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Aim: This guideline (GL) is aimed at providing a reference for the management of non-functioning, benign thyroid nodules causing local symptoms in adults outside of pregnancy. Methods: This GL has been developed following the methods described in the Manual of the National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology(AME) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as “critical” and “important” were considered in the systematic review of evidence and only those classified as “critical” were considered in the formulation of recommendations. Results: The present GL contains recommendations about the respective roles of surgery and minimally invasive treatments for the management of benign symptomatic thyroid nodules. We suggest hemithyroidectomy plus isthmectomy as the first-choice surgical treatment, provided that clinically significant disease is not present in the contralateral thyroid lobe. Total thyroidectomy should be considered for patients with clinically significant disease in the contralateral thyroid lobe. We suggest considering thermo-ablation as an alternative option to surgery for patients with a symptomatic, solid, benign, single, or dominant thyroid nodule. These recommendations apply to outpatients, either in primary care or when referred to specialists. Conclusion: The present GL is directed to endocrinologists, surgeons, and interventional radiologists working in hospitals, in territorial services, or private practice, general practitioners, and patients. The available data suggest that the implementation of this GL recommendations will result in the progressive reduction of surgical procedures for benign thyroid nodular disease, with a decreased number of admissions to surgical departments for non-malignant conditions and more rapid access to patients with thyroid cancer. Importantly, a reduction of indirect costs due to long-term replacement therapy and the management of surgical complications may also be speculated.

Although adrenocortical carcinoma (ACC) during pregnancy is rare, a retrospective review of a case series at our hospital revealed that almost one third of our patients were women in childbearing age. Given that the age of maternity is increasing, dealing with a tumor diagnosis during pregnancy and the need for fertility planning in cancer survivors is likely to become more frequent.We thus carried out a case-based discussion regarding: i) diagnosing and treating an ACC during pregnancy; ii) patients conceiving while on mitotane; iii) ACC survivors with a maternal desire.In each of these cases, it is important to provide patients with sufficient information, to offer medical advice and psychological support, to personalize treatments in accordance with the wishes of the patient and her relatives, and to collaborate with other specialists since a multidisciplinary expert team is required to manage each case individually.

Background\ud \ud The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing).\ud \ud \ud \ud Methods\ud \ud We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800–0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50–138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants.\ud \ud \ud \ud Findings\ud \ud Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53–68]; median follow-up 7·0 years [IQR 4·7–10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19–1·94) and autonomous cortisol secretion (1·77, 1·20–2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93–9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values

Purpose The impact of patient’s characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. Methods We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. Results At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). Conclusions Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

Up to 70% of adrenal masses detected in patients affected by extra-adrenal malignancy are metastatic lesions. Therefore, detection of an adrenal mass in patients with active or previous malignancy requires a careful differential diagnostic workup. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) is increasingly being used to determine the malignant potential of adrenal lesions. We report the case of a 64-year-old man who had a single adrenal metastasis due to non-small-cell lung carcinoma developing on a pre-existing benign adrenal lesion. This metastasis occurred in a phase of perceived oncological remission and was detected thanks to 18F-FDG-PET/CT showing a focal adrenal uptake. Contrast-enhanced computed tomography (CT), performed as part of oncological follow-up, and MRI with chemical shift sequences did not lead to the correct diagnosis. The patient underwent laparoscopic adrenalectomy and the pathological evaluation confirmed a lung carcinoma metastasis. The present case highlights the peculiarity of the follow-up of adrenal masses in cancer patients and the primary role of 18F-FDG-PET/CT in the management of such patients.

Several studies demonstrated the diagnostic accuracy of hair glucocorticoid measurement in patients with overt Cushing syndrome, but few data are available for patients with adrenal incidentaloma (AI) and cortisol autonomy. The aim of our study was to assess whether measurement of 5 corticosteroid hormones with the ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method in the keratin matrix is useful to stratify patients with AI by the presence of autonomous cortisol secretion [ACS] (defined as serum cortisol after 1 mg dexamethasone suppression test (DST) > 138 nmol/l) or possible ACS [PACS] (defined as serum cortisol after 1 mg DST > 50 nmol/l but ≤138 nmol/l). We analysed data of 67 AI patients (32 with cortisol autonomy) and 81 healthy subjects. We did not find any significant statistical difference comparing hair cortisol, cortisone, and 20β-dihydrocortisol concentrations between healthy controls and AI patients, while 6β-hydroxycortisol and 11-deoxycortisol were undetectable. Moreover, no significant difference was found in hair cortisol, cortisone, and 20β-dihydrocortisol levels of AI patients with or without cortisol autonomy. Finally, we did not find any correlation in patients with AI between hormonal concentrations in the keratin matrix and serum, salivary, and urinary cortisol levels, or with body mass index. In conclusion, our findings suggest that hair glucocorticoid measurement is not suitable as a diagnostic test for cortisol autonomy (ACS and PACS).

