Publications by authors named "Pasqualino Malandrino"

39 Publications

Role of FGF System in Neuroendocrine Neoplasms: Potential Therapeutic Applications.

Front Endocrinol (Lausanne) 2021 14;12:665631. Epub 2021 Apr 14.

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

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors originating from neuroendocrine cells dispersed in different organs. Receptor tyrosine kinases are a subclass of tyrosine kinases with a relevant role in several cellular processes including proliferation, differentiation, motility and metabolism. Dysregulation of these receptors is involved in neoplastic development and progression for several tumors, including NENs. In this review, we provide an overview concerning the role of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) system in the development and progression of NENs, the occurrence of fibrotic complications and the onset of drug-resistance. Although no specific FGFR kinase inhibitors have been evaluated in NENs, several clinical trials on multitarget tyrosine kinase inhibitors, acting also on FGF system, showed promising anti-tumor activity with an acceptable and manageable safety profile in patients with advanced NENs. Future studies will need to confirm these issues, particularly with the development of new tyrosine kinase inhibitors highly selective for FGFR.
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http://dx.doi.org/10.3389/fendo.2021.665631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080021PMC
April 2021

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus.

Eur J Endocrinol 2020 Dec;183(6):R197-R215

Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy.

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or
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http://dx.doi.org/10.1530/EJE-20-0506DOI Listing
December 2020

The Possible Role of Cancer Stem Cells in the Resistance to Kinase Inhibitors of Advanced Thyroid Cancer.

Cancers (Basel) 2020 Aug 11;12(8). Epub 2020 Aug 11.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, 95122 Catania, Italy.

Target therapy with various kinase inhibitors (KIs) has been extended to patients with advanced thyroid cancer, but only a subset of these compounds has displayed efficacy in clinical use. However, after an initial response to KIs, dramatic disease progression occurs in most cases. With the discovery of cancer stem cells (CSCs), it is possible to postulate that thyroid cancer resistance to KI therapies, both intrinsic and acquired, may be sustained by this cell subtype. Indeed, CSCs have been considered as the main drivers of metastatic activity and therapeutic resistance, because of their ability to generate heterogeneous secondary cell populations and survive treatment by remaining in a quiescent state. Hence, despite the impressive progress in understanding of the molecular basis of thyroid tumorigenesis, drug resistance is still the major challenge in advanced thyroid cancer management. In this view, definition of the role of CSCs in thyroid cancer resistance may be crucial to identifying new therapeutic targets and preventing resistance to anti-cancer treatments and tumor relapse. The aim of this review is to elucidate the possible role of CSCs in the development of resistance of advanced thyroid cancer to current anti-cancer therapies and their potential implications in the management of these patients.
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http://dx.doi.org/10.3390/cancers12082249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465706PMC
August 2020

Role of selenium and myo-inositol supplementation on autoimmune thyroiditis progression.

Endocr J 2020 Nov 15;67(11):1093-1098. Epub 2020 Jul 15.

Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Via Palermo 636, 95122 Catania, Italy.

Previous reports indicate that selenium supplementation may be useful to reduce cell oxidative stress. In particular, selenium may decrease the level of thyroid autoantibodies in patients with Hashimoto's thyroiditis (HT). Recent studies also indicate that myo-inositol may have beneficial effects on thyroid function in patients with HT. Hence, the aim of the present study is to evaluate whether myo-inositol may enhance the protective effect of selenium on HT progression to hypothyroidism. The study was designed as observational and retrospective. Thyroid hormones were evaluated in patients with HT who were either euthyroid or subclinically hypothyroid. These patients were subdivided into three groups: untreated, treated with selenomethionine alone (Se-meth: 83 μg/day) and treated with Se-meth plus myo-inositol (Se-meth + Myo-I: 83 μg/day + 600 mg/day). Outcome evaluation was performed at baseline and after 6 and 12 months of treatment. High-resolution ultrasound of the thyroid gland was performed to evaluate changes in thyroid echoic pattern during the study. Compared to baseline, levels of thyroid-stimulating hormone (TSH) increased significantly in untreated patients but decreased by 31% and 38%, respectively, in those treated with Se-meth and Se-meth + Myo-I. Moreover, in the latter group the TSH reduction was observed earlier than in the Se-meth-treated group. Densitometric analysis of thyroid ultrasonography showed an echoic pattern improvement in both treated groups compared to untreated patients, although this difference was not statistically significant. Thus, Se-meth treatment is effective in patients with HT and its effect may be improved in combination with Myo-I through earlier achievement of TSH levels closer to physiological concentrations.
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http://dx.doi.org/10.1507/endocrj.EJ20-0062DOI Listing
November 2020

Corticosteroid Pulse Therapy for Graves' Ophthalmopathy Reduces the Relapse Rate of Graves' Hyperthyroidism.

Front Endocrinol (Lausanne) 2020 11;11:367. Epub 2020 Jun 11.

Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, Catania, Italy.

