Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Safety and effectiveness of Omnitrope® in patients with growth hormone deficiency: snapshot analysis of PATRO Adults study in the Italian population.

PURPOSE: PATRO adults is an ongoing, multicenter, observational, post-marketing surveillance study aimed at investigating the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the recombinant human growth hormone (rhGH) Omnitrope® during routine clinical practice. This report describes data from Italian participants in PATRO Adults with growth hormone deficiency (GHD), up to August 2017. METHODS: Participants were adults (aged > 18 years) with GHD requiring rhGH therapy and were prescribed Omnitrope®, including those who had previously received another rhGH product. Adverse events (AEs) were evaluated in all study participants. Data were collected on insulin-like growth factor (IGF)-I levels and cardiovascular risk factors, including blood pressure, lipids, and anthropometric parameters. RESULTS: From September 2007 to August 2017, 88 patients (mean age 48.9 years, 58.0% male) were enrolled at 8 sites in Italy. The mean treatment duration with Omnitrope® was 51.5 ± 37 months. AEs occurred in 54 patients; the most common were asthenia (20.5%), headache (14.8%), and arthralgia (13.6%). Serious AEs occurred in 22 patients (25%), including pneumonia (n = 2) and renal failure (n = 2). Neoplasms (2 benign and 1 malignant) developed in three patients, but none were considered to be drug-related. There were no significant changes in fasting glucose or glycosylated hemoglobin (HbA1c) during the study period. Long-term Omnitrope® therapy showed slight positive effects on lipid profile, while no significant changes were observed in body weight and BMI during the study. CONCLUSION: This snapshot analysis of Italian participants in PATRO Adults confirmed the long-term safety and effectiveness of Omnitrope® in adults with GHD.

Long-term safety and efficacy of Omnitrope® in adults with growth hormone deficiency: Italian interim analysis of the PATRO Adults study.

PURPOSE: To report the long-term effectiveness and safety of the recombinant human growth hormone Omnitrope®, a somatropin biosimilar to Genotropin®, in Italian patients with growth hormone deficiency (GHD) enrolled in the PATRO Adults study. METHODS: The PATRO Adults study is an ongoing observational, longitudinal, non-interventional global post-marketing surveillance study, conducted in several European countries. The primary endpoint is long-term safety; secondary endpoints include the effectiveness of Omnitrope®, which was assessed using serum insulin-like growth factor-1 levels, body composition, bone mineral density and lipid levels. Here we report the data from the Italian patients enrolled in the study. RESULTS: Sixty-seven patients (mean age 50.4 years, 61.2% male) have been enrolled and have received a mean 45.4 ± 24.3 months of Omnitrope®. A total of 55.2% of patients were reported to have experienced adverse events (AEs), including arthralgia, myalgia, abdominal distension and hypoaesthesia, and 4.5% had adverse drug reactions. Fourteen serious AEs have been recorded; none of these are considered related to the study drug. The effectiveness of Omnitrope® was similar to other available somatropin preparations. CONCLUSIONS: This study confirms the effectiveness and safety of Omnitrope® in adult patients with GHD in Italy. However, due to the limited size of the study population, these results need to be further confirmed by the global PATRO Adults study.

A useful ultrasound score to select thyroid nodules requiring fine needle aspiration in an iodine-deficient area.

BACKGROUND: The high prevalence of thyroid nodules in iodine-deficient areas is a practical problem because of the large number of patients requiring fine needle aspiration (FNA) to detect malignant nodules. AIM: To obtain an ultrasound (US) score for predicting malignant nodules and reduce the number of unnecessary and expensive FNA. SUBJECT AND METHOD: All nodules observed from September 2001 to March 2006 were evaluated by US: echostructure, echogenicity, halo, microcalcifications and ratio between antero-posterior and transversal diameters (AP/TR). Two thousand six hundred and forty-two consecutive patients underwent US-guided FNA for a total of 3645 nodules. RESULTS: Logistic regression analysis showed a potent predictive role for solitary nodules and absence/ incomplete halo (p=0.000). A significant predictive role for microcalcifications and AP/TR ratio was also observed. A 10-point score was constructed using the standardized regression coefficient. Nodules with US score or=5.5 had a frequency of malignancy of 0.4, 1.1 and 5.6% (p<0.001), respectively. Nodules with >or=5.5 US score were characterized by a 66% sensitivity and a 76% specificity compared to the diagnostic values of single parameters which were either sensitive or specific. CONCLUSIONS: According to our data, we suggest FNA for nodules reaching a >5.4 US score, whereas a clinical judgement should be used for the intermediate category nodules. When the score is lower than 2.5 we do not recommend FNA. The practical use of this US score can help reduce unnecessary and expensive FNA in iodine-deficient areas.

