Developing new diagnostic and therapeutic approaches in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is an aggressive malignancy with high recurrence rates and poor response to chemotherapy. With this work, we have evaluated a potential new treatment target focusing on the mitochondrial NADPH generator Nicotinamide Nucleotide Transhydrogenase (NNT). NNT has a central role within the mitochondrial antioxidant pathways, which protect cells from oxidative stress. Our hypothesis was that NNT silencing will expose cells to cytotoxic levels of oxidative stress. We knocked down NNT transiently in NCJ-H295R ACC cells in vitro; this led to an increase in cellular oxidative stress and a strong cytotoxic and cytostatic effect. With stable NNT knockdown, we observed the emergence of a partially compensated phenotype over the course of time, with restored redox balance. Surprisingly, steroidogenesis was stimulated by transient NNT loss, challenging current perceptions about the impact of oxidative stress on steroidogenesis. In our clinical study, we evaluated a new diagnostic tool for biochemical detection of ACC recurrence. Serial post-operative urine samples were collected from a large cohort of patients who had undergone complete ACC resection. Standardised review of longitudinal steroid measurements resulted in detection of disease recurrence prior to or concurrently with imaging with high sensitivity in cases where a pre-operative steroid profile had been provided

Minimally invasive video-assisted parathyroidectomy (MIVAP) in the treatment of patients with primary hyperparathyroidism: a systematic review

