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Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).

During differentiation of the male gamete, there is a massive remodelling in the shape and architecture of all the cells in the seminiferous epithelium. The cytoskeleton, as well as many associated proteins, plays a pivotal role in this process. To better characterise the factors involved, we analysed two proteins: the formin, dishevelled-associated activator of morphogenesis 1 (DAAM1), which participates in the regulation of actin polymerisation, and the protease, prolyl endopeptidase (PREP), engaged in microtubule-associated processes. In our previous studies we demonstrated their involvement in cytoskeletal dynamics necessary for correct postnatal development of the rat testis. Here, we used samples of testicular tissue obtained from infertile men by testicular sperm extraction and the spermatozoa of asthenoteratozoospermic patients. By western blot and immunofluorescent analysis, we found that DAAM1 and PREP expression and localisation were impaired in both the testis and spermatozoa, and in particular in the midpiece as well as in the principal and end-pieces of the flagella, as compared with spermatozoa of normospermic men. Our results provide new knowledge of the dynamics of spermatogenesis, raising the possibility of using DAAM1 and PREP as new markers of normal fertility.

Mirror movements (MM) might be observed in congenital and acquired neurodegenerative conditions but their anatomic-functional underpinnings are still largely elusive. This study investigated the spectral changes of resting-state functional connectivity in Kallmann Syndrome (hypogonadotropic hypogonadism with hypo/anosmia with or without congenital MM) searching for insights into the phenomenon of MM. Forty-four Kallmann syndrome patients (21 with MM) and 24 healthy control subjects underwent task (finger tapping) and resting-state functional MRI. The spatial pattern of task-related activations was used to mask regions and select putative motor networks in a spatially independent component analysis of resting-state signals. For each resting-state independent component time-course power spectrum, we extracted the relative contribution of four separate bands: slow-5 (0.01–0.027 Hz), slow-4 (0.027–0.073 Hz), slow-3 (0.073–0.198 Hz), slow-2 (0.198–0.25 Hz), and analyzed the variance between groups. For the sensorimotor network, the analysis revealed a significant group by frequency interaction (P = 0.002) pointing to a frequency shift in the spectral content among subgroups with lower slow-5 band and higher slow-3 band contribution in Kallmann patients with MM versus controls (P = 0.028) and with lower slow-5 band contribution between patients with and without MM (P = 0.057). In specific regions, as obtained from hand motor activation task analysis, spectral analyses demonstrated a lower slow-5 band contribution in Kallmann patients with MM versus both controls and patients without MM (P

Prostate cancer (PC) remains a widespread malignancy in men. Since the androgen/androgen receptor (AR) axis is associated with the pathogenesis of prostate cancer, suppression of AR-dependent signaling by androgen deprivation therapy (ADT) still represents the primary intervention for this disease. Despite the initial response, prostate cancer frequently develops resistance to ADT and progresses. As such, the disease becomes metastatic and few therapeutic options are available at this stage. Although the majority of studies are focused on the role of AR signaling, compelling evidence has shown that estrogens and their receptors control prostate cancer initiation and progression through a still debated mechanism. Epithelial versus mesenchymal transition (EMT) is involved in metastatic spread as well as drug-resistance of human cancers, and many studies on the role of this process in prostate cancer progression have been reported. We discuss here the findings on the role of estrogen/estrogen receptor (ER) axis in epithelial versus mesenchymal transition of prostate cancer cells. The pending questions concerning this issue are presented, together with the impact of the available data in clinical management of prostate cancer patients.

Prostate cancer (PC) is one of the most frequently diagnosed cancers and a leading cause of cancer-related deaths in Western society. Current PC therapies prevalently target the functions of androgen receptor (AR) and may only be effective within short time periods, beyond which the majority of PC patients progress to castration-resistant PC (CRPC) and metastatic disease. The role of estradiol/estradiol receptor (ER) axis in prostate transformation and PC progression is well established. Further, considerable efforts have been made to investigate the mechanism by which somatostatin (SST) and somatostatin receptors (SSTRs) influence PC growth and progression. A number of therapeutic strategies, such as the combination of SST analogues with other drugs, show, indeed, strong promise. However, the effect of the combined treatment of SST analogues and estradiol on proliferation, epithelial mesenchyme transition (EMT) and migration of normal- and cancer-derived prostate cells has not been investigated so far. We now report that estradiol plays anti-proliferative and pro-apoptotic effect in non-transformed EPN prostate cells, which express both ERα and ERβ. A weak apoptotic effect is observed in transformed CPEC cells that only express low levels of ERβ. Estradiol increases, mainly through ERα activation, the expression of SSTRs in EPN, but not CPEC cells. As such, the hormone enhances the anti-proliferative effect of the SST analogue, pasireotide in EPN, but not CPEC cells. Estradiol does not induce EMT and the motility of EPN cells, while it promotes EMT and migration of CPEC cells. Addition of pasireotide does not significantly modify these responses. Altogether, our results suggest that pasireotide may be used, alone or in combination with other drugs, to limit the growth of prostate proliferative diseases, provided that both ER isoforms (α and β) are present. Further investigations are needed to better define the cross talk between estrogens and SSTRs as well as its role in PC.

Background Laparoscopic adrenalectomy is considered the gold standard technique for the treatment of benign small and medium size adrenal masses (

Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable. Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or ß) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment. In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy.

Background The relationship between olfactory function, rhinencephalon and forebrain changes in Kallmann syndrome (KS) have not been adequately investigated. We evaluated a large cohort of male KS patients using Sniffin’ Sticks and MRI in order to study olfactory bulb (OB) volume, olfactory sulcus (OS) depth, cortical thickness close to the OS, and olfactory phenotype. Methods Olfaction was assessed administering Sniffin’ Sticks®, in 38 KS patients and 17 controls (by means of Screening 12 test®). All subjects underwent magnetic resonance imaging (MRI) to study OB volume, sulcus depth, and cortical thickness. Results Compared to controls, KS patients showed smaller OB volume (p

Background In clinically node-negative patients with differentiated thyroid cancer (DTC), indications for routine central lymph node dissection (RCLD) are the subject of intensive research, and surgeons are divided between the pros and cons of this surgery. To better define the role of neck dissection in the treatment of DTC, we analyzed retrospectively the results in three centers in Italy. Methods The clinical records of 752 clinically node-negative patients with DTC who underwent operative treatment between January 1998 and December 2005 in three endocrine surgery referral units were evaluated retrospectively. The complications and medium- and long-term outcomes of total thyroidectomy (TT) alone (performed in 390 patients: group A) and TT combined with bilateral RCLD (362 patients: group B) were analyzed and compared. Results The incidence of permanent hypoparathyroidism and permanent unilateral vocal folds was 1% and 0.8% in group A and 3.6% and 1.7% in the group B, respectively. Bilateral temporary recurrent nerve palsy was observed in one of the 362 patients in group B. After a follow-up of 9.5 ± 3.5 years (mean ± SD), the locoregional recurrence rate with positive cervical lymph nodes was not substantially significantly different between the two groups. Conclusion In our series, TT combined with bilateral RCLD was associated with a greater rate of transient and permanent complications. Similar incidences of locoregional recurrence were reported in the two groups of patients. Considering the recent trend toward routine central lymphadenectomy, further studies are needed to evaluate the benefits of these different approaches.

