosis (54.5%), each accounting for less than 3% of all sellar/parasellar lesions. Most DI cases (68.8%) were associated with anterior pituitary hormonal deficiencies, in contrast to pituitary adenomas that rarely present with DI. The enlargement and enhancement of the pituitary stalk were the most common findings on magnetic resonance imaging besides the loss of the high signal of the posterior pituitary on T1-weighted images. Resolution of DI spontaneously or following systemic and surgical management occurred in 22.4% of cases. Post-operative DI, not evident before surgery, was found in 27.8% of non-adenomatous sellar/parasellar lesions, and was transient in 11.6% of them. Besides distinctive imaging features and symptoms, early recognition of DI in such lesions is important because it directs the diagnosis towards a non-adenomatous sellar/parasellar tumour and the early initiation of appropriate treatment.
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http://dx.doi.org/10.1111/jne.12954DOI Listing
March 2021

Calcitonin-secreting neuroendocrine neoplasms of the lung: a systematic review and narrative synthesis.

Endocr Connect 2021 Apr 26;10(4):447-461. Epub 2021 Apr 26.

Department of Endocrinology ASO/EASO COM, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.

Calcitonin-secreting neuroendocrine neoplasms of the lung are rare, with few cases reported in the literature. Differentiating between medullary thyroid carcinoma and an ectopic source of calcitonin secretion can represent a complex diagnostic conundrum for managing physicians, with cases of unnecessary thyroidectomy reported in the literature. This manuscript reports a case of ectopic hypercalcitonaemia from a metastatic neuroendocrine neoplasm of the lung with concurrent thyroid pathology and summarises the results of a systematic review of the literature. Medical Literature Analysis and Retrieval System Online, Excerpta Medica, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov and SCOPUS databases were systematically and critically appraised for all peer reviewed manuscripts that suitably fulfilled the inclusion criteria established a priori. The protocol for this systematic review was developed according to the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols, and followed methods outlined in The Cochrane Handbook for Systematic Reviews of Interventions. This systematic review is registered with PROSPERO. It is vital to consider diagnoses other than medullary thyroid carcinoma when presented with a patient with raised calcitonin, as it is not pathognomonic of medullary thyroid carcinoma. Lung neuroendocrine neoplasms can appear similar to medullary thyroid carcinoma histologically, they can secrete calcitonin and metastasize to the thyroid. Patients with medullary thyroid carcinoma may show stimulated calcitonin values over two or more times above the basal values, whereas calcitonin-secreting neuroendocrine neoplasms may or may not show response to stimulation tests. The present review summarises existing evidence from cases of ectopic hypercalcitonaemia to lung neuroendocrine neoplasms.
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http://dx.doi.org/10.1530/EC-21-0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111313PMC
April 2021

Misleading GALLIUM-dotatate PET scan in a patient with a history of a phaeochromocytoma: Unsuspected uptake in papillary thyroid carcinoma metastases.

J Neuroendocrinol 2021 Mar 23;33(5):e12964. Epub 2021 Mar 23.

ENETs Centre of Excellence, Royal Free Hospital, London, UK.

Scanning for somatostatin receptors using Ga-dotatate positron emission tomography with co-registration with computed tomography or magnetic resonance imaging is now in widespread use for the identification of neuroendocrine tumours, phaeochromocytomas, and paragangliomas and their metastases. We present a case where a patient with a phaeochromocytoma showed uptake in her neck considered diagnostic of a head-and-neck paraganglioma, which was subsequently confirmed to be a metastatic papillary thyroid carcinoma. We alert clinicians to such falsely-identified tumours using this extensively used imaging technique.
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http://dx.doi.org/10.1111/jne.12964DOI Listing
March 2021

Posterior pituitary tumours: patient outcomes and determinants of disease recurrence or persistence.

Endocr Connect 2021 Apr;10(4):387-400

Department of Endocrinology, Postgraduate Institute of Medical Education and Research, (PGIMER), Chandigarh, India.

