Publications by authors named "Maria Chiara Zatelli"

121 Publications

Neoadjuvant PRRT for advanced pNEN: an unusual highlander.

Endocrine 2021 Mar 4. Epub 2021 Mar 4.

Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

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http://dx.doi.org/10.1007/s12020-021-02662-9DOI Listing
March 2021

NEP-Score Thresholds Predict Survival of Patients With Bronchial Carcinoids.

Front Endocrinol (Lausanne) 2020 8;11:621557. Epub 2021 Feb 8.

Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Survival prognostic markers are extremely needed to better define therapeutic strategies in patients with bronchial carcinoids (BC). We aim to verify the applicability of the NEP-Score in a homogeneous BC cohort and identify a derivative prognostic marker, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up. Sixty-four patients (38 females, and 26 males, mean age at diagnosis 58.9 ± 1.7 years) with BC were retrospectively evaluated. NEP-Score was calculated at the end of follow-up (NEP-T). A derivative score, the NEP-Score at diagnosis (NEP-D) that does not consider new metastases during follow-up, was then assessed. Patients were subdivided according to their living status at the end of follow-up. A NEP-Score threshold was investigated to predict survival. Mean NEP-T and mean NEP-D were significantly lower in live patients at end of follow-up. A NEP-T cut-off >138 significantly predicts survival. Atypical BC relapsed more frequently than Typical BC. Male gender and previous malignancy were negative prognostic factors for survival. We confirmed NEP-Score applicability in BC and NEP-D utility, being the latter a simple, quick, and cheap prognostic score that can help clinicians in decision making. The identified NEP-D threshold can predict NEN aggressiveness and may be used to define the best personalized therapeutic strategy. In this context, a validation study is needed.
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http://dx.doi.org/10.3389/fendo.2020.621557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897663PMC
February 2021

Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?

J Endocr Soc 2021 Mar 9;5(3):bvaa205. Epub 2021 Feb 9.

Royal Veterinary College, University of London, London, UK.

The designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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http://dx.doi.org/10.1210/jendso/bvaa205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874572PMC
March 2021

Hypeprolactinemia: still an insidious diagnosis.

Endocrine 2020 Sep 19. Epub 2020 Sep 19.

Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.

Hyperprolactinemia can have different causes: physiological, pharmacological, and pathological. When investigating the etiology of hyperprolactinemia, clinicians need to be aware of several conditions leading to misdiagnosis. The most popular pitfalls are: acute physical and psychological stress, macroprolactin, hook effect, even though antibodies interferences and biotine use have to be considered. A 52-year-old woman was referred to Endocrinology clinic for oligomenorrhoea and headache. She worked as a butcher. Hormonal evaluation showed very high PRL (305 ng/ml, reference interval: <24 ng/ml) measured with the ECLIA immunoassay analyzer Elecsys 170. The patient's pituitary MRI was normal and macroprolactin was normal. Hormonal workup showed LH: 71.5 mU/ml (2-10.9 mU/ml), FSH: 111.4 mU/ml (3.9-8.8 mU/ml), Estradiol: 110.7 pg/mL (27-122 pg/ml). Since an interference was suspected, the sample was sent to another laboratory using a different assay. After antibody blocking tubes treatment (Heterophilic Blocking Tube, Scantibodies) PRL was 28.8 ng/ml (reference interval < 29.2 ng/ml). Analytical interference should be suspected when assay results are not consistent with the clinical picture. Endogenous antibodies (EA) include heterophile, human anti-animal, autoimmune and other nonspecific antibodies, and rheumatoid factors, that have structural similarities and can cross-react with the antibodies employed by the immunoassay, causing hyperprolactinemia misdiagnosis. The patient's job (butcher), led us to suspect the presence of anti-animal antibodies. Clinicians should also carefully investigate the use of supplements. Biotin can falsely increase hormone concentration in competitive assays. Many clinicians are still not informed about these pitfalls that are not mentioned in some recent reviews on PRL measurement.
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http://dx.doi.org/10.1007/s12020-020-02497-wDOI Listing
September 2020

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Rev Endocr Metab Disord 2020 Sep 15. Epub 2020 Sep 15.

Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.
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http://dx.doi.org/10.1007/s11154-020-09589-yDOI Listing
September 2020

Multidisciplinary management of acromegaly: A consensus.

Rev Endocr Metab Disord 2020 12 10;21(4):667-678. Epub 2020 Sep 10.

Medical Research Unit in Endcrine Diseases, Hospital de Especialidades, Centro Médico Nacional, Siglo XXI, IMSS, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.
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http://dx.doi.org/10.1007/s11154-020-09588-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942783PMC
December 2020

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Thyroid 2021 02 1;31(2):264-271. Epub 2020 Jul 1.

Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.

One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as in 1109 patients (53.6%), in 796 (38.4%), and in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.
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http://dx.doi.org/10.1089/thy.2020.0272DOI Listing
February 2021

Three-Dimensional Primary Cell Culture: A Novel Preclinical Model for Pancreatic Neuroendocrine Tumors.

Neuroendocrinology 2021 3;111(3):273-287. Epub 2020 Apr 3.

Institute of Pathology, University of Bern, Bern, Switzerland,

Molecular mechanisms underlying the development and progression of pancreatic neuroendocrine tumors (PanNETs) are still insufficiently understood. Efficacy of currently approved PanNET therapies is limited. While novel treatment options are being developed, patient stratification permitting more personalized treatment selection in PanNET is yet not feasible since no predictive markers are established. The lack of representative in vitro and in vivo models as well as the rarity and heterogeneity of PanNET are prevailing reasons for this. In this study, we describe an in vitro 3-dimensional (3-D) human primary PanNET culture system as a novel preclinical model for more personalized therapy selection. We present a screening platform allowing multicenter sample collection and drug screening in 3-D cultures of human primary PanNET cells. We demonstrate that primary cells isolated from PanNET patients and cultured in vitro form islet-like tumoroids. Islet-like tumoroids retain a neuroendocrine phenotype and are viable for at least 2 weeks in culture with a high success rate (86%). Viability can be monitored continuously allowing for a per-well normalization. In a proof-of-concept study, islet-like tumoroids were screened with three clinically approved therapies for PanNET: sunitinib, everolimus and temozolomide. Islet-like tumoroids display varying in vitro response profiles to distinct therapeutic regimes. Treatment response of islet-like tumoroids differs also between patient samples. We believe that the presented human PanNET screening platform is suitable for personalized drug testing in a larger patient cohort, and a broader application will help in identifying novel markers predicting treatment response and in refining PanNET therapy.
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http://dx.doi.org/10.1159/000507669DOI Listing
April 2020

Acromegaly in the elderly patients.

Endocrine 2020 04 14;68(1):16-31. Epub 2020 Feb 14.

Section of Endocrinology & Internal Medicine, Dept of Medical Sciences, University of Ferrara, Ferrara, Italy.

Background: Acromegaly is a rare disease characterized by a chronic exposition to growth hormone (GH) and insulin-like growth factor-1 (IGF-1), caused in most cases by a pituitary GH-secreting adenoma. Chronic GH excess induces systemic complications (metabolic, cardiovascular, respiratory, neoplastic, and musculoskeletal) and increased mortality if not appropriately treated. Recent epidemiological data report an improved life span of patients with acromegaly probably due to better acromegaly management; additionally, the number of pituitary incidentaloma in general population also increased over time due to more frequent imaging. Therefore, the number of elderly patients, newly diagnosed with acromegaly or in follow-up, is expected to grow in the coming years and clinicians will need to be aware of particularities in managing these patients.

Purpose: This review aims to explore different aspects of acromegaly of the elderly patients, focusing on epidemiology, diagnosis, clinical presentation, complications, and management options.

Methods: Available literature has been assessed through PubMed (data until August 2019) by specific keywords.

Conclusions: Available data on acromegaly in the elderly patient are sparse, but point to important differences. Further studies are needed comparing elderly with younger patients with acromegaly to better define a tailored diagnostic and therapeutic management.
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http://dx.doi.org/10.1007/s12020-020-02206-7DOI Listing
April 2020

Neck paraganglioma and follicular lymphoma: a case report.

J Med Case Rep 2019 Dec 20;13(1):376. Epub 2019 Dec 20.

