Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.

BACKGROUND: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE: To evaluate gender differences in clinical presentation and outcome of CaS. METHODS: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Clinical presentation, genotype-phenotype correlations, and outcome of pancreatic neuroendocrine tumors in Von Hippel-Lindau syndrome.

PURPOSE: Data regarding the clinical management and follow-up of pancreatic neuroendocrine tumors (PanNETs) associated with Von Hippel-Lindau (VHL) syndrome are limited. This study aimed to assess clinical presentation, genotype-phenotype correlations, treatment and prognosis of PanNETs in a series of VHL syndrome patients. METHODS: Retrospective analysis of data of patients observed between 2005 and 2020. RESULTS: Seventeen patients, including 12 probands and 5 relatives (mean age 30.8 ± 18.4; 7 males), were recruited. PanNETs were found in 13/17 patients (77.5%) at a median age of 37 years: 4/13 (30.7%) at the time of VHL diagnosis and 9 (69.3%) during follow up. Six (46.1%) PanNET patients underwent surgery, whereas seven were conservatively treated (mean tumor diameter: 40 ± 10.9 vs. 15 ± 5.3 mm respectively). Four patients (30.7%) had lymph node metastases and a mean tumor diameter significantly larger than the nonmetastatic PanNETs (44.2 ± 9.3 vs. 17.4 ± 7 mm, p = 0.00049, respectively). Five (83.3%) operated patients had stable disease after a median follow up of 3 years whereas one patient showed liver metastases. Six (85.7%) non-resected PanNETs were stable after a median follow-up of 2 years, whereas one patient developed a new small PanNET and a slight increase in diameter of a pre-existing PanNET. No correlation was found between the type of germline mutation and malignant behavior of PanNETs. CONCLUSIONS: PanNETs are a common disease of the VHL syndrome and can be the presenting feature. Tumor size rather than genetic mutation is a prognostic factor of malignancy.

Is Laparoscopic CME Right Hemicolectomy an Optimal Indication for NET of the Right Colon and Terminal Ileum?

PURPOSE: Since lymphadenectomy is crucial in midgut neuroendocrine tumor (NET) surgery, we adopted laparoscopic CME right hemicolectomy (LRH-CME) for the treatment of right colon and terminal ileum NETs. In this report, we present a series of nine cases of terminal midgut NETs (TM-NETs) treated by LRH-CME with a video demonstrating oncological principles and the surgical technique. METHODS: From September 2014 to November 2019, nine patients affected by TM-NETs underwent LRH-CME at the Unit of General and Hepatobiliary Surgery, University of Verona Hospital Trust, ENETS Center of Excellence. Clinicopathological data, post-operative and oncological outcomes were prospectively collected and analyzed. RESULTS: Tumors were in ileocecal valve or terminal ileum (5 cases), right colon (3 cases), and appendix (one case). Surgery had a curative intent (R0 resection) in 7 cases. Surgical debulking was required in 2 metastatic cases. Mean surgical time was 212 + 41 min and blood loss 47 + 24 mL. No postoperative mortality was observed. Post-operative course was uneventful in all except one case (Clavien-Dindo III). Median number of harvested lymph nodes was 21 (range, 11-31) and eight out of 9 patients were node positive (median 3, range 0-6). At a median follow-up of 18 months (range, 6-50), none of the patients suffered from mesenteric locoregional recurrence and all R0 resected patients were disease-free. CONCLUSIONS: Terminal midgut NETs represent an optimal indication for LRH-CME which increases the chance of complete resection and allows optimal lymphadenectomy. In expert hands, laparoscopic approach should be favored in consideration of good short-term outcomes.

Clinico-pathological features, treatments and survival of malignant insulinomas: a multicenter study.

INTRODUCTION: Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series. AIM OF THE STUDY: To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma. MATERIALS AND METHODS: Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017. RESULTS: The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients. CONCLUSIONS: Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases.

Autoimmune hypoglycaemia caused by alpha-lipoic acid: a rare condition in Caucasian patients.

Insulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions. Learning points: IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients. It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery. It should be suspected in the presence of very high serum insulin levels (100-10 000 µU/mL) associated with high C-peptide levels. There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.

Bone histomorphometry in acromegaly patients with fragility vertebral fractures.

