Evaluating adherence, tolerability and safety of oral calcium citrate in elderly osteopenic subjects: a real-life non-interventional, prospective, multicenter study.

BACKGROUND: Osteoporosis is a common concern in the elderly that leads to fragile bones. Calcium supplementation plays a crucial role in improving bone health, reducing fracture risk, and supporting overall skeletal strength in this vulnerable population. However, there is conflicting evidence on the safety of calcium supplements in elderly individuals. AIM: The aim of this study was to evaluate the adherence, safety and tolerability of calcium citrate supplementation in elderly osteopenic subjects. METHODS: In this non-interventional, prospective, multicenter study, subjects received daily 500 mg calcium citrate supplementation for up to one year. Adherence was calculated based on compliance and persistence. Safety was assessed through adverse reactions (ARs), deaths, and clinical laboratory evaluations. RESULTS: A total of 268 Caucasian subjects (91.4% female, mean age 70 ± 4.5 years) participated in the study. Mean adherence to treatment was 76.6 ± 29.5% and half of subjects had an adherence of 91% and ~ 33% of participants achieved complete (100%) adherence. ARs were reported by nine (3.9%) subjects, primarily gastrointestinal disorders, with no serious ARs. The frequency of all adverse events (including ARs) was significantly higher in subjects with adherence of < 80% (41.6%; 32/77) vs. those with adherence ≥ 80% (11%; 16/145, p < 0.0001). Both systolic and diastolic blood pressure decreased from baseline to follow-up visit (change of -2.8 ± 13.9 mmHg, p = 0.0102 and -2.1 ± 10.4 mmHg, p = 0.0116, respectively). CONCLUSION: This study demonstrated favorable adherence to calcium citrate supplementation in elderly osteopenic subjects. The occurrence of ARs, though generally mild, were associated with lower adherence to calcium supplementation.

Neoadjuvant treatment with lenvatinib and pembrolizumab in a BRAF V600E-mutated anaplastic thyroid cancer: a case report.

Background: Tyrosine kinase inhibitors (TKIs) and immunotherapy have been proposed for advanced metastatic anaplastic thyroid cancer (ATC). We report a case of BRAF V600E-mutated ATC in which lenvatinib (L) plus pembrolizumab (P) enabled neoadjuvant treatment. Case presentation: A male patient aged 65 years presented with a rapidly enlarging left latero-cervical mass. Fine needle aspiration was suggestive of ATC. Surgical consultation excluded radical surgery. While awaiting molecular profile analysis and considering the fast evolution of the disease, treatment with L and P was started. L was started at a dose of 14 mg daily, while P was started at the standard regimen (200 mg every 3 weeks). After 1 month, computerized tomography showed a reduction in the mass with almost complete colliquative degeneration, and the carotid artery wall was free from infiltration. Radical surgery was performed. Histology confirmed papillary thyroid cancer (PTC) in the left lobe and ATC with extensive necrosis in the left latero-cervical lymph node metastasis. The margins were free of tumors (R0). A BRAF V600E mutation was present in both PTC and ATC. At the 1-year follow-up, the patient was free of disease. Conclusion: L and P in combination also appeared to be effective as a neoadjuvant treatment for BRAF V600E-mutated ATC. This combination treatment could be used when there is an opportunity for complete resection of the cancer, and as soon as possible. The intermediate dose of 14 mg of L appeared to be well tolerated and effective.

False-positive radioiodine uptake after radioiodine treatment in differentiated thyroid cancer.

BACKGROUND AND PURPOSE: False-positive radioiodine uptake can sometimes be observed with post-radioiodine treatment (RIT) whole body scanning. Radioiodine pitfall has often been reported as being caused by benign or inflammatory disease, or, in some cases, by tumor lesions. This paper reviews the possible causes of such false-positive imaging, and suggests possible reasons for suspecting these pitfalls. METHODS AND RESULTS: Online databases, including MEDLINE (via PubMed), Embase, ISI Web of Science, Google Scholar, and Scopus, were systematically examined, using different keyword combinations: "radioiodine false-positive imaging", "131 I false-positive imaging" and " RAI false-positive imaging". An illustrative case was described. Excluding cases in which SPECT/CT was not performed, a total of 18 papers was found: 17 case reports and one series regarding false-positive iodine-131 uptake after RIT. CONCLUSIONS: The prevalence of radioiodine pitfall was significantly reduced through the use of SPECT/CT imaging, though its possible presence has always to be taken into account. Inflammation, passive iodine accumulation, other tumors, and, sometimes, unknown causes can all potentially generate false-positive imaging. Missing detection of false-positive imaging could result in over-staging and inappropriate RIT or it could lead to the non-detection of other cancers. We examine the reasons for these possible pitfalls.