University Radiology Unit, Radiology Department, Sant'Anna University Hospital, Ferrara, Italy.

Background: Paragangliomas and pheochromocytomas are sympathetic or parasympathetic tumors derived from the paraganglia and the adrenal medulla, respectively. Paragangliomas and pheochromocytomas can be sporadic or familial, the latter frequently being multifocal and possibly due to succinate dehydrogenase complex genes mutations. In addition, 12% of sporadic paragangliomas are related to covered succinate dehydrogenase complex mutations. The importance of identifying succinate dehydrogenase complex mutations is related to the risk for these patients of developing multiple tumors, including non-endocrine ones, showing an aggressive clinical presentation.

Case Presentation: We report the case of a 45-year-old Caucasian man with an indolent mass in his neck. Ultrasound of his neck, magnetic resonance imaging, and 1,4,7,10-tetraazacyclododecane-N(I),N(II),N(III),N(IIII)-tetraacetic acid(D)-Phe(1)-thy(3)-octreotide (Ga-DOTATOC) positron emission tomography-computed tomography and endocrine work-up were consistent with a carotid body paraganglioma with concomitant nodal enlargement in several body regions, which turned out to be a follicular lymphoma at histology. He was found to carry a germline Succinate dehydrogenase subunit B gene (SDHB) mutation.

Conclusion: It is crucial to look for a second malignancy in the case of a paraganglioma demonstrating succinate dehydrogenase complex germline mutations.
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http://dx.doi.org/10.1186/s13256-019-2323-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924013PMC
December 2019

Evaluation of Spheroid 3D Culture Methods to Study a Pancreatic Neuroendocrine Neoplasm Cell Line.

Front Endocrinol (Lausanne) 2019 4;10:682. Epub 2019 Oct 4.

Section of Endocrinology and Internal Medicine, Department of Medial Sciences, University of Ferrara, Ferrara, Italy.

Pancreatic Neuroendocrine Neoplasms (pNEN) are rare tumors which treatment still represent an important clinical problem, due to the paucity of medical treatments. Due to tumor complexity, techniques as 3D cultures are important to study drug activity in a more realistic model. This study aims to compare three different 3D culture methods in order to understand which one can be considered the best option in terms of experimental easiness and reproducibility in studying the efficacy of a target drug on pNEN. The BON1 cell line was used as a pNEN model and the well-known Receptor Tyrosine Kinase inhibitor Sunitinib was used in order to better investigate the different features of each method. The investigated methods are: (1) 96-well hanging drop plates (HD plates), (2) 24-well plates with a cell-repellent surface, and (3) ultra-low attachment 96-well plates with clear round bottom (ULA plates). The evaluated parameters during the study were: cell seeding, easiness in spheroids formation, morphology, culture maintenance, medium change, spheroids monitoring, picture quality, spheroid perimeter measurement reproducibility error, possibility to perform assays into the seeding plate, overall time of the experiment. Moreover, we investigated how culture methods can influence experimental outcomes evaluating perimeter changes, cell viability and immunohistochemistry of spheroids treated with different Sunitinib concentrations. Results showed that each method has weak and strong points but, considering the easiness of spheroids maintenance and reproducibility results, ULA plates method appears to be the best approach to culture BON1 spheroids and, therefore, to study pNEN.
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http://dx.doi.org/10.3389/fendo.2019.00682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787167PMC
October 2019

A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update.

J Clin Endocrinol Metab 2020 04;105(4)

Department of Medicine, CIBERER, Universidad Autónoma de Madrid, Madrid, Spain.

Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.

Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration.

Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities.

Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system.

Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.
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http://dx.doi.org/10.1210/clinem/dgz096DOI Listing
April 2020

Dual-energy X-ray absorptiometry pitfalls in Thalassemia Major.

Endocrine 2019 09 12;65(3):469-482. Epub 2019 Jul 12.

Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.

