Effects of lenvatinib on glucose, cholesterol, triglycerides and estimated cardiovascular risk in patients with advanced thyroid cancer.

PURPOSE: Multitarget kinase inhibitors (MKIs) are effective options in the treatment of cancer, significantly increasing the progression-free survival (PFS) of many tumors. Data about severity and prevalence of metabolic adverse events is scarce and may be significant in patients with a better survival. The aim of this study was to investigate glucose and lipids values of patients treated with lenvatinib. Secondary aims included evaluating changes in the estimated risk of cardiovascular disease and the relationship between metabolic alterations and tumor response to therapy. METHODS: A retrospective pilot study on 29 patients with advanced differentiated thyroid cancer was conducted. Clinical and biochemical characteristics were collected at the day of therapy initiation and follow up. The 10-year risk of cardiovascular disease was estimated with the SCORE2 and SCORE2-OP algorithms. Tumor burden change was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: No differences in glucose values were observed. A significant increase in total cholesterol (208 ± 41 versus 245 ± 67 mg/dl), triglycerides (112 [interquartile range, 58-326] versus 157 [78-296] mg/dl), calculated LDL cholesterol (128 [66-204] versus 140 [81-308] mg/dl) and cardiovascular risk was observed from baseline to follow up. Furthermore, these parameters increase progressively with increasing tumor response to therapy. CONCLUSIONS: Despite limitations, this study shows an association between the use of lenvatinib and the development of lipid alterations in patients with advanced thyroid cancer. However, further investigation is necessary for a more comprehensive understanding of the adverse metabolic profile of MKIs.

Ultrasound screening for thyroid nodules and cancer in individuals with family history of thyroid cancer: a micro-costing approach.

PURPOSE: Screening programs that target healthy populations are an important tool for identifying unrecognized, asymptomatic disease. However, ultrasound screening for thyroid cancer has no obvious advantage in terms of cost-effectiveness in asymptomatic adults. There is far less consensus (and data) on the indications for screening in high-risk individuals. The aim of the study was to estimate the costs of ultrasound screening for individuals with first-degree family history of thyroid cancer. METHODS: We conducted a prospective cross-sectional study from January 1, 2009 through December 31, 2018 in the Thyroid Cancer Outpatient Clinic of a large teaching hospital in Rome, Italy. We estimated the costs of an ultrasound screening protocol using the micro-costing bottom-up method. RESULTS: For individuals without thyroid nodules, the screening examination had an estimated cost of €66.21 per screenee. For those found to have unsuspicious nodules, the estimated cost rose to €119.52 per screenee, owing to the addition of thyroid function tests. The estimated cost of screening for a subject with newly diagnosed nodules that were submitted to cytology was €259.89. The total cost of screening for the entire population of 1176 individuals was € 118,133.85. The total expenditure to confirm a single thyroid cancer diagnosis was €10,598.71. CONCLUSION: A sonographic screening implies a significant direct expenditure and is likely to detect a very large number of individuals with benign nodules (more than 45 asymptomatic individuals are diagnosed with a thyroid nodule for each newly detected cancer case), whose long-term follow-up will further increase healthcare costs.

The role of miR-139-5p in radioiodine-resistant thyroid cancer.

PURPOSE: Radioiodine I-131 (RAI) is the therapy of choice for differentiated thyroid cancer (DTC). Between 5% and 15% of DTC patients become RAI refractory, due to the loss of expression/function of iodide metabolism components, especially the Na/I symporter (NIS). We searched for a miRNA profile associated with RAI-refractory DTC to identify novel biomarkers that could be potential targets for redifferentiation therapy. METHODS: We analyzed the expression of 754 miRNAs in 26 DTC tissues: 12 responsive (R) and 14 non-responsive (NR) to RAI therapy. We identified 15 dysregulated miRNAs: 14 were upregulated, while only one (miR-139-5p) was downregulated in NR vs. R tumors. We investigated the role of miR-139-5p in iodine uptake metabolism. We overexpressed miR-139-5p in two primary and five immortalized thyroid cancer cell lines, and we analyzed the transcript and protein levels of NIS and its activation through iodine uptake assay and subcellular protein localization. RESULTS: The finding of higher intracellular iodine levels and increased cell membrane protein localization in miR-139-5p overexpressing cells supports the role of this miRNA in the regulation of NIS function. CONCLUSIONS: Our study provides evidence of miR-139-5p involvement in iodine uptake metabolism and suggests its possible role as a therapeutic target in restoring iodine uptake in RAI-refractory DTC.

Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy.

BACKGROUND: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy. METHODS: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data. RESULTS: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively. CONCLUSION: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status.

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.

Thyroid nodule recurrence following lobo-isthmectomy: incidence, patient's characteristics, and risk factors.

PURPOSE: This study was aimed at assessing the incidence and timing of thyroid nodules recurrence, defined as appearance of new benign or malignant nodules in contralateral lobe in patients with benign thyroid nodules or thyroid microcarcinoma treated with lobo-isthmectomy. Patient's characteristics and risk factors associated with this phenomenon were also investigated. METHODS: A retrospective study was performed by evaluating 413 patients undergoing lobo-isthmectomy with a minimum follow-up of 1 year. Clinical characteristics, surgical interventions and complications, histological diagnosis, and thyroid function at last follow-up were collected. RESULTS: Single or multiple thyroid nodule recurrence equally occurred in 80 patients (23%) with a median time to relapse of ~ 5 years (range 0.3-34.5 years) after lobo-isthmectomy. Recurrence was significantly associated with younger age (< 46 years) and number of pregnancies in women. Development of hypothyroidism was not rare either (~ 10%) and appeared in 3-19 months; a preoperative TSH level > 2.43 mIU/L was associated with the need of l-thyroxin replacement therapy after surgery. The most frequent surgical complication was transient hypoparathyroidism (4.6%), while the rate of permanent hypoparathyroidism significantly increased in patients submitted to completion thyroidectomy (5.3%). CONCLUSIONS: Thyroid nodules recurrence following lobo-isthmectomy is not a rare event and occurs within 5 years after surgery, more frequently in younger patients with family history of nodular goiter and in women with multiple pregnancies. Pre-surgical TSH levels may predict the development of post-surgical hypothyroidism, possibly improving the management of patients addressed to surgery.

Influence of thyrotropin and thyroid volume on basal serum calcitonin.

Thyroid volume was found to be a determinant of serum calcitonin levels in animal models and in thyroid-healthy subjects, as recently reported. This study aims to evaluate if this finding is confirmed in patients undergoing ultrasonography-guided fine-needle aspiration cytology of suspicious thyroid nodules. A dataset of 561 patients including basal serum FT4, FT3, TSH, calcitonin, thyroid volume, anti-thyroperoxidase antibodies (TPOAb), and cytology report, was retrospectively analysed. The median thyroid volume was 20.5 ml (14.5-26.8) in males and 12.0 ml (9.3-17.0) in females (p<0.001). The overall median serum calcitonin value was 2.00 pg/ml (2.00-3.10). A Spearman's correlation was performed between serum calcitonin levels and thyroid volume, showing a weak direct relationship (rs=0.173, p<0.001). This relationship is confirmed both in the smokers group (rs=0.337, p=0.003) and in non-smokers group (rs=0.115, p=0.012), and both in the TPOAb-positive patients (rs=0.419, p<0.001) and negative ones (rs=0.107, p=0.025). There is no correlation between serum TSH and calcitonin levels. In patients grouped according to morphologic diagnosis, calcitonin levels are slightly higher in the high-volume groups: the interquartile range was 2.00-2.00 pg/ml in the atrophy, 2.00-2.82 pg/ml in the normal volume, and 2.00-3.85 pg/ml in the goiter group (p=0.02). When males and females are computed separately, the statistical significance is lost. In conclusion, thyroid volume can mildly influence calcitonin levels. Gender acts as a "surrogate marker" of thyroid volume and the application of a gender-specific cut-off can probably overcome this issue in clinical practice.

Total thyroidectomy for Graves' disease treatment.

OBJECTIVES: Graves' disease (GD) is the most common cause of hyperthyroidism, and accounts worldwide for 60-80% of all cases. The diagnosis is based on clinical findings, and is confirmed by the presence of TRAB, suppression of TSH, and elevation of free thyroxin (free T4), and triiodinethyronin (free T3). GD can be treated by antithyroid drugs, radioactive iodine, or surgery. The aim of this study was to review retrospectively the surgical management, in terms of safety and efficacy, in 50 patients operated in the Department of Surgical Sciences since 2005 through 2010 and followed up at the Endocrinology Unit A of the Experimental Medicine Department. We assessed postoperative complications, which included the presence, persistence and development of ophthalmopathy, transient hypocalcemia, permanent hypoparathyroidism and recurrent laryngeal nerve palsy. MATERIALS AND METHODS: We analyzed data from 50 patients with GD who were eligible and underwent Total Thyroidectomy (TT). Thirty-nine patients underwent TT for recurrent hyperthyroidism after medical therapy and eleven patients for severe ophtalmopathy. The mean follow up was 41 months (range: 10-70). RESULTS: Eleven patients had ophtalmopathy before surgery. Four patients developed an ophtalmopathy after surgery. Eleven patients presented hypocalcemia, transient in ten patients and permanent in one patient. Five patients developed a transient disphony. Conclusions. Total thyroidectomy is a safe and radical procedure in Graves' disease treatment. Complications of TT are not different than subtotal thyroidectomy if it's performed by expert surgeons.

