Antongiulio Faggiano

The Medical Treatment of Cushing’s Disease: Effectiveness of Chronic Treatment with the Dopamine Agonist Cabergoline in Patients Unsuccessfully Treated by Surgery

BACKGROUND The role of dopamine agonists in the treatment of Cushings disease (CD) has been previously debated. AIM The aim of this study was to evaluate the effectiveness of short-term (3 months) and long-term (12-24 months) treatment with cabergoline in patients with CD. PATIENTS AND METHODS 20 patients with CD unsuccessfully treated by surgery entered the study. Cabergoline was administered at an initial dose of 1 mg/wk, with a monthly increase of 1 mg, until urinary cortisol levels normalized or the maximal dose of 7 mg/wk was achieved. The responsiveness to treatment was evaluated according to changes in urinary cortisol excretion. A decrease greater than 25% was considered as a partial response, whereas complete normalization was considered as a full response at short-term evaluation; persistence of normal cortisol excretion was the only criterion to evaluate the response at long-term evaluation. RESULTS After short-term treatment, 15 (75%) patients were responsive to cabergoline treatment. Among these, normalization of cortisol excretion was maintained in 10, whereas treatment escape was observed in five patients after 6-18 months. Among the 10 long-term responsive patients, eight were followed for 24 months, whereas the remaining two were followed for 12-18 months, due to cabergoline withdrawal for intolerance. A sustained control of cortisol secretion for 24 month cabergoline treatment at the maximal dose ranging from 1-7 mg/wk (median: 3.5) without significant side effects, was obtained in eight of 20 (40%) patients. CONCLUSIONS The results of this study demonstrated that cabergoline treatment is effective in controlling cortisol secretion for at least 1-2 yr in more than one third of a limited population of patients with CD. If this evidence is confirmed by additional studies, this agent may be considered as a useful treatment option in patients with CD who are unsuccessfully treated by neurosurgery.

Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy

Typing somatostatin receptor expression in neuroendocrine tumors is of relevance to target somatostatin analogue-based diagnostic approach and treatment. The expanding use of immunohistochemistry to detect somatostatin receptors is to date not paralleled by an accurate methodological setting and standardized interpretation of the results. A multicentric study was designed to compare somatostatin receptor immunohistochemical expression with in vivo scintigraphic data and verify its usefulness in the clinical management of neuroendocrine tumors. After methodological setting by testing different somatostatin receptor antibodies, 107 cases of neuroendocrine tumors with available somatostatin receptor scintigraphy data and pathological material were retrospectively analyzed for somatostatin receptor types 2A, 3 and 5 immunohistochemical expression, and compared with scintigraphic images and, whenever available, with the clinical response to somatostatin analogue treatment. Restricting ‘positive cases’ to the presence of a membrane pattern of staining, an overall somatostatin receptor type 2A immunohistochemistry/somatostatin receptor scintigraphy agreement of 77% (χ2 test P<0.0001) was reached. Lower concordance ratios were detected in preoperative and metastatic tumor samples, possibly as a consequence of somatostatin receptor expression heterogeneity. Pure somatostatin receptor type 2A cytoplasmic staining showed poor correlation with somatostatin receptor scintigraphy (54% concordance rate). The immunohistochemical detection of somatostatin receptor types 3 and 5, which showed almost exclusively a cytoplasmic pattern, did not improve the concordance with scintigraphic data. In a pilot series, somatostatin receptor type 2A immunohistochemistry correlated with clinical response in 75% of cases. In conclusion, we propose a scoring system for somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors correlated with in vivo data, based on the evidence that only membrane (rather that cytoplasmic) staining should be considered for a reliable, standardized and clinically relevant report.

Thyroid Nodules and Related Symptoms Are Stably Controlled Two Years After Radiofrequency Thermal Ablation

BACKGROUND Percutaneous radiofrequency thermal ablation (RTA) is a promising new therapeutic approach to manage thyroid nodules (TNs). The aim of this study was to investigate the long-term effectiveness of RTA in inducing shrinkage of TNs as well as in controlling compressive symptoms and thyroid hyperfunction in a large series of elderly subjects with solid or mainly solid benign TNs. METHODS Ninety-four elderly patients with cytologically benign compressive TNs were prospectively enrolled in the study; 66 of them had nontoxic goiter and 28 had toxic or pretoxic goiter. RTA was performed by using a RITA StarBurst Talon hook-umbrella needle inserted in every single TN under ultrasonographic real-time guidance. TN volume, TN-related compressive symptoms and thyroid function were evaluated at baseline and 12 to 24 months after RTA. RESULTS All TNs significantly decreased in size after RTA. The mean decrease in TN volume 12 months after RTA was from 24.5 +/- 2.1 to 7.5 +/- 1.2 mL (p < 0.001), with a mean percent decrease of 78.6 +/- 2.0%. Two years after RTA, a 79.4 +/- 2.5% decrease of TNs size was observed. Compressive symptoms improved in all patients and completely disappeared in 83 of 94 (88%) patients. Hyperthyroidism resolved in most patients allowing methimazole therapy to be completely withdrawn in 79% of patients with pretoxic and toxic TNs (100% with pretoxic TNs and 53% with toxic TNs). The treatment was well tolerated by all patients. No patient needed hospitalization after RTA and no major complications were observed. CONCLUSIONS RTA is an effective and simple procedure for obtaining lasting shrinkage of TNs, controlling compressive symptoms, and treating thyroid hyperfunction. When performed in experienced medical centers, RTA may be a valid alternative to conventional treatments for nontoxic and pretoxic TNs. It is particularly attractive for elderly people for whom surgery and radioiodine therapy are often contraindicated or ineffective.

Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study

Background  The pituitary tumour transforming gene (pttg) plays a central role in pituitary tumorigenesis, but PTTG protein expression is poorly documented and its relationship with tumour cell proliferation and the prognosis of pituitary adenomas is unclear.

US-Guided Percutaneous Radiofrequency Thermal Ablation for the Treatment of Solid Benign Hyperfunctioning or Compressive Thyroid Nodules

The aim of the study was to define the effectiveness and safety of ultrasound-guided percutaneous radiofrequency (RF) thermal ablation in the treatment of compressive solid benign thyroid nodules. Thirty-one patients not eligible for surgery or radioiodine (131I) treatment underwent RF ablation for benign nodules; a total of 33 nodules were treated (2 patients had 2 nodules treated in the same session): 10 cold nodules and 23 hyperfunctioning. Fourteen patients complained of compressive symptoms. Nodule volume, thyroid function and compressive symptoms were evaluated before treatment and at 1, 3 and 6 mo. Ultrasound-guided RF ablation was performed using a Starbust RITA needle, with nine expandable prongs; total exposure time was 6 to 10 min at 95 degrees C in one area or more of the nodule. Baseline volume (measured at the time of RF ablation) was 27.7 +/- 21.5 mL (mean +/- SD), but significantly decreased during follow-up: 19.2 +/- 16.2 at 1 mo (-32.7%; p < 0.001), 15.9 +/- 14.1 mL at 3 mo (-46.4 %; p < 0.001) and 14.6 +/- 12.6 mL at 6 mo (-50.7%; p < 0.001). After treatment, all patients with cold nodules remained euthyroid: five patients with hot nodules normalized thyroid function, and the remaining sixteen showed a partial remission of hyperthyroidism. Besides a sensation of heat and mild swelling of the neck, no major complications were observed. Improvement in compressive symptoms was reported by 13 patients, with a reduction on severity scale from 6.1 +/- 1.4 to 2.2 +/- 1.9 (p < 0.0001). Radiofrequency was effective and safe in reducing volume by about 50% and compressive symptoms in large benign nodules. Hyperfunction was fully controlled in 24% of patients and partially reduced in the others.

Medical therapy for clinically non-functioning pituitary adenomas

Surgery is the first-line treatment of patients with clinically non-functioning pituitary adenomas (NFAs). Because of lack of clinical syndrome these tumours are diagnosed with a variable delay, when patients suffer from compression symptoms (hypopituitarism, headache and visual field defects) due to the extension of the tumour outside the pituitary fossa. Surgery is followed by residual tumour tissue in most patients. In these cases, radiotherapy is generally used to prevent tumour regrowth. However, NFA cell membranes, in analogy with GH- and PRL-secreting adenomas, express somatostatin and dopamine receptors. Treatment with somatostatin analogues (SSA) and dopamine agonists (DA) induced some beneficial effects on visual field defects and was also followed by tumour shrinkage in a minority of cases. DA seem to be more effective on tumour shrinkage than SSA. More recently, a combination treatment with both SSA and DA have been tested in a few patients with interesting results. Lack of randomized, placebo-controlled trials prevents any conclusion on the efficacy of these drugs. By contrast, use of gonatotrophin-releasing hormone analogues has been abandoned.

Epidemiology of gastroenteropancreatic neuroendocrine tumours

Gastroenteropancreatic neuroendocrine tumours are a heterogeneous group of tumours arising from diffuse endocrine cells, causing unique clinical syndromes. These tumours, formerly named carcinoid, can involve any part of the gastrointestinal tract and the endocrine pancreas and have a wide range of malignant potential: from benign to poorly differentiated tumours. In this review we will summarize the data available on the epidemiology of gastroenteropancreatic tumours as it is reported from around the world. This includes annual incidence rates at the various anatomic sites, and trends in incidence rates with time. In addition age and stage at presentation, gender and racial differences and finally prognosis and survival were collected when reported.

Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing's disease: a prospective study.

background Osteoporosis is a frequent, severe and often underestimated consequence of long‐term hypercortisolism, often presenting as bone fracture.

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

OBJECTIVE Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population. METHODS We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres. RESULTS AND CONCLUSIONS The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.

Vitamin D and Cancer

Vitamin D system is a complex pathway that includes precursors, active metabolites, enzymes, and receptors. This complex system actives several molecular pathways and mediates a multitude of functions. In addition to the classical role in calcium and bone homeostasis, vitamin D plays “non-calcemic” effects in host defense, inflammation, immunity, and cancer processes as recognized in vitro and in vivo studies. The aim of this review is to highlight the relationship between vitamin D and cancer, summarizing several mechanisms proposed to explain the potential protective effect of vitamin D against the development and progression of cancer. Vitamin D acts like a transcription factor that influences central mechanisms of tumorigenesis: growth, cell differentiation, and apoptosis. In addition to cellular and molecular studies, epidemiological surveys have shown that sunlight exposure and consequent increased circulating levels of vitamin D are associated with reduced reduced occurrence and a reduced mortality in different histological types of cancer. Another recent field of interest concerns polymorphisms of vitamin D receptor (VDR); in this context, preliminary data suggest that VDR polymorphisms more frequently associated with tumorigenesis are Fok1, Bsm1, Taq1, Apa1, EcoRV, Cdx2; although further studies are needed to clarify their role in the cancer. In this review, the relationship between vitamin D and cancer is discussed.