Objective: Posterior pituitary tumours (PPTs) are rare neoplasms with the four recognised subtypes unified by thyroid transcription factor -1 (TTF-1) expression, according to the 2017 WHO classification. Though traditionally defined as low-grade neoplasms, a substantial proportion of them show recurrence/persistence following surgery.

Methods: We selected patients with PPTs in our cohort of 1760 patients operated for pituitary tumours over the past 10 years (2010-2019). The clinical, radiological, hormonal, histopathological profiles and long-term outcomes of the three cases identified (two pituicytomas and one spindle cell oncocytoma, SCO) were analysed. Following a literature review, data of all published cases with documented TTF-1 positive pituicytomas and SCOs were analysed to determine the predictors of recurrence/persistence in these tumours.

Results: Patients presented with compressive features or hypogonadism. Two had sellar-suprasellar masses. One had a purely suprasellar mass with a pre-operative radiological suspicion of pituicytoma. Two were operated by transsphenoidal surgery and one transcranially guided by neuronavigation. Histopathology confirmed spindle cells in a storiform arrangement and low Ki67 index. Immunohistochemistry showed positive TTF-1, S-100 expression and variable positivity for EMA, vimentin and GFAP. Re-evaluation showed recurrence/persistence in two patients. A literature review of recurrent/persistent pituicytoma (n = 17) and SCO (n = 9) cases revealed clinical clues (headache for pituicytomas, male gender for SCO), baseline tumour size (≥20.5 mm with sensitivity exceeding 80%) and longer follow-up duration as determinants of recurrence/persistence.

Conclusion: PPTs are rare sellar masses with quintessential TTF-1 positivity. Recurrent/persistent disease following surgery is determined by greater tumour size at baseline and duration of follow-up. This warrants intensive and long-term surveillance in these patients.
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http://dx.doi.org/10.1530/EC-20-0621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142326PMC
April 2021

The Pangenomic Classification of Pituitary Neuroendocrine Tumors: Quality Histopathology is Required for Accurate Translational Research.

Endocr Pathol 2021 Sep 3;32(3):415-417. Epub 2021 Mar 3.

Department of Pathology, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, OH, USA.

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http://dx.doi.org/10.1007/s12022-021-09671-4DOI Listing
September 2021

COVID-19-related thyroiditis: A novel disease entity?

Clin Endocrinol (Oxf) 2021 09 3;95(3):369-377. Epub 2021 May 3.

Centre for Endocrinology, Barts, London School of Medicine, Queen Mary University of London, London, UK.

The literature on COVID-19-related thyroid complications has accumulated over the past year or so as the pandemic has accelerated throughout the world. In particular, several recent case reports have been published describing a possible correlation between COVID-19 disease and subacute thyroiditis (SAT). In this review, we briefly present one of our own patients and review the current published literature in this area up to January 2021, including analyses of major series of thyroid function tests in patients with significant COVID-19 infection. We conclude that while the great majority of patients with severe COVID-19 infection may show manifestations of the sick euthyroid syndrome, clinicians should be aware of the possibility of SAT, especially in the early weeks and months following even mild COVID-19 infection.
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http://dx.doi.org/10.1111/cen.14453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014067PMC
September 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Paediatric Cushing's disease: Epidemiology, pathogenesis, clinical management and outcome.

Rev Endocr Metab Disord 2021 Jan 30. Epub 2021 Jan 30.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, UK.

Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70-100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.
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http://dx.doi.org/10.1007/s11154-021-09626-4DOI Listing
January 2021

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors.

Endocr Pathol 2021 Mar 18;32(1):169-191. Epub 2021 Jan 18.

Green Templeton College, University of Oxford and ENETS Centre of Excellence, Royal Free Hospital, London, UK.

Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.
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http://dx.doi.org/10.1007/s12022-021-09662-5DOI Listing
March 2021

Corticotroph tumor progression after bilateral adrenalectomy (Nelson's syndrome): systematic review and expert consensus recommendations.