Recombinant human TSH and ablation of post-surgical thyroid remnants in differentiated thyroid cancer: the effect of pre-treatment with furosemide and furosemide plus lithium.

BACKGROUND AND AIM: Recombinant human TSH (rhTSH) can be used for post-surgical radioiodine (I-131) thyroid remnants ablation in differentiated thyroid cancer (DTC) patients after surgery. Debate exists in literature about the optimal amount of I-131 that should be given for obtaining an effective ablation and about the role of iodine pool during treatment. Therefore, the aim of the present study was to assess whether I-131 ablation during rhTSH stimulus can be improved by reducing the circulating iodine pool and by increasing thyroid cell uptake and retention of I-131 obtained by administering furosemide and lithium. METHODS: A total of 201 consecutive DTC patients were entered in the study: they were treated by total thyroidectomy and I-131 therapy during rhTSH stimulus to ablate thyroid remnants. Patients were divided into two groups according to the TNM stage: group 1 included patients in stage I-II who were treated with a low 30-mCi I-131 dose, while group 2 included patients in stage III-IV who were treated by a high 100-mCi I-131 dose. Moreover, both groups were further subdivided into three subgroups. Subgroup (a) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day withdrawal of L-thyroxine (LT4). Subgroup (b) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day withdrawal of L-T4, and after furosemide administration (25 mg/day orally) during the 3 days before I-131. Subgroup (c) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day L-T4 withdrawal, and after administration of furosemide (25 mg/day orally) during the 3 days prior I-131 and lithium (450 mg/day orally) during the 3 days following I-131. Another group (group 3) of 20 patients characterized by a very low-risk cancer (unifocal tumor <1.0 cm in diameter, without extra-capsular extension, N0) was treated with a 30-mCi I-131 dose under rhTSH stimulus without performing the short 4-day L-4 withdrawal: this group was taken as the control. Follow-up was performed by neck ultrasonography (US), and Tg measurement and I-131 WBS under rhTSH stimulus. RESULTS: Among the patients from group 1, those pre-treated with furosemide or with furosemide plus lithium showed a better outcome of ablation both in terms of undetectable Tg values (97.7% and 95.5 % vs. 79.5%, p < 0.05) and of WBS negativity (97.7% vs. 81.8%, p < 0.05) during the rhTSH stimulus. No similar findings were observed in group 2 patients. Moreover, in patients from group 3 (I-131 30 mCi, without L-T4 withdrawal), the outcome of ablation was significantly lower in comparison to patients from group 1 (I-131 30 mCi, with L-T4 withdrawal) in terms of undetectable Tg during the rhTSH stimulus (55.0%, p < 0.001). CONCLUSION: rhTSH is highly effective for post-surgical thyroid remnant ablation in low-risk cancer patients using the low 30-mCi dose protocol combined with the short 4-day withdrawal of L-T4. Moreover, in these patients the pre-treatment with furosemide seems to play an important role to further improve the outcome of ablation by reducing the iodine pool.

Low-intermediate dose of lenvatinib in anaplastic thyroid cancer is highly effective and safe.

We report two cases of anaplastic thyroid cancer (ATC) which had a very good response to a treatment with lenvatinib at 14 mg. A 73-year-old man with ATC stage IVB was operated on, undergoing a near-total thyroidectomy, and the pathological remnant tissue showed a quick and partial response to treatment with the drug. The patient had a single metastasis in the brain after 9 months, but then died due to bronchopneumonia after undergoing a neurosurgical intervention for the complete removal of the lesion. A 74-year-old woman with ATC stage IV was operated on, undergoing a near-total thyroidectomy after a neoadjuvant treatment with the drug, that was continued after surgical treatment. She had a partial remission of the local disease and of distant metastasis, which lasted for 14 months. She then died 4 months later due to cancer progression. Lenvatinib at 14 mg appears to be effective, fast and well tolerated.

Thyroid disease prevalence in carabineers deployed in a war theater.

