Prognostic Factors Improving ATA Risk System and Dynamic Risk Stratification in Low- and Intermediate-Risk DTC Patients.

CONTEXT: American Thyroid Association (ATA) guidelines do not consider age at diagnosis as a prognostic factor on the estimation of the risk of persistent/recurrent disease in differentiated thyroid carcinoma (DTC) patients. While age at diagnosis has already been assessed in high-risk patients, it remains to be established in low- and intermediate-risk patients. OBJECTIVE: The aim of our study was to investigate the role of age as a prognostic factor in the short- and long-term outcome of DTC patients classified at low and intermediate risk according to the ATA stratification risk system. METHODS: We retrospectively evaluated 863 DTC patients (mean follow-up: 10 ± 6.2 years) 52% classified as low (449/863) and 48% as intermediate risk (414/863). For each ATA-risk class patients were divided into subgroups based on age at diagnosis (<55 or ≥55 years). RESULTS: In the intermediate-risk group, patients aged 55 years or older had a higher rate of structural disease (11.6% vs 8.9%), recurrent disease (4.1% vs 0.7%), and death (4.1% vs 1%) when compared with younger patients (<55 years) (P = .007). Multivariate analysis confirmed that older age at diagnosis (odds ratio [OR] = 3.9; 95% CI, 1.9-8.6; P < .001) was an independent risk factor for worse long-term outcome together with response to initial therapy (OR = 13.0; 95% CI, 6.3-27.9; P < .001), and T (OR = 32; 95% CI, 1.4-7.1; P = .005) and N category (OR = 2.3; 95% CI, 1.1-5.0; P = .03). Nevertheless, a negative effect of older age was documented only in the subgroup of intermediate DTC patients with persistent structural disease after initial therapy. Indeed, the rate of worse long-term outcome rose from 13.3% in the whole population of intermediate DTC patients to 47.8% in patients with persistent structural disease after initial therapy (P < .001) and to 80% in patients older than 55 years and persistent structural disease after initial therapy (P = .02). CONCLUSION: Our results suggest that age at diagnosis further predict individual outcomes in Intermediate-Risk DTC allowing ongoing management to be tailored accordingly.

Pilot Study on the Impact of Polymorphisms Linked to Multi-Kinase Inhibitor Metabolism on Lenvatinib Side Effects in Patients with Advanced Thyroid Cancer.

Multi-kinase inhibitors (MKIs) represent the best therapeutic option in advanced thyroid cancer patients. The therapeutic efficacy and toxicity of MKIs are very heterogeneous and are difficult to predict before starting treatment. Moreover, due to the development of severe adverse events, it is necessary to interrupt the therapy some patients. Using a pharmacogenetic approach, we evaluated polymorphisms in genes coding for proteins involved with the absorption and elimination of the drug in 18 advanced thyroid cancer patients treated with lenvatinib, and correlated the genetic background with (1) diarrhea, nausea, vomiting and epigastric pain; (2) oral mucositis and xerostomia; (3) hypertension and proteinuria; (4) asthenia; (5) anorexia and weight loss; (6) hand foot syndrome. Analyzed variants belong to cytochrome P450 (CYP3A4 rs2242480 and rs2687116 and CYP3A5 rs776746) genes and to ATP-binding cassette transporters (ABCB1 rs1045642, rs2032582 and rs2235048 and ABCG2 rs2231142). Our results suggest that the GG genotype for rs2242480 in CYP3A4 and CC genotype in rs776746 for CYP3A5 were both associated with the presence of hypertension. Being heterozygous for SNPs in the ABCB1 gene (rs1045642 and 2235048) implicated a higher grade of weight loss. The ABCG2 rs2231142 statistically correlated with a higher extent of mucositis and xerostomia (CC genotype). Heterozygous and rare homozygous genotypes for rs2242480 in CYP3A4 and for rs776746 for CYP3A5 were found to be statistically linked to a worse outcome. Evaluating the genetic profile before starting lenvatinib treatment may help to predict the occurrence and grade of some side effects, and may contribute to improving patient management.