Sodium-glucose cotransporters inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA) are glucose-lowering drugs that are proved to reduce the cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM). In this process, the renin-angiotensin-aldosterone system (RAAS) is assumed to play a role. The inhibition of SGLT2 improves hyperglycemia hampering urinary reabsorption of glucose and inducing glycosuria. This “hybrid” diuretic effect, which couples natriuresis with osmotic diuresis, potentially leads to systemic RAAS activation. However, the association between SGLT2-i and systemic RAAS activation is not straightforward. Available data indicate that SGLT2-i cause plasma renin activity (PRA) increase in the early phase of treatment, while PRA and aldosterone levels remain unchanged in chronic treated patients. Furthermore, emerging studies provide evidence that SGLT2-i might have an interfering effect on aldosterone/renin ratio (ARR) in patients with T2DM, due to their diuretic and sympathoinhibition effects. The cardio- and reno-protective effects of GLP-1-RA are at least in part related to the interaction with RAAS. In particular, GLP1-RA counteract the action of angiotensin II (ANG II) inhibiting its synthesis, increasing the inactivation of its circulating form and contrasting its action on target tissue like glomerular endothelial cells and cardiomyocytes. Furthermore, GLP1-RA stimulate natriuresis inhibiting Na+/H+ exchanger NHE-3, which is conversely activated by ANG II. Moreover, GLP1 infusion acutely reduces circulating aldosterone, but this effect does not seem to be chronically maintained in patients treated with GLP1-RA. In conclusion, both SGLT2-i and GLP1-RA seem to have several effects on RAAS, though additional studies are needed to clarify this relationship.

Simple Summary Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and for postoperative adjuvant therapy. It is known that mitotane destroys the adrenal cortex impairing steroidogenesis, although its exact molecular mechanism is still unclear. However, confounding factors affecting in vitro experiments could reduce the relevance of the studies. In this review, we explore in vitro studies on mitotane effects, highlighting how different experimental conditions might contribute to the controversial findings. On this basis, it may be necessary to re-evaluate the experiments taking into account their potential confounding factors such as cell strains, culture serum, lipoprotein concentration, and culture passages, which could hide important molecular results. As a consequence, the identification of novel pharmacological molecular pathways might be used in the future to implement personalized therapy, maximizing the benefit of mitotane treatment while minimizing its toxicity. Abstract Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and is increasingly used for postoperative adjuvant therapy. Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. Although it is known that mitotane destroys the adrenal cortex and impairs steroidogenesis, its exact mechanism of action is still unclear. The most used cell models are H295-derived cell strains and SW13 cell lines. The diverging results obtained in presumably identical cell lines highlight the need for a stable in vitro model and/or a standard methodology to perform experiments on H295 strains. The presence of several enzymatic targets responsive to mitotane in mitochondria and mitochondria-associated membranes causes progressive alteration in mitochondrial structure when cells were exposed to mitotane. Confounding factors of culture affecting in vitro experiments could reduce the significance of any molecular mechanism identified in vitro. To ensure experimental reproducibility, particular care should be taken in the choice of culture conditions: aspects such as cell strains, culture serum, lipoproteins concentration, and culture passages should be carefully considered and explicated in the presentation of results. We aimed to review in vitro studies on mitotane effects, highlighting how different experimental conditions might contribute to the controversial findings. If the concerns pointed out in this review will be overcome, the new insights into mitotane mechanism of action observed in-vitro could allow the identification of novel pharmacological molecular pathways to be used to implement personalized therapy.