CONTEXT: The high risk of vertebral fractures (VFs) in acromegaly patients despite normal bone mineral density (BMD) is well known. The reasons for this paradoxical finding of skeleton fragility are poorly understood due to the limited data on bone histomorphometry in acromegaly. OBJECTIVE: This study aimed to analyze histomorphometric parameters including bone microarchitecture in acromegaly patients with VFs and normal BMD compared to normal subjects, and also to evaluate the differences between active and controlled acromegaly patients. PATIENTS AND METHODS: Forty-seven acromegaly patients (17 active, 30 controlled), median (range) age 57 years (30-88) were evaluated for bone turnover, morphometric VFs and BMD by dual-energy X-ray absorptiometry at lumbar spine and hip; 12 patients with VFs and normal BMD underwent iliac crest bone biopsy; 12 biopsies were taken at the autopsy in healthy sex and age-matched control subjects. RESULTS: The histomorphometric evaluation of acromegaly fractured patients was compared with that of normal controls and showed significantly reduced median (range) levels of bone volume/tissue volume (BV/TV: 15.37% (7.93-26.75) vs. 18.61% (11.75-27.31), p = 0.036), trabecular thickness (TbTh: 77.6 µm (61.7-88.3) vs. 82.7 µm (72.3-92.0) p = 0.045), with increased trabecular separation (TbSp: 536.4 µm (356.2-900.6) vs. 370.3 µm (377.1-546.3) p = 0.038) and increased cortical thickness (1268 µm (752-2521) vs. 1065 µm (851-1205) p = 0.025) and porosity (11.9% (10.2-13.3) vs. 4.8% (1.6-8.8) p = 0.0008). While active acromegaly patients showed histomophometric features of increased bone turnover, patients with controlled disease presented normal bone turnover with significantly lower osteoblastic activity, expressed as osteoblast number (p = 0.001), active osteoblasts and vigor (p = 0.014) in the presence of reduced osteocyte number (p = 0.008) compared to active disease. CONCLUSIONS: The apparent paradox of bone fragility in acromegaly patients with a normal BMD can be explained by increased cortical thickness and porosity and reduced trabecular thickness with increased trabecular separation. These structural and microarchitectural abnormalities persist in the controlled phase of acromegaly despite bone turnover normalization. The main determinant of bone disease after hormonal control is severe osteoblastic dysfunction.

The treatment of hyperinsulinemic hypoglycaemia in adults: an update.

BACKGROUND: Treatment of hyperinsulinemic hypoglycaemia (HH) is challenging due to the rarity of this condition and the difficulty of differential diagnosis. The aim of this article is to give an overview of the recent literature on the management of adult HH. METHODS: A search for reviews, original articles, original case reports between 1995 and 2016 in PubMed using the following keywords: hyperinsulinemic hypoglycaemia, insulinoma, nesidioblastosis, gastric bypass, autoimmune hypoglycaemia, hyperinsulinism, treatment was performed. RESULTS: One hundred and forty articles were selected and analysed focusing on the most recent treatments of HH. CONCLUSIONS: New approaches to treatment of HH are available including mini-invasive surgical techniques and alternative local-regional ablative therapy for benign insulinoma and everolimus for malignant insulinoma. A correct differential diagnosis is of paramount importance to avoid unnecessary surgical operations and to implement the appropriate treatment mainly in the uncommon forms of HH, such as nesidioblastosis and autoimmune hypoglycaemia.

Rare diseases in clinical endocrinology: a taxonomic classification system.

PURPOSE: Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. METHODS AND RESULTS: This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. CONCLUSIONS: This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.

Presentation, diagnostic features and glucose handling in a monocentric series of insulinomas.