Effect of Pre-Existent Sarcopenia on Oncological Outcome of Advanced Thyroid Cancer Patients Treated with Tyrosine Kinase Inhibitors.

(1) Background: Sarcopenia is associated with poor survival and treatment outcomes in several human cancers. The aim of the study was to investigate the prevalence of sarcopenia in a cohort of 58 Caucasian patients with advanced thyroid cancer before and during TKI treatment. The impact of this condition on the outcome of patients was also evaluated. (2) Methods: Sarcopenia was evaluated using the Skeletal Muscle Index (SMI). (3) Results: Pre-treatment sarcopenia was found in 20.7% of patients and this condition significantly affected treatment outcome, emerging as the parameter that has the greatest impact on Progression Free Survival (PFS) (HR 4.29; 95% CI, 1.21−15.11, p = 0.02). A significant reduction in SMI values was observed 3 (p = 0.002) and 12 months (p < 0.0001) after TKI treatment. At a 12-month follow-up, sarcopenia prevalence increased up to 38.5%. Here, 12-month sarcopenia was predicted by a lower SMI (p = 0.029), BMI (p = 0.02) and weight (p = 0.04) and by the presence of bone metastases (p = 0.02). (4) Conclusions: This is the first study that evaluated sarcopenia prevalence and its change over time in Caucasian patients with advanced thyroid cancer under TKI therapy. Sarcopenia seems to be a prognostic factor of TKI treatment outcome, suggesting the importance of the assessment of the nutritional status and body composition in advanced thyroid cancer patients.

No need of glucocorticoid dose adjustment in patients with adrenal insufficiency before COVID-19 vaccine.

Objective: Coronavirus disease-2019 (COVID-19) causes acute respiratory distress syndrome. Patients with adrenal insufficiency (AI) may develop severe complications due to this infection and should undergo COVID-19 vaccination; however, there is no consensus about the management of their replacement therapy. The aim of our study was to evaluate the tolerability and need for glucocorticoid dose adjustment related to COVID-19 mRNA vaccines in a cohort of patients with AI. Design and methods: We prospectively administered to 88 patients (51 M/37 F; mean age: 62.3 ± 16 years), with AI (28 primary and 60 secondary AI), a questionnaire about the occurrence, severity and duration of the side effects and the need for glucocorticoid dose adjustment within 1 week after the first and the second dose of COVID-19 mRNA vaccines (Pfizer-BioNTech and Moderna). Results: Side effects of mild to moderate severity occurred in about 70% of patients after both vaccine doses. The most common adverse events were pain at the injection site, fatigue, fever and flu-like symptoms. The occurrence and severity of the side effects were not correlated to gender, type of AI and mRNA vaccine, but their total number was higher after the second vaccine dose. Doubling the oral glucocorticoid dose was needed in up to 8% of patients, especially after the second vaccine dose, but no parenteral administration was required. Conclusions: COVID-19 mRNA vaccines were well tolerated in patients with AI. Side effects were similar to those observed in the general population, and increasing glucocorticoid replacement therapy before vaccine administration was not needed.

Pre- and Post-operative Circulating Tumoral DNA in Patients With Medullary Thyroid Carcinoma.

CONTEXT: Measurement of driver mutations in circulating tumoral DNA (ctDNA) obtained by liquid biopsy has been shown to be a sensitive biomarker in several human tumors. OBJECTIVE: The aim of this study was to evaluate the clinical relevance of pre- and post-operative ctDNA in sporadic medullary thyroid cancer (sMTC). METHODS: We studied pre- and post-operative ctDNA in 26 and 23 sMTC patients, respectively. ctDNA results were correlated to serum calcitonin (Ct), carcinoembryonic antigen (CEA), and other clinical/pathological features. RESULTS: Twenty-six of 29 (89.7%) sMTCs were mutated either for RET or RAS and 3/29 (10.3%) were negative. Four of 26 (15.4%) cases showed positive pre-operative ctDNA with a significantly higher presence of RET M918T mutation (P = 0.0468). Patients with positive pre-operative ctDNA showed a higher variation allele frequency value of the somatic driver mutation (P = 0.0434) and a higher frequency of persistent disease (P = 0.0221). Post-operative ctDNA was positive only in 3/23 (13%) sMTCs and no one was positive for pre-operative ctDNA. Higher values of both Ct (P = 0.0307) and CEA (P = 0.0013) were found in positive ctDNA cases. Finally, the 7 cases harboring either pre- or post-operative positive ctDNA had a persistent disease (P = 0.0005) showing a higher post-operative serum Ct when compared with cases with negative ctDNA (P = 0.0092). CONCLUSIONS: Pre-operative ctDNA in medullary thyroid cancer is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series, post-operative ctDNA showed a potential for monitoring the response to therapies, but further studies are required to confirm our results.