Adrenocortical carcinoma (ACC) is an aggressive cancer with poor long-term survival. Apart from radical surgery, there is a reduced range of therapeutic possibilities, and mitotane remains the cornerstone of the treatment in the adjuvant and palliative setting. Although many decades after its introduction in clinical practice, there are still many uncertainties surrounding the applied use and the actual benefit of this old drug. Recent adrenocortical carcinoma guidelines suggest adjuvant mitotane for patients at high risk of recurrence and chemotherapy plus mitotane for metastatic disease; moreover, the use of mitotane monotherapy has been proposed in a subset of patients. When using mitotane, physicians have to consider and manage its potential toxicity and endocrine effects that need a complex supporting therapy.

Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I–II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58–4.91; P P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.

Purpose The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing’s syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript. Methods Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]). Results Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ − 1.9; P P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ − 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ − 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms. Conclusions Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. &lt, 50-year category, HR 3.46, 95% CI 1.67–7.15, p &lt, 0.001 for &gt, 60- vs. &lt, 50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.

Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and mitotane remains the cornerstone of medical treatment of ACC in either adjuvant or palliative settings. The aim of adjuvant mitotane therapy is to reduce the risk of ACC recurrence following surgical removal of the tumor. Use of mitotane in an adjuvant setting is off-label, but the recent guidelines endorsed by the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) recommend it in ACC patients at high risk of recurrence. The palliative use of mitotane for treatment of advanced ACC aims at controlling tumor progression and, when present, hormone secretion. In this clinical setting, mitotane is used in association with chemotherapy to treat the more aggressive forms, while mitotane monotherapy is reserved for less progressive ACC. Many years after its introduction in clinical practice, there are still uncertainties surrounding the use of this old drug and the derived benefits. Moreover, physicians who use mitotane should recognize and manage the systemic effects of the drug that need a complex supporting therapy.

Mitotane is widely used for the treatment of adrenocortical cancer (ACC), although the drug-related toxicity complicates its use. The aim of this study is to assess comprehensively the different endocrine and metabolic unwanted effects of the drug, and to provide data on the supportive therapies. We retrospectively analyzed 74 ACC patients adjuvantly treated with mitotane for &ge, 12 months. During the treatment period (40 months, 12&ndash, 195), 32.4% of patients needed replacement therapy for mineralocorticoid deficit, 36.2% for hypothyroidism and 34.3% for male hypogonadism. In fertile women, hypogonadism was uncommon, while 65.4% of women developed ovarian cysts. Although no significant change in low-density lipoprotein (LDL) was observed, statins were started in 50% of patients for a significant increase in total cholesterol and triglycerides. Dyslipidemia occurred early, after a median time of 6 months from mitotane start. Conversely, testosterone replacement was usually started after &gt, 2 years. In many cases, ranging from 29.4% to 50% according to the side effect, toxicity occurred well before the achievement of the target mitotane concentrations. Supportive therapies were able to revert the biochemical alterations induced by mitotane, although higher doses were needed for a likely pharmacokinetic interaction of exogenous steroids and statins with mitotane. In conclusion, adjuvant mitotane therapy is associated with a spectrum of unwanted effects encompassing the function of different endocrine glands and requires a careful clinical and biochemical assessment associated with the therapeutic drug monitoring.

Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for &ge, 3 months, with &ge, 3 measurements of plasma mitotane reported in the Lysosafe Online&reg, database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism. In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of some oxysterols. To verify the possible mechanistic involvement of oxysterols in the anti-ACC effect of mitotane, a gas chromatography mass spectrometry (GC-MS) profiling of oxysterols and the main cholesterol precursors was carried out in H295R cells. Among the oxysterols detected in mitotane-treated cells, 27OHC was markedly produced, as well as lanosterol and lathosterol cholesterol precursors. In this cell model, mitotane was confirmed to affect mitochondrial transmembrane potential and induce apoptosis. Such cytotoxic effects were perfectly matched by H295R cell treatment with a single identical micromolar amount of 27OHC. The mitotane-dependent strong increase in 27OHC was confirmed in vivo, in the plasma of ACC patients under treatment with the drug. Moreover, lanosterol, lathosterol, desmosterol and, to a minor extent, 24-hydroxycholesterol and 25-hydroxycholesterol plasma levels were significantly increased in those patients. The cytotoxic effect of mitotane on ACC cells may be partly related to the increased intracellular level of 27OHC induced by the drug itself.

The literature on an association between acromegaly and cancer is particularly abundant on either colorectal cancer or thyroid cancer, and an endless debate is ongoing whether patients with acromegaly should be submitted to specific oncology screening and surveillance protocols. The aim of the present work is to review the most recent data on the risk of either colorectal cancer or thyroid cancer in acromegaly and discuss the opportunity for specific screening in relation to the accepted procedures in the general population.