The problem of morbidity in deployed military personnel represents a much-debated topic. Because there have been two cases of thyroid cancer in the Tuscania regiment, the aim of the present study was to investigate the prevalence of all types of thyroid disease in a cohort of carabineers. A total of 673 carabineers, including 501 deployed carbineers (DCs) (29-48 years of age) and 172 nondeployed carabineers (NDCs) (29-51 years of age), of the Tuscania regiment were involved in the study. Thyroid volume, percentages of single nodules and multinodular goiter, percentage of autoimmune thyroid disease, and percentages and histological types of thyroid cancer were all measured. No statistical difference between DCs and NDCs was found for any of the data. Furthermore, when we divided DCs into subgroups according to time spent on deployment and time elapsed since the first deployment, we found no differences. However, a high prevalence of thyroid cancer was found in our cohort (2.0% in DCs and 2.5% in NDCs; not significant), and the prevalence of thyroid cancer in nodules in the cohort of carabineers was higher (10.0%) than the prevalence of thyroid cancer in nodules in the civilian population (5.6%, p < 0.001). No differences regarding the prevalence of thyroid diseases were observed when we compared DCs and NDCs, which suggests that no significant difference in exposure to toxic or carcinogenic substances that could have affected the thyroid occurred during deployments. The high prevalence of thyroid cancer in carabineers may merely reflect an increase of this cancer in the general population, or it may suggest the presence of some carcinogenic event in this specific cohort.

Recombinant human thyroid-stimulating hormone is effective for radioiodine ablation of post-surgical thyroid remnants.

OBJECTIVE: To investigate whether recombinant human thyroid-stimulating factor (rhTSH) is effective for the radiometabolic ablation of post-surgery thyroid remnants, using low doses of (131)I. PATIENTS AND METHODS: The study included two groups of patients enrolled consecutively: group 1 consisted of 52 patients with papillary cancer or minimally invasive follicular cancer (stage I and II), and group 2 consisted of 41 patients with the same stage of disease. All patients underwent a total thyroidectomy. Group 1 received 1.11 GBq (30 mCi) (131)I for post-surgical remnants ablation with the aid of rhTSH, while group 2, in the hypothyroid state, received the same amount of radioiodine. To minimize iodine interference, all patients remained on a low iodine diet for 2 weeks and L-thyroxine (L-T4) was stopped for 4 days in the group of patients treated with the aid of rhTSH. To investigate (131)I uptake in this group, a tracer dose was administered 3 h after the second injection of rhTSH and the uptake was evaluated at 24 h just before administration of the therapeutic dose. I was also measured in the patients treated in the hypothyroid state just before the therapeutic dose was given. RESULTS: After 1 year both groups were studied by using whole-body scintigraphy (WBS) and measuring thyroglobulin after rhTSH. In group 1, WBS was negative in 76.9% (40 patients), while thyroglobulin-stimulated levels were <1.0 ng . ml(-1) in 86.5% (45 patients). In Group 2, WBS was negative in 75.6% (31 patients), while thyroglobulin-stimulated levels were <1 ng . ml(-1) in 78.0% (32 patients). (131)I uptake was 2.29+/-0.45 in the group treated with the aid of rhTSH, and 3.30+/-0.7 in the group treated in the hypothyroid state (P=0.2). No patients treated with the aid of rhTSH and with the short stoppage of L-T4 experienced symptoms of hypothyroidism, and free thyroxine (FT4) and thyroid-stimulating hormone levels remained normal. CONCLUSIONS: Our data confirm that, when the interference of iodine is minimized, rhTSH is highly effective for the treatment of post-surgical thyroid remnants using a low dose of (131)I.

Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation.