Risk of Second Malignant Neoplasm in Familial Non-Medullary Thyroid Cancer Patients.

Introduction: Survival rates in patients with non-medullary thyroid carcinoma (NMTC) are high, increasing the possibility to develop a second malignant neoplasm (SMN). Many studies investigated the relationship between increased risk of SMN in NMTC patients treated with radioiodine, but few data are available about the impact of family history (FH) of thyroid cancer on SMN risk. Purpose: To assess the risk of SMN in a large cohort of sporadic and familial NMTC using the standardized incidence ratio (SIR). Patients and methods: We studied 918 NMTC patients (73.9% female patients) followed for a median follow-up of 9 years. In 798/918 (86.9%) patients, NMTC was sporadic, while the remaining 120 (13.1%) were familial NMTC (FNMTC). Results: We identified 119/918 (13%) patients with SMN in association with NMTC. NMTCs had an increased risk of SMN when compared to the general population (SIR 2.1, 95% CI 1.7-2.5). The rate of SMN for all sites was significantly higher in familial compared to sporadic NMTC (20% versus 11.9%, p = 0.01), primarily driven by families with more than two affected members. The risk of SMN was remarkably higher for breast cancer, especially in familial cases (SIR 22.03, 95% CI 14.4-41.2) compared to sporadic cases (SIR:17, 95% CI 11.9-24.6). Conclusions: NMTC patients have a higher risk of SMN compared to the general population and this risk is much higher in patients with FNMTC. This observation raises the hypothesis that genetic risk factors for a first cancer may predispose to SMN, especially among individuals with familial clustering of the same or other tumors.

CONUT Score: A New Tool for Predicting Prognosis in Patients with Advanced Thyroid Cancer Treated with TKI.

(1) Background: The Controlling Nutritional Status (CONUT) score is an immuno-nutritional screening tool based on serum albumin, total cholesterol, and lymphocyte count. The aim of the study was to assess the CONUT score as a potential prognostic factor of response to therapy in patients with advanced thyroid cancer treated with tyrosine kinase inhibitors (TKIs). (2) Methods: We retrospectively evaluated 42 metastatic thyroid cancer patients (54.8% female). The median age at the time of TKI treatment was 69 years. Histological diagnosis was differentiated thyroid cancer in 66.7%, poorly differentiated thyroid cancer in 21.4%, and medullary thyroid cancer in 11.9% of patients. CONUT score was assessed before starting TKI therapy. (3) Results: Progression-free survival (PFS) and overall survival (OS) were significantly influenced by baseline CONUT score. The best CONUT cut-off able to predict the response to treatment was 3. Both PFS and OS were better in patients with CONUT score <3 than in those with CONUT score ≥3 (p < 0.0001). CONUT score was the only independent prognostic factor associated with PFS (p = 0.021) and OS (p = 0.007). (4) Conclusions: CONUT score represents a relatively new screening tool, easily applicable in clinical practice and potentially useful in predicting prognosis in thyroid cancer patients treated with TKIs.

Calcitonin Levels in Thyroid Disease Are Not Affected by Autoimmune Thyroiditis or Differentiated Thyroid Carcinoma.