Adrenocortical carcinoma (ACC) is a rare tumor characterized by poor prognosis in most cases. Moreover, in most cases ACC produces an excess of adrenal steroid hormones with relevant clinical consequences. Areas covered: After an extensive literature search, this narrative review addresses diagnostic management, including hormonal, radiological and pathological assessment, and treatment, which should be directed toward both cancer and hormone related problems. While surgery is the first option in ACC without evidence of metastatic disease, and the only possibility of cure, the therapeutic management of metastatic patients is centered on systemic therapy including mitotane alone or in combination with chemotherapy. Mitotane is also used in the adjuvant setting, because up to 80% of patients with nonmetastatic ACC show locoregional or distant metastases after an apparent complete surgical excision. Expert commentary: Management of ACC patients is fraught with many difficulties and should be limited to experienced physicians. Each step of clinical management, such as diagnosis, prognostication, treatment (both surgical and medical) is challenging and carries the possibility of severe mistakes. For this reason, each step of the management strategy should be decided in the setting of a multidisciplinary team including different expertise (endocrinology, radiology, pathology, oncology), in expert centers.

Adrenocortical carcinoma (ACC) is a rare and aggressive tumor. ACC may be associated with different syndromes of hormone excess, most frequently Cushing's syndrome with or without hypersecretion of androgens. Recent data suggest that cortisol excess is a negative prognostic factor in advanced and localized ACC. Surgery with radical intent, when feasible, is the most effective treatment for ACC with hypercortisolism. Mitotane is the medical treatment of choice, both postoperatively and in inoperable or metastatic cases. Because of its slow onset of action, combination with other antisecretory agents (ie, metyrapone) is helpful to achieve more rapid and effective control of hypercortisolism.

Background: The ESE-ENSAT guidelines on the management of adrenocortical carcinoma (ACC) suggest adjuvant mitotane for patients at high risk of recurrence following radical surgery. This indication has a limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in ACC patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane (MIT) or observation (OBS). The primary endpoint of the study was RFS. Patients who refused randomization were offered inclusion in the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in the ADIUVO study. A total of 91 patients were enrolled in ADIUVO, 45 in the MIT and 46 in the OBS arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with MIT and OBS groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohorts could be analyzed in parallel to those of ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. Tumor size was a predictor of RFS in multivariable analysis. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55–3.32, p=0.54) and HR for death 2.171 (95%CI, 0.52–12.12, p=0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed the findings of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-year RFS is about 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care.

Objective Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic–pituitary–adrenal axis in patients with ACC receiving mitotane. Design and methods We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. Results We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04–275.00) vs 24.53 (6.16–121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32–275.00) vs 67.43 (8.8–179.52) pmol/L P = 0.016). Conclusions The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.

Context The frequency of adrenal incidentalomas and their association with comorbid conditions have been assessed mostly in retrospective studies that may be prone to ascertainment bias. Objective The objective of this work is to evaluate the frequency of adrenal incidentalomas and their associated comorbid conditions. Design A prospective cohort study was conducted. Setting This study took place at a radiology department at a public hospital. Participants Unselected outpatients who underwent an abdominal computed tomography (CT) from January 2017 to June 2018. Patients with known or suspected adrenal disease or malignancy were excluded. Exposure All abdominal CT scans were evaluated by an experienced radiologist. Hormonal workup including a 1-mg dexamethasone suppression test was performed in patients bearing adrenal incidentalomas. Main Outcome and Measure Frequency of adrenal incidentalomas in abdominal CT of unselected patients; frequency of comorbid conditions, and hormonal workup in patients bearing adrenal incidentalomas. Results We recruited 601 patients, and in 7.3% of them an adrenal tumor was found serendipitously. The patients bearing an adrenal incidentaloma had higher body mass index (P = .009) and waist circumference (P = .004) and were more frequently diabetic (P = .0038). At multivariable regression analysis, diabetes was significantly associated with the presence of adrenal incidentalomas (P = .003). Autonomous cortisol secretion was observed in 50% of patients who did not suppress cortisol less than 50 nmol/L after 1 mg dexamethasone. Conclusions The frequency of adrenal incidentalomas is higher than previously reported. Moreover, adrenal incidentalomas are tied to increased risk of type 2 diabetes. This finding is free from ascertainment bias because patients with adrenal incidentalomas were drawn from a prospective cohort with the same risk of diabetes as the background population.