Background: Low mineral mass and reduced bone strength with increased fracture risk are the main causes of morbidity in Thalassemia Major (TM). The pathogenesis is multifactorial and includes ineffective erythropoiesis with medullary expansion, multiple endocrine dysfunctions, direct iron bone deposition, deferoxamine-induced bone dysplasia, and reduced physical activity associated with disease complications. Dual-energy X-ray absorptiometry (DXA) is the "gold standard" for bone mineral density (BMD) assessment and for bone strength and quality evaluation. This method identifies patients at greater risk of fragility fractures, guiding treatment and monitoring response to therapy. In TM, DXA shows limitations concerning BMD calculation accuracy and fracture risk prediction. One of the main challenges in the assessment of bone health in patients with TM is the accurate interpretation of densitometric results.

Purpose: This review investigates the major pitfalls in DXA implementation and interpretation in TM.

Methods: Available literature has been assessed.

Conclusions: DXA shows limitations in assessing bone mineral "status" in TM, especially in the paediatric population, due to the peculiar characteristics of bone architecture and deformities associated with the disease. A radiological technique adjustment in this population is mandatory.
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http://dx.doi.org/10.1007/s12020-019-02003-xDOI Listing
September 2019

EGF and IGF1 affect sunitinib activity in BP-NEN: new putative targets beyond VEGFR?

Endocr Connect 2019 Jun;8(6):680-690

Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, UK.

Broncho-pulmonary neuroendocrine neoplasms (BP-NENs) are neoplasms orphan of an efficient therapy. Available medical treatments derived from clinical trials are not specific for the management of this malignancy. Sunitinib is a multi-receptor tyrosine-kinases (RTKs) inhibitor that has already shown its efficacy in NENs, but there are no available data about its action in BP-NENs. Therefore, our aim was to understand the effects of RTKs inhibition promoted by sunitinib in order to evaluate new putative targets useful in malignancy treatment. Since our results underlined a role for EGFR and IGF1R in modulating sunitinib antiproliferative action, we investigated the effects of erlotinib, an EGFR inhibitor, and linsitinib, an IGF1R inhibitor, in order to understand their function in regulating cells behaviour. Cell viability and caspase activation were evaluated on two immortalised human BP-NEN cell lines and primary cultures. Our results showed that after treatment with sunitinib and/or IGF1, EGF and VEGF, the antiproliferative effect of sunitinib was counteracted by EGF and IGF1 but not by VEGF. Therefore, we evaluated with AlphaScreen technology the phosphorylated EGFR and IGF1R levels in primary cultures treated with sunitinib and/or EGF and IGF1. Results showed a decrease of p-IGF1R after treatment with sunitinib and an increase after co-treatment with IGF1. Then, we assessed cell viability and caspase activation on BP-NEN cell lines after treatment with linsitinib and/or erlotinib. Results demonstrate that these two agents have a stronger antiproliferative effect compared to sunitinib. In conclusion, our results suggest that IGF1R and EGF1R could represent putative molecular targets in BP-NENs treatment.
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http://dx.doi.org/10.1530/EC-19-0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528406PMC
June 2019

Adrenal cavernous hemangioma: a case report.

BMC Surg 2018 Nov 20;18(1):103. Epub 2018 Nov 20.

Department of Clinical and Experimental Medicine, Unit of General Surgery 2, University of Sassari, Sassari, Italy.

Background: Adrenal cavernous hemangiomas are very rare benign tumors that usually present as incidental findings on abdominal imaging. Preoperative differential diagnosis from other benign or malignant adrenal neoplasms may be challenging.

Case Presentation: A 70-year old man was referred for an 8-cm abdominal mass incidentally discovered on a contrast-enhanced computed tomography (CT) performed to investigate a pulmonary nodule. Biochemical tests ruled out any endocrine dysfunction and iodine 123 metaiodobenzylguanidine whole body scintiscan single-photon emission CT excluded a pheocromocitoma. Findings on magnetic resonance imaging were non-specific and the patient was elected for a left adrenalectomy. Histopathological diagnosis revealed a cavernous hemangioma. A portion of the resected tissue was tested for drug sensitivity to mitotane, doxorubicin, and sunitinib.