Thyroid diseases in women with breast cancer.

AIM: Several studies have been undertaken to investigate a possible link between breast cancer and thyroid diseases, notably thyroid carcinoma and autoimmune thyroid diseases, but the issue remains unresolved. The aim of this study is to evaluate, in thyropathic women with and without breast cancer, the following effects: the distribution of different thyroid diseases, the breast-cancer-related prevalence of anti-thyroperoxidase and anti-thyroglobulin antibodies and the role in thyroid pathology of breast-cancer post-surgery therapy with tamoxifene. MATERIALS AND METHODS: One-hundred-ninety thyropathic women with breast cancer (BC group) were recruited, and compared with a control group (C group) of one-hundred-ninety thyropathic women without breast cancer. RESULTS: Nodular disease is the most frequent pathology in both groups. The difference in the incidence of thyroid carcinoma is also not statistically significant. The biochemical increase in the positivity of autoantibodies in BC-group patients is confirmed, but there is no statistically significant difference in the rate of clinical autoimmune diseases between the two groups. No difference in the frequency of any particular thyroid disease is found between those patients who underwent post-operative tamoxifene therapy and those who did not. CONCLUSION: It can be concluded, on the basis of these results, that it is advisable to reduce the clinical weight of the issue. A routine thyroid screening is recommended in women with BC for the management of chronic comorbidities, as would be for women in the general population having the same age and coming from the same iodine-intake area.

Knowledge of iodoprophylaxis and iodized salt consumption among medical students in Italy.

OBJECTIVES: Iodine deficiency is still a notable health-care problem in several regions of Europe and can be responsible for maternal and fetal goiter, miscarriages, stillbirths, reduced fetal growth, congenital hypothyroidisms, damaged reproduction in adult life, and inadequate development and maturation of the fetal brain, which is the major preventable cause of mental defects. The aim of this study was to assess the medical students' knowledge and practices regarding the program of iodized-salt-use and active iodine prophylaxis program launched by the Italian Ministry of Health. MATERIALS AND METHODS: A self-administered, anonymous, 19 single-item questionnaire was developed. We have collected 294 filled forms: 86 from first-year, 118 from fourth-year and 90 from sixth-year medical students at the First Medical School of 'Sapienza' University of Rome, Italy, in May 2009. RESULTS: Two hundred eighty four students (96.6%) affirm that they know of the existence iodized salt, even though only 199 (67.7%) report personal consumption. This level is quite far from the target (consumption by almost 80% of the general population) suggested by the international literature. No statistically relevant difference was observed between the answers of male and female students. CONCLUSIONS: Our study proves that clinical students have a more detailed knowledge on iodized salt if compared with pre-clinical students, but such knowledge remains overall defective and in some cases absolutely incorrect. Additional education is probably needed to prepare physicians to play a critical role in counseling about iodine prophylaxis.

Medical treatment of hyperthyroidism: state of the art.

Methimazole (MMI) and propylthiouracil (PTU) are the main antithyroid drugs used for hyperthyroidism. They inhibit the synthesis of thyroid hormone at various levels and are used as the primary treatment for hyperthyroidism or as a preparation before radioiodine therapy or thyroidectomy. MMI is the drug of choice because of its widespread availability, longer half-life and small number of severe side effects. Drugs of second choice are potassium perchlorate, beta blockers, iodine, lithium carbonate and glucocorticoids. Rituximab, a monoclonal antibody directed against human CD20, was recently proposed as a biological therapy for cases of Graves' disease unresponsive to traditional drugs.

Diagnostic accuracy of rhTSH test with neck ultrasonography in differentiated thyroid cancer follow-up.