A course of anti-thyroid drugs (ATD) is the most common first line treatment for Graves' hyperthyroidism. However, hyperthyroidism relapse is frequent (30-70%). Due to the autoimmune nature of Graves' disease, the immunosuppressive treatment used for active Graves' orbitopathy (GO) may reduce the relapses after ATD discontinuation. To evaluate the recurrence rate in Graves' patients who, in addition to standard ATD, were treated or not treated with parenteral methylprednisolone (MPDS) for GO. Single-center retrospective study in a continuous series of 162 newly diagnosed Graves' patients, with or without GO, all gone into remission and followed-up until hyperthyroidism recurrence or at least 4 years after ATD discontinuation. Patients with moderate-severe active GO underwent middle dose MPDS treatment according to the EuGoGo guidelines. Cox proportional-hazard model was used to comparatively evaluate the risk of recurrence and the predictive factors in patients treated or not treated with MPDS pulse therapy. MPDS treatment was the most significant factor that independently correlated with a reduced risk of hyperthyroidism relapse (HR = 0.53, 95% C.I. = 0.31-0.89). FT3 and female sex were also independent protective factors, while age almost reached the significance level, = 0.062. The efficacy of MPDS was very high in patients aged <40 years (42.1% decrease in relapses, < 0.01) but it was not significant in older patients. Our study found that after ATD discontinuation the frequency of Graves' hyperthyroidism relapse was reduced in patients treated with MPDS pulse therapy for GO. This effect was more marked in young patients.
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http://dx.doi.org/10.3389/fendo.2020.00367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301650PMC
May 2021

Onset of Marine-Lenhart syndrome and Graves' ophthalmopathy in a female patient treated with alemtuzumab for multiple sclerosis.

Hormones (Athens) 2021 Mar 5;20(1):161-165. Epub 2020 Jun 5.

Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636, 95122, Catania, Italy.

Background: Immune checkpoint blockade therapy may lead to thyroid dysfunction in 3-7% of treated patients. Alemtuzumab is a CD52 inhibitor leading to thyroid dysfunction in approximately 40% of patients. A female patient was affected by multiple sclerosis (MS) and subclinical hyperthyroidism due to an autonomously functioning thyroid nodule (AFTN). After alemtuzumab treatment, she developed aggressive clinical hyperthyroidism consistent with Marine-Lenhart syndrome.

Case Presentation: A 36-year-old woman presented in July 2019 with symptoms of hyperthyroidism and eye complaints. Three years earlier, she was diagnosed with MS. Subclinical hyperthyroidism was diagnosed in April 2017. Thyroid scintigraphy showed an intranodular distribution of Tc-pertechnatate consisting of an AFTN in the right lobe of the thyroid. In June 2018, because of the MS, she was treated with alemtuzumab. In November 2018, she was started on methimazole treatment because of the symptoms of hyperthyroidism. In December 2018, thyroid function was normal under methimazole treatment. In June 2019, the patient received a second round of alemtuzumab administration. One month later, she developed symptoms of hyperthyroidism. These symptoms were accompanied by diplopia. Blood tests showed severe hyperthyroidism. Thyroid scintigraphy showed a diffuse distribution of Tc-pertechnatate and the presence of a "cool" area in the right lobe of the thyroid, confirmed by ultrasonography. The nodule was diagnosed as a low-risk indeterminate lesion.

Conclusion: We present a case of Graves' disease with active, moderate-to-severe Graves' ophthalmopathy in a patient with pre-existing AFTN presenting with a coexisting, rare case of Marine-Lenhart syndrome associated with immune reconstitution after alemtuzumab treatment.
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http://dx.doi.org/10.1007/s42000-020-00215-9DOI Listing
March 2021

Epidemiology of pancreatic neuroendocrine neoplasms: a gender perspective.

Endocrine 2020 08 28;69(2):441-450. Epub 2020 May 28.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Purpose: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs.

Methods: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis.

Results: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis.

Conclusions: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.
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http://dx.doi.org/10.1007/s12020-020-02331-3DOI Listing
August 2020

Increased Thyroid Cancer Incidence in Volcanic Areas: A Role of Increased Heavy Metals in the Environment?

Int J Mol Sci 2020 May 12;21(10). Epub 2020 May 12.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, 95122 Catania, Italy.

Thyroid cancer incidence is significantly increased in volcanic areas, where relevant non-anthropogenic pollution with heavy metals is present in the environment. This review will discuss whether chronic lifelong exposure to slightly increased levels of metals can contribute to the increase in thyroid cancer in the residents of a volcanic area. The influence of metals on living cells depends on the physicochemical properties of the metals and their interaction with the target cell metallostasis network, which includes transporters, intracellular binding proteins, and metal-responsive elements. Very little is known about the carcinogenic potential of slightly increased metal levels on the thyroid, which might be more sensitive to mutagenic damage because of its unique biology related to iodine, which is a very reactive and strongly oxidizing agent. Different mechanisms could explain the specific carcinogenic effect of borderline/high environmental levels of metals on the thyroid, including (a) hormesis, the nonlinear response to chemicals causing important biological effects at low concentrations; (b) metal accumulation in the thyroid relative to other tissues; and (c) the specific effects of a mixture of different metals. Recent evidence related to all of these mechanisms is now available, and the data are compatible with a cause-effect relationship between increased metal levels in the environment and an increase in thyroid cancer incidence.
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http://dx.doi.org/10.3390/ijms21103425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279170PMC
May 2020

Is Thyroid Cancer Increasing in Incidence and Aggressiveness?

J Clin Endocrinol Metab 2020 07;105(7)

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

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http://dx.doi.org/10.1210/clinem/dgaa223DOI Listing
July 2020

Fathoming the link between anthropogenic chemical contamination and thyroid cancer.

Crit Rev Oncol Hematol 2020 Jun 10;150:102950. Epub 2020 Apr 10.

