Changes in TSH levels in athyreotic patients with differentiated thyroid cancer during levothyroxine therapy: influence on dose adjustments.

PURPOSE: The aim of the study was to describe the spontaneous TSH level variations and levothyroxine dose adjustments in athyreotic patients with differentiated thyroid cancer (DTC) in real-life practice. METHODS: Patients with DTC were retrospectively evaluated at a tertiary referral center between October 2006 and November 2013. Hormone measurements (TSH and FT4 serum levels), L-T4 prescription information (dose per kg per day) and other medications were recorded at 1 month and 3, 12, 24, 36 and 48 months after primary treatment (surgery ± radioiodine therapy). RESULTS: The cohort was composed of 452 patients; about 20% of patients with stable levothyroxine dose have clinically meaningful spontaneous TSH variations (defined as ΔTSH > 2 mcUI/mL) at yearly follow-up visit. Furthermore, about 25% of athyreotic DTC patients with stable dose have a ΔTSH > 1.5 mcUI/mL and about 40% a ΔTSH > 1 mcUI/mL during each follow-up visit. We further investigated whether this TSH variation would lead to subsequent dose changes. About 19.9-37.7% of DTC patients on stable LT4 dose on the previous visit had their levothyroxine dose reduced, while 7.8-14.9% increased due to TSH variations. We further evaluated the decision to change the dose in relation with the age-specific TSH range. Up to 77.2% of patients had their dose adjusted due to TSH falling below the age-specific range. CONCLUSIONS: Spontaneous serum TSH variations determine levothyroxine replacement therapy in athyreotic patients with DTC, requiring multiple dose changes.

Lack of association between obesity and aggressiveness of differentiated thyroid cancer.

PURPOSE: Aim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort. METHODS: Patients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score. RESULTS: The cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman's ρ - 0.02; p = 0.71) and ATA Initial Risk Stratification System score (ρ 0.03; p = 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate-high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06). CONCLUSIONS: Obesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.

Impact of long-acting octreotide in patients with early-stage MEN1-related duodeno-pancreatic neuroendocrine tumours.

BACKGROUND: Somatostatin analogues (SSA) represent one of the main therapeutic option in patients affected with functioning well-differentiated neuroendocrine tumours (NETs). There are no studies specifically focusing on NETs associated with Multiple Endocrine Neoplasia type 1 (MEN1). AIM: To evaluate the efficacy of the long-acting SSA octreotide in MEN1 patients with early-stage duodeno-pancreatic NETs. PATIENTS AND METHODS: Forty patients with MEN1 were retrospectively evaluated. Twenty patients with evidence of one or more MEN1-related duodeno-pancreatic NETs < 20 mm in size (age range 26-61 years) were treated with octreotide long-acting octreotide (LAR) as first-line therapy. Treatment duration ranged 12-75 months. At the baseline radiological evaluation, multiple duodeno-pancreatic NETs (range 1-8, size 3-18 mm) were detected. RESULTS: An objective tumour response was observed in 10%, stable disease in 80% and progression of disease in 10% of cases. In six patients with abnormally increased CgA, gastrin and/or insulin serum concentrations, a significant clinical and hormonal response occurred in 100% of cases and was stable along the time. CONCLUSIONS: Therapy with SSA is highly safe and effective in patients with early-stage MEN1 duodeno-pancreatic NETs, resulting in long-time suppression of tumour and hormonal activity and 10% objective response. This suggests to early start therapy with SSA in patients with MEN1-related NETs.

Impact of cinacalcet hydrochloride in clinical management of primary hyperparathyroidism in multiple endocrine neoplasia type 1.

AIM: Primary hyperparathyroidism (PHPT) is one of main cause of morbidity in patients with multiple endocrine neoplasia type 1 (MEN1). Medical therapy with cinacalcet-hydrochloride may modify the therapeutic strategy of MEN1 related PHPT. We present an experience with cinacalcet-hydrochloride in two patients with MEN1 PHPT. METHODS: The study included two MEN1 patients belonging to the same family (a 50-year-old woman and her daughter aged 20 years) with PHPT secondary to multiple involvement of parathyroid glands and other MEN1 related tumors. As both patients refused to undergo parathyroid surgery, we decided to start medical treatment with cinacalcet at the dose of 30 mg/day, which was the first treatment for the youngest patient, while the oldest had already been treated with partial parathyroidectomy. Serum concentrations of PTH, calcium and phosphorus, 24-h urine calcium-to-creatinine ratio and renal-threshold-phosphate concentration were evaluated before and after therapy. RESULTS: Serum calcium and PTH levels were normalized after 1 and 6 months of therapy, respectively, and 60 and 54 months after the beginning of cinacalcet remained normal. Hypercalciuria, hypophosphoremia and renal-threshold-phosphate normalized during therapy with cinacalcet. At ultrasonography, parathyroid nodular lesion remained unchanged. Cinacalcet was well tolerated without occurrence of side effects. CONCLUSION: Cinacalcet seems to be highly effective in controlling PHPT in patients with MEN1 either in naïve patients or in those with postsurgical recurrence. If cinacalcet will be confirmed to ensure a long-time control of PHPT or even to prevent the development and progression of PHPT, this may led to modify the therapeutic strategy of MEN1 PHPT.