Conclusions: Adrenal hemangioma is a rare disease but should be included in the differential diagnosis of adrenal tumors. The surgical resection is generally required to exclude malignant disease, resolve pressure-related symptoms, and prevent retroperitoneal hemorrhage. Although specific features in diagnostic imaging are often lacking, if the diagnosis is established preoperatively a laparoscopic adrenalectomy can be performed due to the benign nature of the lesion. Doxorubicin and sunitinib were both capable of reducing primary culture cell viability, this suggest that similar drugs may be useful in the medical treatment of adrenal hemangiomas.
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http://dx.doi.org/10.1186/s12893-018-0429-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247755PMC
November 2018

Evaluation of the Role of V600E Somatic Mutation on Papillary Thyroid Cancer Disease Persistence: A Prospective Study.

Eur Thyroid J 2018 Oct 13;7(5):251-257. Epub 2018 Jul 13.

Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy.

Background: V600E (c.1799T>A) somatic mutation evaluation in fine needle aspiration biopsies (FNAB) is a powerful diagnostic tool in the settings of papillary thyroid cancer (PTC). However, its prognostic value is still a matter of great debate and has been addressed mostly in retrospective studies.

Objectives: To evaluate whether the somatic V600E mutation, assessed by direct sequencing in FNAB material of thyroid nodules, may correlate with disease persistence in PTC patients.

Study Design: We conducted a prospective cohort study investigating 160 PTC patients previously assessed for the somatic V600E mutation, and submitted to total thyroidectomy, with a follow-up of 2-10 years. Patients were matched according to somatic V600E mutation (80 BRAF+ and 80 BRAF- patients) and to the presence (LN+, 40 patients each group) or absence (LN, 40 patients each group) of neck lymphnode metastases. Disease persistence was considered according to basal or TSH-stimulated Thyroglobulin (TG) levels, anti-TG antibodies, neck ultrasound, CT scan where applicable and whole body scan after radioiodine ablation treatment (RAI).

Results: The presence of the somatic V600E mutation did not influence the indication for RAI. None of the enrolled patients showed disease recurrence or died due to disease-related causes. During follow-up, disease persistence did not correlate with the presence of somatic V600E mutation both in patients submitted to RAI nor in those treated more conservatively.

Conclusions: The somatic V600E mutation does not associate with a worse prognosis in low risk PTC and, in our settings, may not be considered an independent risk factor for disease persistence.
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http://dx.doi.org/10.1159/000490699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198787PMC
October 2018

Is receptor profiling useful for predicting pituitary therapy?

Eur J Endocrinol 2018 10 12;179(5):D15-D25. Epub 2018 Oct 12.

Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.

Medical treatment of pituitary tumours may present important challenges in the presence of resistance to first line therapy. In this setting, the availability of specific markers of responsiveness/resistance could be helpful to provide tailored patients' treatment. Pituitary receptor profiling has emerged as a potentially useful tool for predicting the response to specific pituitary-directed medical therapy, mainly somatostatin analogues and dopamine agonists. However, its utility is not always straightforward. In fact, agonist-receptor coupling to the consequent biological response is complex and sometimes jeopardizes the understanding of the molecular basis of pharmacological resistance. Defective expression of pituitary receptors, genetic alterations, truncated variants, impaired signal transduction or involvement of other proteins, such as cytoskeleton proteins or the Aryl hydrocarbon receptor interacting protein amongst others, have been linked to differential tumour phenotype or treatment responsiveness with conflicting results, keeping the debate on the utility of pituitary receptor profiling open. Why does this occur? How can we overcome the difficulties? Is there a true role for pituitary receptor profiling in the near future? All authors of this debate article agree on the need of prospective studies using standardized methods in order to assess the efficacy of receptor profiling as a reliable clinical predictive factor.
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http://dx.doi.org/10.1530/EJE-18-0549DOI Listing
October 2018

Open issues on G3 neuroendocrine neoplasms: back to the future.

Endocr Relat Cancer 2018 06 18;25(6):R375-R384. Epub 2018 Apr 18.

Department of Clinical Medicine and SurgeryFederico II University, Naples, Italy.