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.

Cytotoxic effects of a novel pyrazolopyrimidine derivative entrapped in liposomes in anaplastic thyroid cancer cells in vitro and in xenograft tumors in vivo.

In this study, we evaluated the activity of two novel pyrazolopyrimidine derivatives (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concentrations of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 microM Si 34 determined a decrease of cell counts by approximately 25% and approximately 75% compared with those of control cells respectively. Similar findings were observed using Si 35. Treatment with both Si 34 and Si 35 at 10 microM increased cell mortality also ( approximately 29% and approximately 18% respectively). At these concentrations, a decrease in cyclin D1 levels was observed. To improve the biopharmaceutical properties, a liposome formulation was prepared. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 microM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were associated with weak apoptotic death. Inhibition of epidermal growth factor-stimulated src and ERK phosphorylation, as well as reduction of migration properties of ARO cells was also observed. Moreover, the growth of tumor xenografts induced in severe combined immunodeficiency (SCID) mice was inhibited by i.v. administration of 25-50 mg/kg of the drug liposomal formulation. In conclusion, the liposomal preparation of this novel pyrazolopyrimidine derivative appears to be a promising tool for the treatment of anaplasic thyroid cancer.

M. avium binding to HLA-DR expressed alleles in silico: a model of phenotypic susceptibility to sarcoidosis.

Sarcoidosis is a systemic granulomatosis disease of unknown origin where a number of microbes, in particular M. tuberculosis and non-tuberculous mycobacteria, have been hypothesized to play a role in disease pathogenesis, possibly through bacterial antigen-driven hypersensitivity. To test this concept, we used bioinformatic tools allowing the identification of antigenic peptides in whole microbial genomes to analyze the interaction between the expressed HLA-DR gene allelic variants and the HLA-DR immunome of all pathogenic bacteria in a population of 149 sarcoidosis affected subjects and 447 controls, all HLA-typed at high resolution. We show here that patients with the Löfgren's syndrome, express HLA-DR alleles that recognize in silico a significantly higher number of bacterial antigen epitopes compared to the control population (18,496+9,114 vs 17,954+8,742; p<0.00001), and the chronic sarcoidosis affected population (17,954+8,742; p<0.00001 vs Löfgren's and controls). Further, the analysis of the ability of the HLA-DR allele combinations expressed by the Löfgren's and the chronic sarcoidosis affected subjects to recognize M. avium epitopes demonstrates that a significantly larger number of Löfgren's are capable of top affinity recognition, compared to chronic sarcoidosis (45% vs 17%, p<0.0037). Finally, both Löfgren's and chronic sarcoidosis subjects expressed HLA-DR allele combinations capable of M. tuberculosis and M. avium epitope recognition at higher affinity than tuberculosis affected subjects (p<0.01 all comparisons). In conclusion, we propose that - at least in a subgroup of affected subjects - sarcoidosis might be part of a spectrum of granulomatous responses to several agents where the Löfgren's syndrome represents the hyper-reactive end of the spectrum while pulmonary tuberculosis and atypical mycobacterial infections might represent the opposite end.

Fine needle aspiration cytology of thyroid nodules: conventional vs thin layer technique.

