Maurizio Poggi

Rosiglitazone induces autophagy in H295R and cell cycle deregulation in SW13 adrenocortical cancer cells

Thiazolidinediones, specific peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands, used in type-2 diabetes therapy, show favourable effects in several cancer cells. In this study we demonstrate that the growth of H295R and SW13 adrenocortical cancer cells is inhibited by rosiglitazone, a thiazolidinediones member, even though the mechanisms underlying this effect appeared to be cell-specific. Treatment with GW9662, a selective PPAR-γ-inhibitor, showed that rosiglitazone acts through both PPAR-γ-dependent and -independent mechanisms in H295R, while in SW13 cells the effect seems to be independent of PPAR-γ. H295R cells treated with rosiglitazone undergo an autophagic process, leading to morphological changes detectable by electron microscopy and an increased expression of specific proteins such as AMPKα and beclin-1. The autophagy seems to be independent of PPAR-γ activation and could be related to an increase in oxidative stress mediated by reactive oxygen species production with the disruption of the mitochondrial membrane potential, triggered by rosiglitazone. In SW13 cells, flow cytometry analysis showed an arrest in the G0/G1 phase of the cell cycle with a decrease of cyclin E and cdk2 activity, following the administration of rosiglitazone. Our data show the potential role of rosiglitazone in the therapeutic approach to adrenocortical carcinoma and indicate the molecular mechanisms at the base of its antiproliferative effects, which appear to be manifold and cell-specific in adrenocortical cancer lines.

Increased metastatic lymph node 64 and CYP17 expression are associated with high stage prostate cancer.

The metastatic lymph node 64 (MLN64), which is localized in the human chromosome 17, encodes a protein with strong homology with steroidogenic acute regulatory protein. Its overexpression in human breast carcinomas and MLNs led to the hypothesis that this protein could be involved in intraneoplastic steroidogenesis. In the present study, we investigated the expression of MLN64 in prostate cancer, another hormone-dependent tumor, and compared its expression with that of CYP17, the gene encoding for the key enzyme of androgen synthesis. We investigated by RT-PCR the expression of MLN64 and CYP17 in 60 prostatic tumors and compared their expression with the stage of disease and the appearance of relapses in a follow-up of 24 months. We found MLN64 and CYP17 expressed in all samples examined, with significantly higher expression in neoplastic tissues with respect to normal tissues (NTs). Moreover, only in neoplastic but not in NTs, a positive linear correlation was found between MLN64 and CYP17 gene expression. MLN64 and CYP17 expression seems to correlate with high stage, high Gleason score and short relapse-free time. These data, for the first time, demonstrate the presence of MLN64 and CYP17 expression in both normal and neoplastic prostatic tissues. The biological role of MLN64 in human prostate and, particularly, in neoplastic tissue is still unclear. Our findings concerning MLN64 and CYP17 gene expression and their significant positive correlation in human prostate cancer may suggest their possible role in intraneoplastic autonomous steroidogenesis.

Long-term treatment of somatostatin analog-refractory growth hormone-secreting pituitary tumors with pegvisomant alone or combined with long-acting somatostatin analogs: a retrospective analysis of clinical practice and outcomes

BackgroundPegvisomant (PEGV) is widely used, alone or with somatostatin analogs (SSA), for GH-secreting pituitary tumors poorly controlled by SSAs alone. No information is available on specific indications for or relative efficacies of PEGV?+?SSA versus PEGV monotherapy. Aim of our study was to characterize real-life clinical use of PEGV vs. PEGV?+?SSA for SSA-resistant acromegaly (patient selection, long-term outcomes, adverse event rates, doses required to achieve control).MethodsA retrospective analysis of data collected in 2005–2010 in five hospital-based endocrinology centers in Rome was performed. Sixty-two adult acromegaly patients treated ≥6 months with PEGV (Group 1, n?=?35) or PEGV?+?SSA (Group 2, n?=?27) after unsuccessful maximal-dose SSA monotherapy (≥12 months) were enroled. Groups were compared in terms of clinical/biochemical characteristics at diagnosis and before PEGV or PEGV?+?SSA was started (baseline) and end-of-follow-up outcomes (IGF-I levels, adverse event rates, final PEGV doses).ResultsGroup 2 showed higher IGF-I and GH levels and sleep apnea rates, higher rates residual tumor tissue at baseline, more substantial responses to SSA monotherapy and worse outcomes (IGF-I normalization rates, final IGF-I levels). Tumor growth and hepatotoxicity events were rare in both groups. Final daily PEGV doses were similar and significantly increased with treatment duration in both groups.ConclusionsPEGV and PEGV?+?SSA are safe, effective solutions for managing SSA-refractory acromegaly. PEGV?+?SSA tends to be used for more aggressive disease associated with detectable tumor tissue. With both regimens, ongoing monitoring of responses is important since PEGV doses needed to maintain IGF-I control are likely to increase over time.