INTRODUCTION: Association between hypercalcitoninemia and pathological conditions such as autoimmune thyroiditis (AIT) or differentiated thyroid carcinoma (DTC) has been addressed, with conflicting results. We evaluated the prevalence and the clinical relevance of elevated basal serum calcitonin (CT) levels in non-neoplastic (nodular goiter [NG] and AIT) and neoplastic thyroid diseases (DTC). METHODS: We retrospectively evaluated 3,250 consecutive patients with thyroid nodular disease who underwent fine-needle aspiration cytology with adequate sample. After exclusion of medullary thyroid cancer (MTC) patients were divided according to the presence/absence of thyroid autoimmunity into NG or nodular autoimmune thyroiditis (N-AIT) and, according to cytological results, in benign or suspicious/malignant nodules. RESULTS: One hundred ninety-seven/3,250 patients (6.0%) showed CT level >10 pg/mL. In 11/3,250 (0.3%) cases, a final histological diagnosis of MTC was made, while the remaining 186/3,250 patients (5.7%) had non-MTC-related hypercalcitoninemia (CT > 10 pg/mL). According to cytological diagnosis, the rate of hypercalcitoninemia was similar in class II and class V-VI groups (5.4 vs. 6.9%, p = 0.4). The occurrence of hypercalcitoninemia was significantly higher in patients with NG (166/2,634 [6.3%]) than in patients with N-AIT (20/605 [3.3%]) (p = 0.004). However, after matching by sex, no difference was found between the 2 groups (NG and N-AIT). These results were confirmed in 598 patients submitted to surgery. CONCLUSIONS: AIT and DTC seem not to affect serum CT levels in patients with thyroid nodules. Therefore, hypercalcitoninemia, in these patients, should be submitted to the same diagnostic workup than patients without AIT or DTC.

The Combination of Sonographic Features and the Seven-Gene Panel May be Useful in the Management of Thyroid Nodules With Indeterminate Cytology.

Introduction: The management of patients with indeterminate thyroid nodules, which account for 10-25% of thyroid fine needle aspiration biopsies (FNABs), is still very challenging. Aim: To verify the utility of the seven-gene panel in combination with ultrasound features in the clinical management of indeterminate thyroid nodules. Results: The study group included 188 indeterminate thyroid nodules, divided into TIR3A (56.4%) and TIR3B (43.6%). A significant correlation between US categories and both cytological and molecular results was observed. In detail, TIR3B cytology was more frequent in EU-TIRADS 4 and 5 nodules (54.7 and 50%, respectively) than in EU-TIRADS 2 and 3 nodules (31%, p = 0.04). Similarly, the rate of a nodule with a mutation increased with the increase of US risk class (6.0% in EU-TIRADS 2 and 3, 9.3% in EUTIRADS-4 and 27.8% in EUTIRAD-5, p = 0.01). Among thyroid nodules submitted to surgery, final histology was benign in 61.4% nodules, while malignancy was diagnosed in 38.6% nodules. Using US score as tool for decision-making in TIR3A subgroup, we correctly classified 64.5% of thyroid nodules. The second tool (seven-gene panel test) was used in the subgroup of US high-risk nodules. By multiple tests with a series approach (US in all cases and US plus seven-gene panel in US high risk nodules) 84% of cases were correctly classified. In TIR3B nodules, using only seven-gene panel as tool for decision making, we correctly classified 61.9% of indeterminate nodules. By multiple tests with series approach (seven-gene panel in all cases and seven-gene panel plus US score in non-mutated nodules) only a slight improvement of thyroid nodule classification (66.6%) was observed. Conclusions: US score seems able to correctly discriminate between TIR3A nodules in which a conservative approach may be used, and those in which additional test, such as molecular test, may be indicated. On the contrary, in TIR3B nodules both US risk stratification and seven-gene panel seem to be of little use, because the risk of thyroid cancer remains high regardless of US score and mutational status.

Improvement of Overall Survival Using TKIs as Salvage Therapy in Advanced Thyroid Carcinoma: Real-Life Data on a Single Center Experience.