OBJECTIVE: Liquid-based cytology using the thin layer technique has recently been introduced in thyroid fine needle aspiration cytology together with or in substitution of direct smears, but its usefulness is still controversial and relatively few studies have been published in this field. The aim of the present study was to compare the results obtained from conventional smears with those from thin layer smears. DESIGN: In 3875 thyroid nodules, a double cytologic sampling was taken in randomized order, to prepare conventional or thin layer smears. MAIN OUTCOME: The diagnoses agreed in 2934 (75.7%) cases and disagreed in 941 (24.3%). The analysis of discordant data showed there were fewer non-diagnostic cases in the thin layer smears (377 vs 541, p<0.001) whereas in conventional smears there were more cases positive for carcinoma (27 vs 4, p<0.001). The cytohistologic correlation was available for 194 cases and showed that conventional smears had a greater capacity for revealing carcinomas (44 vs 31). Finally, diagnoses based on conventional smears were more sensitive than thin layer smears (93.6% vs 65.9%) whereas specificity was constant. CONCLUSIONS: From our experience, the conventional smear offers a greater possibility of diagnosis when suspecting malignancy or diagnosing malignancy cases, whereas thin layer smears significantly reduce the number of non-diagnostic cases. For this reason, we suggest combining the two techniques in routine cytologic diagnosis.

Recurrences of thyroid well differentiated cancer: ultrasonography-guided surgical treatment.

AIM: Differentiated thyroid carcinomas (DTC) have a favourable outlook overall. Cornerstone of treatment is total thyroidectomy (TT), followed, if needed, by radiometabolic therapy. Such lesions however show a definite tendency to recur (about 35% of cases), generally in the first decade of follow-up: in 70% of patients such recurrence is local. Surgical resection is the only curative treatment option for local recurrence of well-differentiated thyroid cancer. Intraoperative ultrasonography (US) can be of significant help in facilitating localization and complete resection of lesions. The aim of the study was to review the authors' own experience with the use of such diagnostic method in the clinical setting of thyroid neoplasm recurrence. METHODS: Between January 2005 and March 2008 31 patients with DTC recurrences underwent intraoperative US exploration. Recurrences were easily identified and resected in all patients. Postoperative tireoglobuline (TG) was undetectable. RESULTS: In all 31 patients preoperative US confirmed the presence of the lesion. In 26 patients digital exploration of the surgical field did not yield a definitively positive finding, whereas in 5 the lesion was easily palpable. Intraoperative US revealed the presence of pathologic tissue in all cases, with examination time ranging from 4 to 14 minutes (median 8 minutes). In all cases surgical resection was complete, with pathologic confirmation of the sample, and no necessity to extend ablation. CONCLUSION: Intraoperative US can be of significant help in the identification of DTC recurrences, in particular when lesion dimensions are smaller than 10 mm in diameter and can facilitate a more radical excision of the tumor in a surgical field were anatomical landmarks can be altered by previous surgery and/or radiometabolic therapy.

Surgical treatment of sporadic medullary thyroid carcinoma: strategy and outcome.

BACKGROUND: Medullary Thyroid Carcinoma (MTC) originates from the thyroid C cells and accounts for approximately 5-9% of all thyroid cancers. Aim of this study was to retrospectively evaluate the outcomes of 41 patients with MTC who underwent treatment at our institution. PATIENTS AND METHODS. We reviewed the records of 41 patients who underwent surgery between 1995 and 2004. The patients were divided into two groups: A) patients (n 30) without any previous surgery. B) patients (n 11) previously thyroidectomized and high calcitonin levels with or without radiological evidence of local regional or distant metastases. We performed total thyroidectomy with central compartment lymphadenectomy and ipsilateral modified radical neck dissection in group A patients. Group B patients underwent re-excision of the central neck compartment and bilateral modified radical neck dissection if it had not been previously performed. RESULTS: Most patients had major reduction in postoperative calcitonin levels. Compartmental dissection of the cervical node significantly improved the results of primary surgery and calcitonin returned to normal levels in approximately 60% of the patients in group A, but only the 30% of the patients in group B. CONCLUSIONS: The extent of the primary surgical resection and the evidence of local or distant metastases significantly influence the outcome of MTC patients. An extensive lymphadenectomy performed early in the treatment and re-operative cervical lymphadenectomy in patients with persistently high calcitonin levels after thyroidectomy significantly improved the outcome, although re-operation rarely results in normalized calcitonin levels and is associated with a higher incidence of complications.

Surgical treatment of differentiated thyroid carcinoma: a retrospective study.