Fractionated stereotactic radiotherapy for large and invasive non-functioning pituitary adenomas: Long-term clinical outcomes and volumetric MRI assessment of tumor response

OBJECTIVE We describe the use of fractionated stereotactic radiotherapy (FSRT) for the treatment of large, invasive, nonfunctioning pituitary adenomas (NFPAs). FSRT is frequently employed for the treatment of residual or recurrent pituitary adenomas. PATIENTS AND METHODS Sixty-eight patients with a large residual or recurrent NFPAs were treated between April 2004 and December 2012, including 39 males and 29 females (median age 51 years). Visual defects were present in 34 patients, consisting of visual field defects (n=31) and/or reduced visual acuity (n=12). Forty-five patients had evidence of partial or total hypopituitarism before FSRT. For most of the patients, the treatment was delivered through 5-10 noncoplanar conformal fixed fields using a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions. RESULTS At a median follow-up of 75 months (range 12-120 months), the 5- and 10-year actuarial local control were 97 and 91%, respectively, and overall survival 97 and 93%, respectively. Forty-nine patients had a tumor reduction, 16 remained stable, and three progressed. The relative tumor volume reduction measured using three-dimensional (3D) magnetic resonance imaging (MRI) was 47%. The treatment was well tolerated with minimal acute toxicity. Eighteen patients developed partial or complete hypopituitarism. The actuarial incidence of new anterior pituitary deficits was 40% at 5 years and 72% at 10 years. No other radiation-induced complications occurred. CONCLUSIONS Our results suggest that FSRT is an effective treatment for large or giant pituitary adenomas with low toxicity.

A Rare Case of Follicular Thyroid Carcinoma in a Patient With Thyrotropin-Secreting Pituitary Adenoma

Objective:To report a rare case of a thyrotropin (TSH)-secreting pituitary adenoma associated with thyroid carcinoma. Methods:We report the clinical history, imaging studies, and laboratory and pathologic data in a male patient affected by TSH-secreting pituitary adenoma and goiter; histologic evaluation revealed thyroid carcinoma. Results:A 50-year-old man complained of years of palpitations, hypertensive crisis, and excessive nervousness that tended to progressively worsen. The basal and dynamic hematologic evaluation showed the presence of high free thyroid hormone levels with inappropriate levels of TSH. The thyroid morphologic study using Doppler ultrasonography showed a gland of increased volume with multiple nodular lesions bilaterally. The nuclear magnetic resonance of the pituitary gland described a microadenoma. A total thyroidectomy was performed followed by neurosurgical treatment of the pituitary lesion. The definitive thyroid histologic examination showed the presence of minimally invasive follicular carcinoma of 17 mm diameter. The patient firmly refused surgical removal of the pituitary adenoma. He was started on replacement therapy with thyroxine. Twelve months later, the hematologic examinations showed normal thyroid hormone levels and a TSH of 6.97 uIU/mL. The pituitary nuclear magnetic resonance showed a stable lesion without difference in size. Conclusion:The clinical association between thyroid carcinoma and TSH-producing adenoma is rare, with the removal of the pituitary lesion being mandatory. Pituitary surgery, in this case, is impossible, showing that TSH-producing microadenoma could seldom have an indolent behavior.

Primary empty sella and GH deficiency: prevalence and clinical implications

Primary empty sella (PES) is a particular anatomical condition characterized by the herniation of liquor within the sella turcica. The pathogenesis of this alteration, frequently observed in general population, is not yet completely understood. Recently reports demonstrated, in these patients, that hormonal pituitary dysfunctions, specially growth hormone (GH)/insulin- like growth factor (IGF-I) axis ones, could be relevant. The aim of this paper is to evaluate GH/IGF-I axis in a group of adult patients affected by PES and to verify its clinical relevance. We studied a population of 28 patients with a diagnosis of PES. In each patient we performed a basal study of thyroid, adrenal and gonadal - pituitary axis and a dynamic evaluation of GH/IGF-I after GH-releasing hormone (GHRH) plus arginine stimulation test. To evaluate the clinical significance of GH/IGF-I axis dysfunction we performed a metabolic and bone status evaluation in every patients. We found the presence of GH deficit in 11 patients (39.2%). The group that displayed a GH/IGF-I axis dysfunction showed an impairment in metabolic profile and bone densitometry. This study confirms the necessity to screen the pituitary function in patients affected by PES and above all GH/IGF-I axis. Moreover the presence of GH deficiency could be clinically significant.