The value of salivary cortisol measurement to study stress-related adrenal response is controversial. The study aim was to assess the role of salivary cortisol measurement to detect time-related changes of adrenal response in critically ill patients.Patients with organ failure, sepsis or trauma were prospectively recruited in the Emergency Department. Serum and salivary cortisol were measured at baseline (T0) and after 48 h (T48). In 33 patients ACTH test was also done.Fifty-five patients were studied and classified as septic (22) or non-septic (33). We found a significant correlation between serum and salivary cortisol at T0 and T48. No patient had baseline serum cortisol276 nmol/L and salivary cortisol significantly decreased at T48 in almost all patients. A delta serum cortisol250 nmol/L after ACTH was found in only 4 patients who showed elevated baseline cortisol levels.We found that reduced baseline and post-ACTH cortisol levels are uncommon in our samples. In patients able to provide adequate saliva samples, salivary cortisol may be used to check the degree of stress-induced response and appears as a suitable tool for multiple measurements over time.

Context. The widespread use of cross-sectional imaging in medical practice has increased detection of adrenal tumors, which are most frequently unexpected prior to their discovery (adrenal incidentalomas). Most adrenal incidentalomas (AI) are benign and frequently cause low-grade cortisol excess that may portend adverse clinical consequences. However, this association is subject to confounding by indication since more diagnostic tests are done in diseased patients. Objective. To assess prospectively the prevalence of AI in an unselected adult population performing abdominal CT in our catchment area, and to evaluate the demographic, laboratory and clinical features of AI patients. Design and setting. Monocentric, prospective study. Patients. A consecutive series of 601 unselected patients undergoing abdominal CT as part of their management. Patients with any known adrenal disorder or malignancy were excluded. Results. Of the 601 patients, aged 63.5 ± 14.4 years, 55.4% had hypertension, 15.1% diabetes, 16.8% dyslipidemia and 16% previous CV events. These characteristics are overall comparable to the background general population. We found serendipitously 44 adrenal tumors (7.3%), 43 with radiological features of benign cortical adenoma (density 5.0 μg/dL). Post-DST cortisol levels were not different between diabetic and non-diabetic AI patients (3.5 ± 4.0 µg/dL vs. 2.4 ± 2.5 µg/dL). In multivariate analysis, diabetes was significantly associated with AI (p=0.003). Conclusions. We confirm in a prospective study the high prevalence of previously unsuspected adrenal tumors, most of which are benign adenomas. Moreover, we found a significant association between adrenal incidentalomas and diabetes. Since our patients were recruited at the radiology department, this finding is not confounded by selection bias.

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28−62) with a median maintenance dose of 2.0 g/day (IQR 1.5−2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5−19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7−M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88−0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

The GH-receptor antagonist pegvisomant (PEG) reduces peripheral IGF-1 synthesis and is used to treat acromegaly patients resistant or intolerant to somatostatin analogues (SSA). Medical therapy is generally life-long in patients with acromegaly, since disease remission is very uncommon after SSA discontinuation and has never been reported after PEG withdrawal. Here, we report for the first time the cases of two acromegaly patients treated with PEG monotherapy for many years because of resistance to SSA, who persistently maintained normal serum IGF-1 levels after PEG withdrawal. The first patient autonomously discontinued PEG treatment after 8 years, while in the second case we stopped the treatment after 11 years, because slight hypertransaminasemia occurred. After PEG discontinuation, in both cases IGF-1 values remained persistently normal and GH during OGTT regularly suppressed. To date, both patients are still in remission. Therefore, we suggest that PEG could exert unknown antitumoral effects in pituitary tumor cells and that long-term PEG treatment can induce acromegaly remission in some patients.

Hypertension is one of the most frequent complications in acromegaly, with a median frequency of 33.6% (range, 11%-54.7%). Although the pathogenesis has not been fully elucidated, it probably results from concomitant factors leading to expansion of extracellular fluid volume, increase of peripheral vascular resistance, and development of sleep apnea syndrome. Because the effect of normalization of growth hormone and insulinlike growth factor 1 excess on blood pressure levels is unclear, an early diagnosis of hypertension and prompt antihypertensive treatment are eagerly recommended, regardless of the specific treatment of the acromegalic disease and the level of biochemical control attained.

