Serena Piacentini

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first generation somatostatin analogues: an immunohistochemical study

AIM To gather data regarding factors predicting responsiveness to pasireotide in acromegaly. PATIENTS AND METHODS SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR. RESULTS None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04). CONCLUSION The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

Prognostic factors in ectopic Cushing's syndrome due to neuroendocrine tumors: a multicenter study

OBJECTIVE Evidence is limited regarding outcome of patients with ectopic Cushings syndrome (ECS) due to neuroendocrine tumors (NETs). DESIGN We assessed the prognostic factors affecting the survival of patients with NETs and ECS. METHODS Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers. RESULTS Our series included 110 patients, 58.2% female, with mean (±s.d.) age at diagnosis of 49.5 ± 15.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors (P = 0.033) and in G1-NETs compared with G2 and G3 (P = 0.007). Negative predictive factors for survival were severity of hypercortisolism (P < 0.02), hypokalemia (P = 0.001), diabetes mellitus (P = 0.0146) and distant metastases (P < 0.001). Improved survival was observed in patients who underwent NET removal (P < 0.001). Adrenalectomy improved short-term survival. CONCLUSIONS Multiple factors affect prognosis of ECS patients: type of NET, grading, distant metastases, severity of hypercortisolism, hypokalemia and diabetes mellitus. BCs have the highest curative surgical rate and better survival compared with occult tumors and pNETs. Hypercortisolism plays a primary role in affecting outcome and quality of life; therefore, prompt and vigorous treatment of hormonal excess by NET surgery and medical therapy should be a key therapeutic goal. In refractory cases, adrenalectomy should be considered as it affects outcome positively at least in the first 2 years.

Understanding the effect of acromegaly on the human skeleton

ABSTRACT Introduction: Acromegaly, caused in most cases by Growth Hormone (GH)-secreting pituitary adenomas, is characterized by increased skeletal growth and enlargement of the soft tissue, because GH and its effector Insulin-like Growth factor-1 are important regulators of bone homeostasis and have a central role in the longitudinal bone growth and maintenance of bone mass. Areas covered: Despite the anabolic effect of these hormones is well known, as a result of the stimulation of bone turnover and especially of bone formation, many acromegalic patients are suffering from a form of secondary osteoporosis with increased risk of fractures. Expert commentary: In this review, we summarize the pathophysiology, diagnosis, clinical picture, disease course and management of skeletal complications of acromegaly, focusing in particular on secondary osteoporosis and fracture risk in acromegaly.

Systemic mastocytosis mimicking carcinoid syndrome

We report the case of a 70-year-old woman who came to our attention in January 2013 complaining of recurrent episodes of severe flushing, diarrhea, dyspnea, and hypotension, that had started in 2011 and were considerably worsening over time, and were partially responsive to steroid and antihistamine drugs. In 2012, suspecting carcinoid syndrome, the patient underwent dosing of chromogranin A (56 ng/ml, n.v.\90), urinary 5-HIAA (6 mg/24 h, n.v. 2–6), and urinary serotonin ? 5-OH tryptophan, which came mildly elevated (11 mg/24 h, n.v. 0–5). A CT scan did not show any liver lesions or other malignancies, and an Octreoscan scintigraphy was negative as well. Nonetheless, the patient was put on octreotide LAR treatment and, in the following weeks, she presented a slight symptomatic improvement. In January 2013, however, the frequency of these crises increased, and the patient was hospitalized at our Institution. Considering the recurring crises and suspecting carcinoid syndrome, short-acting octreotide treatment was started with some improvement. Chromogranin A came normal (33.5 ng/ml, n.v. 19.4–98.1) and urinary 5-HIAA was mildly elevated (19.2 mg/24 h, n.v. 1–10). A new CT scan did not show focal lesions, and a Ga-DOTANOC PET-CT did not reveal any pathologic hyperuptake of the tracer. Suspecting systemic mastocytosis, we measured serum tryptase, a serine proteinase contained in mast cells: the levels were markedly elevated (200 mcg/l, n.v. \9.4). Her blood count was unremarkable, and no skin involvement was seen. Bone marrow biopsy was done, and it confirmed the diagnosis of systemic mastocytosis (Fig. 1). Moreover, the KIT D816V mutation was revealed in the bone marrow aspirate. Somatostatin analogue treatment was withdrawn and treatment with dasatinib, a second generation tyrosine kinase inhibitor, was started at the dosage of 100 mg/day. After more than 12 months of treatment, the patient is doing well, without any crises relapse. According to the WHO 2008 classification, major criterion for the diagnosis of systemic mastocytosis is the presence of multifocal dense mast cell (MC) infiltrates in the bone marrow or in another extracutaneous organ; minor criteria are (1) [25 % spindle-shaped cells in MC-infiltrates or [25 % of all MC being atypical MC in bone marrow smears, (2) expression of CD2 and/or CD25 in bone marrow MC, (3) serum tryptase level[20 ng/ml, and (4) KIT point mutation at codon 816 (mostly D816V) in bone marrow or in another extracutaneous organ. The diagnosis can be established if at least 1 major and 1 minor or 3 minor criteria are fulfilled. Indeed our patient presented 1 major and 2 minor criteria for the diagnosis of systemic mastocytosis. We report a case of systemic mastocytosis mimicking carcinoid syndrome. The clinical and biochemical features of these conditions can be highly overlapping [1] and D. Iacovazzo (&) F. Lugli S. Piacentini A. Bianchi L. De Marinis Endocrinology, Catholic University, Policlinico ‘‘A. Gemelli’’, Largo A. Gemelli, 8, 00168 Rome, Italy e-mail: donatoiacovazzo@gmail.com