Search

Anaplastic thyroid carcinomas (ATCs) are rare cancers with a globally very poor prognosis, because of their immensely aggressive behaviour, resulting in predominantly advanced stage of disease at diagnosis. Response to available therapies is still disappointing. Aim of the present review is to illustrate the diverse new strategies under investigation, to improve the poor outcome of these patients.Applying molecular analysis in ATC is unravelling potentially actionable targets of therapy. If a mutation of BRAF V600E is found, a combination of Dabrafenib and Trametinib is the recommended treatment. In the presence of another druggable mutation, a specific targeted therapy may be proposed. In the absence of druggable mutations, immunotherapy is an alternative approach, especially in case of significant PD-L1 expression.The molecular profiling of tumour samples is elucidating the genetic alterations involved in ATC development, and new preclinical models are under study to define innovative approaches for individualized treatment of such patients. Hopefully this approach could improve ATC prognosis.

The neoplastic proliferation of parafollicular thyroid cells (C cells) may occur as either medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH) and is generically defined C cell disease. Since Calcitonin (CT) expression is fully maintained in neoplastic C cells, this hormone represents a sensitive marker for neoplasia of C cell derivation such as CCH and MTC. Serum CT levels display a high prognostic value and accurate estimation of tumor burden, allowing early detection of persistence/relapse and representing a reliable marker of response to treatment. Indeed, elevated CT levels can occur in other non-C cell-related conditions (i.e., other malignancies, systemic diseases, and pharmacological treatments). Moreover, some de-differentiated, more aggressive MTCs may present disproportionately low-circulating CT levels, as compared with tumor burden. During the postsurgical follow-up of MTC patients, CT levels usually parallel tumor progression and their increase unambiguously announces persistence/relapse. In this respect, CT Doubling Time (DT) has been proposed as prognostic factor of potential use for the identification of more aggressive MTCs. The present review will summarize the novel achievements on the clinical suitability of CT as a biomarker in clinical oncology and will point the attention to the most recent results concerning the usefulness and the possible drawbacks of circulating CT as a surrogate marker for the identification of rapidly progressing MTC patients, such as those candidate to targeted therapies. The emerging role of circulating CT as a parameter of response to local and systemic therapies will also be illustrated.

Radioiodine-refractory thyroid cancers represent the main cause of thyroid cancer-related death. At present, targeted therapies with multikinase inhibitors represent a unique therapeutic tool, though they have limited benefit on patient survival and severe drug-associated adverse events. This review summarizes current treatment strategies for radioiodine-refractory thyroid cancer and focuses on novel approaches to redifferentiate thyroid cancer cells to restore responsiveness to radioiodine administration.We summarize and discuss recent clinical trial findings and early data from real-life experiences with multikinase-inhibiting drugs. Possible alternative strategies to traditional redifferentiation are also discussed.The current review focuses primarily on the major advancements in the knowledge of the pathophysiology of iodine transport and metabolism and the genetic and epigenetic alterations occurring in thyroid neoplasia as described using preclinical models. Results of clinical studies employing new compounds to induce thyroid cancer cell redifferentiation by acting against specific molecular targets are also discussed. Finally, we describe the current scenario emerging from such findings as well as future perspectives.

Purpose of review Several molecularly targeted drugs for treating radioiodine resistant differentiated thyroid carcinomas (RAIR-DTC) have been identified. Among these, sorafenib and lenvatinib have been approved for clinical use in many countries. The present review will analyze efficacy and safety 'real-world' data (RWD) emerging after their commercialization. Recent findings RWDs confirmed sorafenib and lenvatinib efficacy in terms of progression-free survival and, perhaps, overall survival improvement in patients with RAIR-DTC. Lenvatinib performance in RWDs appeared somehow lower than in randomized clinical trials (RCT), probably because the decision to start treatment in 'real life' was made when patients were in worse clinical conditions than in RCTs. Concerning safety, RWD studies corroborated RCT evidence of elevated overall and serious adverse event incidence. Notably, adverse events were manageable in most cases with appropriate treatment or dose reduction/interruption, so that the need for definitive withdrawal was limited. The suitability of multikinase inhibitors (MKI) as salvage therapy in RAIR-DTCs was also confirmed by RWD experience, at least for lenvatinib in the second-line setting. Summary RWD analysis has corroborated RCT results in terms of MKI efficacy for both first-line and salvage treatment in patients with RAIR-DTC. The safety profiles emerging from RWDs seem to justify the caution recommended by most scientific guidelines.