Background: Tyrosine kinase inhibitors (TKIs) have improved progression-free survival in patients with advanced thyroid cancer. So far, few studies have investigated the efficacy of TKIs in a second-line setting. The purpose of our study was to explore the salvage therapy efficacy in patients with advanced thyroid cancer. Methods: We retrospectively evaluated 63 patients with progressive advanced thyroid carcinoma treated with TKIs divided into a Study group (23 patients) treated with salvage therapy, and a Control group (40 patients) treated with only one TKI. Results: Similar clinical benefits (stable disease + partial response) and progression free survival between the first and the second line TKI were observed in the Study group (p > 0.99 and p = 0.5, respectively). Median overall survival (OS) was 67.7 months in the Study group and 22.6 months in the Control group (HR 2.46; 95% CI 1.34-4.52, p = 0.004). After stratifying the whole population by age (<65 and ≥65 years), OS was significantly different (p < 0.001) with the best survival curve in younger patients, treated with salvage therapy and the worst in older subjects, treated with only one TKI. Conclusions: Salvage therapy showed a significant improvement of OS in patients with advanced thyroid cancer who experienced disease progression during prior TKI therapies.

Validation of American Thyroid Association Ultrasound Risk-Adapted Approach for Repeating Cytology in Benign Thyroid Nodules.

Background: The 2015 American Thyroid Association (ATA) ultrasound (US) risk stratification system is used to identify thyroid nodules in which fine-needle aspiration cytology (FNAC) should be performed. In addition, this system is used to plan the long-term follow-up of patients with cytological benign thyroid nodules. The aim of our study was to evaluate the ATA US risk-adapted approach for repeating cytology in a large retrospective cohort of consecutive benign nodules with a second FNAC repeated after a median follow-up of 3.8 years (range 1.0-14.2 years). Methods: We retrospectively evaluated 1010 thyroid nodules, with an initial benign cytological diagnosis, that underwent at least one repeat FNAC during the follow-up. Results: The rate of missed cancer in the whole cohort of thyroid nodules was 1.0%, and it increased along by the US risk class (0.8% in very low/low-risk, 1.2% in intermediate-risk, and 3.1% in high-risk nodules). The 2015 ATA US risk stratification system showed a very high accuracy in selecting nodules that did not require a second FNAC (negative predictive value = 99.1%). In addition, the rate of missed cancer significantly increased along with the increase in the US risk class in nodules that showed an enlarged volume (0.4% in the low-risk class and 6.4% in the high-risk class, p = 0.005), while it was very low and not associated with the US features in the subgroup of thyroid nodules that did not grow during the follow-up (p = 0.96). Conclusions: Our results confirm the accuracy of the ATA recommendations in selecting benign nodules for FNAC repetition during the follow-up. An additional cytological evaluation maybe avoided in benign thyroid nodules with low-risk US features, regardless of the evidence of growth during the follow-up. While the utility of the routine repeat FNAC in all benign nodules with high-risk US features remains to be defined, based on our results, repetition of FNAC seems to be indicated in nodules with evidence of growth during the follow-up.

Long-Term Clinical Outcome in Familial and Sporadic Papillary Thyroid Carcinoma.

BACKGROUND: The definition and the behaviour of familial papillary thyroid cancer (FPTC) compared to the sporadic form (SPTC) are still debated. Some authors believe that only families with 3 or more affected members represent an actual example of familial diseases. OBJECTIVES: The objective of the study was to analyse the clinicopathological features and the outcome of sporadic and familial PTC patients also according to the number of affected members. METHODS: Among 731 patients, we identified 101 (13.8%) with familial diseases, 79 with 2 affected members (FPTC-2) and 22 with 3 or more affected members (FPTC-3) followed for a mean period of 10 years. RESULTS: FPTC patients had more frequently bilateral tumour (p = 0.007). No difference was found between the 2 groups for the other evaluated variables. At the time of the first follow-up (1-2 years after initial therapy), FPTC patients had a higher rate of persistent disease. However, at the last follow-up, the clinical outcome was not different between sporadic and familial patients. When the comparison between SPTC and FPTC was performed, according to the number of affected members, a significant trend between the 3 groups was observed for tumour diameter (p = 0.002) and bilaterality (p = 0.003), while we did not observe a significant trend for both response to initial therapy (p = 0.15) and last clinical outcome (p = 0.22). CONCLUSIONS: Our results suggest that, although the clinicopathological features of FPTC may be more aggressive, the long-term outcome is similar between FPTC and SPTC. A possible explanation is that PTC has a favourable prognosis, even when clinical presentation is more aggressive.