Eur J Endocrinol 2021 Mar;184(3):P1-P16

Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA.

Background: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing.

Methods: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018.

Results: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients).

Conclusions: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
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http://dx.doi.org/10.1530/EJE-20-1088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060870PMC
March 2021

Distinctive features of pancreatic neuroendocrine neoplasms exhibiting an increment in proliferative activity during the course of the disease.

Endocrine 2021 04 11;72(1):279-286. Epub 2020 Nov 11.

ENETS Center of Excellence, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Purpose: Neuroendocrine neoplasms (NENs) differ in their biological behavior and growth potential in a way that can be predicted using histological classification and grading systems. A subset of pancreatic NENs (pNENs) may develop a more aggressive phenotype during the course of the disease, associated with an increase in the Ki-67 proliferation index (PI). The purpose of the study was to present the clinical characteristics of these patients.

Methods: Using re-biopsy of growing lesions, we investigated the increase in Ki-67 PI sufficient to change initial grading (G).

Results: Of 264 patients with well differentiated (WD) pNENs who showed progressive disease during follow-up, 15 (6%) exhibited an increase in Ki-67 PI at a median time 36.8 (9.3-255.8) months. All neoplasms had WD-morphology: five had G1 (Ki-67 median value 1%), nine G2 (median value 5%), one G3 (25%) grades. Upon change of Ki-67 PI, 3 patients had G2 (8%) and 12 G3 (57.5%) NENs, while all retained their WD-morphology. At last follow-up, eight patients were alive with a median overall survival (OS) of 52.5 (9.5-264.3) months. Μedian OS was shorter in patients who had a change in Ki-67 PI before 36 months compared to those who had a change of Ki-67 PI at a later stage (27.5 95%CI: 11.88-43.06 vs. 120.87 95%CI: 96.05-145.69; log-rank p = 0.018).

Conclusions: During the course of their disease, 6% patients with progressive pNENs develop an increase in Ki-67 PI resulting in an increase in grading status while maintaining their morphology. This process is associated with worse OS when it occurs at an early stage.
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http://dx.doi.org/10.1007/s12020-020-02540-wDOI Listing
April 2021

High-dose Somatostatin Analogues for Progressive Neuroendocrine Tumours.

Eur Endocrinol 2020 Oct 6;16(2):93-95. Epub 2020 Oct 6.

Green Templeton College, University of Oxford, Oxford, UK.

Neuroendocrine tumours are a heterogeneous group of neoplasms with a variety of treatment options, but studies suggest they should in most cases, if they are not curable surgically, be treated initially with monthly long-acting somatostatin analogues. New data recently published suggest that if patients show progression on the current analogues at the recommended doses, increasing the dose or frequency of these analogues may provide a further therapeutic effect, although proper randomised trials will be necessary to confirm this effect.
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http://dx.doi.org/10.17925/EE.2020.16.2.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572164PMC
October 2020

Understanding the Treatment Algorithm of Patients with Metastatic Pancreatic Neuroendocrine Neoplasms: A Single-Institution Retrospective Analysis Comparing Outcomes of Chemotherapy, Molecular Targeted Therapy, and Peptide Receptor Radionuclide Therapy in 255 Patients.

Neuroendocrinology 2021 18;111(9):863-875. Epub 2020 Sep 18.

Department of Oncology, Royal Free Hospital, London, United Kingdom.

Background: The number of therapeutic options for patients with pancreatic neuroendocrine neoplasms (PNEN) has increased, but the optimal therapeutic algorithm has not been defined due to lack of randomised trials comparing different modalities.

Methods: We performed a retrospective study in patients with metastatic PNEN treated with ≥1 line of systemic therapy. The relationship between baseline characteristics, treatment type, and time to treatment failure (TTF), time to progression (TTP), and overall survival (OS) was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model.