Serum thyroglobulin levels measurement after injection of recombinant human thyrotropin (rh-TSH) represents the most important advance in the follow-up of patients with differentiated thyroid cancer, obtaining TSH elevation without L-thyroxine withdrawal, avoiding marked hypothyroidism symptoms. During a 4-yr period (2004-2008), 66 consecutive patients with DTC (59 papillary and 7 follicular carcinomas) were examined after rh-TSH Tg test and neck ultrasonography. In all patients basal Tg was <0.25 ng/ml. In twelve (18.5%) examined patients rh-TSH Tg was >0.25 ng/ml, and in seven (58.3%) of these was demonstrated persistent or recurrent disease. These data indicate that rhTSH-Tg>0.25 ng/ml should be considered diagnostic for persistent or recurrent disease and suggests further exams (neck ultrasonography, whole body scan or cytology) to localize the disease. Furthermore, neck ultrasonography has demonstrated high accuracy in detecting lymph nodal metastases and should be always combined with rh-TSH test.

Pulmonary blastoma: report of two cases.

Pulmonary blastomas are a group of rare malignant neoplasms subdivided into three categories: classic biphasic pulmonary blastoma (CBPB), well-differentiated fetal adenocarcinoma (WDFA), and pleuropulmonary blastoma (PPB). We report herein the cases of two men with CBPB. Both were heavy smokers and presented with a history of hemoptysis. Physical examination revealed slightly significant findings, chest radiographs showed a large pulmonary mass, confirmed by computed tomography, and bronchoscopic biopsies were not diagnostic. A left and right inferior lobectomy was performed and a diagnosis of CPBP was confirmed by histological examination. In the first patient, local recurrence with multiple bilateral lung metastases was found 6 months later and despite chemotherapy, he died of respiratory failure 1 year after his operation. In the second patient, a subcutaneous metastasis was found in the right subscapular region 2 months later, and a cerebral metastasis in the right posterior parietal lobe 4 months later. Partial remission was achieved by cerebral irradiation, but 6 months later the patient died of cardiac failure while in a coma. We conclude that more aggressive and multidisciplinary treatment should be adopted for CBPB, and because of its low incidence, it is important to unify individual experiences in a central registry to gather as much information as possible regarding the biological and clinical features of this unusual disease.

A pitfall with the use of 111In-pentetreotide scintigraphy in the resected bronchopulmonary carcinoids follow-up: a case report.

AIM: To re-evaluate the use of 111In-pentetreotide scintigraphy (Octreoscan) in the follow-up of patients operated for carcinoids, as second-step investigation, after chest X-ray, CT-scan and serological marker' levels. METHODS AND RESULTS: We describe the case of a female patient, 58-year-old, operated on for a non-secretory lung carcinoid. Five years after surgery, the CT-scan showed the enlargement of the bilateral hylo-mediastinal lymph nodes, suggestive for carcinoid recurrences. In order to confirm that, the patient was submitted to an Octreoscan that showed the presence of enlarged hylo-mediastinal adenopathies matching with the lesions observed at the CT-scan. Because the serological examination of NSE, chromogranin and serotonin, and the 5-HIIA were in the normal range, the patient was submitted to a lymph node biopsy through a mediastinoscopy. The histological examination of the specimens revealed a sarcoidosis and the patient was started on steroid therapy with good outcome. CONCLUSIONS: We conclude that: 1. the octreoscan scintigraphy in the follow-up of resected carcinoids can give false-positive results and 2. in consequence, the mediastinoscopy is a discriminating investigation in case of mediastinal lymph nodes disease.

Difficulties with CT-guided needle biopsy and VATS, as combined approach for the diagnosis and treatment of peripheral pulmonary nodules: a case report.

AIM: To re-evaluate the use of CT-guided needle biopsy and VATS, as our combined approach protocol for the diagnosis and treatment of peripheral pulmonary nodules. METHODS AND RESULTS: We describe the case of a male smoking patient, 50-year-old, who came to our service for the histological diagnosis of a right pulmonary lesion incidentally revealed. He was submitted to our diagnostic and therapeutic protocol for peripheral pulmonary nodules, that is a combined approach of CT-guided needle biopsy, anchorage of the lesion and VATS resection. Difficulties with this technique can raise when: 1. the cytological CT-guided needle biopsy is not diagnostic, 2. the anchorage is not successful, 3. the malignancy of the lesion cannot be surely determined by the extemporary histological examination. In this patient all these difficulties were encountered. CONCLUSIONS: We conclude that our diagnostic and therapeutic protocol for peripheral pulmonary nodules is not invalidated by this experience, even in consideration of the fact that we applied successfully the protocol in several previous cases.