The recent recognition that grade 3 (G3) neuroendocrine neoplasms (NENs) can be divided into two different categories according to the histopathological differentiation, that is G3 neuroendocrine tumors (NETs) and G3 neuroendocrine carcinomas (NECs) has generated a lot of interest concerning not only the diagnosis, but also the differential management of such new group of NENs. However, several issues need to be fully clarified in order to put G3 NETs and G3 NECs in the right place. The aim of this review is to focus on those issues that are still undetermined starting from the current knowledge, evaluating the available evidence and the possible clinical implications.
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http://dx.doi.org/10.1530/ERC-17-0507DOI Listing
June 2018

HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

Calcif Tissue Int 2018 08 6;103(2):151-163. Epub 2018 Mar 6.

Bone Metabolic Diseases Unit, University Hospital of Florence, Florence, Italy.

Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.
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http://dx.doi.org/10.1007/s00223-018-0411-7DOI Listing
August 2018

Pathogenesis of non-functioning pituitary adenomas.

Pituitary 2018 Apr;21(2):130-137

Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Via Ariosto 35, 44100, Ferrara, Italy.

The pathogenesis of non functioning pituitary adenomas (NFPA) is a complex process involving several factors, from molecular to genetic and epigenetic modifications, where tumor suppressor genes, oncogenes, cell cycle derangements have been demonstrated to play an important role. MicroRNAs (miRNAs) have also been identified as possible players in NFPA tumorigenesis and pituitary stem cells have been investigated for their potential role in pituitary tumor initiation. However, a critical role for paracrine signalling has also been highlighted. This review focuses on the current knowledge on the involvement of these factors in NFPA pathogenesis.
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http://dx.doi.org/10.1007/s11102-018-0874-6DOI Listing
April 2018

PI3K/Akt/mTOR pathway involvement in regulating growth hormone secretion in a rat pituitary adenoma cell line.

Endocrine 2018 05 27;60(2):308-316. Epub 2017 Oct 27.

Department of Medical Sciences, Section of Endocrinology & Internal Medicine, University of Ferrara, Ferrara, Italy.

Purpose: Insulin-like growth factor 1 (IGF1) controls growth hormone (GH) secretion via a negative feed-back loop that may disclose novel mechanisms possibly useful to control GH hyper-secretion. Our aim was to understand whether PI3K/Akt/mTOR pathway is involved in IGF1 negative feedback on GH secretion.

Methods: Cell viability, GH secretion, Akt, and Erk 1/2 phosphorylation levels in the rat GH3 cell line were assessed under treatment with IGF1 and/or everolimus, an mTOR inhitior.

Results: We found that IGF1 improves rat GH3 somatotroph cell viability via the PI3K/Akt/mTOR pathway and confirmed that IGF1 exerts a negative feedback on GH secretion by a transcriptional mechanism. We demonstrated that the negative IGF1 loop on GH secretion requires Akt activation that seems to play a pivotal role in the control of GH secretion. Furthermore, Akt activation is independent of PI3K and probably mediated by mTORC2. In addition, we found that Erk 1/2 is not involved in GH3 cell viability regulation, but may have a role in controlling GH secretion, independently of IGF1.

Conclusion: Our data confirm that mTOR inhibitors may be useful to reduce pituitary adenoma cell viability, while Erk 1/2 pathway may be considered as a useful therapeutic target to control GH secretion. Our results open the field for further studies searching for effective drugs to control GH hyper-secretion.
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http://dx.doi.org/10.1007/s12020-017-1432-0DOI Listing
May 2018

Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame.

Endocr Relat Cancer 2018 01 24;25(1):R11-R29. Epub 2017 Oct 24.

Thyroid and Parathyroid Surgery UnitIstituto Nazionale per lo Studio e la Cura dei Tumori 'Fondazione G. Pascale' - IRCCS, Naples, Italy.

Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30-50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.
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http://dx.doi.org/10.1530/ERC-17-0269DOI Listing
January 2018

Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH).

Eur J Endocrinol 2018 01 7;178(1):23-32. Epub 2017 Sep 7.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Objective: Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.

Design: Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.

Methods: We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH ( = 275), KS ( = 184), AO-nIHH ( = 36) and AO-doIHH (AO-IHH with defective olfaction,  = 8).

Results: 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann's syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.

Conclusions: Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.
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http://dx.doi.org/10.1530/EJE-17-0065DOI Listing
January 2018

Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma.

Eur J Endocrinol 2017 Oct 5;177(4):361-367. Epub 2017 Aug 5.