Struttura Complessa Chirurgia Oncologica della Tiroide, ISTITUTO NAZIONALE TUMORI - IRCCS - FONDAZIONE G.PASCALE, NAPOLI, Italy. Electronic address:

Incidence and mortality of thyroid cancer are increasing, thus making mandatory to improve the knowledge of disease etiology. The hypothesis of a role for anthropogenic chemicals is raising wide consideration. A series of occupational studies revealed that job exposures with high risk of chemical contamination were usually more prone to thyroid cancer development. These include shoe manufacture, preserving industry, building activities, pulp/papermaker industry and the wood processing, agricultural activities, and other work categories characterized by contact with chemicals, such as chemists and pharmacists. However, such epidemiological analyses cannot define a causal relationship. Thyroid-disrupting activity has emerged for a broad set of anthropogenic chemicals, with the best evidence being gained for polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, bisphenols, phthalates, pesticides, and heavy metals. A series of case-control studies, assessing exposure to thyroid-disrupting agents, as measured on biological matrices, have been recently performed providing the following insights: a) positive relationship with thyroid cancer was found for phthalates, bisphenols, the heavy metals cadmium, copper, and lead; b) polybrominated diphenyl ethers exposure showed no relationship with thyroid cancer c) controversial results were reported for polychlorinated biphenyls and pesticides. However, such studies cannot demonstrate the causal link with disease occurrence, as exposure is assessed after tumour development. Studies with different methodological approach are therefore required for defining the role of anthropogenic environmental chemicals in thyroid carcinogenesis.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102950DOI Listing
June 2020

Concentration of Metals and Trace Elements in the Normal Human and Rat Thyroid: Comparison with Muscle and Adipose Tissue and Volcanic Versus Control Areas.

Thyroid 2020 02 3;30(2):290-299. Epub 2020 Feb 3.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

The concentration of trace elements and metals in the thyroid is the result of exposure, uptake, retention, and clearance. The specificity and selectivity of thyroid capacity to concentrate these elements relative to other tissues are not known. To obtain this information, we measured the tissue concentration of 26 elements in the thyroid, muscle, and fat of euthyroid human subjects and also in normal rats. At programmed surgery, small (<1 g) tissue fragments were collected in 77 euthyroid subjects. Macroscopically normal thyroid tissue, sternothyroid muscle, and neck subcutaneous fat samples were excised, and thyroid tissue was confirmed to be morphologically normal through microscopy. Tissue specimens (thyroid, hindlimb muscle, and abdominal fat) were also obtained from normal rats. Measurements of trace elements were performed on tissues using inductively coupled plasma mass spectrometry (DRC-ICP-MS). Only 19 of the 26 investigated elements were measurable as 7 elements were below the limit of detection. The ranking concentration in human thyroid tissue, not considering iodide, indicated that Zn, Br, Cu, Cr, Se, and Mn represented over 95% of the measured elements. A similar ranking was observed in the rat thyroid. A comparison with other tissues indicated that in addition to I, also Br, Mn, Se, and Sn were significantly more concentrated in the thyroid, and this was also the case for the recognized carcinogens As, Cd, and Hg. As and Hg, but not Cd (which was not detectable in any of the rat tissues), were also more concentrated in the rat thyroid. Since human thyroid specimens were also obtained from residents of a volcanic area, where environmental pollution may cause human biocontamination, we compared the trace element concentration in specimens from the volcanic area with controls. Many trace elements were slightly, but not significantly, increased in the volcanic area specimens. In the normal human thyroid, many trace elements, including Br, Mn, Se, and Sn, and the recognized carcinogens, As, Cd, and Hg, are significantly more concentrated than in muscle and fat of the same individual. Similar data were observed in rats. The reason for the differential element accumulation in the thyroid is unclear; a better understanding may be useful to further clarify thyroid biology.
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http://dx.doi.org/10.1089/thy.2019.0244DOI Listing
February 2020

Mitotane Concentrations Influence the Risk of Recurrence in Adrenocortical Carcinoma Patients on Adjuvant Treatment.

J Clin Med 2019 Nov 2;8(11). Epub 2019 Nov 2.

Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, 10043 Orbassano, Italy.

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28-62) with a median maintenance dose of 2.0 g/day (IQR 1.5-2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5-19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7-M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88-0.98, < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.
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http://dx.doi.org/10.3390/jcm8111850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912753PMC
November 2019

Combined use of sonographic and elastosonographic parameters can improve the diagnostic accuracy in thyroid nodules at risk of malignancy at cytological examination.

Minerva Endocrinol 2020 Mar 11;45(1):3-11. Epub 2019 Oct 11.

Ultrasound Diagnostic Medical Center, Catania, Italy.

Background: Thyroid nodules diagnosed as Thy3B at fine-needle aspiration biopsy have a relevant risk of malignancy (15-30%) and are usually addressed to surgery. However surgery will result unnecessary in most cases. The present study aims at evaluating the possible increase of diagnostic accuracy for predicting malignancy using novel sonographic and elastographic parameters.

Methods: In fifty patients undergoing thyroidectomy because of a Thy3B thyroid nodule, sonographic and elastosonographic evaluation was carried out by single operator before surgery. Five sonographic parameters (echogenicity, irregular margins, microcalcifications, intra-nodule blood flow and its irregularity) and two elastosonographic parameters (intra-nodule stiffness and its extension to adjacent tissue) were considered. After obtaining histological diagnosis, diagnostic accuracy was calculated.

Results: When the two procedures were analyzed separately, sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were 100%, 85%, 63% and 100% for ultrasonography and 60%, 92.5%, 67%, 90% for elastrosonography, respectively. The newly introduced evaluation procedures increased sensitivity. When a combined sonographic and elastosonographic evaluation was introduced, diagnostic accuracy was significantly improved: when ≥4 out of the seven parameters indicated were present, the risk of malignancy was very high (sensitivity 100%, specificity 92.55%, PPV 77%, NPV 100%).