The main steps in the management of differentiated thyroid cancer are thyroidectomy, treatment with iodine-131 ((131)I), and follow-up with whole-body scanning (WBS) and serum thyroglobulin (Tg) determination. Both (131)I treatment and follow-up require maximum stimulation of normal or pathological thyroid remnants by TSH. The use of recombinant human TSH (rhTSH) has been shown to be useful for follow-up, whereas previous reports are not univocal regarding the use of (131)I postsurgical ablation of thyroid remnants, at least when low doses (30 mCi) of (131)I are administered. A possible explanation for the diminished effectiveness of (131)I treatment after rhTSH may be the interference of iodine content of L-thyroxine (L-T4) therapy during the protocol of administration of rhTSH. We have evaluated the effectiveness of stimulation by rhTSH for radioiodine ablation of postsurgical remnants, stopping L-T4 the day before the first injection of rhTSH and restarting L-T4 the day after (131)I. The study included two groups of patients: group 1 included 16 patients with differentiated thyroid cancer (15 papillary cancers and 1 follicular cancer, stages I and II), who were treated with 30 mCi (131)I with the aid of rhTSH, using the standard protocol but stopping L-T4 as stated previously; and group 2 included 24 patients with the same features (histology and stage) of disease treated with 30 mCi in the hypothyroid state after L-T4 withdrawal. In both groups, serum TSH reached a very good stimulation level [76-210 U/liter (mean, 112 +/- 11 SE) and 38-82 U/liter (mean, 51 +/- 3 SE), respectively]. At the first WBS (after (131)I treatment), all patients showed thyroid remnants. Furthermore, two patients of the first group and three patients of the second group showed lymph node metastases. After 1 yr, all patients were studied again and underwent WBS with a tracer dose of (131)I and serum Tg measurement using rhTSH with the same protocol in both groups. The percentage of ablation (undetectable Tg and a negative WBS) was higher, although not reaching statistical significance, in patients treated with rhTSH: 81.2% in patients treated by rhTSH withdrawal and 75.0% in patients treated by L-T4 withdrawal, respectively. No patient experienced symptoms of hypothyroidism during the 4 d of L-T4 interruption, and serum T4 remained in the normal range. Urinary iodine was analyzed in both groups and compared with a control group of patients who received, for diagnostic purposes, rhTSH without stopping L-T4. In the first group, urinary iodine was 47.2 +/- 4.0 microg/liter (mean +/- SE; P = 0.21 vs. the second group, P = 0.019 vs. control group). In the second group, urinary iodine was 38.6 +/- 4.0 microg/liter (mean +/- SE; P < 0.001 vs. control group); urinary iodine in the control group was 76.4 +/- 9.3 microg/liter (mean +/- SE). Our data show that rhTSH, as administered in the protocol stated previously, allows at least the same rate of ablation of thyroid remnants when low doses (30 mCi) of (131)I are used. The possible role of interference of iodine content in L-T4 is not surprising if we consider that the amount of iodine in 30 mCi is negligible (5 microg) compared with the amount of iodine content in a daily dose of T(4) ( approximately 50 microg). The cost of rhTSH seems modest compared with the high cost of complex therapeutic regimens in other areas of oncology and in consideration of the well-being of patients and of the high level of effectiveness of the treatment.

Genetic analysis of TTF-2 gene in children with congenital hypothyroidism and cleft palate, congenital hypothyroidism, or isolated cleft palate.

Homozygous null mice for thyroid transcription factor (TTF)-2 gene exhibit cleft palate and thyroid malformation. We performed a genetic analysis of the TTF-2 gene in 2 children with congenital hypothyroidism (CH) and cleft palate, 45 children with thyroid dysgenesis, 19 children with isolated cleft palate or cleft lip, 4 patients with thyroid hemiagenesis. The entire coding-region of the TTF-2 gene was analyzed by direct sequencing. Direct sequencing of the TTF-2 gene revealed polymorphisms in the length of the polyalanine tract. The most frequent stretch length was 14 residues and it was found in 50 of 70 (71%) and in 45 of 53 (85%) normal healthy controls. A polyalanine tract of 16 residues in the heterozygous state was seen in 18 of 70 (26%) cases and in 4 of 53 (7%) normal subjects. In 1 of 4 (25%) case of hemiagenesis a polyalanine tract of 16 residues in the homozygous state was observed. In 1 of 26 agenesis the polyalanine tract consisted of 12 residues in the heterozygous state. Direct sequencing also revealed the presence of two silent polymorphisms. No mutations were identified in the TTF-2 gene. In conclusion, our results show that no genetic alteration was present in the TTF-2 gene of these patients, suggesting that defects in the TTF-2 gene are a rare event.

Assay of free thyroxine and free triiodothyronine in fine-needle aspiration of thyroid nodules: a useful and low-cost assessment.

OBJECTIVE: To evaluate whether analysis of thyroid hormones in fine-needle aspiration (FNA) of thyroid nodules can provide information about the functional status and the nature of the nodules. METHODS: We studied 4 groups of patients: group 1, 17 patients with autonomous hyperfunctioning thyroid nodules; group 2, 52 patients with cold nonfunctioning thyroid nodules; group 3, 12 patients with malignant thyroid nodules; and group 4 (control group), 10 patients with nonthyroid nodular lesions (enlarged parathyroid glands or lymph nodes). The assay of thyroid hormones was performed in FNA after the washing of needles and, with patient consent, also in normal thyroid parenchyma. RESULTS: The free thyroxine (FT(4)) and free triiodothyronine (FT(3)) values were remarkably high in group 1 (mean, 5.5 +/- 0.53 ng/dL and 27.6 +/- 3.1 pg/mL, respectively; P<0.05 versus group 2 and group 4, the control group). The levels of FT(4) and FT(3) were very low in group 3 (<0.2 ng/dL and <1.0 pg/mL, respectively; P<0.05 versus group 2). Thyroglobulin values in FNA specimens were much higher than the normal range in human serum, but no significant differences were found between the various groups. The control group had low levels of FT(4) and FT(3) (<0.2 ng/dL and <1.0 pg/mL, respectively) in conjunction with low levels of thyroglobulin, whereas parathyroid hormone levels were high in parathyroid nodules. CONCLUSION: These results show that assay of FT(4) and FT(3) in FNA can yield information about the functional status of thyroid nodules and, indirectly, about the nature of nodules. In this era of sophisticated new molecular markers in FNA cytology, this low-cost diagnostic method can be readily performed in every laboratory.