Context:The European Thyroid Association (ETA) has classified posttreatment cervical ultrasound findings in thyroid cancer patients based on their association with disease persistence/recurrence.Objective:The objective of the study was to assess this classification's ability to predict the growth and persistence of such lesions during active posttreatment surveillance of patients with differentiated thyroid cancer (DTC).Design:This was a retrospective, observational study.Setting:The study was conducted at a thyroid cancer center in a large Italian teaching hospital.Patients:Center referrals (2005–2014) were reviewed and patients selected with pathologically-confirmed DTC; total thyroidectomy, with or without neck dissection and/or radioiodine remnant ablation; abnormal findings on two or more consecutive posttreatment neck sonograms; and subsequent follow-up consisting of active surveillance. Baseline ultrasound abnormalities (thyroid bed masses, lymph nodes) were classified according to the ETA system. Patients were divided into group S (those with one or more lesions classified as suspicious) and group I (indeterminate lesions only). We recorded baseline and follow-up clinical data through June 30, 2015.Main Outcomes:The main outcomes were patients with growth (>3 mm, largest diameter) of one or more lesions during follow-up and patients with one or more persistent lesions at the final visit.Results:The cohort included 58 of the 637 DTC cases screened (9%). A total of 113 lesions were followed up (18 thyroid bed masses, 95 lymph nodes). During surveillance (median 3.7 y), group I had significantly lower rates than group S of lesion growth (8% vs 36%, P = .01) and persistence (64% vs 97%, P = .014). The median time to scan normalization was 2.9 years.Conclusions:The ETA's evidence-based classification of sonographically detected neck abnormalities can help identify papillary thyroid cancer patients eligible for more relaxed follow-up.

Corticosteroid agents (CA) are widely used in the treatment of metastatic castration-resistant prostate cancer (mCRPC) either as concomitant treatment with active agents such as docetaxel, cabazitaxel and abiraterone or in a palliative setting, predominantly due to their anti-inflammatory activity. However, the chronic use of CA has numerous side effects, especially in case of steroid-induced adrenal insufficiency. Furthermore, the latest clinical and preclinical data demonstrate that CA themselves are likely to promote tumour progression in certain populations of patients with mCRPC. Therefore, the role of CA in advanced disease should be carefully weighed for each patient and their withdrawal should be considered in some patients. This is necessary, especially in clinical trials that need good performance status patients to evaluate the activity and the safety of emerging drugs in mCRPC that do not require the concurrent use of CA. In oncology, there is no consensus on an algorithm of gradual steroid tapering and frequently the approach to this procedure is empirical. An algorithm is presented in this article based on clinical observations. Prospective studies are necessary to evaluate the efficacy and safety of the above-proposed algorithm in metastatic castration-resistant prostate cancer.

The neoplastic proliferation of parafollicular thyroid cells (C cells), generically defined as C cell disease, may occur as either medullary thyroid carcinoma (MTC) or C cell hyperplasia (CCH).