Permanent diabetes insipidus in a patient with mesothelioma treated with immunotherapy

SUMMARY Checkpoint inhibitors have substantially improved the prognosis for patients with advanced malignancy. Treatment with immunomodulants has the ability to reactivate the immune system against tumor cells, but can also trigger the development of immune-related adverse events that reflects a loss of tolerance of the immune system for self-antigens. Regarding the endocrine system, thyroid and pituitary are the most frequent glands involved; in particular hypophysitis is commonly observed with anti-CTLA4 with a variable impaired anterior pituitary dysfunction (mainly ACTH and TSH dysregulation) while a posterior pituitary dysfunction has been rarely described. A 68-year-old man with a diagnosis of metastatic mesothelioma started in September 2016 first-line treatment with tremelimumab and durvalumab. After 3 cycles he presented sudden onset of polydipsia and polyuria without other symptoms. Diagnostic work-up, including a water deprivation test, established a diagnosis of central diabetes insipidus. Patient started sublingual desmopressin 60 mcg three times a day, that was subsequently increased up to 480 mcg/die. At magnetic resonance imaging the posterior lobe of pituitary gland did not show high signal intensity on T1-weighted images. After regression of diabetes insipidus symptoms under desmopressin, patient restarted cancer treatment and received additional 10 doses without worsening of endocrinological toxicity or further treatment-related toxicities, maintaining the same desmopressin dosage. Posterior pituitary dysfunction has been rarely observed in patients treated with immunomodulants. To our knowledge, this is the first observation of permanent central diabetes insipidus in patients treated with combined immune checkpoint inhibitors (tremelimumab and durvalumab).

Permanent diabetes insipidus in a patient with mesothelioma treated with immunotherapy.

Checkpoint inhibitors have substantially improved the prognosis for patients with advanced malignancy. Treatment with immunomodulants has the ability to reactivate the immune system against tumor cells, but can also trigger the development of immune-related adverse events that reflects a loss of tolerance of the immune system for self-antigens. Regarding the endocrine system, thyroid and pituitary are the most frequent glands involved; in particular hypophysitis is commonly observed with anti-CTLA4 with a variable impaired anterior pituitary dysfunction (mainly ACTH and TSH dysregulation) while a posterior pituitary dysfunction has been rarely described. A 68-year-old man with a diagnosis of metastatic mesothelioma started in September 2016 first-line treatment with tremelimumab and durvalumab. After 3 cycles he presented sudden onset of polydipsia and polyuria without other symptoms. Diagnostic work-up, including a water deprivation test, established a diagnosis of central diabetes insipidus. Patient started sublingual desmopressin 60 mcg three times a day, that was subsequently increased up to 480 mcg/die. At magnetic resonance imaging the posterior lobe of pituitary gland did not show high signal intensity on T1-weighted images. After regression of diabetes insipidus symptoms under desmopressin, patient restarted cancer treatment and received additional 10 doses without worsening of endocrinological toxicity or further treatment-related toxicities, maintaining the same desmopressin dosage. Posterior pituitary dysfunction has been rarely observed in patients treated with immunomodulants. To our knowledge, this is the first observation of permanent central diabetes insipidus in patients treated with combined immune checkpoint inhibitors (tremelimumab and durvalumab).