Internal Medicine 1Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

Objective: Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane.

Design And Methods: We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test.

Results: We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L,  = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L  = 0.016).

Conclusions: The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.
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http://dx.doi.org/10.1530/EJE-17-0452DOI Listing
October 2017

Circulating tumor cells and miRNAs as prognostic markers in neuroendocrine neoplasms.

Endocr Relat Cancer 2017 06 7;24(6):R223-R237. Epub 2017 Apr 7.

IOS & COLEMAN SrlNaples, Italy.

The prognosis of neuroendocrine neoplasms (NENs) is widely variable and has been shown to associate with several tissue- and blood-based biomarkers in different settings. The identification of prognostic factors predicting NEN outcome is of paramount importance to select the best clinical management for these patients. Prognostic markers have been intensively investigated, also taking advantage of the most modern techniques, in the perspective of personalized medicine and appropriate resource utilization. This review summarizes the available data on the possible role of circulating tumor cells and microRNAs as prognostic markers in NENs.
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http://dx.doi.org/10.1530/ERC-17-0091DOI Listing
June 2017

Real-time elastography in autonomously functioning thyroid nodules: relationship with TSH levels, scintigraphy, and ultrasound patterns.

Endocrine 2017 Dec 11;58(3):488-494. Epub 2017 Mar 11.

Department of Nuclear Medicine and Thyroid Centre, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.

Background: Real-time elastography has been proposed to increase the sensitivity of ultrasound and improve the detection of thyroid nodules at risk of malignancy. To date sparse data on real-time elastography assessment of autonomously functioning thyroid nodules exist. Here, we investigated the potential role of real-time elastography in autonomously functioning thyroid nodule assessment. Specifically, the correlation between serum hormones and real-time elastography score, as well as other clinical and ultrasound features, was analyzed.

Methods: Patients with autonomously functioning thyroid nodule identified by I-123 scintigraphy from September 2015 to July 2016 and undergoing ultrasound, real-time elastography, and thyroid function evaluation were selected. All autonomously functioning thyroid nodule were classified as RTE I (prevalence of red or green color with blue in up to 25% of the nodule area), RTE II (blue in 25-75%), or RTE III (blue in more than 75%). The association between suppressed thyroid stimulating hormone and patient's age, nodule's size, ultrasound presentation, and real-time elastography scoring was analyzed by Odds Ratio in univariate fashion and multivariate model.

Results: A number of 47 subjects with single autonomously functioning thyroid nodule were enrolled. Median age of 63 years, median size of 2.0 cm, and suppressed thyroid stimulating hormone levels in 32% of cases were found. Those nodules classified by ultrasound at high risk underwent fine-needle aspiration cytology and cancer was excluded. At real-time elastography evaluation, a 45% of autonomously functioning thyroid nodule had a hard appearance (RTE III) and had thyroid stimulating hormone significantly lower than the other (p < 0.0001). A model of multivariate logistic regression including nodule's size, ultrasound characteristics, and elastographic presentation showed that only RTE III was significantly associated with suppressed thyroid stimulating hormone (Odds Ratio of 50).

Conclusions: Autonomously functioning thyroid nodule may have variable elasticity at real-time elastography examination, being hard score associated with reduced/suppressed thyroid stimulating hormone. For clinical practice, the presence of autonomously functioning thyroid nodule should be considered in patients with hard lesions. Also, as quoted by the most recent ATA guidelines, elastography should not be accounted for risk stratification of thyroid nodules.
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http://dx.doi.org/10.1007/s12020-017-1277-6DOI Listing
December 2017

Prognostic factors in ectopic Cushing's syndrome due to neuroendocrine tumors: a multicenter study.

Eur J Endocrinol 2017 Apr;176(4):453-461

Section of EndocrinologyDepartment of Medicine, University of Verona, Verona, Italy.

Objective: Evidence is limited regarding outcome of patients with ectopic Cushing's syndrome (ECS) due to neuroendocrine tumors (NETs).

Design: We assessed the prognostic factors affecting the survival of patients with NETs and ECS.

Methods: Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers.