Ipogonadismo ed infertilita possono essere presenti in ragazzi con sindromi genetiche rare dominate da malformazioni somatiche o alterazioni sistemiche. I disordini riproduttivi sono dovuti a difetti testicolari primitivi (sindrome di Klinefelter, del maschio XX, di Noonan, difetto d’azione degli androgeni, iperplasia surrenale congenita), secondari (sindrome di Kallmann, deficit ipofisario multiplo, displasia setto ottica, sindrome di Bardet-Biedl) o misti (sindrome di Prader-Willi, distrofia miotonica tipo 2, atassia cerebellare, sindrome di Wolfram), oppure ad alterazioni post-testicolari (s. Denys-Drash, Frasier, malattia policistica renale, discinesia ciliare primitiva, sordita-infertilita). L’ipogonadismo e in genere diagnosticato in eta adolescenziale. La diagnosi di ipogonadismo sindromico e del difetto genetico e importante per la definizione eziologica e la prevenzione.

Pheochromocytoma (PCC), a rare neuroendocrine tumor, shows a prevalence ranging between 0.1% and 0.6% in individuals suffering from hypertension. To date, an increasing number of patients with hereditary forms or subclinical PCCs have been diagnosed. We reviewed the main controversies and the most recent updates, especially inheritance genetics and surgical management. According to the “rule of 10”, in 1/10 patients with pheochromocytoma it is malignant, in 1/10 of cases the tumor is bilateral, in 1/10 extra-adrenal and in 1/10 familial. Surgical resection, the only curative treatment, carries a high risk of hypertensive crises due to massive catecholamine release. Alpha 1 blocker therapy, alone or in combination with beta blockers, calcium antagonists, and plasma volume expansion, is the most commonly used preoperative treatment protocol. Minimally invasive adrenalectomy (laparoscopic and retro-peritoneoscopic) allows earlier mobilization and recovery, reducing the risk of pulmonary infections and thromb-oembolic complications, and is associated with lower morbidity and mortality rates than traditional surgery; it is currently considered the gold standard for the treatment of adrenal tumors ≤6 cm in diameter and weighing

In the last years, especially thanks to a large diffusion of ultrasound-guided FNBs, a surprising increased incidence of differentiated thyroid cancer (DTC), "small" tumors and microcarcinomas have been reported in the international series. This led endocrinologists and surgeons to search for "tailored" and "less aggressive" therapeutic protocols avoiding risky morbidity and useless "overtreatment". Considering the most recent guidelines of referral endocrine societies, we analyzed the role of routine or so-called prophylactic central compartment lymph node dissection (RCLD), also considering its benefits and risks. Literature data showed that the debate is still open and the surgeons are divided between proponents and opponents of its use. Even if lymph node metastases are commonly observed, and in up to 90% of DTC cases micrometastases are reported, the impact of lymphatic involvement on long-term survival is subject to intensive research and the best indications of lymph node dissection are still controversial. Identification of prognostic factors for central compartment metastases could assist surgeons in determining whether to perform RLCD. Considering available evidence, a general agreement to definitely reserve RCLD to "high-risk" cases was observed. More clinical researches, in order to identify risk factors of meaningful predictive power and prospective long-term randomized trials, should be useful to validate this selective approach. In the last years, especially thanks to a large diffusion of ultrasound-guided FNBs, a surprising increased incidence of differentiated thyroid cancer (DTC), "small" tumors and microcarcinomas have been reported in the international series. This led endocrinologists and surgeons to search for "tailored" and "less aggressive" therapeutic protocols avoiding risky morbidity and useless "overtreatment". Considering the most recent guidelines of referral endocrine societies, we analyzed the role of routine or so-called prophylactic central compartment lymph node dissection (RCLD), also considering its benefits and risks. Literature data showed that the debate is still open and the surgeons are divided between proponents and opponents of its use. Even if lymph node metastases are commonly observed, and in up to 90 % of DTC cases micrometastases are reported, the impact of lymphatic involvement on long-term survival is subject to intensive research and the best indications of lymph node dissection are still controversial. Identification of prognostic factors for central compartment metastases could assist surgeons in determining whether to perform RLCD. Considering available evidence, a general agreement to definitely reserve RCLD to "high-risk" cases was observed. More clinical researches, in order to identify risk factors of meaningful predictive power and prospective long-term randomized trials, should be useful to validate this selective approach.

Subclinical central diabetes insipidus (CDI) can be the outcome of a number of diseases that affect the hypothalamus–infundibulum–post hypophysis axis. One of the most common forms of subclinical CDI is linked to an autoimmune pathogenesis even if other causes may be also responsible. Among these, pregnancy, traumatic and surgical brain injury and some infiltrative, vascular, infectious and neoplastic diseases have been reported with increasing frequency. The natural history of autoimmune CDI seems to evolve through 4 functional stages according to the presence of antibodies to vasopressin-secreting cells (AVPcAb) and the relationship between their behavior overtime, the variations of posterior pituitary function and the characteristics of hypothalamic–hypophyseal region on magnetic resonance imaging. This staging is of crucial importance for the therapeutic strategy, taking into account that some stages could be still reversible. Several medical treatments have been suggested to interrupt the progression toward clinical CDI but the results are still discussed.

Previous case reports and retrospective studies suggest that pituitary dysfunction may occur after acute bacterial or viral meningitis. In this prospective study we assessed the pituitary functions, lipid profile and anthropometric measures in adults with acute bacterial or viral meningitis. Moreover, in order to investigate whether autoimmune mechanisms could play a role in the pathogenesis of acute meningitis-induced hypopituitarism we also investigated the anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) prospectively. Sixteen patients (10 males, 6 females; mean +/- A SD age 40.9 +/- A 15.9) with acute infectious meningitis were included and the patients were evaluated in the acute phase, and at 6 and 12 months after the acute meningitis. In the acute phase 18.7% of the patients had GH deficiency, 12.5% had ACTH and FSH/LH deficiencies. At 12 months after acute meningitis 6 of 14 patients (42.8%) had GH deficiency, 1 of 14 patients (7.1%) had ACTH and FSH/LH deficiencies. Two of 14 patients (14.3%) had combined hormone deficiencies and four patients (28.6%) had isolated hormone deficiencies at 12 months. Four of 9 (44.4%) hormone deficiencies at 6 months were recovered at 12 months, and 3 of 8 (37.5%) hormone deficiencies at 12 months were new-onset hormone deficiencies. At 12 months there were significant negative correlations between IGF-I level vs. LDL-C, and IGF-I level vs. total cholesterol. The frequency of AHA and APA positivity was substantially high, ranging from 35 to 50% of the patients throughout the 12 months period. However there were no significant correlations between AHA or APA positivity and hypopituitarism. The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months. In addition, the occurrence of AHA and APA positivity due to acute infectious meningitis was demonstrated for the first time. Further longer-term prospective investigations need to be carried out on a larger cohort of patients to understand the role of autoimmunity in the pathogenesis of late hypopituitarism after acute infectious meningitis.