INTRODUCTION: We carried out a retrospective analysis of our experience in the management of Differentiated Thyroid Carcinoma (DTC), in order to better define prognostic factors (age, gender, histological type, stage) and outline a standard procedure, where it's possible, for surgical treatment. PATIENTS AND METHODS: Patient population consisted of 432 cases, operated from 1978 to 2003. We carried out 285 operations of total thyroidectomy of which 39 associated to some kind of lymphadenectomy, 66 totalization (21 pts had been operated in other institutes), 60 subtotal thyroidectomies and 21 lobo-isthmectomies. Survival and mortality curves for age, sex, histological type, grading and staging have been calculated. Kaplan-Meyer statistical elaboration for disease-free interval and Mann-Whitney test for the comparison of different clinical and pathological data have been employed. RESULTS: The statistical analysis puts in evidence that on 432 cases examined, with a follow-up from 1 to 25 ys (median = 6.33 ys) and with a drop-out of 60 cases (13.8 %), total mortality for cancer has been of 24 cases (6,4%), with a median interval free by disease of 4.2 ys (range 5 months to 25 ys), and a probability to stay free by disease at 12 and 24 months respectively of 95.1% and 91.6%. The median survival is resulted of 5.8 ys (range 1 to 25 ys) with a probability of survival at 24 and 48 months respectively of 97.5% and 94.3%. The multivariate analysis evidences the most important variables, i.e. age > 45 ys, tumor of intermediate malignancy, with size 1.5 cm, operative M+, significantly condition the prognosis, noticeably getting worse it, independently by the kind of carried out operation. CONCLUSION: Our present therapeutic choices are: 1. total thyroidectomy in the treatment of the apparently benign pathology when bilaterally with spread; the checking at the final histological exam of a cancer makes however think adequate the carried out operation; 2. lobo-isthmectomy in the treatment of unilateral benign pathology or with suspect FNAB for follicular neoplasm; the histological checking of a cancer makes think the operation adequate only in presence of favourable prognostic parameters, but in presence even of just one unfavourable variable, we consider necessary the totalization; 3. total thyroidectomy in presence of a certain or strongly suspected preoperative diagnosis of cancer.

Biochemical and molecular characterization of the novel BRAF(V599Ins) mutation detected in a classic papillary thyroid carcinoma.

Activating mutations of the BRAF gene are the most common genetic alterations in papillary thyroid carcinomas (PTCs) and the T1799A transversion, resulting in BRAFV600E, appeared virtually unique in this cancer type. Here, we report on the identification in a classic PTC of a novel BRAF mutation, namely a 1795GTT insertion, resulting in BRAFV599Ins, and describe its biochemical and molecular characterization. Kinase assays carried out on BRAFV599Ins and BRAFV600E revealed a three- to five-fold increase in the enzymatic activity of both mutants with respect to BRAFWT. Similarly, evaluation of BRAF-induced phosphorylation of MEK, MAPK and RSK revealed a significant MAPK cascade activation in cells expressing BRAFV599Ins or BRAFV600E, but not in cells expressing BRAFWT. Molecular dynamic simulations showed a destabilization of the inactive conformation of the enzyme in both BRAFV599Ins and BRAFV600E mutants, but not in BRAFWT. The analysis of the interaction energies inside the catalytic site allowed to demonstrate the presence of repulsive electrostatic forces acting on the activation loop and moving from inward to outward of the mutant enzymes. Finally, focus assays in NIH-3T3 cells confirmed a high transformation rate in the cells transfected either with BRAFV599Ins or BRAFV600E. In conclusion, this study demonstrated that BRAFV599Ins, as BRAFV600E, is a 'gain of function' mutation, characterized by a constitutive catalytic activation, which accounts for its causative role in the studied PTC.

BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism.