Conclusions: A novel combined sonographic and elastosonographic parameter evaluation improved diagnostic accuracy for identifying thyroid nodules suspicious of malignancy.
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http://dx.doi.org/10.23736/S0391-1977.19.02945-6DOI Listing
March 2020

Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment.

Int J Mol Sci 2019 Jul 2;20(13). Epub 2019 Jul 2.

Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.

The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)-comprising papillary (PTC) and follicular (FTC) tumors-respond to radioiodine therapy, while undifferentiated tumors-including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)-are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.
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http://dx.doi.org/10.3390/ijms20133258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651760PMC
July 2019

Effect of low-dose tungsten on human thyroid stem/precursor cells and their progeny.

Endocr Relat Cancer 2019 08;26(8):713-725

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.
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http://dx.doi.org/10.1530/ERC-19-0176DOI Listing
August 2019

Challenges in the treatment of parathyroid carcinoma: a case report.

Hormones (Athens) 2019 Sep 23;18(3):325-328. Epub 2019 Mar 23.

Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Via Palermo 636, 95122, Catania, Italy.

Introduction: Parathyroid carcinoma (PC) is a rare neoplasm with a high rate of recurrence and an indolent course. It is frequently functional, causing nearly 1% of the cases of primary hyperparathyroidism (HPT), and in some cases, it may be complicated by brown tumors, mimicking bone metastases. Synchronous parathyroid and papillary thyroid carcinomas are rare.

Case Report: We present a patient with HPT due to PC, misdiagnosed at first evaluation, which exhibited multiple hypermetabolic lytic lesions in the skeleton, suggesting bone metastases. Their regression after PTH reduction suggested the diagnosis of brown tumors due to severe HPT. Given the persistence of HPT, the patient underwent a number of neck surgeries, and a papillary thyroid microcarcinoma with a nodal metastasis was diagnosed. A genetic test discovered a previously unreported mutation of the CDC73 (HRPT2) gene, codifying for parafibromin and resulting in a premature stop codon (c.580A>Tp.Arg194). Because of the persistence of HPT, cinacalcet therapy was started in order to control hypercalcemia.

Conclusion: This is a very unusual patient with a newly discovered variant of the CDC73 gene and a phenotype characterized by recurrent PC, brown tumors, and N1a metastasized thyroid carcinoma. The present case confirms that PC may not exhibit clear malignant properties at first assessment, contributing to inadequate initial surgical treatment. Although infrequently, PC can be associated with papillary thyroid cancer. The diagnosis of brown tumor should be considered in patients with severe HPT and multiple destructive bone lesions mimicking metastases on PET/CT imaging.
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http://dx.doi.org/10.1007/s42000-019-00104-wDOI Listing
September 2019

Differentiated thyroid cancer in children: Heterogeneity of predictive risk factors.

Pediatr Blood Cancer 2018 09 16;65(9):e27226. Epub 2018 May 16.

Endocrinology Division, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, Catania, Italy.

Objective: To correlate clinical and pathological characteristics at diagnosis with patient long-term outcomes and to evaluate ongoing risk stratifications in a large series of paediatric differentiated thyroid cancers (DTC).

Study Design: Retrospective analysis of clinical and pathological prognostic factors of 124 paediatric patients with DTC (age at diagnosis <19 years) followed up for 10.4 ± 8.4 years. Patients with a follow-up >3 years (n = 104) were re-classified 18 months after surgery on the basis of their response to therapy (ongoing risk stratification).

Results: Most patients had a papillary histotype (96.0%), were older than 15 years (75.0%) and were diagnosed because of clinical local symptoms (63.7%). Persistent/recurrent disease was present in 31.5% of cases during follow-up, but at the last evaluation, only 12.9% had biochemical or structural disease. The presence of metastases in the lymph nodes of the lateral compartment (OR 3.2, 95% CI, 1.28-7.16, P = 0.01) was the only independent factor associated with recurrent/persistent disease during follow-up. At the last evaluation, biochemical/structural disease was associated with node metastases (N1a, N1b) by univariate but not multivariate analysis. Ongoing risk stratification compared to the initial risk classification method better identified patients with a lower probability of persistent/recurrent disease (NPV = 100%).

Conclusions: In spite of the aggressive presentations at diagnosis, paediatric patients with DTC show an excellent response to treatment and often a favourable outcome. N1b status should be considered a strong predictor of persistent/recurrent disease which, as in adults, is better predicted by ongoing risk stratification.
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http://dx.doi.org/10.1002/pbc.27226DOI Listing
September 2018

Anaplastic Thyroid Cancer in Sicily: The Role of Environmental Characteristics.

Front Endocrinol (Lausanne) 2017 20;8:277. Epub 2017 Oct 20.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

Background: Anaplastic thyroid cancer (ATC) is a rare but extremely aggressive cancer of the thyroid, contributing up to 30-40% of thyroid cancer-specific mortality. We analyzed ATC characteristics and survival rates in Sicily to evaluate the possible influence of environmental factors. With this aim, data regarding ATC incidences in urban/rural and industrial, iodine-deficient, and volcanic vs control areas were compared in Sicily as well as ATC data from Sicily and USA.

Methods: Using the Sicilian Register of Thyroid Cancer (SRTC) database incidence, age, gender, tumor size and histotype, extrathyroidal extension, stage, and coexistence with pre-existing differentiated thyroid cancer (DTC) were evaluated in different areas of Sicily and also compared with Surveillance Epidemiology and End Results data in USA.