Objective Antipituitary (APA) but not antihypothalamus antibodies (AHA) have been investigated in patients with idiopathic hypopituitarism. This study searched for APA and AHA in some of these patients to investigate whether pituitary or hypothalamic autoimmunity could play a role in their pituitary dysfunction. Design Sixty-six patients with selective idiopathic hypopituitarism were studied: 27 with ACTH deficiency, 20 with GH deficiency and 19 with hypogonadotropic hypogonadism. Twenty patients with hypopituitarism secondary to hypophysectomy and 50 healthy subjects were enrolled as controls. Measurements Antipituitary and AHA were evaluated by indirect immunofluorescence in sera of patients and controls. Positive sera were retested by a four-layer double immunofluorescence to identify the cells targeted by these antibodies. Results Antipituitary were present at high titre in 4 of 27 patients with ACTH deficiency (14·8%), 4 of 20 with GH deficiency (26%) and 5 of 19 with hypogonadotropic hypogonadism (21%) and targeted, respectively, corticotrophs, somatotrophs and gonadotrophs. AHA were found at high titre only in 5 patients with ACTH deficiency (18·5%), mostly targeting corticotrophin-releasing hormone-secreting cells; none of these 5 patients resulted positive for antipituitary antibodies. Among the controls, only 1 hypophysectomized patient resulted APA positive at low titre. Conclusions Our results suggest that in patients with selective idiopathic hypopituitarism, detection of APA or AHA could better characterize an autoimmune process involving the pituitary or hypothalamus, respectively. In particular, detection of antibodies targeting selectively ACTH-secreting or corticotrophin-releasing hormone-secreting cells may differentiate, respectively secondary from tertiary variants of autoimmune hypoadrenalism.

Surgery is the primary therapy for pheochromocytoma (PHEO), a catecholamine-producing tumor. Benign and malignant PHEO could develop recurrences, and the intraoperative risk of recurrent PHEO is an important unresolved issue. Non-surgical treatments of PHEO recurrence would therefore better prepare patients for reintervention as well as provide them with palliative management. We investigated the effects of the new somatostatin analog (pasireotide) SOM230 versus octreotide (OCT) in primary PHEO cell cultures (Pheo-c). Pheo-c from six benign surgical samples were set up and characterized by immunocytochemistry. Real-time PCR, using both PHEO tissues and Pheo-c, showed different levels of somatostatin receptor1–5 mRNA expression. Cells treated with various doses of OCT or SOM230 for 48 and 72 h were analyzed to assess their effects on cell proliferation and apoptosis and catecholamine levels. Even if reduction of cell viability was observed in Pheo-c treated for 48 h with either OCT or SOM230 and this effect increased after 72 h, a more significant inhibition of cell growth as well as a significantly higher induction of apoptosis was seen in Pheo-c treated with SOM230 versus OCT. In particular, apoptosis in Pheo-c was detected after 48 h and was associated with increased expression and activation of caspase-3 and cleaved poly(ADP-ribose) polymerase. OCT 10−6 M and SOM230 10−7 M significantly reduced catecholamine levels. Our results indicate that while both OCT and SOM230 modulate cell growth and apoptosis and catecholamine levels in Pheo-c through specific receptors, SOM230 is more effective. This improves our knowledge on the mechanism of SOM230 action in PHEO and supports a possible therapeutic use in benign PHEO recurrence.

Histone deacetylase inhibitors (HDACIs) represent a new class of targeted anticancer agents. Here, we evaluate the effects of butyrate (BuA) and other HDACIs on p57(Kip2), a cyclin-dependent kinase inhibitor (cki). We observed that inhibitors of class I/II histone deacetylases (HDACs), but not of class III HDACs, induce a remarkable accumulation of p57(Kip2) in several cells. The cki upregulation is associated with an increased gene expression that was not prevented by cycloheximide, indicating that HDACIs affect directly p57(Kip2) transcription. The characterization of p57(Kip2) promoter indicates that the first 165 bp are mostly involved in the BuA effects. Chromatin immunoprecipitation studies demonstrated that the BuA treatment causes the recruitment of Sp1 transcription factor. The Sp1 importance was confirmed by the reduction of BuA effects by mithramycin A (an Sp1 antagonist) and, most stringently, by Sp1 downregulation due to Sp1 siRNA. Moreover, both the treatments reduce the p57(Kip2) transcription in untreated cells, suggesting that Sp1 is required for the constitutive cki expression. Studies employing plasmids containing parts of the 165 bp of p57(Kip2) promoter indicate that the promoter region between -87 and -113 bp, which includes two putative Sp1 consensus sequences, plays a critical role in the response to HDACIs. Since this p57(Kip2) promoter region also embraces the consensus sequence for the transcriptional repressor chicken ovalbumin upstream promoter transcription factor-interacting protein 2 (CTIP2), we evaluated whether this factor is involved into the BuA effect. When CTIP2 was downregulated by a specific siRNA, we observed the enhancement of BuA activity on p57(Kip2) expression suggesting that CTIP2 might also be involved in HDACIs effects.

In Kallmann syndrome (KS), congenital hypogonadism is associated with olfactory impairment. To evaluate flavor perception-related disability in KS patients, 30 patients with KS, 12 with normosmic hypogonadism (nIHH), 24 with acquired anosmia (AA), and 58 healthy controls entered the study. All participants completed questionnaires concerning dietary habits, olfaction-related quality of life (QoL), and self-determined olfactory, flavor, and taste abilities prior to undergoing standardized olfactometry and gustometry. Each subject underwent flavor testing, using orally administered aqueous aromatic solutions, identifying 21 different compounds by choosing each out of 5 alternative items. Flavor score (FS) was calculated as the sum of correct answers (range 0-21). Flavor perception by self-assessment was similar between KS, nIHH, and controls, and was mostly reduced only in AA. FS was similar between KS (5.4 +/- A 1.4) and AA (6.4 +/- A 1.9), and lower than in nIHH (16.2 +/- A 2.4, p < 0.001) and controls (16.8 +/- A 1.7, p < 0.0001). FS showed strong reproducibility, and correlated with olfactory scores in the overall population. KS and AA patients identified aromatics eliciting trigeminal stimulation better than pure odorants. Olfaction-related QoL was more impaired in AA than in KS. We report significant flavor impairment in KS. This contrasts with routine clinic evidence; KS patients, in contrast with AA, do not complain of flavor perception impairment, perhaps owing to the congenital nature of the dysfunction. Flavor perception impairment should be considered a specific KS disability, because of important detrimental effects on physical and mental health and on QoL. KS patients should also be advised of this impairment in order to prevent accidental and life-threatening events.