Assessment and clinical implications of RANK/RANKL/OPG pathway as markers of bone tumor progression in patients with NET harboring bone metastases.

INTRODUCTION: The impact on the survival of bone metastases (BM) in patients with neuroendocrine tumor (NET) is a matter of debate. BM have a key role in causing symptoms and in decreasing patients' quality of life. Although the mechanisms of the development of BM are not completely clear, it is now well understood that the Receptor Activator of Nuclear factor Kappa-B-/Ligand (RANK/RANKL)/osteoprotegerin (OPG) pathway plays a relevant role. AIM: To characterize the RANK/RANKL/OPG pathway in patients affected with NET. PATIENTS AND METHODS: Two cohorts of 15 patients each were enrolled in the study; one cohort was affected with NET without BM and the second cohort was affected with NET with BM. The serum RANK/RANKL/OPG pathway was assessed in both the groups. RESULTS: Serum OPG levels and RANKL/OPG ratio were lower and higher, respectively, in NET patients harboring BM than in those without BM. During the ROC analysis, a cut-off value of 1071 pg/ml for OPG and 0.62 for RANKL/OPG ratio were able to significantly distinguish between the two groups. CONCLUSIONS: This study indicates that RANK/RANKL/OPG pathway is imbalanced in patients with NET harboring BM. Specific alterations of this pathway could predict an early development of BM.

Thyroid nodules treated with percutaneous radiofrequency thermal ablation: a comparative study.

PURPOSE: Percutaneous radiofrequency thermal ablation (RTA) was reported as an effective tool for the management of thyroid nodules (TNs). The aim of this study was to investigate the effects of RTA and to establish whether they were treatment-related by comparison with a matched, untreated control group. PATIENTS AND METHODS: The study population included 40 patients with compressive TNs: 22 had nontoxic TNs, and 18 had toxic TNs and were treated with methimazole. In all patients, a fine-needle aspiration cytology was performed to exclude a thyroid malignancy. STUDY DESIGN: Twenty patients were treated with RTA (group A), and 20 others did not receive any treatment (group B). At baseline, age, gender, and TN features did not differ significantly between groups. All patients were clinically, biochemically, and morphologically evaluated at baseline and after 1, 3, 6, and 12 months. RESULTS: TN volume significantly decreased in group A (1.8 ± 0.3 ml at 12 months vs. 13.3 ± 1.8 ml at baseline; P < 0.0001) and remained stable in group B [11.7 ± 1.5 ml at 12 months vs. 11.2 ± 1.5 ml at baseline; P = not significant (NS)]. At 3-, 6-, and 12-month evaluations, TN volume was significantly lower in group A than in group B (P < 0.005). At the end of the follow-up, pressure symptoms were improved in all patients in group A but persisted unchanged in group B. In group A, hyperthyroidism completely recovered in 40% and improved in 40% of patients with toxic TNs, whereas it persisted in all patients with toxic TNs in group B. RTA was safe and well tolerated in all patients. CONCLUSIONS: RTA induced a marked TN volume shrinkage resulting in parallel improvement of pressure symptoms. In most patients with toxic TNs, hyperthyroidism significantly improved as well. RTA may represent a valid therapeutic approach in patients with TNs not receiving conventional treatments.

Shortened interval of long-acting octreotide administration is effective in patients with well-differentiated neuroendocrine carcinomas in progression on standard doses.