The term "nodular goiter" has long been used to refer to a nodular thyroid gland, based on the assumption that nodule growth may be associated with hyperplasia of the surrounding non-nodular tissue. The aim of this prospective, multicenter, observational study was to determine whether nodule growth is accompanied by growth in the non-nodular tissue.Eight Italian thyroid-disease referral centers enrolled 992 consecutive patients with one to four benign nodules. Nodular and non-nodular thyroid tissue volumes were assessed for five years with annual ultrasound examinations.In participants whose nodules remained stable (n = 839), thyroid volumes did not change (baseline 15.0 mL [confidence interval (CI) 14.5-15.6]; five-year evaluation 15.1 mL [CI 14.5-15.7]). In participants with significant growth of one or more nodule (n = 153), thyroid volumes increased and by year 5 were significantly greater than those of the former group (17.4 mL [CI 16-18.7]). In 76 individuals with unilateral nodules that grew, the mean nodular lobe volume significantly exceeded that of the contralateral lobe (8.6 mL [CI 7.4-9.8] vs. 6.7 mL [CI 6-7.4]). The unaffected lobe volumes remained stable over time, while nodular lobes grew steadily and were significantly greater at the end of follow-up (10.1 mL [CI 8.9-11.3]). Excluding the volume of the largest growing nodule in these cases, the remaining volume of the affected lobe remained virtually unchanged with respect to its baseline value. Furthermore, there was no significant difference in the non-nodular tissue volume between the unaffected lobe and the affected lobe (with the largest growing nodule volume subtracted), both at baseline and at the end of follow-up.The growth of thyroid nodules is a local process, not associated with growth of the surrounding non-nodular tissue. Therefore, a normal-sized thyroid containing nodules should be referred to as a "uni- or multinodular thyroid gland" and considered a distinct entity from "uni- or multinodular goiter."

Objective: The aim of this review was to analyze the existing literature concerning the relationship between Hashimoto thyroiditis (HT) and vestibular dysfunction. Methods: We used electronic databases (PubMed, EMBASE, Cochrane Library) to search and collect all published articles about the association between HT and vestibular disorders. Results: Several observational and retrospective studies have postulated a relationship between thyroid autoimmunity and vestibular disorders. In most cases, an appropriate control group was lacking, and the impact of thyroid functional status could not precisely be established. In recent years, two well-designed prospective studies have provided convincing evidence that the association is not random. One article reported that patients with Meniere disease (MD) had a significantly higher prevalence of positive anti-thyroid autoantibody as compared to healthy controls. Moreover, more than half of MD patients had either positive anti-thyroid or non–organ-specific autoantibody titers, compared to less than 30% of both patients with unilateral vestibular paresis without cochlear involvement and healthy controls. Another study found that patients with benign paroxysmal positional vertigo (BPPV) had significantly higher serum thyroid-stimulating hormone and antithyroid autoantibody levels than healthy controls. Additionally, almost one-fifth of euthyroid patients with HT had signs of BPPV. Conclusion: The published results indicate that patients with MD or BPPV are potential candidates to also develop HT. Thus, in HT patients, the presence of even slight symptoms or signs potentially related to vestibular lesions should be carefully investigated. Abbreviations: AITD = autoimmune thyroid disease; BPPV = benign paroxysmal positional vertigo; EH = endolymphatic hydrops; HT = Hashimoto thyroiditis; L-T4 = L-thyroxine; MD = Meniere disease; PS = Pendred syndrome; Tg = thyroglobulin; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone

Because virtually all medullary thyroid cancers (MTCs) are associated with elevated circulating levels of serum calcitonin (CT), routine CT measurement has been proposed as a tool for early MTC diagnosis. The usefulness of universal screening with CT in thyroid nodular disease patients is, however, controversial. Basal CT determination, in fact, displays a high false-positive rate, resulting in low positive predictive value (PPV). Provocative tests (i.e., pentagastrin or calcium gluconate administration) are often necessary to improve the specificity of the screening procedure. Nonetheless, surgical pathology indicates C-cell hyperplasia (CCH) in a substantial proportion of thyroid nodular disease patients who display positive results at CT testing (basal and/or stimulated). A basal CT >100 pg/ml is the most reliable cutoff for MTC. Below this cutoff, the threshold for discriminating CCH from MTC is not well defined.