ΥΠΟΒΑΘΡΟ: Η ανοικτή αμφοτερόπλευρη διερεύνηση του τραχήλου (BNE), υπήρξε ως πρόσφατα η επέμβαση εκλογής για τη χειρουργική θεραπεία του πρωτοπαθούς υπερπαραθυρεοειδισμού (pHPT). Τελευταία, μια στροφή προς την ελάχιστα επεμβατική παραθυρεοειδεκτομή έχει επισυμβεί. Ο σκοπός αυτής της συστηματικής ανασκόπησης είναι να συγκρίνει την ελάχιστα επεμβατική βίντεο-υποβοηθούμενη παραθυρεοειδεκτομή (MIVAP) με την παραδοσιακή BNE και τις υπόλοιπες ελάχιστα επεμβατικές τεχνικές, να επιβεβαιώσει τις ενδείξεις, τα πλεονεκτήματα και μειονεκτήματά της, και να αναζητήσει πιθανή επέκταση των υπαρχουσών ενδείξεών της. ΥΛΙΚΟ ΚΑΙ ΜΕΘΟΔΟΣ: Δεδομένα από τυχαιοποιημένες κλινικές δοκιμές, προοπτικές και αναδρομικές ανασκοπήσεις, καθώς και άλλες μελέτες συνελέγησαν από τη βάση Pubmed. Δεκατέσσερις μελέτες πραγματεύθηκαν μια άμεση σύγκριση της MIVAP με την ανοικτή BNE, ενώ 8 άλλες συνέκριναν την πρώτη με άλλες ελάχιστα επεμβατικές τεχνικές, ιδιαίτερα την ανοικτή ελάχιστα επεμβατική παραθυρεοειδεκτομή (OMIP). Επιπρόσθετες πληροφορίες συνελέγησαν από άλλες μελέτες και αφορούσαν προεκτάσεις ως προς την αναισθησία και επιπλέον πιθανές ενδείξεις για την MIVAP. Η αναγνώριση των σφαλμάτων σε αυτές τις μελέτες κατέστη δυνατή και αναφέρθηκε όπου ήταν απαραίτητο. Τα κύρια αποτελέσματα στα οποία η σύγκριση αυτή βασίσθηκε ήταν η ασφάλεια, η αποτελεσματικότητα, το κοσμητικό αποτέλεσμα, ο μετεγχειρητικός πόνος, η διάρκεια της νοσηλείας στο νοσοκομείο, ο εγχειρητικός χρόνος και το κόστος. ΑΠΟΤΕΛΕΣΜΑΤΑ: Η MIVAP έχει σταθερά επιδείξει ίδια ποσοστά ίασης (ως και 98%) με την ανοικτή BNE, με παρόμοιους αριθμούς επιπλοκών, που κυμαίνονται από 2,7% ως 7,7% για παροδική υπασβεστιαιμία και <1% για μόνιμη πάρεση του παλίνδρομου λαρυγγικού νεύρου. Επιδεικνύει υπεροχή όσον αφορά το κοσμητικό αποτέλεσμα, με μικρότερες τομές (1,5-2 εκ.) και μεγαλύτερη ικανοποίηση των ασθενών (που προσεγγίζει το 90%) βραχυπρόθεσμα και μακροπρόθεσμα. Επιπρόσθετα, η MIVAP συνδέεται με μειωμένο μετεγχειρητικό πόνο και απαιτήσεις σε αναλγησία, μειωμένη διάρκεια νοσηλείας στο νοσοκομείο και εγχειρητικό χρόνο, καλύτερη αναγνώριση του παλίνδρομου λαρυγγικού νεύρου, και επίσης προσφέρει τη δυνατότητα για βίντεο-υποβοηθούμενη αμφοτερόπλευρη διερεύνηση του τραχήλου (BNE) και θεραπεία σύγχρονης παθολογίας του θυρεοειδούς αδένα. Τα ποσοστά μετατροπής κυμαίνονται από 0,9% ως 8% στις περισσότερες μελέτες. Εν τούτοις, η MIVAP είναι πιο ακριβή από την BNE, παρόλα αυτά η σχέση κόστους- αποτελεσματικότητας της τεχνικής συνεχώς βελτιώνεται. Τα ίδια πλεονεκτήματα ισχύουν όταν συγκρίνεται η MIVAP με την OMIP, με εξαίρεση τον εγχειρητικό χρόνο και το κόστος, όπου η τελευταία πλεονεκτεί (25% λιγότερο ακριβή από την MIVAP). Είναι επίσης ιδανική για αδενώματα που εντοπίζονται σε οπίσθιο ή εν τω βάθει πλάνο. Επίσης, η MIVAP είναι περισσότερο αξιόπιστη από την γάμμα κεφαλή [63] (gamma probe) που χρησιμοποιείται στην ελάχιστα επεμβατική ραδιο- υποβοηθούμενη παραθυρεοειδεκτομή (MIRP), έχει λιγότερες αντενδείξεις από την βίντεο-υποβοηθούμενη παραθυρεοειδεκτομή μέσω πλάγιας προσπέλασης (VAPLA) και την ενδοσκοπική παραθυρεοειδεκτομή (EP), και δύναται να χρησιμοποιηθεί σε περιπτώσεις πολυαδενικής νόσου, οικογενούς και δευτεροπαθούς υπερπαραθυρεοειδισμού, λόγω της ικανότητάς της για διενέργεια βίντεο- υποβοηθούμενης BNE. ΣΥΜΠΕΡΑΣΜΑΤΑ: Η MIVAP είναι ανώτερη της ανοικτής BNE για τη θεραπεία επιλεγμένων περιπτώσεων πρωτοπαθούς υπερπαραθυρεοειδισμού (μονήρη, καλώς εντοπισμένα αδενώματα παραθυρεοειδών), καθώς όχι μόνο είναι εξίσου ασφαλής και αποτελεσματική με τη δεύτερη, αλλά ακόμη επιδεικνύει σημαντικά πλεονεκτήματα όσον αφορά το κοσμητικό αποτέλεσμα, το μετεγχειρητικό πόνο, και την ικανοποίηση των ασθενών. Επιπρόσθετα, είναι προτιμότερη από άλλες ελάχιστα επεμβατικές τεχνικές, καθώς επιτρέπει βίντεο-υποβοηθούμενη BNE και ταυτόχρονη θεραπεία παθήσεων του θυρεοειδούς αδένα. Το σχετιζόμενο κόστος αποτελεί ένα ζήτημα, αλλά είναι κάτι που συνεχώς βελτιώνεται. Μια