BACKGROUND: In patients with well-differentiated (WD) neuroendocrine tumors (NET), long-acting octreotide (LAR), conventionally administered at a dose of 30 mg every 28 days, has well-documented anti-secretive but limited antiproliferative effects. AIM: The objective of this study was to evaluate a different schedule of LAR treatment consistent with a shorter interval between administrations (21 days) in WDNET patients with progressive disease at standard-dose interval. SUBJECTS AND METHODS: Twenty-eight patients followed for diagnosis and therapy of WDNET who had tumor progression during therapy with LAR 30 mg every 28 days were enrolled. Clinical, biological, and objective tumor response was evaluated after LAR 30 mg every 21 days. Time to progression was also evaluated after LAR 30 mg every 21 days and compared to LAR 30 mg every 28 days. RESULTS: The treatment with LAR 30 mg every 21 days resulted in complete and partial control of clinical symptoms in 40% and 60% of cases, respectively. Circulating neuroendocrine markers were significantly decreased in 30% of cases. A stabilization of disease was obtained in 93% and objective response in 7%. The median time to progression was significantly longer by using the shortened interval of LAR administration as compared to the standard one (30 vs 9 months, p<0.0001). The treatment was safe and well tolerated. CONCLUSIONS: The shortened schedule of LAR administration was able to re-institute control of clinical symptoms, to decrease level of circulating neuroendocrine markers and to increase time to progression in patients previously escaping from a standard schedule treatment.

Everolimus is an active agent in medullary thyroid cancer: a clinical and in vitro study.

Everolimus, an mTOR inhibitor, which has been demonstrated to induce anti-tumour effects in different types of neuroendocrine tumours, has never been evaluated in patients with medullary thyroid cancer (MTC). The aim of this study was to evaluate the in vitro and in vivo effects of everolimus in combination with octreotide in MTC. Two patients with progressive metastatic MTC and high calcitonin levels were treated with everolimus 5-10 mg/day. Both patients were under treatment with octreotide LAR at the study entry. An in vitro study was also performed to assess everolimus effects on MTC cell lines (TT and MZ-CRC-1 cells). A tumour response was observed in both patients. Serum calcitonin decreased by 86% in patient 1 and by 42% in patient 2. In TT and MZ-CRC-1 cells, everolimus induced a significant dose-dependent inhibition in cell proliferation. This effect seems to be related to a cell cycle arrest in G(0) /G(1) phase in both cell lines and to the induction of cellular senescence in TT cells. Everolimus in combination with octreotide may be active as anti-tumour therapy in patients with progressive metastatic MTC, suggesting to further evaluate this agent in MTC patients in a large prospective study.

Clinical and prognostic implications of the genetic diagnosis of hereditary NET syndromes in asymptomatic patients.

Neuroendocrine tumors (NETs) can be sporadic or they can arise in complex hereditary syndromes. Patients with hereditary NETs can be identified before the development of tumors by performing genetic screenings. The aim of the study was to evaluate the clinical and prognostic impact of a preclinical genetic screening in subjects with hereditary NET syndromes. 46 subjects referred for hereditary NET syndrome [22 MEN1, 12 MEN2, 12 Familial Paragangliomatosis (FPGL)] were enrolled and divided in 2 groups (group A, 20 subjects with clinical appearance of NET before the genetic diagnosis; group B, 26 subjects with genetic diagnosis of hereditary NET syndromes before the clinical appearance of NETs). The main outcome measures were severity of disease, prognosis, and survival. The rate of surgery for MEN1-, MEN2-, FPGL4-related tumors was 90% in group A and 35% in group B (p<0.01). Both symptoms related to tumors and symptoms related to therapies were significantly less frequent in group B than in group A (p<0.05). Tumor stage was locally advanced or metastatic in 50% of group A and in no one of group B (p<0.01). The mortality rate was 25% in group A and 0% in group B (p<0.05). An early genetic screening for hereditary NET syndromes results in an improvement in clinical presentation and morbidity. A potential impact of the genetic screening on the mortality rate of these subjects is suggested and needs to be investigated in further and more appropriate studies.

Thyroid diseases in elderly.