Item does not contain fulltext BACKGROUND: Current surgical standard of care in sporadic medullary thyroid carcinoma (sMTC) consists of a minimum of total thyroidectomy with central neck dissection. Some have suggested thyroid lobectomy with isthmusectomy and central neck dissection for patients with sMTC, given their lower frequency of bilateral disease, although this topic has not been thoroughly studied. This study assessed the prevalence of multifocality in sMTC via a large international multi-institutional retrospective review to quantify this prevalence, including the impact of geography, to assess more accurately the risks associated with alternative surgical approaches. METHODS: A retrospective chart review of sMTC patients from 11 institutions over 29 years (1983-2011) was undertaken. Data regarding focality, extent of disease, RET germline analysis plus family and clinical history for multiple endocrine neoplasia type 2 (MEN2), and demographic data were collected and analyzed. RESULTS: Patients from four continents and seven countries were included in the sample. Data for 313 patients with documented sMTC were collected. Of these, 81.2% were confirmed with negative RET germline testing, while the remaining 18.8% demonstrated a negative family history and no manifestations of MEN2 syndromes other than MTC. Bilateral disease was identified in 17/306 (5.6%) patients, while multifocal disease was noted in 50/312 (16.0%) sMTC patients. When only accounting for germline negative patients, these rates were not significantly different (5.6% and 17%, respectively). Among them, when disease was unifocal in the ipsilateral lobe and isthmus, bilateral disease was present in 6/212 (2.8%) cases. When disease was multifocal in the ipsilateral lobe or isthmus, then bilateral disease was present in 8/37 (21.6%) cases (p < 0.001). No geographic differences in focality were identified. CONCLUSIONS: The 5.6% prevalence of bilateral foci in sMTC suggests that total thyroidectomy should remain the standard of care for initial surgery, as less complete thyroid surgery may fail to address fully the primary site of disease. Whether ipsilateral tumor focality should be an independent factor determining the need for completion thyroidectomy when sMTC is diagnosed after hemithyroidectomy remains to be determined.

Efficient treatment of radio refractory thyroid cancer is still a major challenge. The recent identification of genetic and epigenetic alterations present in almost all differentiated tumors has revealed novel molecular targets, which can hopefully be exploited to create new treatments for these tumors. This review looks briefly at some of the innovative strategies currently being investigated for the treatment the radioiodine-resistant thyroid cancers.

Objective: We report the case of a female patient with multiple endocrine neoplasia type 2A (MEN2A) who was found to have a double mutation in the RET (rearranged during transfection) proto-oncogene. Methods:RET mutational analysis was performed by Sanger DNA sequencing. Results: The proband was a compound heterozygote for the RET germline mutations Val648Ile and Val804Leu on exons 11 and 14, respectively. Genetic analysis of family members showed the presence of the Val648Ile mutation in all except 1 daughter who carried the Val804Leu mutation. However, none of them showed any clinical, biochemical, or histologic signs of neoplastic disease either in the thyroid or adrenal gland. Furthermore, a daughter and the proband's sister who underwent a prophylactic thyroidectomy did not show pathologic evidence of C-cell disease. Conclusions: We hypothesize that the combined effect of the 2 mutations may have induced the development of pheochromocytoma (PHEO) in our patient. Thus, in the presence of single RET-induced mild medullary thyroid cancer (MTC) phenotype, the search for additional genetic anomalies may lead to the discovery of rare but potentially more aggressive double mutation genotypes. Abbreviations: ACTH = adrenocorticotropic hormone ATA = American Thyroid Association CT = calcitonin FMTC = familial medullary thyroid cancer HSCR = Hirschsprung disease MEN2A/B = multiple endocrine neoplasia type 2A/2B MTC = medullary thyroid cancer PHEO = pheochromocytoma RET = rearranged during transfection SDHB/D = succinate dehydrogenase subunits B/D VHL = Von Hippel-Lindau