CONTEXT: BRAF mutations are common in papillary thyroid carcinomas (PTCs). By affecting the expression of genes critically related to the development and differentiation of thyroid cancer, they may influence the prognosis of these tumors. OBJECTIVE: Our objective was to characterize the expression of thyroid-specific genes associated with BRAF mutation in PTCs. DESIGN/SETTING AND PATIENTS: We examined the expression of key markers of thyrocyte differentiation in 56 PTCs with BRAF mutations (BRAF-mut) and 37 with wild-type BRAF (BRAF-wt). Eight samples of normal thyroid tissue were analyzed as controls. Quantitative PCR was used to measure mRNA levels for the sodium/iodide symporter (NIS), apical iodide transporter (AIT-B), thyroglobulin (Tg), thyroperoxidase (TPO), TSH receptor (TSH-R), the transcription factor PAX8, and glucose transporter type 1 (Glut1). NIS protein expression and localization was also analyzed by immunohistochemistry. RESULTS: mRNA levels for all thyroid-specific genes were reduced in all PTCs vs. normal thyroid tissues. NIS, AIT-B, Tg, and TPO expression was significantly lower in BRAF-mut tumors than in the BRAF-wt group. Glut-1 transcript levels were increased in all PTCs, and additional increases were noted in BRAF-mut tumors. In both tumor subsets, the NIS protein that was expressed was abnormally retained in the cytoplasm. CONCLUSION: BRAF V600E mutation in PTCs is associated with reduced expression of key genes involved in iodine metabolism. This effect may alter the effectiveness of diagnostic and/or therapeutic use of radioiodine in BRAF-mut PTCs.

Doping and respiratory system.

Historically many different drugs have been used to enhance sporting performances. The magic elixir is still elusive and the drugs are still used despite the heavy adverse effects. The respiratory system is regularly involved in this research probably because of its central location in the body with several connections to the cardiovascular system. Moreover people are aware that O2 consumption and its delivery to mitochondria firstly depend on ventilation and on the respiratory exchanges. The second step consists in the tendency to increase V'O2 max and to prolong its availability with the aim of improving the endurance time and to relieve the fatigue. Many methods and substances had been used in order to gain an artificial success. Additional oxygen, autologous and homologous transfusion and erythropoietin, mainly the synthetic type, have been administered with the aim of increasing the amount of oxygen being delivered to the tissues. Some compounds like stimulants and caffeine are endowed of excitatory activity on the CNS and stimulate pulmonary ventilation. They did not prove to have any real activity in supporting the athletic performances. Beta-adrenergic drugs, particularly clenbuterol, when administered orally or parenterally develop a clear illicit activity on the myosin fibres and on the muscles as a whole. Salbutamol, terbutaline, salmeterol and formoterol are legally admitted when administrated by MDI in the treatment of asthma. The prevalence of asthma and bronchial hyperactivity is higher in athletes than amongst the general population. This implies that clear rules must be provided to set a correct diagnosis of asthma in the athletes and a correct therapy to align with the actual guidelines according to the same rights of the "other" asthmatic patients.

Long-term efficacy and safety of fourth-line multikinase inhibitor treatment with lenvatinib in a young papillary thyroid carcinoma patient.

Lenvatinib, a multikinase inhibitor, is approved for the treatment of patients with radioiodine-refractory metastatic thyroid cancer on the basis of a Phase III, prospective, double-blind, randomized, placebo-controlled trial that showed longer progression-free survival in the drug-treated arm. Here, we report the case of a young papillary thyroid cancer patient, pretreated with three other kinase inhibitors, who achieved a long-term clinical benefit from lenvatinib in the fourth-line setting.

Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature.

Recently, a somatic point mutation of the B-RAF gene (V600E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC), with a prevalence variable among different series. Since discordant data on the clinico-pathologic features of B-RAF mutated PTC are present in the literature, the aim of the present co-operative study was to establish the prevalence of this genetic alteration and to perform a genotype-phenotype correlation in a large cohort of patients with PTC. To this purpose, a series of 260 sporadic PTCs with different histological variants were included in the study. The mutational analysis of the B-RAF gene was performed either by RT-PCR followed by single-stranded conformational polymorphism or by PCR and direct sequencing. Statistical analyses were obtained by means of chi2/Fisher's exact test and t-test. Overall, a heterozygous T > A transversion at nucleotide 1799 (V600E) was found in 99 out of 260 PTCs (38%). According to the histological type of the tumor, the B-RAF (V600E) mutation was present in 48.3% of cases of classic PTCs (85 out of 176), in 17.6% (nine out of 51) of follicular variants of PTCs, in 21.7% (five out of 23) in other PTC variants and in none of the ten poorly differentiated tumors. B-RAF (V600E) was significantly associated with the classic variant of PTC (P = 0.0001) and with an older age at diagnosis (P = 0.01). No statistically significant correlation was found among the presence of B-RAF (V600E) and gender, tumor node metastasis (TNM), multicentricity of the tumor, stage at diagnosis and outcome. In conclusion, the present study reports the prevalence of B-RAF (V600E) (38%) in the largest series of sporadic PTCs, including 260 cases from three different Italian referring centers. This prevalence is similar to that calculated by pooling together all data previously reported, 39.6% (759 out of 1914 cases), thus indicating that the prevalence of this genetic event lies around 38-40%. Furthermore, B-RAF (V600E) was confirmed to be associated with the papillary growth pattern, but not with poorer differentiated PTC variants. A significant association of B-RAF mutation was also found with an older age at diagnosis, the mutation being very rare in childhood and adolescent PTCs. Finally, no correlation was found with a poorer prognosis and a worse outcome after a median follow-up of 72 months.