επέκταση του υπάρχοντος φάσματος ενδείξεων της MIVAP επιχειρείται, για θεραπεία της παλυαδενικής νόσου, του οικογενούς και δευτεροπαθούς υπερπαραθυρεοειδισμού, με ενθαρρυντικά αποτελέσματα, δίνοντας κίνητρα για μελλοντική έρευνα στο ρόλο αυτής της τεχνικής στη χειρουργική αντιμετώπισης της κοινής αυτής ενδοκρινικής νόσου.BACKGROUND: Open bilateral neck exploration (BNE) has until recently been the gold standard for the surgical treatment of primary hyperparathyroidism (pHPT). Lately, a shift towards minimally invasive parathyroidectomy has occurred. The aim of this systematic review is to compare minimally invasive video-assisted parathyroidectomy (MIVAP) with traditional BNE and the remaining minimally invasive techniques, confirm its indications, advantages and drawbacks, and seek for potential expansion of its current indications. MATERIAL AND METHODS: Data from randomised control trials, prospective and retrospective reviews, as well as other studies, were collected from Pubmed. Fourteen studies contemplated a direct comparison of MIVAP with open BNE, while 8 others compared the former with other minimally invasive techniques, especially open minimally invasive parathyroidectomy (OMIP). Additional information was collected from other reviews regarding anaesthetic implications and further potential indications for MIVAP. Recognition of bias in these studies was achieved and mentioned where appropriate. The main outcomes on which this comparison has been founded were safety, effectiveness, cosmesis, post-operative pain, length of hospital stay, operative time and cost. RESULTS: MIVAP has consistently demonstrated equal cure rates (up to 98%) as open BNE, with similar numbers of complications, ranging from 2.7-7.7% for transient hypocalcaemia and <1% for permanent RLN palsy. It shows superiority in terms of cosmetic outcome, with smaller incisions (1.5-2cm) and greater patient satisfaction (approaching 90%) in the short and long term. Furthermore, MIVAP is associated with reduced post-operative pain and analgesia requirements, diminished length of hospital stay and operative time, better visualisation of the RLN, in addition to providing the opportunity for video-assisted BNE and treatment of concurrent thyroid pathology. Conversion rates range from 0.9% to 8% in most studies. Nevertheless, MIVAP is more expensive than BNE, however the cost-effectiveness of the procedure is continuously being improved. The same advantages apply when comparing MIVAP to OMIP, with the exception of operative time and cost, where the latter supersedes (25% less expensive than MIVAP). It is also ideal for posteriorly or deeply located adenomas. MIVAP is also more reliable than the gamma probe used in minimally invasive radio-guided parathyroidectomy (MIRP), has fewer contraindications than video-assisted parathyroidectomy by the lateral approach (VAPLA) and endoscopic parathyroidectomy (EP), and may be considered for cases of multiglandular disease, familial and secondary hyperparathyroidism, due to its ability to perform video-assisted BNE. CONCLUSIONS: MIVAP is superior to open BNE for the treatment of selected cases of pHPT (solitary, well-localised parathyroid adenomas), as it not only is similarly [61] safe and effective as the latter, but also displays significant advantages in terms of cosmesis, post-operative pain and patient satisfaction. In addition, it is preferred to other minimally invasive techniques, as it allows for video-assisted BNE and simultaneous treatment of thyroid disease. Associated cost is an issue but this is constantly being improved. An expansion of the existing spectrum of indications for MIVAP is being attempted, for treatment of multiglandular disease, familial and secondary hyperparathyroidism, with encouraging results, motivating future research in this technique’s role for the surgical managment of this common endocrinopathy