BACKGROUND: Small papillary thyroid carcinomas have contributed to the worldwide increased incidence of differentiated thyroid cancer observed over the past decades. However, the mortality rate has not changed over the same period of time, raising questions about the possibility that thyroid cancer patients, especially those with small tumors, are overdiagnosed and overtreated. Molecular prognostic marker able to discriminate aggressive thyroid cancers from those with an indolent course would be of great relevance to tailor the therapeutic approach and reduce overtreatment. Mutations in the TERT promoter were recently reported to correlate strongly with aggressiveness in advanced forms of thyroid cancer, holding promise for a possible clinical application. The occurrence and potential clinical relevance of TERT mutations in papillary thyroid microcarcinomas (mPTCs) is currently unknown. This study aimed to analyze the occurrence of two TERT promoter mutations (-124C>T and -146C>T) and their potential association with unfavorable clinical features in a large cohort of mPTCs. METHODS: A total of 431 mPTCs cases were collected from six Italian institutions, and TERT promoter mutational status was assessed by a next-generation sequencing approach. RESULTS: TERT promoter mutations were found in 4.7% of the analyzed mPTCs, showing that even microcarcinomas carry mutations in this gene. Correlation analysis showed that TERT promoter mutations are not associated with aggressive features or clinical outcome in the cohort analyzed. CONCLUSIONS: TERT mutations are present but uncommon in mPTCs. Apparently, in mPTCs, the occurrence of TERT mutations is not correlated with unfavorable clinical features

Detection of asymptomatic thyroid nodules has increased. Consensus is lacking regarding the optimal follow-up of cytologically proven benign lesions and sonographically nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and reassessment of cytology if significant growth is observed.To determine the frequency, magnitude, and factors associated with changes in thyroid nodule size.Prospective, multicenter, observational study involving 992 consecutive patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed.Baseline nodule growth (primary end point) was assessed with yearly thyroid ultrasound examinations. Size changes were considered significant for growth if an increase of 20% or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm. Baseline factors associated with growth were identified. Secondary end points were the sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up.Nodule growth occurred in 153 patients (15.4% [95% CI, 14.3%-16.5%]). One hundred seventy-four of the 1567 original nodules (11.1% [95% CI, 10.3%-11.9%]) increased in size, with a mean 5-year largest diameter increase of 4.9 mm (95% CI, 4.2-5.5 mm), from 13.2 mm (95% CI, 12.1-14.2 mm) to 18.1 mm (95% CI, 16.7-19.4 mm). Nodule growth was associated with presence of multiple nodules (OR, 2.2 [95% CI 1.4-3.4] for 2 nodules; OR, 3.2 [95% CI, 1.8-5.6 for 3 nodules; and OR, 8.9 [95% CI, 4.4-18.0] for 4 nodules), main nodule volumes larger than 0.2 mL (OR, 2.9 [95% CI, 1.7-4.9] for volumes0.2 to1 mL and OR, 3.0 [95% CI, 1.8-5.1] for volumes ≥1 mL), and male sex (OR, 1.7 [95% CI, 1.1-2.6]), whereas an age of 60 years or older was associated with a lower risk of growth than age younger than 45 years (OR, 0.5 [95% CI 0.3-0.9]). In 184 individuals (18.5% [95% CI, 16.4%-20.9%]), nodules shrank spontaneously. Thyroid cancer was diagnosed in 5 original nodules (0.3% [95% CI, 0.0%-0.6%]). Only 2 had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3% [95% CI, 7.5%-11.1%]), with detection of one cancer.Among patients with asymptomatic, sonographically or cytologically benign thyroid nodules, the majority of nodules exhibited no significant size increase during 5 years of follow-up and thyroid cancer was rare. These findings support consideration of revision of current guideline recommendations for follow-up of asymptomatic thyroid nodules.