BACKGROUND: New aspects have emerged in the clinical and diagnostic scenarios of insulinoma: current guidelines have lowered the diagnostic insulin threshold to 3 µU/ml in the presence of hypoglycemia (<55 mg/dl); post-prandial hypoglycemia has been reported as the only presenting symptom; preexisting diabetes mellitus (DM) was recognized in some patients. AIM: To evaluate clinical features, diagnostic criteria and glucose metabolic profile in a monocentric series of patients affected by insulinomas including two subgroups: sporadic and multiple endocrine neoplasia type-1 syndrome (MEN-1). SUBJECTS AND METHODS: Clinical, pathological and biochemical data regarding 33 patients were analyzed. RESULTS: following the current guidelines the 72-h fasting test was initially positive in all cases but one. In this case the test, initially negative, became positive after a 2-yr follow-up. Nadir insulin level was ≥ 3 µU/ml but <6 µU/ml in 3 patients and ≥ 6 µU/ml in the remaining 30 cases. At presentation, 27 patients (82%) reported only fasting symptoms, 3 (9%) only post-prandial and 3 (9%) both. Seven cases (21%) had previously been affected by type 2 DM or impaired glucose metabolism. CONCLUSIONS: In our series the new cut-off of insulin increased the sensitivity of the 72-h fasting test from 87% to 97%. The absence of hypoglycemia during the test cannot definitively rule out the diagnosis and the test should be repeated in every highly suspicious case. Post-prandial hypoglycemia can be the only presenting symptom. DM may be associated with the occurrence of insulinoma. So that a possible diagnosis of insulinoma must not be ignored if previous impaired glucose handling is evident.

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-enteropancreatic 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 hypersecretions. 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.

Hyperinsulinemic hypoglycemia associated with ectopic Cushing's syndrome due to a pancreatic endocrine tumor in a Type 2 diabetes mellitus patient: clinical implications of a rare association.

BACKGROUND: The coexistence of insulin and ACTH hypersecretion in the same patient is extremely rare. A diabetic patient with a pancreatic endocrine tumor (PET) co-secreting insulin and ACTH is even rarer and has never been described. The combination of these two endocrine syndromes results in a peculiar clinical picture. AIM: To determine the cause of glycemic variations in a patient with previously stable diabetes mellitus. SUBJECTS AND METHODS: This is a clinical case report from the Endocrinology Unit of Aosta Hospital and Internal Medicine and Surgical Unit of Verona University. A 69-yr-old diabetic patient was hospitalized for recurrent severe hypoglycemic events persistent after withdrawal of anti-diabetic drugs. The causes of hypoglycemia and subsequent resumption of hyperglycemia were investigated. RESULTS: An insulin-secreting PET was diagnosed. Diazoxide and octreotide therapy initially was able to control hypoglycemic symptoms, then, a Cushing's syndrome occurred resulting in worsening of diabetes control. ACTH was found to be released by the PET previously diagnosed as an insulin-secreting tumor. The tumor was removed and the histology was consistent with a well differentiated endocrine carcinoma. After surgery, adrenal function was normal and insulin therapy was again necessary to control diabetes. CONCLUSIONS: A single PET may be responsible for both a hyperinsulinemic and a Cushing's syndrome. When this rare association occurs, each of the two syndromes may affect the other resulting in a peculiar clinical course. Finally, an insulin-secreting PET has to be kept in mind as a rare cause of hypoglycemia in diabetic patients.

Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia.

BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27(KIP1) encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors. METHODS: Germline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated. RESULTS: Two novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49+/-18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families. CONCLUSION: AIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27(KIP1) is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.

Carcinoid crisis induced by receptor radionuclide therapy with 90Y-DOTATOC in a case of liver metastases from bronchial neuroendocrine tumor (atypical carcinoid).

SS receptors are overexpressed in many tumors, mainly of neuroendocrine origin, thus enabling the treatment with SS analogs. The clinical experience of receptor radionuclide therapy with the new analog [90Y-DOTA0-Tyr3 ]-octreotide [90Y-DOTATOC] has been developed over the last decade and is gaining a pivotal role in the therapeutic workout of these tumors. It is well known that some procedures performed in diagnostic and therapeutic management of endocrine tumors, such as agobiopsy and hepatic chemoembolization, can be associated with the occurrence of symptoms related to the release of vasoactive amines and/or hormonal peptides from tumor cell lysis. This is the first report of a severe carcinoid crisis developed after receptor radionuclide therapy with 90Y-DOTATOC administered in a patient affected by liver metastases from bronchial neuroendocrine tumor (atypical carcinoid). Despite protection with H1 receptor antagonists, octreotide and corticosteroids, few days after the therapy the patient complained of persistent flushing of the face and upper trunk, severe labial and periocular oedema, diarrhoea and loss of appetite. These symptoms increased and required new hospitalisation. The patient received iv infusion of octreotide associated with H1 and H2 receptor antagonists and corticosteroid therapy, which induced symptom remission within few days. The case here reported confirms that radionuclide therapy is highly effective in determining early rupture of metastatic tissue and also suggests that pre-medication should be implemented before the radiopeptide administration associated with a close monitoring of the patient in the following days.