Results: Forty-three ATCs were identified in Sicily in the period 2002-2009. In our series only age <70 years at diagnosis ( = 0.01), coexistence with DTC ( = 0.027) and tumor size ≤6 cm ( = 0.012) were significant factors for increased survival at univariate analysis (only age at multivariate analysis). No difference in ATC incidence was found in urban vs rural areas and in iodine-deficient and industrial vs control areas. By contrast, in the volcanic area of Sicily, where DTC incidence is doubled relative to the rest of the island, also ATC incidence was increased. ATC data in Sicily were similar to those reported in the same period in the USA where overall survival rate at 6 and 12 months, however, was smaller.

Conclusion: The similar ATC data observed in Sicily and USA (having different genetic background and lifestyle) and the increased ATC incidence in the volcanic area of Sicily paralleling the increased incidence of papillary thyroid cancer are compatible with the possibility that casual additional mutations, more frequent in a background of increased cell replication like DCT, are the major causes of ATC rather than genetic background and/or direct environmental influences.
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http://dx.doi.org/10.3389/fendo.2017.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662896PMC
October 2017

Intake of Boron, Cadmium, and Molybdenum enhances rat thyroid cell transformation.

J Exp Clin Cancer Res 2017 06 2;36(1):73. Epub 2017 Jun 2.

Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), Via del Fosso di Fiorano, 64, 00143, Rome, Italy.

Background: Epidemiologic data in volcanic areas suggest that environmental factors might be involved in the increase of thyroid cancer (TC) incidence. Recent reports indicate that several heavy metals and metalloids are increased in volcanic areas. This study aims to evaluate the combined effect of three of these elements Boron (B), Cadmium (Cd), and Molybdenum (Mo) - all increased in the volcanic area of Mt. Etna, in Italy - on thyroid tumorigenesis in the rat.

Methods: Female Wistar rats prone to develop thyroid tumors by low-iodine diet and methimazole treatment received ad libitum drinking water supplemented with B, Cd, and Mo at concentrations in the range found in the urine samples of residents of the volcanic area. At 5 and 10 months animals were euthanized, and their thyroid analysed. Statistical analysis was performed with a 2-way unpaired t-test.

Results: No toxic effect of the three elements on the growth of the animals was observed. A significant increase of histological features of transformation was observed in thyroid follicular cells of rats treated with B, Cd, and Mo compared with those of control group. These abnormalities were associated with decreased iodine content in the thyroid.

Conclusions: This study provides the evidence that slightly increased environmental concentrations of B, Cd, and Mo can accelerate the appearance of transformation marks in the thyroid gland of hypothyroid rats.
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http://dx.doi.org/10.1186/s13046-017-0543-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455132PMC
June 2017

Everolimus as first line therapy for pancreatic neuroendocrine tumours: current knowledge and future perspectives.

J Cancer Res Clin Oncol 2017 Jul 12;143(7):1209-1224. Epub 2017 Apr 12.

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

Purpose: Everolimus has been shown to be effective for advanced pancreatic neuroendocrine tumours (pNETs), but its positioning in the therapeutic algorithm for pNETs is matter of debate.

Methods: With the aim to shed light on this point, we performed an up-to-date critical review taking into account the results of both retrospective and prospective published studies, and the recommendations of international guidelines. In addition, we performed an extensive search on the Clinical Trial Registries databases worldwide, to gather information on the ongoing clinical trials related to this specific topic.

Results: We identified eight retrospective published studies, two prospective published studies, and five registered clinical trials. Moreover, we analyzed the content of four widespread international guidelines.

Conclusions: Our critical review confirms the lack of high-quality data to recommend everolimus as the first line therapy for pNETs. The ongoing clinical trials reported in this review will hopefully help clinicians, in the near future, to better evaluate the role of everolimus as the first line therapy for pNETs. However, at the moment, there is already enough evidence to recommend everolimus as the first line therapy for patients with symptomatic malignant unresectable insulin-secreting pNETs, to control the endocrine syndrome regardless of tumour growth.
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http://dx.doi.org/10.1007/s00432-017-2407-5DOI Listing
July 2017

Thyroid Cancer in the Pediatric Age in Sicily: Influence of the Volcanic Environment.

Anticancer Res 2017 03;37(3):1515-1522

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy.

Background/aim: Pediatric thyroid cancer (TC) is rare but its incidence is increasing. We analyzed incidence and characteristics of pediatric TC in Sicily and comparatively evaluated data from the volcanic and non-volcanic areas.

Materials And Methods: All incident pediatric (0-19 years) TCs in Sicily between 2002-2009 were analyzed for the area of residence and compared to data for adults.

Results: A total of 54 differentiated TCs (DTC) and nine medullary TCs were diagnosed in Sicily in children between 2002-2009. DTC age standardized rate for the world population (ASRw) was 0.8/10 in females and 0.2/10 in males, with a higher incidence in the volcanic area (ASRw=1.4/10 in females, 0.5/10 in males) vs. the rest of Sicily (ASRw=0.6/10 in females, 0.1/10 in males). Pediatric TCs were larger in size and more frequently with extrathyroid extension and lymph-node involvement in comparison to TCs in adults.

Conclusion: In the volcanic environment of Sicily, TC incidence is markedly increased in children, suggesting a short-term effect of unidentified carcinogens of volcanic origin.
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http://dx.doi.org/10.21873/anticanres.11479DOI Listing
March 2017

Prognostic Factors for Adrenocortical Carcinoma Outcomes.

Front Endocrinol (Lausanne) 2016 25;7:99. Epub 2016 Jul 25.

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania , Catania , Italy.

Purpose: Adrenocortical carcinoma (ACC) is an aggressive tumor characterized by a high recurrence rate and poor response to treatment. This study analyzes a consecutive series of ACC patients to evaluate the prognostic value of various clinical and pathological characteristics.