Un possibile declino della spermatogenesi correlato al tempo nelle popolazioni occidentali era stato prospettato gia negli anni’ 70 ed e stato evidenziato in una serie di studi pubblicati negli anni’ 90, tuttavia, non mancano lavori che mostrano una stabilita o addirittura un incremento della concentrazione spermatica (CS) negli ultimi decenni. Il dibattito sul continuo declino della CS rimane aperto per le evidenze contraddittorie degli studi, per le difficolta di utilizzare i dati storici e per l’impossibilita di eliminare tutti i possibili fattori di confusione legati alla campionatura della popolazione, alla metodologia di valutazione del liquido seminale e all’analisi statistica applicata ai dati. La riduzione della CS trova un importante punto di forza nelle evidenze di altri trend secolari, come l’aumento di incidenza del cancro testicolare e delle malformazioni del tratto genitale maschile, che depongono per un declino generale della salute riproduttiva maschile nelle popolazioni occidentali. Sia il declino della CS che l’incidenza del cancro testicolare presentano differenze tra popolazioni di aree geografiche diverse o fra zone rurali ed urbane. Questi fenomeni sono stati correlati all’influenza dei fattori ambientali e dello stile di vita sulla riproduzione maschile. Infatti, dati sperimentali in vitro e nell’animale ed alcune evidenze epidemiologiche hanno sostanziato la convinzione che i fattori legati all’ambiente di vita e di lavoro, lo stile di vita e le abitudini alimentari possano influenzare la funzione riproduttiva maschile. Per alcuni di questi fattori, come il calore, vi sono sufficienti prove di un’ azione negativa sulla qualita della spermatogenesi e sulla fertilita maschile; per altri, come gli inquinanti chimici, non vi sono ancora prove definitive. Anche se sono necessari ulteriori studi per comprendere i possibili meccanismi attraverso i quali questi agenti possano influire sulla salute riproduttiva dell’individuo, nella pratica clinica e opportuno tenere conto dei loro potenziali effetti dannosi.

An increased secretion of cytokines and growth factors has been hypothesised to play a role in the abnormal growth of keloid fibroblasts. The aim of this study was to evaluate the effect of the calcium antagonist verapamil on the interleukin-6 (IL-6) and vascular endothetial growth factor (VEGF) secretion, as well as on cellular growth, in primary cultures of fibroblasts derived from the central part of keloid lesions. These cells grew faster than peripheral keloid and nonkeloid fibroblasts, and, in long-term cultures, became stratified assuming a three-dimensional structure. Compared with peripheral and nonkeloid fibroblasts, central keloid fibroblasts presented an increased production of both IL-6 and VEGF (P

In this study, we evaluated by reverse transcription-polymerase chain reaction (RT-PCR) the expression pattern of retinoic acid receptors (RAR) alpha, beta, and gamma and cellular retinoic acid binding protein-I (CRBP-I) genes in 12 primary cultures of fibroblasts (F) from orbital tissue of Graves' ophthalmopathy (GO) patients. We also studied the in vitro effects of all-trans retinoic acid (RA) and N-(4-hydroxyphenil)-retinamide (4HPR), a less toxic and better tolerated synthetic derivative of RA, on cell morphology, growth, apoptosis, and cyclic adenosine monophosphate (cAMP) accumulation. All primary cultures expressed RAR alpha, beta, gamma, and CRBP-I. FGO treated with RA and 4HPR (10(-7) mol/L) presented morphologic changes and significantly inhibited cell growth after 72 hours. At 96 hours of drug exposure, apoptosis was detected in 15% and 50% of RA- and 4HPR (10(-7) mol/L)-treated cells, and p53 protein increased in cell lysates. 4HPR induced a 70% decrease of Bcl-2 protein. After 30 minutes of RA and 4HPR (10(-7) mol/L) exposure, a 20% decrease of basal cAMP accumulation was seen, and forskolin cAMP-induced increase was abolished. The expression of RAR alpha, beta, gamma, and CRBP-I in primary cultures of FGO indicates that they are targets for retinoids. Moreover, we show that RA and 4HPR are able to induce morphologic changes, inhibition of cell growth, and apoptosis in FGO exerting their effects through RAR-modulated pathways. The rapid inhibition of cAMP accumulation indicates that a novel nonclassic retinoid pathway may also be involved. Finally, the potent in vitro effects of 4HPR, a retinoid derivative with fewer adverse reactions in vivo, could justify further investigations on a clinical application of retinoids in GO.

Lymphocytic hypophysitis (LYH) is an uncommon autoimmune disease in which the pituitary gland is infiltrated by lymphocytes, plasma cells and macrophages and its function is usually impaired. It has to be suspected in pregnant women and in women with recent delivery presenting with hyperprolactinemia, headache, visual field alterations and changes of one or more pituitary hormone secretions with secondary impairment of related peripheral target glands, especially when associated with other autoimmune endocrine or non-endocrine disorders. It can also occur less frequently in prepubertal or post-menopausal women and in men. Headache, visual field impairment and more rarely diplopia are due to extrasellar pituitary enlargement with optic chiasma compression and/or to invasion of cavernous sinuses. Among the 'isolated' pituitary hormone deficiencies, ACTH deficit is usually the earliest and most frequent hormonal impairment and in rare cases can induce an acute secondary hyposurrenalism as the first sign of the disease, with high mortality in affected patients. Histopathological findings from pituitary biopsy show lymphoplasmacytic infiltrate with lymphoid aggregates surrounding atropic acini of pituitary cells; immunohistochemical analysis shows numerous mast cells randomly distributed and also localized in the vicinity of capillaries, suggesting a possible influence on capillary permeability and angiogenesis, thus favoring the inflammatory and immunological aggression against pituitary cells. Nuclear magnetic resonance imaging shows uniform sellar floor depression and an extrasellar symmetrical pituitary enlargement, usually displacing the optic chiasma, which shows a rapid homogeneous enhancement after gadolinium also involving the adjacent dura (dural tail). Antipituitary antibodies have been detected in several patients with LYH but their role needs to be clarified. Since a possible spontaneous remission can occur, a careful follow-up is required in subclinical patients without important hyposurrenalism or symptomatic extrasellar expansion. Medical (immunosuppressive, replacement and antiprolactinemic) and neurosurgical (decompression) treatments are needed in clinical symptomatic patients.

Aims: Ovarian granulosa cell tumour (OGCT) is a sex-cord stromal tumour with a general trend toward late relapse and/or metastasis. However, mortality rate corrected for long-term follow-up shows that about 50% of patients die within 20 years of diagnosis. Classical clinicopathological parameters are unable to predict the biological behaviour of OGCT. The involvement of a recently characterized subtype of oestrogen receptor, ERβ, in ovarian carcinogenesis has been hypothesized. Methods and results: We examined by immunohistochemistry the expression of ERβ, proliferating cell nuclear antigen (PCNA) and p53 in a selected series of 30 OGCT, to evaluate their role in the prognostic evaluation of this tumour. Immunohistochemistry was performed on formalin-fixed paraffin-embedded sections. Results were compared with the DNA-ploidy of the tumours (evaluated by image analysis) and with the follow-up data of the patients. Conclusions: Loss of ERβ expression, high PCNA expression and aneuploidy, characterized a subgroup of OGCT with a worse outcome. The identification of a high-risk subclass of OGCT may be of primary importance in addressing appropriate therapeutic strategies, offering the chance to prevent relapses and metastases by using adjunctive, specifically targetted, more aggressive therapies.