Blockade of the programmed death ligand 1 (PD-L1) as potential therapy for anaplastic thyroid cancer.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive form of thyroid cancer (TC) characterized by an aggressive behavior and poor prognosis, resulting in patients' death within a year. Standard treatments, such as chemo and radiotherapy, as well as tyrosine kinase inhibitors, are ineffective for ATC treatment. Cancer immunotherapy is one of the most promising research area in oncology. The PD-1/PD-L1 axis is of particular interest, in light of promising data showing a restoration of host immunity against tumors, with the prospect of long-lasting remissions. METHODS: In this study, we evaluated PD-L1 expression in a large series of TCs (20 cases) showing a progressive dedifferentiation of the thyroid tumor from well differentiated TC to ATC, employing two different antibodies [R&D Systems and VENTANA PD-L1 (SP263) Rabbit Monoclonal Primary Antibody]. We also tested the anti PD-L1 mAb in an in vivo animal model. RESULTS: We found that approximately 70-90% of ATC cases were positive for PD-L1 whereas normal thyroid and differentiated TC were negative. Moreover, all analyzed cases presented immunopositive staining in the endothelium of vessels within or in close proximity to the tumor, while normal thyroid vessels were negative. PD-L1 mAb was also effective in inhibiting ATC growth in an in vivo model. CONCLUSIONS: These data suggest that immunotherapy may be a promising treatment specific for ATC suggesting the need to start with clinical TRIALs.

Prospective Validation of ATA and ETA Sonographic Pattern Risk of Thyroid Nodules Selected for FNAC.

Context: Recently, the American Thyroid Association (ATA) and the European Thyroid Association (ETA) have proposed that thyroid ultrasound (US) should be used to stratify the risk of malignancy in thyroid nodules and to aid decision-making about whether fine-needle aspiration cytology (FNAC) is indicated. Objective: To validate and to compare the ATA and ETA US risk stratification systems of thyroid nodules in a prospective series of thyroid nodules submitted to FNAC. Setting: We prospectively evaluated 432 thyroid nodules selected for FNAC from 340 patients. Cytology reports were based on the five categories according to the criteria of the British Thyroid Association. Results: The proportion of Thy2 nodules decreased significantly, whereas the proportion of Thy4/Thy5 nodules significantly increased with increasing US risk class (P < 0.0001). The ability to identify benign and malignant nodules was similar between ATA and ETA systems. According to ATA and ETA US risk stratification systems, 23.7% and 56.0% nodules did not meet the criteria for FNAC, respectively. Considering only categories at lower risk of malignancy, the cumulative malignancy rate in these nodules was 1.2% for ATA and 1.7% for ETA US risk stratification systems. Conclusions: ETA and ATA US risk stratification systems provide effective malignancy risk stratification for thyroid nodules. In clinical practice, using this approach, we should be able to reduce the number of unnecessary FNAC without losing clinically relevant thyroid cancer.

Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab.

OBJECTIVE: Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4, that has been shown to significantly improve survival in patients with metastatic melanoma. Blocking cytotoxic T-lymphocyte antigen-4 elicits T cell activation, proliferation and anti-tumor response, but can also trigger immune-related adverse events. Among immune-related endocrinopathies, hypophysitis represents the most frequent, with an incidence up to 17% in patients treated with ipilimumab. DESIGN AND METHODS: We report nine cases of ipilimumab-induced hypophysitis in a cohort of 273 patients treated with ipilimumab between 2006 and 2015, as part of clinical trials or after its marketing. Thyroid function tests were scheduled at screening and during follow up (every 21 days) in all patients. Cortisol, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, and estradiol (for females) or testosterone (for males), prolactin, growth hormone, insulin-like growth factor 1 were measured only in case of clinical suspicion. RESULTS: The incidence of hypophysitis was 3.3%. The most frequent pituitary failure was adrenocorticotropic hormone and thyroid stimulating hormone secretion with a complete recovery of thyroid stimulating hormone, but not of adrenocorticotropic hormone during follow up. All patients had negative pituitary antibodies. The main symptoms at diagnosis were fatigue and headache. CONCLUSION: Clinicians should be aware about the risk of hypophysitis during treatment with immune check-point inhibitors and the necessity of investigating pituitary function during therapy. Pituitary magnetic resonance imaging does not seem pivotal for a definite diagnosis if not performed at the onset of disease.

