Diego Ferone

Increased arterial intima‐media thickness by B‐M mode echodoppler ultrasonography in acromegaly

BACKGROUND Patients with acromegaly have an increased morbidity and mortality for cardiovascular diseases. Despite the increasing evidence for the existence of a specific cardiomyopathy in acromegaly, the presence of vascular abnormalities has been never investigated.

Effectiveness and tolerability of slow release lanreotide treatment in active acromegaly

This single-center open sequential study aimed at comparing the efficacy of a 6-month treatment with lanreotide (LAN) (60-90 mg/month im), to that of octreotide (OCT) (0.3-0.6 mg/day sc) in 45 patients with active acromegaly (GH, 63.2±12.1 ng/ml, IGF-I, 757±67.1 ng/ml). After 6 months of OCT treatment, safe GH (fasting <2.5, glucose suppressed <1 ng/ml) and IGF-I (normalized for age) levels were achieved in 23 patients. After treatment withdrawal, GH levels significantly increased in all patients, though remaining slightly lower than pre-OCT therapy (39.2±5.8 ng/ml) while plasma IGF-I levels were unchanged (654±59.4 ng/ml). After 6 months of LAN treatment, safe GH and IGF-I levels were achieved in 26 patients (57.7%). After OCT or LAN treatments, no significant difference was found between nadir GH (6±1 vs 5.9±1.1 ng/ml) and IGF-I levels (281±23.3 vs 262±20.6 ng/ml). Four out of the 20 patients poorly responsive to OCT achieved safe GH and IGF-I levels after LAN treatment. Among the 20 non-operated patients, a significant tumor shrinkage was documented by CT and/or MRI in 5 patients after OCT and in 1 patient after LAN treatment. All patients referred a notable improvement of soft tissue swelling, arthralgia, headache and weakness, both after OCT and LAN treatments. During the first days of OCT treatment, abdominal discomfort was referred by 12 patients and steatorrhea by 5 patients: side effects disappeared spontaneously in 6 cases while during treatment with pancreatic enzymes in the remaining ones. After the first injections of LAN, abdominal discomfort was referred by 10 patients and steatorrhea by 2 of them. No difference in the prevalence of both early and late side effects was noted after treatment with OCT and LAN (χ2, 0.49). The majority of these poorly tolerant patients had side effects with both compounds. During LAN treatment, side effects were mild and spontaneously disappeared but recurred after the injection of the drug in six patients. Gallstones were detected in one patient during OCT and in another during LAN, sludge was noted in 6 patients after OCT and in 2 after LAN treatment. In conclusion, the treatment with LAN allowed to achieve safe GH and IGF-I levels in 57.7% of acromegalics with an excellent patients’ compliance. LAN treatment possessed similar efficacy and caused side effects with a similar incidence of OCT treatment. The recurrence of side effects after LAN injection suggests the necessity of a careful monitoring of adverse reactions.

Effect of surgery and radiotherapy on visual and endocrine function in nonfunctioning pituitary adenomas

The effect of surgery alone or followed by radiotherapy in recovering visual abnormalities, debulking tumor mass and restoring hormone impairments was evaluated in 84 patients with clinically nonfunctioning pituitary adenomas (NFPA) subjected to 1–10 yr follow-up. All patients underwent surgery via transsphenoidal (in 69) or transcranic-pterional approach (in 15). Radiotherapy was performed after surgery in 59 of 72 patients with incomplete tumor removal. The assessment of pituitary function was performed in all patients before and every 1–2 yr after surgery and/or radiotherapy. Radiological and ophthalmologic assessment was performed before and 3, 6 and 12 months after surgery, then yearly. At diagnosis, headache and visual disturbances occurred in 63 and 58 patients, respectively, while deficiency of GH, TSH, ACTH, FSH, LH and ADH was documented in 55, 7, 19, 47 and 6 patients, respectively. After surgery, gonadal function recovered in 12 women, visual disturbances improved in 43 patients (15 regained normal vision), pituitary function improved in 8 of 62 patients, worsened in 34 patients. At MRI, complete tumor removal was documented in 12 of 84 patients. After surgery alone, tumor regrowth was observed in 7 patients between 3–7 yr. After radiotherapy, vision improved in 9, remained unchanged in 49 and worsened in 1 of 59 patients. After radiotherapy, tumor regrowth was documented in 9 patients between 2–12 yr and the prevalence of hypopituitarism raised from 28.8% to 92% after 1 and 10 yr. In conclusion, surgery alone is effective only in a minority of patients (14.3%) and radiotherapy causes hypopituitarism in rather the totality of patients after 10 yr. The prevalence of tumor regrowth was similar in irradiated ones (15%) and non irradiated patients (28%; χ2, p=0.4). Therefore, a careful radiological follow-up is suggested after surgery so that radiotherapy can be performed promptly on the basis of clinical data, tumor regrowth and/or invasiveness documented at histology.

