Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy.

BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.

A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: from genetic characterization to clinical phenotype.

ARMC5 mutations have recently been identified as a common genetic cause of primary bilateral macronodular adrenal hyperplasia (PBMAH). We aimed to assess the prevalence of ARMC5 germline mutations and correlate genotype with phenotype in a large cohort of PBMAH patients. A multicenter study was performed, collecting patients from different endocrinology units in Italy. Seventy-one PBMAH patients were screened for small mutations and large rearrangements in the ARMC5 gene: 53 were cortisol-secreting (two with a family history of adrenal hyperplasia) and 18 were non-secreting cases of PBMAH. Non-mutated and mutated patients' clinical phenotypes were compared and related to the type of mutation. A likely causative germline ARMC5 mutation was only identified in cortisol-secreting PBMAH patients (one with a family history of adrenal hyperplasia and ten apparently sporadic cases). Screening in eight first-degree relatives of three index cases revealed four carriers of an ARMC5 mutation. Evidence of a second hit at somatic level was identified in five nodules. Mutated patients had higher cortisol levels (p = 0.062), and more severe hypertension and diabetes (p < 0.05). Adrenal glands were significantly larger, with a multinodular phenotype, in the mutant group (p < 0.01). No correlation emerged between type of mutation and clinical parameters. ARMC5 mutations are frequent in cortisol-secreting PBMAH and seem to be associated with a particular pattern of the adrenal masses. Their identification may have implications for the clinical care of PBMAH cases and their relatives.

An analysis of different therapeutic options in patients with Cushing's syndrome due to bilateral macronodular adrenal hyperplasia: a single-centre experience.

CONTEXT: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of Cushing's syndrome (CS). A variety of in vivo tests to identify aberrant receptor expression have been proposed to guide medical treatment. Unilateral adrenalectomy (UA) may be effective in selected patients, but little is known about recurrence during follow-up. OBJECTIVE: To describe a series of patients with BMAH and CS treated by different approaches, with a particular focus on the benefit of UA. DESIGN AND PATIENTS: We retrospectively assessed 16 patients with BMAH and CS (11 females, five males), analysing the in vivo cortisol response to different provocative tests. Twelve of the 16 patients underwent UA and were monitored over the long term. RESULTS: Based on in vivo test results, octreotide LAR or propranolol was administered in one case of food-dependent CS and two patients with a positive postural test. A significant improvement in biochemical values was seen in all patients but with limited clinical response. UA was performed in 12 patients, producing long-term remission in three (106 ± 28 months; range: 80-135), recurrence in eight (after 54 ± 56 months; range 12-180) and persistence in one other. Four patients subsequently underwent contralateral adrenalectomy for overt CS, one received ketoconazole, and four other patients remain under observation for subclinical CS. CONCLUSIONS: Medical treatment based on cortisol response to provocative tests had a limited role in our patients, whereas UA was useful in some of them. Although recurrence is likely, the timing of onset is variable and close follow-up is mandatory to identify it.

Adrenal lesions in acromegaly: do metabolic aspects and aryl hydrocarbon receptor interacting protein gene have a role? Evaluation at baseline and after long-term follow-up.

BACKGROUND: Adrenal lesions are discovered in acromegaly more frequently than in general population, without relationship with primary disease. Some patients, carriers of aryl hydrocarbon receptor interacting protein (AIP) gene mutations, developed an adrenal neoplasm. AIM: To evaluate the role of metabolic and genetic aspects and the follow-up of adrenal nodules in acromegaly. MATERIAL AND METHODS: We studied 69 acromegalic patients (30 male and 39 female, 56 ± 15 yr) who had been referred to the Endocrinology Unit of Padua. In all patients we determined body mass index (BMI) and waist-to-hip ratio (WHR); we performed an oral glucose tolerance test (OGTT) whenever possible. If adrenal computed tomography revealed a lesion, the patient underwent an endocrine and genetic study. RESULTS: Adrenal lesions were identified in 14 patients and were not related to gender, duration of disease, GH or IGF-I concentrations, basal and after-OGTT glucose and insulin levels, log(HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) values, whereas BMI and WHR were higher in patients with adrenal lesions. Baseline endocrine and radiological study revealed benign lesions; during mean 4-yr follow-up none of the patients showed hormone excess, even though some lesions increased in size. We did not find any mutation in AIP gene, except heterozygous silent alteration (T48T). CONCLUSIONS: The frequency of non-functioning adrenal lesions in acromegaly is not associated with the considered aspects, except BMI and WHR. The prolonged follow-up showed that these lesions have a tendency to increase in size independently of the control of acromegaly, so a morphological follow- up is recommended.

Concomitant therapies (glucocorticoids and sex hormones) in adult patients with growth hormone deficiency.

Adult-onset GH deficiency (GHD), mostly due to organic lesions of the pituitary-hypothalamic region, is frequently associated with multiple anterior pituitary deficiencies that need long-term substitutive treatment. The GH-IGF-I axis may play an important role in modulating peripheral metabolism of hormones (adrenal, thyroid, and sex hormones) and these interactions may have clinically significant implications on the phenotypes of adult GHD patients and on the effects of the combined replacement hormonal treatment of this condition. By accelerating the peripheral metabolism of cortisol, GH therapy may precipitate adrenal insufficiency in susceptible hypopituitary patients; estrogen replacement blunts the response to GH in women whereas in men with androgen substitution the responsivity increases over time. Endocrinologists should be mindful of these phenomena when starting patients with hypopituitarism on GH replacement therapy.