Long-term quiescence of ectopic Cushing's syndrome caused by pulmonary neuroendocrine tumor (typical carcinoid) and tumorlets: spontaneous remission or therapeutic effect of bromocriptine?

In 1990, a 55-yr-old woman was admitted to the Medical Department of our hospital for severe hypercortisolism complicated by secondary diabetes mellitus and serious hypokalemia. Although inferior petrosal sinus sampling did not show any significant difference between central and peripheral ACTH concentration, suggesting an ectopic source of ACTH secretion, diagnostic imaging was negative and Cushing's disease due to hyperplasia of the pituitary intermediate lobe was suspected. Medical treatment with bromocriptine and cyproheptadine led to a rapid and stabile normalization of adrenal function, so that after two months cyproheptadine was stopped and bromocriptine was tapered to a smaller dose. An attempt to discontinue medical treatment, carried out 3 yr later, was followed by a quick increase of ACTH and cortisol levels, which were normalized by the resumption of the bromocriptine. Adrenal function remained normal until 1994 when hypercortisolism relapsed despite the treatment. Chest radiography and computed tomography (CT) scan detected a 6 mm nodule in the middle lobe of the lung which proved to be a neuroendocrine tumor, with immunohistochemical positivity for ACTH. Nests of neuroendocrine cells (tumorlets) were also demonstrated in the surrounding lung tissue. After the lobectomy, the patient recovered completely from Cushing's syndrome and no symptoms and/or signs of recurrence have been observed over the subsequent follow-up period. Although cyclical spontaneous Cushing's syndrome could not be excluded, there was strong evidence that medical treatment with bromocriptine might have played a key role in long-lasting remission. To our knowledge, this is the second case described in literature of Cushing's syndrome caused by neuroendocrine lung tumor responsive to bromocriptine.

Heterogeneity of nuclear DNA pattern and its relationship with cell cycle activity parameters in multinodular goitre.

OBJECTIVE: Recent studies suggest that the malignancy rate in multinodular goitre is not significantly different from that observed in solitary nodules and that chromosomal aberrations are not infrequent in multinodular goitre. To further investigate this topic we determined the DNA pattern in multinodular goitres. DESIGN: DNA ploidy and cell cycle activity parameters were determined in multinodular goitres. PATIENTS: We evaluated 235 patients (185 female, 50 male, mean age 52 +/- 13 years), who had undergone thyroidectomy; 11 of them harboured occult differentiated microcarcinoma. MEASUREMENTS: DNA index (DI), coefficient of variation of G0/G1 phase (CV), percentage of cells in S phase (%S) and in G2+M phase (%G2-M) and proliferative index (PI = %S+%G2-M) were determined by flow cytometric analysis (FCM) in tissue samples taken from 3 different areas of the thyroid gland. RESULTS: Aneuploid DNA was found in 50 goitres without carcinoma (22.3%) and in 5 goitres with carcinoma (45.5%). The mean PI of euploid cells in the goitre without carcinoma was significantly higher in the goitres with an aneuploid component compared to the goitres without aneuploidy (10.8 +/- 1.3 SEM vs 6 +/- 0.32; P +/- 0.001). Also, the percentage difference between maximal and minimal PI found within each goitre (delta PI %) was higher in the former group (373 +/- 49 SEM vs 142 +/- 11.3; P < 0.0001). The PI was significantly higher in goitres with carcinoma compared to the goitres without carcinoma (12.9 +/- 3.2 SEM vs 7.07 +/- 0.40; P < 0.05). CONCLUSIONS: The findings of increased proliferation rate in goitres with an aneuploid or neoplastic component suggests that some factors involved in goitrogenesis could also be responsible for the development of chromosomal aberrations and/or for the selection of cellular clones endowed with high growth potential.

[Cushing's disease associated with empty sella: a clinical case treated for years with ketoconazole]. / Malattia di Cushing associata a sella vuota: un caso clinico trattato per sette anni con ketoconazolo.