A large percentage of patients affected by SARS-CoV-2 disease (COVID) have associated comorbidities such as arterial hypertension, obesity, diabetes mellitus and thrombophilia. On the contrary, the prevalence in COVID patients of diseases of the adrenal glands has not been reported. Since the visualization of the adrenal glands is almost always available in chest CT performed in patients with suspected or confirmed SARS-CoV-2 infection, the evaluation of the frequency and characteristics of morphological disorders of the adrenal masses in such patients appears of interest. We carried out a prospective consecutive series of 402 patients (M 222, 55.2%; F 180, 44.8%) with a median age of 76 years (IQR 64–84 years), admitted in the emergency department for suspected SARS-CoV-2 infection. One hundred patients had a PCR-confirmed diagnosis of infection on a naso-pharyngeal swab (24.9%). All patients underwent a chest MDCT study including the adrenal region and clinical assessment of co-morbidities. Compared to subjects without confirmed disease, COVID patients had more frequently close contact with other positive subjects (24% vs 4.6%, p

The efficacy of levoketoconazole in treating hypercortisolism was demonstrated in an open-label phase 3 study (SONICS) of adults with endogenous Cushing's syndrome (CS) and baseline mean urinary free cortisol (mUFC) ≥ 1.5× ULN. Clinical signs and symptoms and patient-reported outcomes from the SONICS trial were evaluated in the current manuscript.Patients titrated to an individualized therapeutic dose entered a 6-month maintenance phase. Secondary endpoints included investigator-graded clinical signs and symptoms of CS during the maintenance phase, and patient-reported quality of life (CushingQoL questionnaire) and depression symptoms (Beck Depression Inventory II [BDI-II]).Of 94 enrolled patients, 77 entered the maintenance phase following individualized dose titration. Significant mean improvements from baseline were noted at end of maintenance (Month 6) for acne, hirsutism (females only), and peripheral edema. These improvements were observed as early as Day 1 of maintenance for hirsutism (mean baseline score, 7.8; ∆ - 1.9; P 0.0001), end of Month 1 for acne (mean baseline score, 2.8; ∆ - 1.2; P = 0.0481), and Month 4 for peripheral edema (mean baseline score, 1.0; ∆ - 0.5; P = 0.0052). Significant mean improvements from baseline were observed by Month 3 of maintenance for CushingQoL (mean baseline score, 44.3; ∆ + 6.9; P = 0.0018) and at Month 6 for BDI-II (mean baseline score, 17.1; ∆ - 4.3; P = 0.0043) scores. No significant mean improvement was identified in a composite score of 7 other clinical signs and symptoms.Treatment with levoketoconazole was associated with sustained, meaningful improvements in QoL, depression, and certain clinical signs and symptoms characteristic of CS. ClinialTrials.gov identifier: NCT01838551.

In current practice, an adrenal adenoma usually comes as an unexpected byproduct of an imaging study performed for unrelated reasons, without any prior suspect of adrenal disease. Therefore, these tumors currently represent a public health challenge because they are increasingly recognized due to the widespread use of high-resolution cross-sectional imaging for diagnostic purposes. In radiology series, the prevalence of adrenal adenomas increases steeply with age, from around 3% below the age of 50 years up to 10% in the ageing population. These tumors may have clinical relevance because they are able to secrete cortisol autonomously, independently from the pituitary control, in up to 20-30% of patients. In most of the cases the resulting cortisol excess is insufficient to produce a typical Cushing phenotype but may have clinical consequences, such as hypertension, diabetes, obesity, dyslipidemia and osteoporosis. Despite some controversy on the most effective diagnostic algorithm to define this subtle hypercortisolism, there is mounting evidence that a simple approach by using the 1-mg overnight dexamethasone suppression test (DST) may stratify patients for their cardiovascular risk. Cross-sectional, retrospective studies showed that patients with increasingly higher cortisol following DST have an adverse cardiovascular risk profile and are at increased risk of death. Therefore, also a subtle autonomous cortisol excess is associated with increased morbidity and mortality, mainly of cardiovascular origin.