Polyclonal antibodies against somatostatin receptors (SSTRs) available up to now recognizing intracellular sites of receptors and their recycling products do not detect bioactive ligand binding domains (LBDs) and are of limited performance in paraffin-embedded tissues. Aim of this study was to evaluate by immunohistochemistry the expression of SSTR5 on an archival series of pituitary tumors using a new MoAbs against the SST-binding domain (Y-SSTR5). Methods: We used paraffined tissue sections from 20 non-secreting pituitary tumors (NS) and 14 PRL-secreting (PRL) adenomas and, as control, sections from normal tissue surrounding the same tumor. A standard streptavidin-biotin-labeled peroxidase immunostaining was performed. Negative controls were performed with non immune serum. The degree of immunopositivity was evaluated semi-quantitatively according to an arbitrary scale. Results: Immunostaining for SSTR5 was found in 90% of NS (low-medium 55%, high 35%) and in 100% of PRLS adenomas (low-medium 14%, high 86%). Conclusion: SSTR5 was found in the majority of pituitary tumors examined. PRLS adenomas showed a tendency to higher expression of receptor protein. Y SSTR5 MoAb can be used to detect SSTR5 on the membrane of pituitary cells in classical paraffin embedded histological sections. The specific detection of LBD SSTR5 by MoAb can support a potential choice of panligand or SST analogues targeting SSTR5 in resistant/recurrent pituitary tumors.

L’ipogonadismo maschile puo essere causato da alterazioni congenite o acquisite a livello testicolare (primario) o a livello ipotalamo-ipofisario (secondario). L’ipogonadismo primario e caratterizzato dalla compromissione della spermatogenesi, deficit variabile di testosterone (T) ed incremento dei livelli di gonadotropine (ipogonadismo ipergonadotropo). L’ipogonadismo secondario e caratterizzato da bassi livelli di T e bassi/normali livelli di gonadotropine (ipogonadismo ipogonadotropo). Clinicamente, l’ipogonadismo si manifesta con la compromissione dello sviluppo dei genitali esterni e dei caratteri sessuali secondari e proporzioni corporee eunucoidi, se insorto in epoca prepuberale, con il deficit della funzione sessuale associato o meno all’infertilita, alterazione del tono dell’umore, della forza muscolare ed osteoporosi, nell’epoca post-puberale o nell’anziano. La diagnosi si basa, oltre che sull’anamnesi e sull’esame clinico, sulla determinazione del livello plasmatico del T e delle gonadotropine. L’esame del cariotipo, la diagnostica d’immagine e lo studio molecolare sono utili per definire l’eziologia. La terapia dell’ipogonadismo ha come obiettivi l’induzione della puberta, il mantenimento dei caratteri e dell’attivita sessuali, la prevenzione dell’osteoporosi e dei disordini del metabolismo lipidico e l’induzione della spermatogenesi. La maturazione puberale e il mantenimento della funzione sessuale possono essere ottenuti con la somministrazione di preparati di T (per via orale, intramuscolare e transdermica), o stimolando la produzione di T endogeno con la somministrazione di hCG; la spermatogenesi puo essere indotta, nei soggetti con ipogonadismo ipogonadotropo che desiderino la fertilita, con la somministrazione delle gonadotropine (hCG associata ad hMG, FSH puro o ricombinante) o di GnRH pulsatile. Il monitoraggio della terapia va fatto con periodici controlli clinici e di laboratorio (T, PSA, ematocrito, transaminasi, assetto lipidico, esame del liquido seminale) al fine di assicurare che i livelli plasmatici di T siano nel range normale e che non vi siano effetti collaterali indesiderati o dannosi.

Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.

INTRODUCTION: Defects of prokineticin pathway affect the neuroendocrine control of reproduction, but their role in the pathogenesis of central hypogonadism remains undefined, and the functional impact of the missense PROKR2 variants has been incompletely characterized. MATERIAL AND METHODS: In a series of 246 idiopathic central hypogonadism patients, we found three novel (p.V158I, p.V334M, and p.N15TfsX30) and six already known (p.L173R, p.T260M, p.R268C, p.V274D, p.V331M, and p.H20MfsX23) germline variants in the PROKR2 gene. We evaluated the effects of seven missense alterations on two different prokineticin receptor 2 (PROKR2)-dependent pathways: inositol phosphate-Ca(2+) (Gq coupling) and cAMP (Gs coupling). RESULTS: PROKR2 variants were found in 16 patients (6.5%). Expression levels of variants p.V158I and p.V331M were moderately reduced, whereas they were markedly impaired in the remaining cases, except p.V334M, which was significantly overexpressed. The variants p.T260M, p.R268C, and p.V331M showed no remarkable changes in cAMP response (EC50) whereas the IP signaling appeared more profoundly affected. In contrast, cAMP accumulation cannot be stimulated through the p.L173R and p.V274D, but IP EC50 was similar to wt inp.L173R and increased by 10-fold in p.V274D. The variant p.V334M led to a 3-fold increase of EC50 for both cAMP and IP. CONCLUSION: Our study shows that single PROKR2 missense allelic variants can either affect both signaling pathways differently or selectively. Thus, the integrity of both PROKR2-dependent cAMP and IP signals should be evaluated for a complete functional testing of novel identified allelic variants.

Introduction: In the surgical management of the patients with Cushing syndrome (CS), minimal invasive adrenalectomy (MA) has become the procedure of choice to treat adrenal tumors with a benign appearance � 6 cm in diameter. Authors evaluated medium- and long-term outcomes of laparoscopic adrenalectomy (LA) for CS or subclinical CS (sCS), performed for ten years in an endocrine surgery unit. Methods: We retrospectively reviewed 21 consecutive patients undergone LA for CS or sCS from 2003 to 2013. Postoperative clinical and cardiovascular status modifications and surgical medium and long-term outcomes were analyzed. Results: In each patient surgery determined a normalization of the hormonal profile. There was no mortality neither major post-operative complications. Mean operative time was higher during the learning curve, there was no conversion, and morbidity rate was 6.3%. Regression of the main clinical symptoms occurred slowly in twelve months. Conclusions: LA is a safe, effective and well-tolerated procedure for the treatment of CS and sCS reducing arterial blood pressure, body weight and fasting glucose levels. Following the learning curve a morbidity rate similar to that reported in the MA series for other adrenal diseases is observed. © 2014 Published by Elsevier Ltd on behalf of Surgical Associates Ltd.

Background/Aim. To evaluate the efficacy of methotrexate for the treatment of thyroid eye disease (TED). Methods. 36 consecutive patients with active TED, previously treated with corticosteroids but stopped due to the occurrence of side effects, were commenced on methotrexate therapy. Two different weekly doses were administered depending on the weight of the patient (7.5 mg or 10 mg). Clinical activity score (7-CAS), visual acuity (VA), ocular motility, exophthalmos, and eyelid position were retrospectively evaluated at 3, 6, and 12 months and compared with baseline data. Results. There was a statistically significant improvement in 7-CAS at 3, 6, and 12 months after treatment ( ). There was no significant change in visual acuity. Ocular motility disturbances improved at 6 and 12 months ( ). There was no significant change in exophthalmos (mean 24 mm, SD 3 mm) or eyelid position (marginal reflex distance mean 6 mm, SD 1.5 mm) during the follow-up period. No side effects were registered. Conclusions. Methotrexate therapy is effective in reducing CAS and ocular motility disturbances. No significant improvement in proptosis or eyelid retraction should be expected from this treatment. Eventually, it might be considered a suitable alternative treatment in TED for patients who cannot tolerate steroids.