Methods: We retrospectively evaluated 32 ACC patients followed at our Medical Center from 1997 to 2015 and evaluated the prognostic value of age at diagnosis, gender, tumor functional status, stage, and type of treatment with respect to overall survival (OS) and disease-free survival (DFS), as determined by Kaplan-Meier curves.

Results: ACC was associated with hormonal overproduction in 50% of cases, and patients with isolated hyperandrogenism had a better prognosis. Recurrence was observed in 12/26 (46.2%) patients with no evidence of disease after surgery. Tumor size [hazard ratio (HR) 1.32, 95% confidential intervals (CI) 1.12-1.64; p = 0.007], ki-67 (HR 1.06, 95% CI 1.02-1.11; p = 0.009) and advanced stage at diagnosis (III-IV) (HR 6.51, 95% CI 1.65-24.68; p = 0.006) were associated with recurrence in the 26 R0 patients in the univariate analysis. Advanced stage was an independent risk factor for recurrence in the multivariate analysis (HR 8.10, 95% CI 1.55-41.35; p = 0.01). Five-year survival was 40.0%. Positive resection margins (HR 10.61, 95% CI 3.02-38.31; p = < 0.001), ki-67 (HR 1.04, 95% CI 1.01-1.07; p = 0.01) and advanced stage (HR 11.31, 95% CI 1.45-87.76; p = 0.02) were associated with poor survival in all 32 patients, but only positive resection margins were an independent predictor of mortality in the multivariate analysis (HR 6.22, 95% CI 1.44-26.05; p = 0.01).

Conclusion: ACC has a poor prognosis with a high recurrence rate. Tumor stage at diagnosis and the completeness of surgical excision are the most relevant prognostic factors.
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http://dx.doi.org/10.3389/fendo.2016.00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4958635PMC
August 2016

Outcome of the Diffuse Sclerosing Variant of Papillary Thyroid Cancer: A Meta-Analysis.

Thyroid 2016 09 22;26(9):1285-92. Epub 2016 Jul 22.

1 Endocrinology, Department of Clinical and Experimental Medicine, University of Catania , Garibaldi-Nesima Medical Center, Catania, Italy .

Introduction: The diffuse sclerosing variant (DSV) of papillary thyroid cancer (PTC) is considered an aggressive histotype associated with poor prognosis. However, the available data for both the outcome and best management of this disease are inconsistent.

Methods: This study reviewed the current literature by searching PubMed up to November 30, 2015, using the search terms "diffuse sclerosing variant" and "papillary thyroid cancer (or carcinoma)" and selecting only studies evaluating recurrent/persistent disease and cancer-related mortality in both DSV and classic PTC (cPTC). The association with some features of aggressiveness at diagnosis, the risk of recurrence or persistence, and the risk of cancer-related death were reported as odds ratio (OR) with confidence intervals (CI). Meta-regression analysis was used to assess the effect of covariates across the studies.

Results: Ten studies met the eligibility criteria and contributed 585 DSV and 64,611 cPTC patients. Relative to patients with cPTC, patients with DSV exhibited a higher risk of extrathyroidal extension and lymph node and distant metastases. The risk of persistent/recurrent disease was three times higher in patients with DSV than it was in cPTC patients (OR = 3.19 [CI 1.86-5.49]). This risk was not different when only studies where post-surgical (131)I was routinely administered were considered (OR = 2.07 [CI 0.88-4.90]). The risk of cancer-related mortality was not different between DSV and cPTC (OR = 1.34 [CI 0.76-2.38]).

Conclusions: This meta-analysis confirms the aggressive biological behavior of DSV thyroid cancer. When preoperatively suspected, total thyroidectomy with lymph node excision followed by radioiodine therapy should be the correct management for DSV.
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http://dx.doi.org/10.1089/thy.2016.0168DOI Listing
September 2016

Efficacy and Safety of Everolimus in Extrapancreatic Neuroendocrine Tumor: A Comprehensive Review of Literature.

Oncologist 2016 07 6;21(7):875-86. Epub 2016 Apr 6.

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

Background: Everolimus, an oral mTOR (mammalian target of rapamycin) inhibitor, is currently approved for the treatment of progressive pancreatic neuroendocrine tumors (NETs). Although promising, only scattered data, often from nondedicated studies, are available for extrapancreatic NETs.

Patients And Methods: A systematic review of the published data was performed concerning the use of everolimus in extrapancreatic NET, with the aim of summarizing the current knowledge on its efficacy and tolerability. Moreover, the usefulness of everolimus was evaluated according to the different sites of the primary.

Results: The present study included 22 different publications, including 874 patients and 456 extrapancreatic NETs treated with everolimus. Nine different primary sites of extrapancreatic NETs were found. The median progression-free survival ranged from 12.0 to 29.9 months. The median time to progression was not reached in a phase II prospective study, and the interval to progression ranged from 12 to 36 months in 5 clinical cases. Objective responses were observed in 7 prospective studies, 2 retrospective studies, and 2 case reports. Stabilization of the disease was obtained in a high rate of patients, ranging from 67.4% to 100%. The toxicity of everolimus in extrapancreatic NETs is consistent with the known safety profile of the drug. Most adverse events were either grade 1 or 2 and easy manageable with a dose reduction or temporary interruption and only rarely requiring discontinuation.

Conclusion: Treatment with everolimus in patients with extrapancreatic NETs appears to be a promising strategy that is safe and well tolerated. The use of this emerging opportunity needs to be validated with clinical trials specifically designed on this topic.