Thyroid diseases are the commonest endocrine disorders in the general population. In most of the cases, they are consistent with benign conditions which may be asymptomatic or affect people at a variable extent. Since they often represent chronic conditions their prevalence increases by age and reaches in elderly the highest rates. Thyroid nodules are a common clinical finding. Most subjects with thyroid nodules have few or no symptoms. Thyroid nodules are more commonly non-functioning. However, in elderly, toxic multinodular goiter is the most frequent cause of spontaneous hyperthyroidism and often, it emerges insidiously from nontoxic multinodular goiter. Although autoimmune thyroiditis is the most common cause of hypothyroidism in elderly subjects, other causes, such as drugs, neck radiotherapy, thyroidectomy or radioiodine therapy, are frequently observed among these subjects. A small subset of medications including dopamine agonists, glucocorticoids and somatostatin analogs affect thyroid function through suppression of TSH. Other medications that may affect TSH levels are metformin, antiepileptic medications, lithium carbonate and iodine-containing medications. Other drugs can alter T4 absorption, T4 and T3 transport in serum and metabolism of T4 and T3, such as proton-pump inhibitors and antacids, estrogens, mitotane and fluorouracil, phenobarbital and rifampin. Amiodarone administration is associated with thyrotoxicosis or hypothyroidism. Thyroid cancer has similar characteristics in elderly as in general population, however the rate of aggressive forms such as the anaplastic histotype, is higher in older than younger subjects. Diagnosis of thyroid diseases includes a comprehensive medical history and physical examination and appropriate laboratory tests. A correct diagnosis of thyroid diseases in the elderly is crucial for proper treatment, which consists in the removal of medications that may alter thyroid function, in the use of levo-thyroxine in case of hypothyroidism, anti-thyroid drugs in case of hyperthyroidism and use of surgery, radioiodine therapy and percutaneous ablative procedures in selected cases. In conclusion, thyroid diseases in patients older than 60 years deserve attention from different points of view: the prevalence is different from the young adult; symptoms are more nuanced and makes difficult the diagnosis; age and comorbidity often force therapeutic choices and may limit safety and efficacy of therapy. Finally, in elderly patients for whom specific therapy is necessary, more gradual and careful therapeutic approach and close follow-up are recommended in order to minimize the alterations of thyroid function which are induced by many drugs commonly used in clinical practice.

Thyroid function in Fabry disease before and after enzyme replacement therapy.

UNLABELLED: AM: Patients with Fabry disease (FD), a genetic disorder caused by lysosomal a-galactosidase-A enzyme deficiency and characterized by a systemic accumulation of globotriaosylceramides, present high prevalence of subclinical hypothyroidism. The pathogenic mechanism is thought not to be related to anti-thyroid autoimmunity and may be dependent by intra-thyroid lipid accumulation. In this study, it was investigated whether thyroid function recovers in FD after long-term enzyme replacement therapy (ERT). METHODS: Study population included 14 FD patients (7 females, 7 males, aged 21-62 years) and 14 sex- and age-matched normal subjects. Thyroid function was evaluated in each patient at baseline and after the beginning of ERT with rh-a-galactosidase-A (1 mg/kg/BW every 2 weeks) for three years. RESULTS: TSH levels were higher in FD patients than in controls (P<0.05). In FD patients, TSH levels were higher before than after ERT (1.9±0.2 vs 1.2±0.2 mU/L, P<0.01) while fT3 and fT4 levels were normal at baseline and unchanged after ERT. At baseline, TSH levels were >3 mU/L in three patients and normalize after ERT. Anti-Tg and/or anti-TPO titres were positive in 14% of patients and 21% of controls. After ERT, the rate of autoimmunity was unchanged. At the thyroid ultrasonography, a slight hypoechoic pattern was found in 71% of patients at baseline and decreased to 43% after ERT. CONCLUSION: Primary hypothyroidism in FD patients is reverted after long-term ERT. A screening of thyroid function and periodical re-evaluation during ERT is mandatory in all FD patients.

Cinacalcet hydrochloride in combination with alendronate normalizes hypercalcemia and improves bone mineral density in patients with primary hyperparathyroidism.

Cinacalcet is effective in controlling the biochemical abnormalities in patients with primary hyperparathyroidism (PHPT) but it seems to be less effective on bone mineral density (BMD). In the same patients, bisphosphonates are reported to be effective on bone resorption but less effective on calcium and PTH excess. In this study, the efficacy of cinacalcet in combination with alendronate has been retrospectively evaluated in patients with PHPT. Twenty-three patients with PHPT who had not been operated were retrospectively investigated. Cinacalcet was evaluated in combination with alendronate in 10 of the 23 patients, and in monotherapy in 13 other patients. Serum calcium, phosphorus and PTH, 24 h urine calcium and phosphorus as well as BMD, evaluated by DXA and expressed as T-score, were measured before and after treatment. In all patients serum calcium and phosphorus and urinary calcium excretion were effectively and stably controlled and PTH was significantly decreased after treatment. There was no difference in the rate of serum calcium and PTH decrease between subjects treated with cinacalcet plus alendronate and those treated with cinacalcet alone. T-score increased by 9.6% at lumbar spine and 3.9% at femur level in the cinacalcet plus alendronate subgroup and was unchanged in the cinacalcet subgroup (P < 0.01). In patients with PHPT, the biochemical abnormalities are rapidly improved by cinacalcet regardless from the administration in monotherapy or in combination with alendronate. BMD is significantly improved in patients receiving cinacalcet plus alendronate and stable in those receiving cinacalcet in monotherapy.