Results: Two hundred and fifty-five patients with metastatic PNEN had 491 evaluable lines of therapy. Independent predictors of TTF included treatment type, Ki-67, tumour grade, and chromogranin A. To reduce selection bias, a subgroup of 114 patients with grade 2 (G2) metastatic pancreatic neuroendocrine tumours (PNET) was analysed separately. These patients had received 234 lines of treatment (105 chemotherapy, 82 molecular targeted therapy, and 47 peptide receptor radionuclide therapy [PRRT]). In the G2 cohort, TTF and TTP were superior for PRRT compared with both chemotherapy and molecular targeted therapy. OS in the G2 cohort was also superior for those that had received PRRT compared with those that had not (median 84 vs. 56 months; HR 0.55, 95% CI: 0.31-0.98, p = 0.04).

Conclusions: This study suggests that PRRT is associated with superior clinical outcomes relative to other systemic therapies for G2 metastatic PNET. Prospective studies are required to confirm these observations.
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http://dx.doi.org/10.1159/000511662DOI Listing
September 2020

The role of the tumour microenvironment in the angiogenesis of pituitary tumours.

Endocrine 2020 12 18;70(3):593-606. Epub 2020 Sep 18.

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Purpose: Angiogenesis has been studied in pituitary neuroendocrine tumours (PitNETs), but the role of the tumour microenvironment (TME) in regulating PitNET angiogenesis remains unknown. We aimed to characterise the role of TME components in determining the angiogenetic PitNET profile, focusing on immune cells and tumour-derived cytokines.

Methods: Immune cells were studied by immunohistochemistry in 24 human PitNETs (16 non-functioning-PitNETs (NF-PitNETs) and 8 somatotrophinomas): macrophages (CD68, CD163, HLA-DR), cytotoxic (CD8) and T helper (CD4) lymphocytes, regulatory T cells (FOXP3), B cells (CD20) and neutrophils (neutrophil elastase); endothelial cells were assessed with CD31. Five normal pituitaries (NP) were included for comparison. Microvessel density and vascular morphology were estimated with ImageJ. The cytokine secretome from these PitNETs were assessed on culture supernatants using a multiplex immunoassay panel.

Results: Microvessel density/area was higher in NP than PitNETs, which also had rounder and more regular vessels. NF-PitNETs had vessels of increased calibre compared to somatotrophinomas. The M2:M1 macrophage ratio correlated with microvessel area. PitNETs with more CD4+ T cells had higher microvessel area, while tumours with more FOXP3+ cells were associated with lower microvessel density. PitNETs with more B cells had rounder vessels. Of the 42 PitNET-derived cytokines studied, CCL2, CXCL10 and CX3CL1 correlated with microvessel density and vessel architecture parameters.

Conclusions: M2 macrophages appear to play a role in PitNET neovascularisation, while B, CD4+ and FOXP3+ lymphocytes, as well as non-cellular TME elements such as CCL2, CXCL10 and CX3CL1, may also modulate the angiogenesis of PitNETs.
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http://dx.doi.org/10.1007/s12020-020-02478-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674353PMC
December 2020

The Impact of SARS-Cov-2 Virus Infection on the Endocrine System.

J Endocr Soc 2020 Aug 2;4(8):bvaa082. Epub 2020 Jul 2.

Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, London, UK.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has spread across the globe rapidly causing an unprecedented pandemic. Because of the novelty of the disease, the possible impact on the endocrine system is not clear. To compile a mini-review describing possible endocrine consequences of SARS-CoV-2 infection, we performed a literature survey using the key words Covid-19, Coronavirus, SARS CoV-1, SARS Cov-2, Endocrine, and related terms in medical databases including PubMed, Google Scholar, and MedARXiv from the year 2000. Additional references were identified through manual screening of bibliographies and via citations in the selected articles. The literature review is current until April 28, 2020. In light of the literature, we discuss SARS-CoV-2 and explore the endocrine consequences based on the experience with structurally-similar SARS-CoV-1. Studies from the SARS -CoV-1 epidemic have reported variable changes in the endocrine organs. SARS-CoV-2 attaches to the ACE2 system in the pancreas causing perturbation of insulin production resulting in hyperglycemic emergencies. In patients with preexisting endocrine disorders who develop COVID-19, several factors warrant management decisions. Hydrocortisone dose adjustments are required in patients with adrenal insufficiency. Identification and management of critical illness-related corticosteroid insufficiency is crucial. Patients with Cushing syndrome may have poorer outcomes because of the associated immunodeficiency and coagulopathy. Vitamin D deficiency appears to be associated with increased susceptibility or severity to SARS-CoV-2 infection, and replacement may improve outcomes. Robust strategies required for the optimal management of endocrinopathies in COVID-19 are discussed extensively in this mini-review.
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http://dx.doi.org/10.1210/jendso/bvaa082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337839PMC
August 2020