Implications For Practice: The present study reviewed all the available published data concerning the use of everolimus in 456 extrapancreatic neuroendocrine tumors (NETs) and summarized the current knowledge on the efficacy and safety of this drug, not yet approved except for pancreatic NETs. The progression-free survival rates and some objective responses seem promising and support the extension of the use of this drug. The site-by-site analysis seems to suggest that some subtypes of NETs, such as colorectal, could be more sensitive to everolimus than other primary NETs. No severe adverse events were usually reported and discontinuation was rarely required; thus, everolimus should be considered a valid therapeutic option for extrapancreatic NETs.
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http://dx.doi.org/10.1634/theoncologist.2015-0420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943387PMC
July 2016

Predictive factors of response to mTOR inhibitors in neuroendocrine tumours.

Endocr Relat Cancer 2016 Mar 14;23(3):R173-83. Epub 2015 Dec 14.

Section of Endocrinology and Internal MedicineDepartment of Medical Sciences, University of Ferrara, Via Aldo Moro 8, 44124 Cona - Ferrara, ItalyNeuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, ItalyEndocrinology UnitGaribaldi Nesima Medical Center, Catania, ItalyDepartment of Clinical Medicine and Surgery"Federico II" University of Naples, Naples, ItalyThyroid and Parathyroid Surgery UnitIstituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy.

Medical treatment of neuroendocrine tumours (NETs) has drawn a lot of attention due to the recent demonstration of efficacy of several drugs on progression-free survival, including somatostatin analogs, small tyrosine kinase inhibitors and mTOR inhibitors (or rapalogs). The latter are approved as therapeutic agents in advanced pancreatic NETs and have been demonstrated to be effective in different types of NETs, with variable efficacy due to the development of resistance to treatment. Early detection of patients that may benefit from rapalogs treatment is of paramount importance in order to select the better treatment and avoid ineffective and expensive treatments. Predictive markers for therapeutic response are under intensive investigation, aiming at a tailored patient management and more appropriate resource utilization. This review summarizes the available data on the tissue, circulating and imaging markers that are potentially predictive of rapalog efficacy in NETs.
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http://dx.doi.org/10.1530/ERC-15-0413DOI Listing
March 2016

Increased thyroid cancer incidence in a basaltic volcanic area is associated with non-anthropogenic pollution and biocontamination.

Endocrine 2016 Aug 5;53(2):471-9. Epub 2015 Oct 5.

Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, via Palermo n. 636, 95122, Catania, Italy.

The increased thyroid cancer incidence in volcanic areas suggests an environmental effect of volcanic-originated carcinogens. To address this problem, we evaluated environmental pollution and biocontamination in a volcanic area of Sicily with increased thyroid cancer incidence. Thyroid cancer epidemiology was obtained from the Sicilian Regional Registry for Thyroid Cancer. Twenty-seven trace elements were measured by quadrupole mass spectrometry in the drinking water and lichens (to characterize environmental pollution) and in the urine of residents (to identify biocontamination) in the Mt. Etna volcanic area and in adjacent control areas. Thyroid cancer incidence was 18.5 and 9.6/10(5) inhabitants in the volcanic and the control areas, respectively. The increase was exclusively due to the papillary histotype. Compared with control areas, in the volcanic area many trace elements were increased in both drinking water and lichens, indicating both water and atmospheric pollution. Differences were greater for water. Additionally, in the urine of the residents of the volcanic area, the average levels of many trace elements were significantly increased, with values higher two-fold or more than in residents of the control area: cadmium (×2.1), mercury (×2.6), manganese (×3.0), palladium (×9.0), thallium (×2.0), uranium (×2.0), vanadium (×8.0), and tungsten (×2.4). Urine concentrations were significantly correlated with values in water but not in lichens. Our findings reveal a complex non-anthropogenic biocontamination with many trace elements in residents of an active volcanic area where thyroid cancer incidence is increased. The possible carcinogenic effect of these chemicals on the thyroid and other tissues cannot be excluded and should be investigated.
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http://dx.doi.org/10.1007/s12020-015-0761-0DOI Listing
August 2016

Familial Non-Medullary Thyroid Cancer Represents an Independent Risk Factor for Increased Cancer Aggressiveness: A Retrospective Analysis of 74 Families.

Front Endocrinol (Lausanne) 2015 3;6:117. Epub 2015 Aug 3.

Endocrinology, Garibaldi Nesima Hospital , Catania , Italy.

Objectives: To assess whether familial non-medullary thyroid cancer (FNMTC) represents an independent risk factor for increased aggressiveness of the tumor, as concern as the clinical presentation and the long-term follow-up in respect of sporadic differentiated thyroid cancer (SDTC).

Design: Retrospective study; 1976-2014.

Patients And Methods: Seventy-four FNMTC families (151 affected individuals): family relationship and number of affected family members were evaluated. Clinical and histopathological features and outcome were compared to that of 643 SDTC patients followed in the same period according to the same institutional protocols. Median follow-up was 57.7 months (range 12-136) in FNMTC and 59.7 (range 15-94.6) in SDTC patients.

Results: Three cases occurred in 3 families and 2 cases in the other 71. F:M was 3.7:1 in FNMTC and 4.3:1 in SDTC (NS). The family relationship was siblings in 62.2%. Mean age at diagnosis was lower in FNMTC than in SDTC (p < 0.005). Papillary/follicular histotype distribution was similar (86%). Papillary tumors were more frequently multifocal in FNMTC (p = 0.004) and with lymph-node metastases (p = 0.016). Disease-free survival (DFS) was shorter in FNMTC vs. SDTC (p < 0.0001) with 74.8 vs. 90.8% patients free of disease at the last control (p < 0.005). Three patients died in FNMTC group vs. 1 in SDTC (p = 0.02).

