Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆.

Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing's syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2-3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.

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ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of Cushing's syndrome.

Context Inferior petrosal sinus sampling (IPSS) is used to diagnose Cushing's disease (CD) when dexamethasone-suppression and CRH tests, and pituitary magnetic resonance imaging (MRI), are negative or give discordant results However, IPSS is an invasive procedure and its availability is limited Objective To test a noninvasive diagnostic strategy associated with 100% positive predictive value (PPV) for CD Design Retrospective study Setting Two university hospitals Patients A total of 167 patients with CD and 27 patients with ectopic ACTH-syndrome investigated between 2001 and 2016 Main outcome measure(s) Performance of a strategy involving the CRH and desmopressin tests with pituitary MRI followed by thin-slice whole-body computed tomography (CT) scan in patients with inconclusive results Results Using thresholds of a cortisol increase > 17% with an ACTH increase > 37% during the CRH test and a cortisol increase > 18% with an ACTH increase > 33% during the desmopressin test, the combination of both tests gave 73% sensitivity and 98% PPV of CD The sensitivity and PPV for pituitary MRI were 71% and 99%, respectively CT scan identified 67% EAS at presentation with no false-positives The PPV for CD was 100% in patients with positive responses to both tests, with negative pituitary MRI and CT scan The Negative Predictive Value was 100% in patients with negative responses to both tests, with negative pituitary MRI and positive CT scan Using this strategy, IPPS could have been avoided in 47% of patients in whom it is currently recommended Conclusions In conjunction with expert radiologic interpretation, the non-invasive algorithm studied significantly reduces the need for IPSS in the investigation of ACTH-dependent Cushing's syndrome

Non-invasive Diagnostic Strategy in ACTH-dependent Cushing’s Syndrome

CONTEXT The human corticotropin-releasing hormone (CRH) test (hCRHtest) is used to differentiate Cushing disease (CD) from ectopic adrenocorticotropin (ACTH) secretion (EAS), to assess autonomous cortisol secretion by the adrenal glands, and to characterize pseudo-Cushing syndrome (CS) or adrenal insufficiency (AI). MAIN OUTCOME MEASURE The main outcome measure of this study was to assess the diagnostic accuracy of the hCRHtest. METHODS We measured ACTH and cortisol levels; collected the peak values (peakACTH and peakcortisol), and calculated the percentage increases (∆%ACTH and ∆%cortisol) after an intravenous bolus of 100 μg hCRH. DESIGN AND SETTING This cross-sectional study of hCRH tests from 2010 to 2019 took place in a referral university hospital center. PATIENTS We enrolled 200 patients: 86 CD, 15 EAS, 18 adrenal CS, 25 mild adrenal autonomous cortisol secretion, 31 pseudo-CS, and 25 suspected AI. RESULTS The hCRHtest was performed mainly for the differential diagnosis of ACTH-dependent CS or adrenal lesions (P = .048). PeakACTH and peakcortisol were higher in CD, and ∆%ACTH and ∆%cortisol were able to differentiate CD from EAS with a sensitivity and specificity greater than 80%. In patients with low (< 10 pg/mL) or indeterminate (10-20 pg/mL) basalACTH levels, an absent or reduced peakACTH response was able to differentiate adrenal from ACTH-dependent forms. PeakACTH and peakcortisol after hCRHtest were lower in pseudo-CS than in CD, but ∆%ACTH and ∆%cortisol were similar. The role of hCRHtest in patients with AI was limited. CONCLUSIONS The hCRHtest test is the mainstay of the differential diagnosis of ACTH-dependent CS. It is also useful for pointing to a diagnosis of CD in the event of bilateral adrenal masses, and in patients with low basalACTH.

Human Corticotropin-Releasing Hormone Tests: 10 Years of Real-Life Experience in Pituitary and Adrenal Disease

Cushing's syndrome (CS) is a rare but detrimental endocrine disorder. Early diagnosis and prompt treatment are essential since the duration of hypercortisolism has an adverse impact on the extent of comorbidities and overall survival. The diagnostic approach involves a stepwise process that includes (1) screening and confirming the diagnosis and (2) establishing the aetiology of CS. The tests currently used to confirm the diagnosis of CS include urinary free cortisol measurements, the dexamethasone suppression test and late‐ night salivary cortisol or midnight serum cortisol measurements. None of these tests are ideal; all have pitfalls and require careful interpretation. Following confirmation of CS, measurement of ACTH discriminates between ACTH‐dependent and non‐ACTH dependent causes of CS. Adrenal imaging provides clues for the aetiology of non‐ACTH dependent forms. Differentiation between the ACTH‐dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and include pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling and, when required imaging modalities to detect ectopic ACTH secreting lesions. This review, which is part of a special issue on "Update of Cushing's syndrome: 100 years after Minnie G" will provide an update on our current diagnostic workup for the confirmation and differential diagnosis of CS.

Diagnostic workup of Cushing’s syndrome

Ectopic ACTH syndrome (EAS) is rare but is frequently a severe condition because of the intensity of the hypercortisolism that may be dissociated from the tumoral condition. EAS should often be considered as an endocrine emergency requiring an emergency response both in terms of diagnostic procedures and therapeutic interventions. Patient management is complex and necessitates dual skills, in the diagnosis and treatment of CS and in the specific management of neuroendocrine tumors (NET). Therefore, initial management should be performed ideally by experienced endocrinology teams in collaboration with specialized hormonal laboratory, modern imaging platforms and intensive care units. Diagnostic procedures vary according to the endocrine and tumoral contexts but should be reduced to a minimum in intense hypercortisolism. Preventive and curative treatments of cortisol-induced comorbidities, non-specific management of hypercortisolism and etiological treatments should be considered simultaneously. Therapeutic strategies vary according to (1.) the intensity of hypercortisolism, the general condition of the patient and associated comorbidities and (2.) the tumoral status, ranging from resectable ACTH secreting tumors to non-resectable metastatic endocrine tumors or occult tumors. The ideal treatment is complete excision of the ACTH-secreting tumor that can be performed rapidly or after preoperative preparation using cortisol-lowering drugs. When this is not possible, the therapeutic strategy should be discussed by a multidisciplinary experienced team in a personalized perspective and include variable combinations of pharmacological agents, bilateral adrenalectomy and non-specific tumoral interventions. Here we discuss the diagnosis and therapeutic strategies including the modern, currently available tools and emphasize on the operational effectiveness of care.

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MANAGEMENT OF ENDOCRINE DISEASE: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion

Abstract Context Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS). Objective This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS. Methods A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n = 6), block and replace (n = 16), or titration followed by block and replace (n = 11). Results In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 × upper limit of normal [ULN; 2.9-659] to 0.11 × ULN [0.08-14.9]; P < .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 × ULN [1.1-144] to 0.22 × ULN [0.12-0.66]; P < .01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h-UFC from 11.8 × ULN (0.3-247) to 0.43 × ULN (0.33-2.4) (P < .01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients. Conclusion Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect.

Oceana Viera-Pinto

Papers

MANAGEMENT OF ENDOCRINE DISEASE: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion

Efficacy and Safety of Osilodrostat in Paraneoplastic Cushing Syndrome: A Real-World Multicenter Study in France