Evaluation of goiter using ultrasound criteria: a survey in a middle schoolchildren population of a mountain area in Central Italy.

Iodine deficiency is still an important health care problem in the world. In Italy, as in most European countries, it is responsible for the development of mild to moderate endemic goiter. In 1995 we conducted a goiter survey in the Gubbio township, an area of Umbria region in Italy, close to the Appenine mountain chain. This study demonstrated a high prevalence of goiter in the middle schoolchildren population, indicating the presence of moderate endemic goiter. Soon after, a goiter prevention campaign aimed at implementing the consumption of iodinated salt was started. In 2001, a second survey was conducted in the middle schoolchildren (age 11-14 yr old) of Gubbio and neighbour townships. Eight hundred thirteen subjects were studied. Data obtained in 240 age-matched children, studied in the same area in 1995, were used for comparison to monitor changes 5 yr after the beginning of iodine prophylaxis. Thyroid volume was measured by ultrasonography. Gland volume was expressed in ml. A large population living in a iodine-sufficient area, previously reported by others, was used as control. Urinary iodine excretion was measured randomly in 20% of the children. The overall prevalence of goiter decreased between 1995 and 2001 from 29 to 8%. Goiter odds ratio (OR), corrected for age, was 4.0 (95% CI 2.8-5.9) for 1995 compared to 2001 (p<0.000). Mean thyroid volume in the matched populations was 7.6+/-2.5 ml in 1995 and 5.7+/-2.1 ml in 2001. Median iodine urinary excretion increased from 72.6 to 93.5 mug/l, at the limit of statistical significance. Living in a rural area, no consumption of iodized salt and familiarity for goiter represented independent risk factors for goiter development. This study was the first conducted in Umbria region and confirmed that an implementation campaign for iodized salt consumption is a simple and useful instrument to prevent endemic goiter and related diseases. A new survey to evaluate goiter prevalence in the same area 10 yr after the beginning of iodine prophylaxis is already planned.

Androgen receptor mutations in prostate cancer.

We analyzed the frequency and relevance of mutations in the coding region of the androgen receptor (AR) in genomic DNA extracted from 137 specimens of prostate cancer. The specimens were obtained from the primary tumors of patients affected by stage B disease [15 nonmicrodissected (group 1A) and 84 microdissected (group 1B)] and from the metastatic deposits of individuals with stage D1 disease [8 nonmicrodissected (group 2A) and 30 microdissected (group 2B)] who had not undergone androgen ablation therapy. The study was conducted by PCR-single strand conformational polymorphism (SSCP) analysis of exons 2-8 in the four groups and direct sequence analysis of exon 1 in group 1B. As positive and negative controls, we used genomic DNA extracted from genital skin fibroblasts of patients affected by various forms of androgen resistance with known mutations in the AR. To control for genetic instability, PCR-SSCP analysis of exon 2 of the human progesterone receptor was carried out on each specimen. The overall number of mutations detected was 11 (8%). No mutations were detected in any of the 99 patients with stage B disease. Eleven mutations were detected in exons 2-8 in 8 of the 38 patients with stage D1 disease (all in group 2B). Simultaneous analysis of exon 2 of the progesterone receptor was carried out, and no SSCP changes were identified. These data suggest that AR mutations are rare and presumably do not play a role in the initial phase of prostatic carcinogenesis. The presence of a significant number of AR mutations in metastatic disease indicates that mutations of this molecule may play a role in the most advanced phases of the natural history of this disease, either by facilitating growth or acquisition of the metastatic phenotype.