Conclusion: Familial non-medullary thyroid cancer displays distinct characteristics as earlier age of onset and increased aggressiveness at diagnosis and a higher rate of persistent/recurrent disease and mortality with a shorter DFS in respect with SDTC. FNMTC patients, therefore, should be followed accurately. As the specific gene (or genes) responsible for susceptibility for FNMTC has not yet been identified, a low frequency periodic screening of relatives DTC patients may be useful to identify FNMTC patients at early stage of disease.
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http://dx.doi.org/10.3389/fendo.2015.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522563PMC
August 2015

Several Site-specific Cancers are Increased in the Volcanic Area in Sicily.

Anticancer Res 2015 Jul;35(7):3995-4001

Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Medical Center, Catania, Italy Humanitas, Catania Oncology Center, Catania, Italy.

Background: Worldwide, thyroid cancer incidence is increased in many volcanic areas. Whether the incidence of other types of cancers are also increased is not known.

Materials And Methods: We analyzed cancer registries covering 82% of the population of Sicily to compare the incidence of 34 site-specific types of cancer in area around the volcano Mt. Etna (where thyroid cancer is very high) with adjacent non-volcanic areas. Differences in crude incidence rate ratios (IRR) between the two areas were calculated.

Results: Considering 72,197 incident cases, thyroid cancer (IRR=1.68 in females and 1.40 in males) and lymphatic leukemia (IRR: females=1.48, males=1.39) were significantly increased in the volcanic area in both men and women. Hodgkin's lymphoma, stomach and breast cancer in women and prostate cancer in men were also significantly increased in the volcanic area.

Conclusion: Several, but not all types of cancers are significantly increased in the volcanic area of Sicily, indicating that an active volcanic environment may be a risk factor for cancer other than thyroid cancer.
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July 2015

The changing epidemiology of thyroid cancer: why is incidence increasing?

Curr Opin Oncol 2015 Jan;27(1):1-7

aEndocrinology, Garibaldi Hospital Medical Center and Department of Clinical and Molecular Biomedicine, University of Catania bHumanitas, Catania Center of Oncology cMedical Oncology, University of Catania Medical School, Catania, Italy.

Purpose Of Review: Thyroid cancer incidence is increasing worldwide. Causes are highly debated.

Recent Findings: Thyroid cancer increase has been associated to socioeconomic status, better access to healthcare and rising use of thyroid imaging. Therefore, the rise could be apparent because of the useless identification of a large reservoir of subclinical papillary lesions that will never affect patient health (overdiagnosis).However, not all epidemiological and clinical data support this hypothesis. The increasing number of large tumors, the increasing thyroid cancer-related mortality in spite of earlier treatment and the changes in thyroid cancer molecular profile suggest a true increase. Recently increased and thyroid-specific environmental carcinogens could be responsible, such as radiation (mostly medical radiation), increased iodine intake and chronic lymphocytic thyroiditis and environmental pollutants such as nitrates, heavy metals and other compounds largely used in the industrialized society. Possible mechanisms await further investigation.

Summary: The increased incidence of thyroid cancer is the likely result of two coexisting processes: increased detection (apparent increase) and increased number of cases (true increase) due to unrecognized thyroid-specific carcinogens.To identify causal factors and to differentiate stationary cancers from those that will progress are major urgent requirements for both clinical and scientific purposes.
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http://dx.doi.org/10.1097/CCO.0000000000000148DOI Listing
January 2015

The BRAF(V600E) mutation influences the short- and medium-term outcomes of classic papillary thyroid cancer, but is not an independent predictor of unfavorable outcome.

Thyroid 2014 Aug 11;24(8):1267-74. Epub 2014 Jun 11.

1 Endocrinology, Department of Clinical and Molecular Biomedicine, University of Catania , Catania, Italy .

Introduction: The prognostic usefulness of BRAF(V600E) evaluation in papillary thyroid cancer (PTC) has been analyzed in many studies, with controversial conclusions.

Aim: To analyze the clinical relevance of BRAF(V600E) measurement in a homogenous series of PTC patients followed in a single institution.

Methods: One hundred three classical variant PTC patients who underwent total thyroidectomy in the 3-year period between 2005 and 2008 were retrospectively selected, and BRAF(V600E) assessment was performed using paraffin-embedded archival specimens in 2013. All patients were actively followed at our medical center, with an average follow-up of 55±13 months.

Results: BRAF(V600E) mutation-positive cancers (55.3%) were more frequently associated with lymph node metastasis (p=0.01) and advanced TNM stage (III-IV) (p=0.03). These findings were also confirmed in the subset of 42 microcarcinomas. BRAF(V600E)-positive patients were also at a higher risk of persistent disease (OR 3.5 [95% confidence interval {CI} 1.2-10.3], p=0.03) in univariate but not multivariate analysis (OR 2.8 [CI 0.7-11.8], p=0.2). Lymph node involvement was an independent predictor of persistent disease (OR 30.9 [CI 6.0-159.0], p<0.0001). Kaplan-Meier curves confirmed a higher percentage of persistent/recurrent disease in BRAF(V600E)-positive patients (p=0.02). However, the BRAF(V600E) mutation did not change the recurrence rate of PTC in subgroup analyses on the basis of other established risk factors (p=0.2).

Conclusions: BRAF(V600E)-positive tumors were at higher risk of developing more aggressive behavior and were associated with less favorable outcomes in the short and medium term, but the BRAF(V600E) mutation was not an independent predictor of unfavorable outcome. Therefore, its use as a prognostic marker in clinical practice is not advisable.
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http://dx.doi.org/10.1089/thy.2013.0675DOI Listing
August 2014