Thyroid malignancy markers on sonography are common in patients with benign thyroid disease and previous iodine deficiency.

OBJECTIVES: The purpose of this study was to evaluate the characteristics of benign thyroid nodules on sonography and ultrasound elastography in a population exposed to iodine deficiency. METHODS: We conducted a prospective systematic evaluation of preoperative thyroid sonography and elastography in patients assigned for surgical excision of benign thyroid nodules. Two experienced sonographers performed all sonographic and elastographic examinations. Thyroid nodules were evaluated by 7 generally accepted sonographic malignancy risk markers and assigned an elasticity score on elastography. The final diagnosis of a benign thyroid nodule was based on histopathologic analysis of resected thyroid gland tissue. RESULTS: We evaluated 232 thyroid nodules in 105 patients (86 women and 19 men). In total, 57% of the examined nodules had 1 or 2 malignancy risk markers present, and 24% did not have any markers present. A solid nodule larger than 15 mm was the most common malignancy risk marker observed (63%), followed by low elasticity (33%), microcalcifications (26%), and hypoechogenicity (15%). In an analysis stratified according to the number of nodules (solitary versus multiple), low elasticity was described more frequently in solitary nodules (61.9% versus 30.4%; P= .004). A large nodular volume was a predictor (P < .05) of microcalcifications and intranodular vascularization, whereas an absent halo sign and a solid nodule were found less frequently in nodules with larger volumes. CONCLUSIONS: Our results show that routine preoperative malignancy risk evaluation of presumably benign thyroid nodules is of little value when performed on patients exposed to iodine deficiency.

Targeted therapy in refractory thyroid cancer: current achievements and limitations.

Thyroid cancer refractory to conventional treatments lacks effective treatment. Targeted therapy is an emerging therapeutic strategy for these cancers, based on preliminary promising results. Tyrosine kinase inhibitors target both specific oncogenic pathways involved in thyroid cancer progression and aspecific mechanisms such as neoangiogenesis. They are generally well tolerated and most adverse events have low-to-moderate severity. Other classes of drugs have been tested, alone or in combination with tyrosine kinase inhibitors, but so far the results have been limited. The aim of this article is to describe the benefits and limitations of innovative drugs that are currently under investigation in patients with refractory thyroid cancer.

Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology.

CONTEXT: Fine-needle aspiration cytology (FNAC) is the gold standard for the differential diagnosis of thyroid nodules but has the limitation of inadequate sampling or indeterminate lesions. OBJECTIVE: We aimed to verify whether search of thyroid cancer-associated protooncogene mutations in cytological samples may improve the diagnostic accuracy of FNAC. STUDY DESIGN: One hundred seventy-four consecutive patients undergoing thyroid surgery were submitted to FNAC (on 235 thyroid nodules) that was used for cytology and molecular analysis of BRAF, RAS, RET, TRK, and PPRgamma mutations. At surgery these nodules were sampled to perform the same molecular testing. RESULTS: Mutations were found in 67 of 235 (28.5%) cytological samples. Of the 67 mutated samples, 23 (34.3%) were mutated by RAS, 33 (49.3%) by BRAF, and 11 (16.4%) by RET/PTC. In 88.2% of the cases, the mutation was confirmed in tissue sample. The presence of mutations at cytology was associated with cancer 91.1% of the times and follicular adenoma 8.9% of the time. BRAF or RET/PTC mutations were always associated with cancer, whereas RAS mutations were mainly associated with cancer (74%) but also follicular adenoma (26%). The diagnostic performance of molecular analysis was superior to that of traditional cytology, with better sensitivity and specificity, and the combination of the two techniques further contributed to improve the total accuracy (93.2%), compared with molecular analysis (90.2%) or traditional cytology (83.0%). CONCLUSIONS: Our findings demonstrate that molecular analysis of cytological specimens is feasible and that its results in combination with cytology improves the diagnostic performance of traditional cytology.