Somatostatin Receptor Subtypes in Human Thymoma and Inhibition of Cell Proliferation by Octreotide in Vitro

Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst1-5, are heterogeneously expressed in the normal human thymus. This suggests their involvement in controlling the immune and/or neuroendocrine functions in this organ. Moreover, recently a high in vivo uptake of [111In-DTPA-D-Phe1]octreotide has been reported in patients bearing thymoma. The present study characterizes in vivo and in vitro, functional SS-binding sites in a human thymoma. A high uptake of [111In-DTPA-D-Phe1]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of [125I-Tyr11] SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (Kd, 47.5 +/- 2.5 pmol/L) with low maximum binding capacity (23.5 +/- 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed sst3 mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By immunohistochemistry, the tumor cells highly expressed sst3 receptors, weakly expressed sst1 receptors, and showed no immunostaining for sst2A receptors. sst2A immunoreactivity was found in the stromal compartment of the tumor, particularly on the endothelium of small intratumoral blood vessels. In primary cultured tumor cells, both SS and octreotide (10 nmol/L) significantly inhibited [3H]thymidine incorporation by 40.6% and 43.2%, respectively. The following conclusions were reached. 1) As this tumor displayed a high immunoreactivity for sst3 and the cultured tumor cells expressed the sst3 mRNA only, this SSR may be the subtype involved in the inhibition of epithelial tumor cell proliferation by octreotide in vitro. 2) A loss of endogenous SS production in this thymoma might be implicated in the uncontrolled cell growth. 3) In this case, the sst3 may play a role in determining the uptake of [111In-DTPA-D-Phe1]octreotide by in vivo SS receptor scintigraphy.

Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian Epidemiological study: THE NET MANAGEMENT STUDY

Background: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. Aim: To investigate epidemiology, clinical presentation, and natural history of NET. Design and setting: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-entero-pancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. Results: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0±16.4 yr, significantly anticipated in MEN1 patients (47.7±16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hyper-secretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1 -associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. Conclusions: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.

Hormone levels and tumour size response to quinagolide and cabergoline in patients with prolactin‐secreting and clinically non‐functioning pituitary adenomas: predictive value of pituitary scintigraphy with 123I‐methoxybenzamide

BACKGROUND Dopamine agonists are indicated as primary therapy for PRL‐secreting pituitary adenomas, while controversial results have been reported in nonfunctioning adenomas (NFA).

EFFECT OF GROWTH HORMONE ON CARDIAC FUNCTION

At present, there is a growing body of evidence implicating growth hormone (GH) and/or insulin-like growth factor-I (IGF-I) in the intricate cascade of events connected with the regulation of heart development and hypertrophy. In addition, advanced clinical manifestations of abnormal GH levels almost always include impaired cardiac function, which may reduce life expectancy. This finding is related both to a primary impairment of heart structure and function and to metabolic changes such as hyperlipidaemia, increased body fat and premature atherosclerosis. Acromegalic cardiomyopathy is better correlated with disease duration than with GH or IGF-I levels. Myocardial hypertrophy with interstitial fibrosis, lymphomononuclear infiltration and areas of monocyte necrosis often result in increased right and left ventricular mass concentric hypertrophy. Conversely, patients with childhood or adult-onset GH deficiency (GHD) have a reduced left ventricular mass (LVM) and ejection fraction (EF) and the indices of left ventricular systolic function remained markedly depressed during exercise. Cardiac function is reported to improve during octreotide and GH replacement treatment in acromegaly and GHD, respectively. The evidence that GH can increase cardiac mass suggests its use in the treatment of idiopathic dilated cardiomyopathy. In a recent study on such patients, the administration of recombinant GH (rGH) was demonstrated to increase myocardial mass and reduce the size of the left ventricular chamber, resulting in improved haemodynamics, myocardial energy metabolism and clinical status.

Failure of long-term therapy with sodium valproate in Cushing’s disease

The aim of the current study was to evaluate the effectiveness of a long-term treatment with sodium valproate in 19 patients with Cushing’s disease. Before therapy beginning, the patients were subjected to acute test with 600 mg sodium valproate. Then, they were subjected to a 3-month therapy with sodium valproate at the dose of 600 mg/day before surgery (presurgical study). The 7 patients not surgically cured were subjected again to a 3-month therapy with sodium valproate at the dose of 600 mg/day after surgery (postsurgical study). Circulating ACTH and cortisol and urinary free cortisol levels were evaluated before and monthly after the beginning of the therapy. A decrease of plasma ACTH and serum cortisol levels greater than 50% of baseline was considered as positive response to acute test whereas the normalization of plasma ACTH, serum cortisol and urinary free cortisol levels and the clinical remission were considered as positive response to the long-term treatment. At acute test, 8 patients were considered responders and 11 patients non-responders. In no patient plasma ACTH, serum cortisol and urinary free cortisol were normalized during the long-term treatment. Urinary free cortisol levels significantly decreased (483.2±33.8 vs 699.4±67.0 ug/24 h), whereas plasma ACTH (302.8±17.7 vs 183.3±25.0 ng/l) and serum cortisol (466.5±23.2 vs 356.7±19.6 µg/l) significantly increased during sodium valproate administration in the 19 patients enrolled in the presurgical study. Plasma ACTH (247.7±22.3 vs 168.6±15.0 ng/l), serum cortisol (387.4±35.8 vs 282.0±16.0 µg/l) and urinary free cortisol (370.9±70.6 vs 261.3±37.8 µg/24 h) levels significantly increased in the 7 patients enrolled in the postsurgical study. No patient had clinical remission of Cushing’s disease. In conclusion, the current study showed that long-term therapy with sodium valproate is not useful in the therapeutic management of Cushing’s disease neither as alternative nor as adjunctive therapy to surgery.