The natural history and treatment of non-functioning pituitary adenomas (non-functioning PitNETs).

Endocr Relat Cancer 2020 10;27(10):R375-R390

Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK.

Non-functioning pituitary adenomas, recently alternatively termed pituitary neuroendocrine tumours (NFpitNETs), are mostly benign neoplasms that are not associated with a hormonal hypersecretory syndrome. The clinical spectrum of NFpitNETs varies from completely asymptomatic to the development of panhypopituitarism and manifestations attributed to mass effects on nearby structures. NFpitNETs follow generally an indolent course, but in 5-10% of cases they exhibit more aggressive behaviour, characterised by rapid growth, invasiveness and early recurrence. The initial size of the adenoma, the presence of symptoms and the histological subtype are related to the natural course of NFpitNETs. Active surveillance is usually the strategy of choice in the case of an asymptomatic NFpitNET, while surgical resection is recommended in case of visual and/or neurological abnormalities or rapid tumour growth. Based on previous and emerging data, approximately 50% of patients show tumour growth, while 20% of patients with NF-macroadenomas on active surveillance may require further intervention during a follow-up period of 7 years. Adjuvant radiotherapy is usually considered for large residual tumours or recurrent and/or aggressive adenomas, but there is evidence that medical therapy, especially with cabergoline, can occasionally be beneficial, whereas newer molecular agents are under investigation. Thus, while highly effective medical therapy is awaited, a move towards a more conservative approach seems appropriate, at least until we have better molecular markers of progressiveness.
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http://dx.doi.org/10.1530/ERC-20-0136DOI Listing
October 2020

ENDOCRINOLOGY IN THE TIME OF COVID-19: Clinical management of neuroendocrine neoplasms (NENs).

Eur J Endocrinol 2020 Aug;183(2):G79-G88

Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

In viral pandemics, most specifically Covid-19, many patients with neuroendocrine neoplasms (NENs), including phaeochromocytomas, paragangliomas and medullary thyroid carcinoma, may develop Covid-19 in a mild or severe form, or be concerned about the influence of viral infection relative to their anti-tumoral therapy. In general, newly presenting patients should be assessed, and patients recently receiving chemotherapy, targeted therapy or radionuclide therapy, or showing tumour growth, should be closely followed. For previously diagnosed patients, who have indolent disease, some delay in routine follow-up or treatment may not be problematic. However, patients developing acute secretory syndromes due to functional neuroendocrine neoplasms (such as of the pancreas, intestine or lung), phaeochromocytomas and paragangliomas, will require prompt treatment. Patients with life-threatening Covid-19-related symptoms should be urgently treated and long-term anti-tumoral treatments may be temporarily delayed. In patients with especially aggressive NENs, a careful judgement should be made regarding the severity of any Covid-19 illness, tumour grade, and the immunosuppressant effects of any planned chemotherapy, immunotherapy (e.g. interferon-alpha), targeted therapy or related treatment. In other cases, especially patients with completely resected NENs, or who are under surveillance for a genetic disorder, a telephone or delayed consultation may be in order, balancing the risk of a delay against that of the possible development of Covid-19.
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http://dx.doi.org/10.1530/EJE-20-0424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938008PMC
August 2020
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