Objective Metyrapone has been approved for the treatment of patients with Cushing’s syndrome (CS), but only few retrospective clinical studies are available. The aim of our study was the prospective assessment of metyrapone as pre-operative treatment. Design and methods Before adrenalectomy, seven patients with ACTH-independent CS due to adrenal adenoma were prospectively treated with metyrapone for 3 months in three tertiary academic centers, with endocrine work-up and clinical evaluation at screening and at predefined evaluation time points (Days 14, 31, 48, 65, 82). Results In all patients, UFC levels decreased up to normal range from baseline to Day 82 (609 (188–1476) vs 69 (28–152) nmol/24 h, P

Objective Metyrapone has been approved for the treatment of patients with Cushing’s syndrome (CS), but only few retrospective clinical studies are available. The aim of our study was the prospective assessment of metyrapone as pre-operative treatment. Design and methods Before adrenalectomy, seven patients with ACTH-independent CS due to adrenal adenoma were prospectively treated with metyrapone for 3 months in three tertiary academic centers, with endocrine work-up and clinical evaluation at screening and at predefined evaluation time points (Days 14, 31, 48, 65, 82). Results In all patients, UFC levels decreased up to normal range from baseline to Day 82 (609 (188–1476) vs 69 (28–152) nmol/24 h, P P P P Conclusions This prospective pilot study demonstrated that metyrapone is effective in normalizing biochemical and clinical parameters in patients with CS due to adrenal adenoma before surgical intervention, with minimal side effects.

Purpose: Pegvisomant (PEGV) treatment in acromegaly patients resistant to somatostatin analogues is less effective in the real life than in clinical trials. This is a multicenter, observational, retrospective, longitudinal study. The aim was to detect characteristics which improve long-term PEGV effectiveness. Methods: 87 acromegalic patients treated with PEGV have been enrolled in seven referral Italian centres. PEGV was administered for up to 4years, at doses up titrated until IGF-1 normalization or to≥30mg/day. The rate of patients who reached IGF-1 normalization at last visit has been calculated. Results: IGF-1 was normalized in 75.9% of patients after 1year and in 89.6% at last visit. Disease control was associated with lower baseline GH, IGF-1 and IGF-1 xULN and was more frequent when baseline IGF-1 was2.7×ULN (p1.0mg/BMI/day were administered more frequently when baseline IGF-1 was>2.0×ULN (p=0.03). PEGV resistance was associated with higher BMI (p=0.006) and was more frequent when BMI was>30kg/m2 (p=0.07). There were no significant differences between patients treated with monotherapy or combined treatment. IGF-1 normalization, PEGV dose and rate of associated treatment were similar between males and females. PEGV effectiveness was independent from previous management. Diabetic patients needed higher doses of PEGV than non-diabetic ones. Conclusions: PEGV effectiveness improves when up titration is appropriate. Higher PEGV doses at start and a more rapid up-titration are necessary in patients with obesity and/or IGF-1>2.7×ULN.

CONTEXT: Patients with adrenal incidentalomas (AI) may experience detrimental consequences due to a minimal cortisol excess sustained by adrenal adenoma. SNPs of the glucocorticoid receptor gene (NR3C1) modulate individual sensitivity to glucocorticoids and may interfere with the clinical presentation. ----- OBJECTIVE: To compare the frequency of N363S, ER22/23EK and BclI SNPs in patients with AI with the general population and to evaluate whether these SNPs are linked to consequences of cortisol excess. ----- SETTING: Multicentric, retrospective analysis of patients referred from 2010 to 2014 to 4 centers (Orbassano, Milano, Messina [Italy] and Zagreb [Croatia]). ----- PATIENTS: 411 patients with AI; 153 males and 258 females and 186 from blood donors. ----- MAIN OUTCOMES MEASURES: All patients and controls were genotyped for BclI, N363S and ER22/23EK and SNPs frequency was associated with clinical and hormonal features. ----- RESULTS: SNP frequency was: SNP frequency was: N363S 5.4% (MAF 0.027), BclI 54.7% (MAF 0.328), ER22/23EK 4.4% (MAF 0.022), without any significant difference between patients and controls. N363S was more frequent in hypertensive patients (p = 0.03) and was associated with hypertension (p = 0.015) in patients with suppressed cortisol after the 1-mg DST. ----- CONCLUSIONS: Our results demonstrate that SNPs of the glucocorticoid receptor gene do not play a pathogenetic role for AI. The impact of any single SNP on the phenotypic expression of minimal cortisol excess is limited and their analysis does not provide additional data that may be exploited for patient management.