Results: Our series included 110 patients, 58.2% female, with mean (±s.d.) age at diagnosis of 49.5 ± 15.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors ( = 0.033) and in G1-NETs compared with G2 and G3 ( = 0.007). Negative predictive factors for survival were severity of hypercortisolism ( < 0.02), hypokalemia ( = 0.001), diabetes mellitus ( = 0.0146) and distant metastases ( < 0.001). Improved survival was observed in patients who underwent NET removal ( < 0.001). Adrenalectomy improved short-term survival.

Conclusions: Multiple factors affect prognosis of ECS patients: type of NET, grading, distant metastases, severity of hypercortisolism, hypokalemia and diabetes mellitus. BCs have the highest curative surgical rate and better survival compared with occult tumors and pNETs. Hypercortisolism plays a primary role in affecting outcome and quality of life; therefore, prompt and vigorous treatment of hormonal excess by NET surgery and medical therapy should be a key therapeutic goal. In refractory cases, adrenalectomy should be considered as it affects outcome positively at least in the first 2 years.
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http://dx.doi.org/10.1530/EJE-16-0809DOI Listing
April 2017

HHV-6A in vitro infection of thyrocytes and T cells alters the expression of miRNA associated to autoimmune thyroiditis.

Virol J 2017 01 11;14(1). Epub 2017 Jan 11.

Department of Medical Sciences, Section of Microbiology and Medical Genetics, University of Ferrara, via L. Borsari 46, 44121, Ferrara, Italy.

Background: Human herpesviruses have been hypothesized as environmental triggers in the development of autoimmune thyroid diseases (AITD), and in particular active human herpesvirus 6A (HHV-6A) infection was detected in thyrocytes of Hashimoto's thyroiditis (HT) patients, who also show specific anti-viral immune responses. On the other hand, AITD patients display modulation of specific miRNAs in thyroid tissue and blood. We wanted to ascertain whether HHV-6A infection might be correlated to the miRNA dysregulation observed in AITD.

Methods: Human thyroid and T-cell lines were infected in vitro with HHV-6A,-6B or -7, and analysed for miRNAs expression, either by microarray or by specific RT-PCR assays detecting miRNAs associated with AITD in vivo.

Results: HHV-6A infection, but not -6B or -7 infections, induced a decrease in miR-155_2 expression and an increase in miR-1238 expression in thyrocytes, as well as an increase in the expression levels of several autoimmunity-associated miRNAs in T lymphocytes, including miR-16_1, miR34a, miR-130a, miR-143_1, miR-202, miR-301b, miR-302c, miR-449b, miR-451_1, and miR-1238_2.

Conclusions: HHV-6A infection modulates miRNAs expression in the cell types involved in the development of AITD. Notably, our in vitro findings correlate with what observed in AITD patients, further supporting the association between HHV-6A infection and AITD development. Moreover, these effects are 6A-specific, emphasizing the differences between the two HHV-6 virus species, and suggesting diverse virus mechanisms of action and therapeutic approaches.
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http://dx.doi.org/10.1186/s12985-016-0672-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234148PMC
January 2017

Strategies to use microRNAs as therapeutic targets.

Best Pract Res Clin Endocrinol Metab 2016 10 15;30(5):629-639. Epub 2016 Nov 15.

Section of Endocrinology and Internal Medicine, Dept. of Medical Sciences, University of Ferrara, Italy. Electronic address:

MicroRNAs (miRNAs) are non-coding RNAs generated from endogenous hairpin-shaped transcripts that powerfully regulate gene expression at post-transcriptional level. Each miRNA is capable to regulate the expression levels of hundreds of transcripts and each mRNA may have more than one miRNA recognition sequence. There is emerging evidence that deregulation of miRNA expression leads to the alteration of pivotal physiological functions contributing to the development of diseases and neoplasms, including pituitary adenoma. This review is aimed at providing the up-to-date knowledge concerning deregulated miRNAs of pituitary tumors and their functions. In order to take stock, pituitary tumors have been sub-divided in different classes on the basis of tumor features (histotype, dimension, aggressiveness). The overview takes full consideration of the recent advances in miRNAs role as potential therapeutics and biomarkers.
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http://dx.doi.org/10.1016/j.beem.2016.10.002DOI Listing
October 2016