Prevalence of growth hormone deficiency in adult polytransfused β-thalassemia patients and correlation with transfusional and chelation parameters

Background: Dysfunction of GH-IGF-I axis has been described in many patients affected by β-thalassemia major (TM), especially in children and in adolescents. Recent studies have demonstrated the necessity to evaluate adult patients affected by TM to establish the presence of this alteration which could be relevant in the pathogenesis of cardiac and bone disease, frequently present in this hematological condition. The pathogenesis of this alteration, correlated in the past with iron overload, is not yet completely understood. Aim: The aim of this paper is to evaluate GH-IGF-I axis in a group of adult polytransfused β-thalassemic patients (TM) and to correlate the results with transfusional and chelation parameters. Subjects and methods: We performed an arginine plus GHRH stimulation test in 28 adult TM patients. Ferritin, IGF-I, liver enzymes, and liver iron concentration, assessed by a superconducting quantum interference device (SQUID) susceptometer were also determined. Moreover, in each patient we evaluated the bone status by a dual-energy X-ray absorptiometry study. Results: We found the presence of GH deficit in 9 patients (32.1%). There were no significant differences between the two groups regarding the value of ferritin, liver enzymes, and liver iron concentration, assessed by SQUID. The group affected by GH deficit showed a worse bone profile. Conclusions: This study confirms the necessity to screen the status of GH/IGF-I axis in this group of patients, even in adult age. The presence of GH deficiency does not seem to be correlated with the efficacy parameters of transfusional and chelation therapy. Other mechanisms, additional to iron overload, could therefore play a role in the pathogenesis of this clinical condition. The presence of GH deficit seems to be very important on clinical aspects, like bone disease, that are crucial for quality of life in these patients.

Malignancies in β-thalassemia patients: first description of two cases of thyroid cancer and review of the literature.

β-Thalassemias are a group of hereditary blood disorders characterized by abnormalities in the synthesis of the β hemoglobin (Hb) chains. This disease causes excessive storage of iron in all organs and endocrine glands. Treatment of β-thalassemia major (β-TM) consists of regular blood transfusions, iron chelation and management of secondary complications of iron overload. Endocrine abnormalities are frequently observed. In the last 25 years, the clinical picture of the disease has changed progressively thanks to improvement of treatments. Today, the majority of thalassemic patients reach adult age. The better prognosis and the longer lifespan of affected patients could be responsible for the susceptibility to other concomitant diseases which can manifest during their life. In this context, the possibility and recent literature reports about some cases of malignancy in thalassemic patients open new scenarios for oncoming years. We describe first reports of endocrine malignancies in thalassemic patients.

Characteristics of adult patients with growth hormone deficiency who underwent neurosurgery for functioning and non-functioning pituitary adenomas and craniopharyngiomas

The aim of the present study was to evaluate the characteristics of GH deficiency (GHD) in adult patients after neurosurgery for pituitary adenomas and craniopharingiomas. One hundred and one GHD patients, (42 F/59 M), aged 47.58±14.4 yr (mean±SD; range 21–78), body mass index (BMI) 28.6±0.6, with a history of adult-onset hypothalamic-pituitary disease, were recruited for the study. The whole group included: 45 non-functioning pituitary adenomas, 23 craniopharyngiomas, 16 PRLomas, 8 GHomas, 7 ACTHomas and 2 FSHomas; in particular 51 were macroadenomasand 27 microadenomas. At study entry, GHD diagnosis was carried out by assessing GH secretion after GHRH+arginine. All patients were submitted to the study at least 12 months after neurosurgery and, where needed, subjects were replaced with an appropriate treatment. GHD was mild in 3/101 (3%) and severe in 98/101 patients (97%). Other hormone deficiencies associated with GHD were considered: TSH, ACTH, FSH/LH, ADH. The distribution of peak GH among all patients, according to the type of disease before neurosurgery, showed that patients with Cushing disease were characterized by the presence of higher peak GH. According to the number of additional hormone deficits, the distribution of peak GH among all patients was as follows: GHD was isolated in 4/101 subjects (4%; group A), while it was associated with 1 (14/101, 14%; group B), 2 (22/101, 22%; group C), 3 (44/101, 43%; group D) and 4 hormone deficits (17/101, 16%; group E). GHD was severe in all patients in the panhypopituitaric group. Total IGF-I plasma levels in the whole group of GHD patients were 95.2±4.2 μg/l. In all groups of patients IGF-I was lower in subjects with severe GHD than in those with mild GHD (93.6±4.1 vs 148.6±33.6 μg/l, p<0.03). In particular, according to the type of disease presented before neurosurgery, patients with Cushing disease were characterized by the presence of higher IGF-I plasma levels compared to the other. According to the number of additional deficits, the distribution of IGF-I plasma levels was characterized by higher values when GHD was isolated than when it was associated with multiple hormone deficiencies. IGF-I plasma levels were positively associated to peak GH during GHRH+arginine (r=0.4, p<0.0005). We conclude that patients after neurosurgery approach for sellar and parasellar neoplasia, within an appropriate clinical context, and both the presence of additional pituitary hormone deficiency and low levels of IGF-I can be considered a clear GHD condition, and therefore do not require provocative tests evaluating GH secretion.

Characteristics and outcomes of Italian patients from the observational, multicentre, hypopituitary control and complications study (HypoCCS) according to tertiles of growth hormone peak concentration following stimulation testing at study entry

To determine whether characteristics and outcomes of Italian patients in the observational global Hypopituitary Control and Complication Study (HypoCCS) differed according to the degree of GH deficiency (GHD).