BACKGROUND Prostate cancer is a worldwide significant health care problem, due to its high incidence and mortality. In particular, androgen-independent tumors have the worst prognosis, because they are refractory to almost all kinds of available therapy. Hence, there is the need of new treatment opportunities targeting androgen-independent, growth factor-mediated, tumor signaling. One of these new promising opportunities is vitamin D3 and its related analogues. METHODS We investigated the effect of a vitamin D3 analogue, analogue (V), on proliferation of several human prostate cancer cells in basal condition and after treatment with KGF, one of the intraprostatic growth factors that might participate in the progression of prostate cancer. In addition, in the androgen-independent cell line DU 145, we also studied the effect of analogue (V), KGF, and their mutual interaction on protein tyrosine phosphorylation, bcl-2 expression and apoptosis. RESULTS Overall, we found that analogue (V) dose-dependently decreased basal and KGF-induced prostate cancer cell growth, although to a different extent. Maximal effect was obtained in DU 145 cells. In these cells, KGF stimulated tyrosine phosphorylation of a protein corresponding to its receptor, induced bcl-2 expression, and prolonged cell survival. Analogue (V) not only counteracted all these KGF-mediated events, but also decreased basal bcl-2 expression, therefore, allowing DU 145 cells to undergo an apoptotic program. CONCLUSIONS Our results indicated that in prostate cancer cells analogue (V) decreased basal and KGF-induced cell proliferation. This effect, at least in DU 145 cells, is in part mediated by negative interactions with cell survival and KGF signaling. Prostate 50: 15–26, 2002. © 2002 Wiley-Liss, Inc.

Estrogen receptor subtype beta (ERbeta) is highly expressed in rat prostate epithelium, but its presence in human prostate needs to be confirmed. Here we investigated the expression of ERbeta in five benign (normal and/or hyperplastic) and 10 malignant (Gleasons' score 2-7) prostate tissue specimens using immunohistochemistry. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections, using a commercially available ERbeta polyclonal antibody developed against the C-terminal amino acid residue. Nuclear ERbeta expression was found in the nuclei of glandular epithelium of benign prostate tissue specimens; faint nuclear ERbeta positivity was also present in a few stromal cells around normal epithelium. Nuclear ERbeta specific immunostaining was undetectable in all prostate cancer sections.

The aim of this study was to investigate the expression of estrogen receptor (ER) beta and alpha genes in normal (N) and malignant (C) primary cultures of human prostate epithelial cells (PEC) and fibroblasts (PFC) and in the prostate tissue donors. Both ERbeta and ERalpha messenger ribonucleic acids were found by RT-PCR analysis in six NPECs and normal prostate tissues and in only one of six CPECs and in the respective cancer tissue donor. The other five CPECs and related cancer tissue donors and all normal and cancer PFCs expressed ERalpha messenger ribonucleic acid alone. Immunoblot analysis, using a polyclonal anti-ERbeta (C-terminal) antibody, demonstrated ERbeta protein in all NPEC lysates and in one of the six CPECS: ERalpha protein was expressed in both NPECs and CPECs when a polyclonal antibody directed against the ERalpha N-terminal domain was used. In contrast, ERalpha protein was not detected in two of the six CPEC lysates when ERalpha C-terminal monoclonal antibodies were used. Using a set of primers designed to amplify the region from exons 6-8, RT-PCR analysis demonstrated the absence of the expected transcript in these cells. The present study shows that the ERbeta gene is expressed together with ERalpha in normal prostates and NPECs, whereas it is barely detectable in prostate cancer and CPECS: Moreover, in some CPECs, the ERalpha gene may be transcribed in a changed protein, resulting from the expression of a deletion variant. Together, these data suggest that prostate malignancy is associated with a potential disorder of ER-mediated pathways.

We treated primary epithelial cells from human normal prostate (NEPC) and prostate cancer (CEPC) with all-trans-retinoic acid (RA) to study whether it regulates the activity of tissue transglutaminase (tTGase), an enzyme that accumulates in cells undergoing apoptosis. tTGase activity was assessed by [14C]spermidine incorporation; tTGase, P53, Bcl-2, and p21 protein levels were evaluated by Western blotting; and RA receptors (RAR alpha, -beta, and -gamma), tTGase, retinol-binding protein (RBP), and cellular RBP type I transcripts were determined by semiquantitative RT-PCR. After 72-96 h of 10(-6) mol/L RA treatment, cell growth inhibition and apoptosis were associated with increased tTGase activity in both NEPC and CEPC, and with increased tTGase protein and messenger ribonucleic acid levels only in NEPC. Moreover, RA down-regulated RAR alpha and -beta and increased RBP messenger ribonucleic acid levels in NEPC, whereas it increased RAR beta gene expression and decreased Bcl-2 protein levels in CEPC. Our results suggest that RA induces tTGase gene expression and enzyme activity in normal prostate cells, and that RA-regulated pathways are impaired in cancer cells. Moreover, down-regulation of Bcl-2 protein and up-regulation of RAR beta suggest that retinoid may act on the genetic defect responsible for prostate cancer progression.

Thyroid-associated ophthalmopathy is an autoimmune disorder of the extraocular muscles and orbital connective tissue, which is usually associated with Graves' hyperthyroidism. Well-studied markers of ophthalmopathy are eye muscle membrane antigens, reportedly of approximately 64-kDa molecular mass. One, originally identified only as the 64-kDa protein, has recently been shown to be the flavoprotein (Fp) subunit of mitochondrial succinate dehydrogenase, which has a correct molecular mass of 67 kDa. We have used purified beef heart Fp as antigen in an enzyme-linked immunosorbent assay for cross-reactive human autoantibodies. Sera have been screened from patients with thyroid-associated ophthalmopathy classified according to activity and presence or not of eye muscle disease, and from those with Graves' hyperthyroidism without eye involvement. Also examined were serum samples taken periodically from 20 patients with Graves' hyperthyroidism during 24 months of treatment of their hyperthyroidism with antithyroid drugs. Four of these patients had ophthalmopathy at the onset, 12 developed ophthalmopathy, and 4 did not develop any eye signs during treatment. Anti-Fp subunit antibodies were detected in 73% of patients with active ophthalmopathy and evidence of eye muscle involvement but only in 25% if there was only congestive ophthalmopathy. These values were 0% and 11% for patients with chronic ophthalmopathy, with or without eye muscle dysfunction, respectively. The antibodies were also detected in 14% of patients with Graves' hyperthyroidism without evident ophthalmopathy, 11% of patients with nonimmunologic thyroid disorders, 12% of type I diabetics, and 12% of age- and sex-matched normal subjects. Significantly, appearance of anti-Fp antibodies predicted the development of ophthalmopathy in 5 of the 6 patients with Graves' hyperthyroidism, who developed eye muscle dysfunction after treatment of the hyperthyroidism, and coincided with the onset of eye muscle signs in the other patient. Antibodies were not detected in any of 6 patients who developed congestive ophthalmopathy without evidence of eye muscle damage or in 4 patients who did not develop any eye signs. In conclusion, we have shown a close relationship between eye muscle disease and serum antibodies against the Fp subunit of succinate dehydrogenase in patients with Graves' hyperthyroidism.