The BRAF V600E mutation in papillary thyroid cancer with positive or suspected pre-surgical cytological finding is not associated with advanced stages or worse prognosis.

The mutation BRAF V600E is thought to be a putative prognostic marker of the aggressiveness of several cancers among which is also papillary thyroid cancer. Our study aimed to evaluate whether this mutation is associated with advanced stages of disease or with a worse prognosis in a series of patients with cytological findings of Thyr 4 and Thyr 5 and who were undergoing total thyroidectomy and routine central compartment lymph-node dissection. 110 patients were consecutively enrolled over an 18-month period from September 2010 to March 2012. All patients had cytological findings that were either indicative of, or positive for papillary thyroid cancer, Thyr 4 or Thyr 5. Detection of BRAF mutation was made on fine-needle aspiration specimen by pyrosequencing after microdissection and DNA extraction of neoplastic cells. After surgical intervention, the patients underwent radioiodine ablation according to our protocol, and follow-up was performed after 8 months. The BRAF V600E mutation was found in 79 % of our cases: 85.7 % of these cases represented the classical variant, 57.8 % the follicular variant, 89.6 % the tall cell variant, and 33.3 % the solid variant. All patients had confirmation of papillary thyroid cancer after histology, with no differences being seen in pTNM presentation between patients with BRAF wild-type and patients with BRAF V600E mutation. Ninety-nine patients underwent radioiodine ablation. Results at follow-up 8 months after radioiodine ablation showed no differences in the rate of ablation between patients harboring BRAF V600E mutation and those having BRAF wild-type. The BRAF V600E mutation doesn't appear to be a reliable risk factor for the aggressiveness of a tumor. BRAF analysis should neither be the only guide for pre-surgical decisions regarding the extent of surgery nor for post-surgical decisions regarding the aggressiveness of the treatment.

Percutaneous laser ablation in the treatment of toxic and pretoxic nodular goiter.

OBJECTIVE: To report data regarding treatment with use of percutaneous laser ablation (PLA) in autonomously functioning thyroid nodules (AFTN). METHODS: We treated 18 patients (10 women and 8 men, 31 to 80 years old) who presented with a single hyperfunctioning thyroid nodule (8 patients) or a multi-nodular goiter (10 patients) with clearly hyperfunctioning areas on a thyroid scintiscan. In 5 cases, free thyroxine (FT4) and free triiodothyronine (FT3) levels were high, and in these patients and a further 9 patients with cardiovascular symptoms, methimazole therapy was initiated to restore euthyroidism. The total number of PLA sessions ranged from 1 to 5 (median, 3). Thyroid-stimulating hormone, FT4, FT3, thyroglobulin, and antithyroglobulin and anti-thyroid peroxidase antibodies were measured by a commercial kit the day after PLA treatment, then weekly during the first month, and monthly thereafter. The Student t test was used for statistical analyses, and data are reported as mean values +/- SE. RESULTS: After each PLA session, there was a transient and mild increase in FT4 and FT3-5.2% to 18.1% (mean, 11.1 +/- 0.69%) (P<0.001) in patients not treated with methimazole and 4.0% to 8.3% (mean, 5.9 +/- 0.31%) (P<0.001) in patients treated with methimazole-relative to values before treatment; however, these values never reached the range of hyperthyroidism. In addition, thyroglobulin showed a remarkable increase after 24 hours- 115% to 390% (mean, 266.0 +/- 12.7%) (P<0.001). Thyroid-stimulating hormone increased in all cases and reached normal values in all patients with single AFTN and in 5 patients (50%) with multinodular goiter within 3 months after PLA. At 1-year follow-up, the decrease in nodular volume was 24% to 72% (mean, 59.3 +/- 8.2%; P<0.001). CONCLUSION: Our data show that PLA can be a useful treatment in AFTN and particularly in single toxic nodules. Possible elective indications are patients who refuse surgical or radioiodine treatment and patients with cardiovascular comorbidity who need rapid restoration of the euthyroid state and who cannot tolerate the discontinuation of antithyroid drugs for radioiodine treatment.