ENETS Consensus Guidelines Update for Colorectal Neuroendocrine Neoplasms

a Gastroenterology Department, Hampshire Hospitals NHS Trust, Hampshire , UK; b Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam , The Netherlands; c Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome , d NET Centre, Umbria Regional Cancer Network, Università degli Studi di Perugia, Perugia , and e Department of Endocrine and Metabolic Sciences (DIMI), University of Genoa, Genoa , Italy; f Pancreatic Diseases Branch, Kyushu University Hospital, Fukuoka , Japan; g Department of Gastroenterology, Beaujon Hospital, Clichy , France; h Department of Radiology, Section for Molecular Imaging, University Hospital, Uppsala , Sweden; i Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, N.Y. , USA; j Department of Endocrinology, Peking Union Medical College Hospital, Beijing , China; k Netherlands Cancer Centre, Lijnden , The Netherlands; l Department of Visceral and Transplant Surgery, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Berlin , Germany

The pituitary uptake of 111In-DTPA-D-Phe1-octreotide in the normal pituitary and in pituitary adenomas

The aim of this study was to compare the pituitary 111In-DTPA-D-Phe1-octreotide uptake measured in 49 patients subjected to the scintigraphy for SS-R expressing tumors not located in the sellar region with that measured in 38 patients with pituitary adenomas. The 87 subjects enrolled in this study were divided into two groups: the first included SSR-expressing tumors (SS-ET), 10 thymomas, 13 differentiated thyroid carcinomas, 4 carcinoids, 5 neuroendocrine tumors, 5 insulinomas, 6 melanomas, 2 renal carcinomas, 2 pheocromocytomas, and 2 parathyroid tumors, while the second included pituitary adenomas, 25 GH-secreting, 4 GH/PRL-mixed and 9 clinically nonfunctioning adenomas (NFA). Planar and single-photon-emission tomography images of the head were obtained 2–4 and 24 hours after the injection of 77–103 MBq of 111In-DTPAD- Phe1-octreotide and pituitary uptake was measured by the region of interest method. A 4 point score was used to grade the pituitary-to-blood (T-to-B) ratios: 0=negative; 1=faint (T-to-B=<1.5); 2=moderate (T-to-B=1.6–3.5); 3=intense (T-to-B=>3.5). In patients with pituitary adenomas, the percent suppression of GH and α-subunit levels after 6–12 months of octreotide treatment (0.3–0.6 mg/day) was correlated to T-to-B ratios. After 2–4 hr from injection, pituitary 111In-DTPA-DPhe1-octreotide uptake was moderate/intense in 2 out of 49 SS-ET (4%), 18 out of 29 acromegalics (62%) and 6 NFA (66.6%), while a faint uptake was detected in 4 SS-ET (8%), 8 GH-secreting adenomas (27.5%) and 3 NFA (33.3%). Negative scan was detected in the remaining 43 SS-ET (87.7%) and 3 GH-secreting microadenomas (10.3%). 24 hr after injection, pituitary 111In-DTPA-D-Phe1-octreotide uptake was moderate/ intense in SS-ET (10.2%), 21 GH-secreting adenomas (72.4%), and 9 NFA (100%) while a faint uptake was detectable in 15 SS-ET (30.6%), and 6 GH-secreting adenomas (20.7%). No uptake was visualized in 29 SS-ET, and 2 GH-secreting adenomas. By MRI a pituitary tumor was shown in the 2 SS-ET with early moderate tracer uptake. Normalization of circulating GH/IGF-I levels and suppression of α-subunit levels was achieved in 16 of 18 acromegalics (88.9%) and 5 of 6 NFA-bearing patients, respectively, with scan scored 2–3 at early images. Eleven acromegalics (37.9%) and 2 NFA (22.2%) displayed significant tumor shrinkage (≥30% of baseline size) during long-term octreotide therapy. Both in GHsecreting and in NFA, a significant correlation was found between percent GH or α-subunit suppression after 6-12 months of octreotide therapy and T-to-B ratios both in early (r=0.626; p<0.0001 and r=0.738, p=0.003, respectively) and late images (r=0.569; p=0.002 and r=0.8, p=0.01, respectively). In conclusion, the 111In-DTPA- D-Phe1-octreotide uptake in pituitary adenomas was significantly correlated to octreotide treatment. However, since pituitary 111In-DTPAD- Phe1-octreotide uptake was clearly detectable in 40% of patients with SS-ET not located in the pituitary region at 24 hr post-injection, 111In-DTPA- D-Phe1-octreotide scintigraphy with late pituitary images can not be considered an useful method to predict the chronic responsiveness to octreotide in individual patients. Caution should also be taken in evaluating the results of the scintigraphy with early images in patients with scant uptake before excluding them from treatment.