PURPOSE: We verified the prevalence of serum antisperm antibodies at diagnosis in a large group of cryptorchid boys, and determined whether it may be influenced by orchiopexy. MATERIALS AND METHODS: We prospectively evaluated serum antisperm antibodies in 186 and 23 boys 0.67 to 14.25 years old with unilateral and bilateral cryptorchidism, respectively, before, and 3, 12 and 24 months after surgery. At diagnosis Tanner stage was 1 and 2 or 3 in 188 and 21 cases, respectively. During the 2-year followup 23 boys entered puberty. A total of 111 normal prepubertal (Tanner stage 1) and 54 pubertal (Tanner stage 2 or 3) boys served as controls. Antisperm antibodies were detected using the tray agglutination and indirect immunobead tests. RESULTS: At diagnosis 29 cryptorchid boys (13.8%) were antisperm antibody positive, including 21 of the 188 prepubertal (11.1%) and 8 of the 21 pubertal (38%) boys (significantly different, chi-square test p

The transcripts of five SRIH receptor subtypes (SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5) were investigated by RT-PCR in epithelial cells (EC) and stromal cells (SC) from primary cultures of five normal human prostates and six prostate cancers. Primary cultures of prostate EC were established in serum-free keratynocyte medium with 5% FCS, epidermal growth factor, and bovine pituitary extract; SC were cultured in MEM with 10% FCS. Total RNA was extracted from EC and SC using a modified guanidine thiocyanate method. RT-PCR was performed after deoxyribonuclease treatment, using SSTR1-, SSTR2-, SSTR3-, SSTR4-, and SSTR5-specific primers and adding glyceraldehyde-3-phosphate dehydrogenase-specific primers as internal control. A PCR product of the expected size of 334 bp, corresponding to SSTR1, was expressed only in EC from prostate cancer, whereas the expected 461-bp product of SSTR2 was found only in EC from normal prostate. SSTR3 messenger RNA was undetectable in normal and cancer EC, whereas SSTR4 and SSTR5 w...

Detection of antipituitary antibodies (APA) at high levels and with a particular immunofluorescence pattern in patients with autoimmune polyendocrine syndromes may indicate a possible future autoimmune pituitary involvement. This longitudinal study was aimed at characterizing in patients with a single organ-specific autoimmune disease the pituitary cells targeted by APA at start, verifying whether this characterization allows to foresee the kind of possible subsequent hypopituitarism.Thirty-six APA positive and 40 APA negative patients with isolated autoimmune diseases participated in the study. None of them had pituitary dysfunction at entry. Characterization by four-layer immunofluorescence of pituitary cells targeted by APA in APA positive patients at entry and study of pituitary function in all patients were performed every 6 months during a 5 year follow-up.Antipituitary antibodies immunostained selectively one type of pituitary-secreting cells in 21 patients (58.3 %, group 1), and several types of pituitary cells in the remaining 15 (41.7 %, group 2). All patients in group 1 showed subsequently a pituitary insufficiency, corresponding to the type of cells targeted by APA in 18 of them (85.7 %). Only 8 out of 15 patients in group 2 (53.3 %) showed a hypopituitarism, isolated in 7 and combined in the other one. None of APA negative patients showed hypopituitarism.The characterization of pituitary cells targeted by APA in patients with isolated autoimmune diseases, when the pituitary function is still normal, may help to foresee the kind of subsequent hypopituitarism, especially when APA immunostained selectively only one type of pituitary cells. A careful follow-up of pituitary function in these patients is advisable to allow an early diagnosis of hypopituitarism, even in subclinical phase and a consequent timely replacement therapy.

In the last decades, a surprising increased incidence of differentiated thyroid cancer (DTC), along with a precocious diagnosis of "small" tumors and microcarcinomas have been observed. In these cases, better oncological outcomes are expected, and a "tailored" and "less aggressive" multimodal therapeutic protocol should be considered, avoiding an unfavorable even if minimal morbidity following an "overtreatment." In order to better define the most suitable surgical approach, its benefits and risks, we discuss the role of surgery in the current management of DTCs in the light of data appeared in the literature. Even if lymph node metastases are commonly observed, and in up to 90 % of DTC cases micrometastases are reported, the impact of lymphatic involvement on long-term survival is still argument of intensive research, and indications and extension of lymph node dissection (LD) are still under debate. In particular, endocrine and neck surgeons are still divided between proponents and opponents of routine central LD (RCLD). Considering the available evidence, there is agreement about total thyroidectomy, therapeutic LD in clinically node-positive DTC patients, and RCLD in "high risk" cases. Nevertheless, indications to the best surgical treatment of clinically node-negative "low risk" patients are still subject of research. Considering on the one hand, the recent trend toward routine central lymphadenectomy, avoiding radioactive treatment, and on the other hand, the satisfactory results obtained reserving prophylactic LD to "high risk" patients, we think that further prospective randomized trials are needed to evaluate the best choice between the different surgical approaches.

Traumatic brain injury (TBI) has been recently recognized as a common cause of pituitary dysfunction. However, there are not sufficient numbers of prospective studies to understand the natural history of TBI induced hypopituitarism. The aim was to report the results of five years' prospective follow-up of anterior pituitary function in patients with mild, moderate and severe TBI. Moreover, we have prospectively investigated the associations between TBI induced hypopituitarism and presence of anti-hypothalamus antibodies (AHA) and anti-pituitary antibodies (APA). Twenty five patients (20 men, five women) were included who were prospectively evaluated 12 months and five years after TBI, and 17 of them also had a third-year evaluation. Growth hormone (GH) deficiency is the most common pituitary hormone deficit at one, three, and five years after TBI. Although most of the pituitary hormone deficiencies improve over time, there were substantial percentages of pituitary hormone deficiencies at the fifth year (28% GH, 4% adrenocorticotropic hormone [ACTH], and 4% gonadotropin deficiencies). Pituitary dysfunction was significantly higher in strongly AHA- and APA-positive (titers ≥1/16) patients at the fifth year. In patients with mild and moderate TBI, ACTH and GH deficiencies may improve over time in a considerable number of patients but, although rarely, may also worsen over the five-year period. However in severe TBI, ACTH and GH status of the patients at the first year evaluation persisted at the fifth year. Therefore, screening pituitary function after TBI for five years is important, especially in patients with mild TBI. Moreover, close strong associations between the presence of high titers of APA and/or AHA and hypopituitarism at the fifth year were shown for the first time.