Pheochromocytomas Most Commonly Present As Adrenal Incidentalomas:A Large Tertiary Center Experience

Context: Pheochromocytomas are increasingly diagnosed in incidentally detected adrenal masses. However, the characteristics of incidental pheochromocytomas are unclear.Objective: We aimed to assess the proportion and clinical, biochemical, radiological, genetic, histopathological, and follow-up characteristics of incidental pheochromocytomas.Methods: A retrospective review was conducted of patients with pheochromocytoma seen between January 2010 and October 2022 at a large UK tertiary care center. The diagnosis was confirmed histologically or by the combined presence of increased plasma and/or urinary metanephrines (MN), indeterminate adrenal mass on cross-sectional imaging, and metaiodobenzylguanidine avidity.Results: We identified 167 patients with pheochromocytoma; 144 (86.2%) underwent adrenalectomy, for 23 (13.8%) surgery was either awaited, deemed unsuitable due to frailty or other metastatic malignancy, or declined by the patients. Excluding pheochromocytomas diagnosed via screening genetically predisposed individuals (N = 20), 37 of 132 (28.0%) presented with adrenergic symptoms and/or uncontrolled hypertension, while 91 of 132 (69.0%) patients presented with an incidentally detected adrenal mass. Incidentally detected patients were older (median age 62 years) than those detected due to clinical suspicion (aged 42 years) or after genetic screening (aged 33 years) (all P < .05). Incidentally detected pheochromocytomas were smaller (median 42 mm) than tumors detected due to adrenergic symptoms/uncontrolled hypertension (60 mm), but larger than tumors identified by genetic screening (30 mm) (all P < .05). Increased MN excretion showed a similar pattern (symptomatic/uncontrolled hypertension > incidental > genetic screening) (all P < .05). Hereditary predisposition was detected in 20.4% of patients (incidental, 15.3%; symptomatic/uncontrolled hypertension, 42.9%).Conclusion: The majority of pheochromocytomas are diagnosed incidentally and have distinct clinical, radiological, biochemical, and genetic features. Their detection at older age but smaller size may point to a different underlying tumor biology

Centrifuge modeling of the impact of local and global scour erosion on the monotonic lateral response of a monopile in sand

Copyright © 2020 by ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. The majority of offshore wind turbines are founded on large-diameter, open-ended steel monopiles. Monopiles must resist lateral loads and overturning moments because of environmental (wind and wave) actions, whereas vertical loads tend to be comparatively small. Recent developments in turbine sizes and increases in hub heights have resulted in pile diameters increasing rapidly, whereas the embedment length to diameter ratio (L/D) is reducing. Soil erosion around piles, termed scour, changes the soil strength and stiffness properties and affects the system's load resistance characteristics. In practice, design scour depths of up to 1.3D are routinely assumed during the turbine lifetime; however, the impact on monopiles with low L/D is not yet fully understood. In this article, centrifuge tests are performed to assess the effect of scour on the performance of piles with low L/D. In particular, the effect of combined loads, scour type (global, local), and depth are considered. A loading system is developed that enables application of realistic load eccentricity and combined vertical, horizontal, and moment loading at the seabed level. An instrumented 1.8-m-diameter pile with L/D = 5 is used. A friction-reducing ball-type connection is designed to transfer lateral loads to the pile without inducing any rotational pile-head constraint, which is associated with loading rigs in tests of this nature. Results suggest that vertical and lateral load interaction is minimal. Scour has a significant impact on the lateral load-bearing capacity and stiffness of the pile, leads to increases in bending moment magnitude along the pile shaft, and lowers the location of peak pile bending moment. The response varies with scour type, with global scour resulting in larger moments than local scour. The size of the local scour hole is found to have a significant impact on the pile response, suggesting that scour hole width should be explicitly considered in design

Bilateral testicular tumors resulting in recurrent Cushing's syndrome after bilateral adrenalectomy

Contains fulltext : 170123.pdf (publisher's version ) (Closed access)Context: Recurrence of hypercortisolism in patients after bilateral adrenalectomy for Cushing disease is extremely rare. Patient: We present a 27-year-old man who previously underwent bilateral adrenalectomy for Cushing disease with complete clinical resolution. Cushingoid features recurred 12 years later, with bilateral testicular enlargement. Hormonal tests confirmed adrenocorticotropic hormone (ACTH)-dependent Cushing disease. Surgical resection of the testicular tumors led to clinical and biochemical remission. Design and Results: Gene expression analysis of the tumor tissue by quantitative polymerase chain reaction showed high expression of all key steroidogenic enzymes. Adrenocortical-specific genes were 5.1 x 105 (CYP11B1), 1.8 x 102 (CYP11B2), and 6.3 x 104 (MC2R) times higher than nonsteroidogenic fibroblast control. This correlated with urine steroid metabolome profiling showing 2 fivefold increases in the excretion of the metabolites of 11-deoxycortisol, 21-deoxycortisol, and total glucocorticoids. Leydig-specific genes were 4.3 x 101 (LHCGR) and 9.3 x 100 (HSD17B3) times higher than control, and urinary steroid profiling showed twofold increased excretion of the major androgen metabolites androsterone and etiocholanolone. These distinctly increased steroid metabolites were suppressed by dexamethasone but unresponsive to human chorionic gonadotropin stimulation, supporting the role of ACTH, but not luteinizing hormone, in regulating tumor-specific steroid excess. Conclusion: We report bilateral testicular tumors occurring in a patient with recurrent Cushing disease 12 years after bilateral adrenalectomy. Using mRNA expression analysis and steroid metabolome profiling, the tumors demonstrated both adrenocortical and gonadal steroidogenic properties, similar to testicular adrenal rest tumors found in patients with congenital adrenal hyperplasia, suggesting the presence of pluripotent cells even in patients without congenital adrenal hyperplasia