A decrease of calcitonin serum concentrations less than 50 percent 30 minutes after thyroid surgery suggests incomplete C-cell tumor tissue removal.

CONTEXT AND OBJECTIVES: The prognosis of medullary thyroid carcinoma (MTC) depends on the completeness of the first surgical treatment. To date, it is not possible to predict whether the tumor has been completely removed after surgery. The aim of this study was to evaluate the reliability of an intraoperative calcitonin monitoring as a predictor of the final outcome after surgery in patients with MTC. PATIENTS AND METHODS: Twenty patients underwent total thyroidectomy and central lymph node dissection on the basis of a positive pentagastrin test. In six cases a preoperative diagnosis of MTC was achieved at the cytological examination. During the surgical intervention, calcitonin was measured at the time of anesthesia, at the time of manipulation, and 10 and 30 min after surgical excision. At the histological examination, 10 patients had MTC and 10 had C cell hyperplasia. RESULTS: As compared with calcitonin levels before thyroidectomy, a decrease of calcitonin greater than 50% 30 min after surgery was able to significantly distinguish patients who were cured from those who experienced persistence of disease. It was not possible to find a similar result when the decrease of calcitonin 10 min after surgery was considered. CONCLUSIONS: A rate of calcitonin decrease less than 50% 30 min after thyroidectomy plus central neck lymph node dissection suggests the persistence of tumor tissue in patients operated for MTC. These results indicate that intraoperative calcitonin monitoring may be a useful tool to predict the completeness of surgery in patients with MTC.

Predictive value of pentagastrin test for preoperative differential diagnosis between C-cell hyperplasia and medullary thyroid carcinoma in patients with moderately elevated basal calcitonin levels.

BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-secreting neuroendocrine tumour originating from thyroid C cells. Serum CT concentrations are helpful in the early detection of MTC, while it is still unclear whether they can be used also for the differential diagnosis between MTC and C-cell hyperplasia (CCH), a precancerous condition in familial MTCs but with unclear clinical significance in sporadic MTCs. Nowadays, surgery is recommended in all patients with basal or pentagastrin (PG)-stimulated CT value of 100 pg/ml or more, without discriminating if they are affected with MTC or CCH only. The objective of this study was to investigate the utility of the PG test for CT in distinguishing CCH from MTC before surgery. PATIENTS AND METHODS: Sixteen of 20 patients with thyroid nodules and basal CT levels between 15 and 100 ng/l had a positive PG test (>100 ng/l PG CT peak) and form the basis of the data analysis. A diagnosis of MTC was histologically proved on surgical samples in seven patients and of CCH in nine other patients. Four patients with neither FNAB nor PG test consistent with a diagnosis of MTC did not undergo thyroidectomy. RESULTS: A peak of CT of 275 ng/l after PG was able to significantly distinguish patients with MTC from patients with CCH, with 100% sensitivity and 89% specificity (P = 0.002). PG-stimulated calcitonin levels >275 ng/l had a positive predictive value (PPV) value for diagnosis of MTC of 100%, and PG-stimulated calcitonin levels <275 had a PPV for the diagnosis of CCH of 89%. CONCLUSIONS: A CT cut-off after PG of 275 ng/l is suggested to be highly predictive in distinguishing CCH from MTC before surgery, and this may be helpful in selecting patients for thyroid surgery.

[Widespread endemic goiter and iodine deficiency in the province of Avellino]. / Diffusione del gozzo endemico e della carenza iodica in provincia di Avellino.

1352 schoolchildren between 6-14 years old (699 males and 653 females) and 943 adults (176 males and 767 females) from eight villages of the province of Avellino were studied. All subjects were examined for thyroid size by at least two expert examiners. In most of them urine samples were collected for iodine determinations. 387 schoolchildren and 161 adults from Flumeri and Villanova were evaluated by thyroid echography. The prevalence of goiter was from 23.5 to 52.2% and the median urinary iodine excretion was from 42.3 to 66.2 micrograms/l in schoolchildren. In adults the prevalence of goiter was from 41.2 to 86.7% and the median urinary iodine excretion was from 37.1 to 53.7 micrograms/l. Our data showed a degree of iodine deficiency from low to moderate. The echography permitted to point out a greater prevalence of nodules than the thyroid palpation.