Pituitary and thyroid autoimmunity can be triggered by pregnancy. We report the first association of combined growth hormone (GH) and prolactin secretion deficiency due to autoimmune damage to GH- and prolactin-secreting cells in a patient with postdelivery lactation failure, presenting subsequently with primary autoimmune hypothyroidism.A 34-year-old woman presented with lactation failure following the delivery of her first child. She had a family history of hypothyroidism without a history of pituitary dysfunction. Physical examination did not show any abnormal findings. Laboratory investigations showed normal gonadotropin levels after the restoration of normal menstrual cycles following pregnancy, normal basal and stimulated cortisol levels, but an impaired GH response to insulin-induced hypoglycemia, and low basal prolactin and insulin-like growth factor-1 concentrations. Thyroid function was normal when initially investigated three months after delivery, but five months later, marked primary hypothyroidism (thyrotropin levels100 mIU/L) occurred. Immunological investigation revealed the presence of antipituitary antibodies, identified by double immunofluorescence and targeting GH- and prolactin-secreting cells. Antithyroid antibodies, in the normal range three months postpartum, became significantly elevated when the hypothyroidism appeared. Autoimmune hypophysitis is responsible for selective or multiple pituitary-hormone deficiencies, sometimes involving thyrotropin secretion and causing secondary hypothyroidism, but usually associated with hyperprolactinemia. To our knowledge, this is the first observation of autoimmune hypopituitarism involving deficient growth hormone and prolactin secretion in a patient with lactation failure after delivery, subsequently followed by severe primary autoimmune hypothyroidism, thus falling into an unusual constellation of autoimmune polyendocrine syndrome type 3.Considering the well-known relationship between pregnancy and autoimmunity, an early postdelivery immunological and functional investigation in women presenting with disorders of lactation may be useful to detect potential pituitary and thyroid dysfunction even at a subclinical stage.

Total thyroidectomy (TT) is the standard of care for differentiated thyroid cancer (DTC), but still there is no consensus about the role of routine use of prophylactic central lymph node dissection. The aim of this study was to analyze our results of TT without prophylactic central lymphadenectomy in the treatment of DTC. Clinical records, between January 1998 and December 2005, of 221 patients undergoing TT, without prophylactic central lymph node dissection, were retrospectively evaluated. Two hundred and eleven patients (95.47 %) also underwent radioiodine (RAI) ablation followed by thyroid stimulating hormone (TSH) suppression therapy. In patients with loco-regional lymph nodal recurrence, lateral and central lymph node dissection was performed. The incidence of permanent hypoparathyroidism (iPTH

Authors evaluated the effects of selective adrenergic blockade by means of doxazosin on blood pressure in 48 patients operated on for pheochromocytoma by a multicenter retrospective study. Age, tumor size, surgical approach, and operative time were analyzed as predictive factors of intraoperative hypertensive crises. Forty-eight patients underwent adrenalectomy—four open surgery and 44 laparoscopic surgery—for pheochromocytoma of adrenal glands from 1998 to 2008 after preoperative administration of doxazosin. Perioperative cardiovascular status modifications and surgical medium- and long-term outcomes were analyzed. There was no mortality, conversion rate was 4.5 per cent, and morbidity rate was 8.3 per cent. Intraoperative hypertensive crises (180/ 90 mmHg or higher) were observed in 14.5 per cent (seven of 48) of patients and were treated pharmacologically with no aftermath. None of the examined variables influenced the occurrence of intraoperative hypertensive episodes. Postoperative hypotension (lower than 90/60 mmHg) was observed in four of 48 patients (8.3%) and was treated by crystalloids and hydrocortisone. In the surgical treatment of pheochromocytoma, the preoperative adrenergic blockade by doxazosin does not prevent intraoperative hypertensive crises. Nevertheless, in our series, they were of short duration and were not associated with major cardiovascular complications. Perioperative hemodynamic instability was managed bypreoperative pharmacological treatment, allowing low morbidity.

Background Minimally invasive adrenalectomy for pheochromocytoma (PCC) is a complex surgical procedure especially because of the haemodynamic instability due to the excessive secretion of cathecolamines, which may result in a considerable risk of conversion and complications. Aim By a multicentric retrospective study, the authors reported the results of laparoscopic adrenalectomies in patients operated for adrenal pheochromocytomas with the aim of investigating the role of the laparoscopic approach in managing adrenal disease. Methods Sixty patients, preoperatively treated with a selective alpha1-blocker, underwent 61 laparoscopic adrenalectomies for PCC smaller or larger than 6 cm – group A (≤6 cm), group B (>6 cm). We compared the two groups of patients analyzing haemodynamic instability, operative time, conversion rate, incidence of complications, length of hospital stay and medium and long-term outcomes. Results In 23 cases tumor was >6 cm in diameter. Average operative time was 165 min, with a 5% conversion rate. There was no mortality and morbidity rate was 8.3%. Intraoperative hypertensive crises were registered in 15% of patients, whereas 5/60 patients had hypotensive crises. After comparing the two groups of patients, no statistically significant differences in terms of haemodynamic instability, operative time, conversion rate, morbidity and length of hospital stay were observed. Conclusions As a surgical treatment of pheochromocytomas, laparoscopic adrenalectomy is an effective and safe approach, in selected cases even for PCCs >6 cm in diameter, although patients with such large tumors may have a higher conversion rate and more intraoperative hypertensive crises. Preoperative selective adrenergic blockade does not prevent intraoperative hypertensive crises, but by facilitating the pharmacological management of the perioperative haemodynamic instability, may avoid the onset of major adverse cardiovascular complications.

Context: Kallmannsyndrome (KS) is characterized by congenital hypogonadotropic hypogonadism (CHH) and an impaired sense of smell related to defective development of the olfactory system. Objective: The aim of the study was to use high-resolution computed tomography (CT) to detect specific abnormalities in the ethmoid bone region surrounding the olfactory bulbs in patients with KS. Patients: Thirty-seven KS patients were compared to normosmic CHH (nCHH) patients (n=15) and controls (n=30) of similar age. Design and Methods: We conducted a prospective study in a single referral center. Subjects underwent CT in bone windows with axial, coronal, and sagittal reconstructions centered on the olfactory fossa (OF) and cribriform plate (CP). We characterized the OF structure by measuring OF height, width, and surface area and a series of angles. The CP foramina were counted bilaterally. Olfactory bulb magnetic resonance imaging, performed in parallel, was compared with CT findings. Results: OF height, width, and surface area were all significantly lower in KS patients than in nCHH patients and controls (P < .0001). KS patients also had wider angles than nCHH patients and controls (P < .0001). KS subjects with olfactory bulb agenesis on magnetic resonance imaging or who harbored KAL1 mutations had the most marked changes in OF measurements and angles. Coronal OF height distinguished KS patients from controls with the best sensitivity and specificity. The mean number of CP foramina was similar in KS, nCHH, and control subjects. Conclusions: KS is associated with specific ethmoid bone abnormalities. The preserved number of CP foramina in KS patients suggests that the integrity of olfactory structures is not mandatory for their formation during fetal development or their maintenance in adult life.