Cushing's disease and empty sella without evidence of pituitary adenoma are rarely observed. To our knowledge, there is very little documentation on long-term therapeutic follow-up with the steroidogenesis inhibitor ketoconazole. A 48-year-old woman with uncontrolled insulin-dependent diabetes mellitus, severe hypertension, and clinical findings of hypercortisolism was referred to our hospital. Endocrine evaluation of adrenocortical function evidenced hypothalamic-pituitary-hypercortisolism, and excluded adrenal tumor or an ectopic corticotropin source. Magnetic resonance imaging disclosed an empty sella turcica but not pituitary adenoma. The patient was treated with a steroidogenesis inhibitor, ketoconazole (600 mg daily) which reduced urinary cortisol excretion to within the normal range. Serum cortisol levels also returned to normal in the morning but not in the evening. The patient has continued on ketoconazole therapy for the past 7 years, with neither side effects nor tachyphylaxis. The reduction of cortisol secretion brought about significantly improved control of diabetes mellitus and hypertension, although signs of hypercortisolism have persisted. Radiographic studies of the hypophysis during follow-up have not evidenced adenoma.

An unusual case of adrenal failure due to isolated metastases of breast cancer.

We describe a patient affected by adrenal insufficiency due to metastases of breast cancer. Adrenal involvement became clinically evident 20 years after radical mastectomy and it was the only secondary localization of the tumor. There is still no evidence of other metastases after a two year follow-up. This case suggests that adrenal function evaluation should be included in periodical follow-ups of patients who underwent radical mastectomy for breast cancer.

[Nuclear DNA in neoplastic pathology of the thyroid gland]. / Il DNA nucleare nella patologia neoplastica della tiroide.

We have analysed the nuclear DNA content in a series of 33 thyroid tumours (18 carcinomas and 15 adenomas) and, for comparison, in 189 nodular strumas and 17 tissue samples of normal thyroids, calculating cell cycle parameters and presence of aneuploid DNA. Cell suspensions were prepared for each of three tissue fragments taken for different areas of the surgical specimens. Cell subpopulations with aneuploid DNA content were present in 39% of carcinomas, 27% of adenomas, 20% of strumas, but were absent in the samples from normal thyroids. The presence of hyperdiploid DNA was much more frequent than that of hypodiploid DNA in all pathologic tissues. The mean proliferation index was 14.1 in the carcinomas, 6.6 in the adenomas, 7.1 in the strumas and 6.1 in normal thyroid tissues. The percent of histograms with a coefficient of variation of the G0-G1 peak greater than 5 was highest in the carcinomas (26%). The significance and implications of the reported data are discussed for the interpretation of thyroid neoplastic pathologies.

[Hormonal therapy in differentiated carcinoma of the thyroid gland]. / La terapia ormonale del carcinoma differenziato della tiroide.

Thyrotropin (TSH) suppression therapy using thyroid hormone plays an important role in the management of patients thyroidectomized for differentiated thyroid cancer. The rationale for TSH suppression is that differentiated thyroid cancer cells have TSH receptors and show increased adenylate cyclase activity following TSH exposure. L-thyroxine is used for long-term therapy. L-triiodothyronine is preferred when suppressive therapy must be discontinued for radioiodine scan, since its shorter half-life allows more rapid increases of TSH levels. The assessment of TSH suppression is still uncertain. The development of second and third TSH assay generations with progressive improvement in sensitivity has made the TRH test unnecessary and has raised the issue of the TSH level indicative of TSH suppression. In clinical practice TSH values below 0.1 mU/L are considered compatible with appropriate TSH suppression. Serum thyroglobulin is a reliable marker of metastatic disease after total surgical and radioiodine ablation of the thyroid gland and it is useful in the surveillance of patients with differentiated thyroid cancer.

Effect of deflazacort on growth hormone response to insulin tolerance test.

Deflazacort (DF) has been claimed to be provided with a reduced distribution into the central nervous system, therefore it is conceivable that this glucocorticoid holds a lower inhibitory effect on GH secretion. To test this hypothesis we studied the GH response to insulin tolerance test (ITT) in two matched groups of patients given equivalent doses of DF and prednisone (PN). The serum glucose changes induced by ITT were similar in the two groups and in control subjects; the mean increase in plasma GH, in particular the peak and the area under the curve (delta AUC), were not different in control subjects and DF-treated patients (25 +/- 12.5 ng/ml and 1790 +/- 904 ng/ml/min versus 27.7 +/- 21.5 ng/ml and 1578 +/- 1242 ng/ml/min) but were significantly reduced in PN-treated patients (8.8 +/- 9.7 ng/ml and 431.6 +/- 451 ng/ml/min). Our study demonstrates that DF does not interfere with the GH response to ITT as PN does.