Primary adrenal insufficiency is associated with impaired natural killer cell function:a potential link to increased mortality

Objective Mortality in patients with primary adrenal insufficiency (PAI) is significantly increased, with respiratory infections as a major cause of death. Moreover, patients with PAI report an increased rate of non-fatal infections. Neutrophils and natural killer (NK) cells are innate immune cells that provide frontline protection against invading pathogens. Thus, we compared the function and phenotype of NK cells and neutrophils isolated from PAI patients and healthy controls to ascertain whether altered innate immune responses could be a contributory factor for the increased susceptibility of PAI patients to infection. Design and methods We undertook a cross-sectional study of 42 patients with PAI due to autoimmune adrenalitis (n = 37) or bilateral adrenalectomy (n = 5) and 58 sex- and age-matched controls. A comprehensive screen of innate immune function, consisting of measurements of neutrophil phagocytosis, reactive oxygen species production, NK cell cytotoxicity (NKCC) and NK cell surface receptor expression, was performed on all subjects. Results Neutrophil function did not differ between PAI and controls. However, NKCC was significantly reduced in PAI (12.0 ± 1.5% vs 21.1 ± 2.6%, P &lt; 0.0001). Phenotypically, the percentage of NK cells expressing the activating receptors NKG2D and NKp46 was significantly lower in PAI, as was the surface density of NKG2D (all P &lt; 0.0001). Intracellular granzyme B expression was significantly increased in NK cells from PAI patients (P &lt; 0.01). Conclusions Adrenal insufficiency is associated with significantly decreased NKCC, thereby potentially compromising early recognition and elimination of virally infected cells. This potential impairment in anti-viral immune defense may contribute to the increased rate of respiratory infections and ultimately mortality in PAI. </jats:sec

Mitotane treatment in patients with metastatic testicular Leydig cell tutor associated with severe androgen excess

Mitotane (o,p′DDD) is established in the adjuvant and advanced-stage treatment of adrenocortical carcinoma and counteracts both tumor growth and tumor-related steroid production. Both the adrenal glands and the gonads are steroidogenically active organs and share a common embryogenic origin. Here, we describe the effects of mitotane in two patients with metastatic Leydig cell tumor (LCT) of the testes and associated severe androgen excess (serum testosterone 93 and 88 nmol/L, respectively; male reference range 7–27 nmol/L). Both men suffered from severe restlessness, insomnia and irritability, which they described as intolerable and disrupting normal life activities. Urinary steroid profiling by gas chromatography–mass spectrometry (GC–MS) confirmed excess androgen production and revealed concurrent overproduction of glucocorticoids and glucocorticoid precursors, which under physiological conditions are produced only by the adrenal glands but not by the gonads. In a palliative approach, they were commenced on mitotane, which achieved swift control of the hormone excess and the debilitating clinical symptoms, restoring normal quality of life. GC–MS demonstrated normalization of steroid production and decreased 5α-reductase activity, resulting in decreased androgen activation, and imaging demonstrated disease stabilization for 4–10 months. In conclusion, mitotane can be highly effective in controlling steroid excess in metastatic LCTs, with anti-tumor activity in some cases.</jats:p