Search

Purpose: Presence of venous vascular invasion is a criterion of intermediate risk of recurrence in papillary thyroid carcinoma (PTC). However, the presence and type of vascular invasion (lymphatic or venous) is often underreported and its impact on PTCs without other risk features remains unknown. The aim of this study was to evaluate the impact of both lymphatic and venous invasion on the risk of recurrence/persistence on otherwise low-risk PTCs., Methods: Retrospective study including patients with otherwise low-risk PTCs but with vascular invasion, diagnosed between 2013 and 2019. The persistence/recurrence during the follow-up was evaluated. Pathology was reviewed to confirm the presence of lymphovascular invasion and determine the type of invasion., Results: A total of 141 patients were included. Lymphovascular invasion was confirmed in 20.6%. After surgery, 48.9% (N = 69) of the patients received radioactive iodine (RAI). The median follow-up time was 4 [3-6] years. Overall, 6 (4.2%) patients experienced persistent/recurrent disease in the neck, including 3 with lymphovascular invasion, confirmed as "only lymphatic". Overall, patients with tumors harboring lymphovascular invasion had sensibly more persistent/recurrence disease compared with those without lymphovascular invasion (10.3% vs 2.7%, p = 0.1), especially in the subgroup of patients not treated with RAI (20% vs 1.6%, p = 0.049) [OR 15.25, 95% CI 1.24-187.85, p = 0.033]., Conclusion: Lymphovascular invasion, including lymphatic invasion only, is associated with a sensibly higher risk of persistent/recurrent disease in otherwise low-risk PTCs, namely in patients not treated with RAI. Lymphatic invasion could have a role in risk-stratification systems for decision making., (© 2023. The Author(s).)

Background: Patients with metastatic medullary thyroid cancer (MTC) who progressed under tyrosine kinase inhibitors can benefit from an alkylating agent such as dacarbazine or temozolomide. Patient Findings: We describe two patients with metastatic MTC who developed a hypermutant phenotype after alkylating agent treatment. This phenotype was characterized by a high tumor mutational burden (TMB) and a mutational signature indicative of alkylating agent mutagenesis (single-base substitution 11). Both patients received immune checkpoint inhibitors, with partial morphological responses, clinical benefit, and progression-free survival of 6 and 9 months, respectively. Summary and Conclusions: Based on the described observations, we suggest that a hypermutant phenotype may be induced after alkylating agent treatment for MTC and the sequential use of immunotherapy should be further explored as a treatment option for MTC patients with increased TMB.

Background: The response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown., Methods: To test the hypothesis that preconditioning of the immune system modulates the therapeutic effect of ICIs, we used a murine model where PTC and iodine exacerbated thyroiditis (IET) can be induced in a temporally predictable fashion. A total of 122 mice were divided into 3 experimental groups. In the first one, named concomitant IET and PTC (No.=40), IET, and PTC were induced at the same time; in the second one, named pre-existing IET (No.=44), IET was induced prior to the induction of PTC; in the third one, named no IET (No.=38), only PTC was induced. Following disease induction, mice of each group were treated with anti-PD-1 antibody, anti-lymphocyte activation gene 3 antibody (anti-Lag3), anti-T-cell immunoglobulin and mucin domain 3 antibody (anti-Tim3), or IgG control. Ten weeks after the initial ICI injection, mice were sacrificed to collect the thyroid gland for histological analysis, to quantify the incidence and burden of PTC, and to perform high-throughput single-cell RNA sequencing of infiltrating CD45 + cells., Results: In the concomitant IET and PTC group, ICI treatment reduced PTC incidence (p=0.002 comparing treatment with any ICI vs control), while it had no effect in the pre-existing IET and no IET groups. Single-cell sequencing of thyroidal CD45 + cells showed that the different ICIs tested had both specific and shared effects on all the components of the thyroidal immune cell infiltrate. The shared effect of the tested ICIs was dependent on the presence of pre-existing versus concomitant IET. In the context of concomitant IET, ICI treatment resulted in the modulation of a greater number of pathways related to both innate and adaptive immunity., Conclusions: Response to ICIs depends on the status of the immune system of the treated individual. Modulation of the immune system should be explored as a tool to improve response to ICIs in patients with PTC or other forms of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies, remaining controversial. Experimental evidence has recently shown that pre-existing thyroiditis has a beneficial effect on PTC growth and progression by a distinctive expansion of effector memory CD8 T cells. Although the link between inflammation and PTC might involve different components of the immune system, a deep characterization of them which includes T cells, B cells and tertiary lymphoid structures, Mye-loid cells, Neutrophils, NK cells and dendritic cells will be desirable. The present review article considers the role of the adaptive and innate immune response surrounding PTC in the context of Hashimoto's thyroiditis. This review will focus on the current knowledge by in vivo and in vitro studies specifically performed on animals' models; thyroid cancer cells and human samples including (i) the dual role of tumor-infiltrating lymphocytes; (ii) the emerging role of B cells and tertiary lymphoid structures; (iii) the role of myeloid cells, dendritic cells, and natural killer cells; (iv) the current knowledge of the molecular biomarkers implicated in the complex link between thyroiditis and PTC and the potential implication of cancer immunotherapy in PTC patients in the context of thyroiditis.

Background: The pathogenesis of thyroiditis caused by immune-checkpoint inhibitors (ICIs) such as antiprogrammed death receptor-1 (PD-1) and anticytotoxic T lymphocyte antigen-4 (CTLA-4) is incompletely understood. To gain mechanistic insights, we developed a mouse model of ICI-related thyroiditis and assessed the clinical, hormonal, and cytokine profiles. Methods: Forty NOD-H2 h4 mice, 112 days old at the start of the experiments, were divided into two sequential cohorts. In the first one (No. = 21), mice were injected with both anti-PD-1 and anti-CTLA-4 checkpoint inhibitors while drinking either regular water or iodine-supplemented water. In the second cohort (No. = 19), mice were injected with either anti-PD-1 or anti-CTLA-4 while drinking iodine-supplemented water. Mice were sacrificed two months after the initial injection to collect thyroid gland for histopathology (to assess thyroiditis severity) and flow cytometry (to identify immune cell subsets and tissue-resident memory T cell markers). Mice were also studied before sacrifice to determine thyroid area and structure (by ultrasound), thyroid function (serum total thyroxine, thyrotropin, thyroid antibodies), and cytokine profile (by bead-based Luminex technology). Results: Thyroiditis was more severe upon PD-1 than CTLA-4 blockade ( p  = 0.01) and significantly correlated with the number of CD45 + cells infiltrating the thyroid (cumulative odds ratio [OR] 1.2 [95% confidence interval, CI 1.1-1.3], p  < 0.001, that is 20% greater odds of a higher severity score for every 170-unit increase in CD45 infiltrating cells). Thyroiditis was instead more prevalent (100% vs. 63%, p  < 0.01) in the anti-CTLA-4 mice, which also showed a larger thyroid area (17 ± 8.2 mm) than those treated with anti-PD-1 (11 ± 4.2 mm) and controls ( p  < 0.01). Serum IL-6 was markedly increased upon PD-1 blockade (40 pg/mL at baseline, 198 pg/mL on day 172), an increase not seen in the anti-CTLA-4 group ( p  = 0.01). IL-6 mirrored thyroiditis severity, with highest serum values found in greatest histopathology scores (cumulative OR 1.1 [CI 1.02-1.15], p  = 0.009). GM-CSF and MIP1β increased more in the anti-CTLA-4 group ( p  < 0.001 for both), whereas the other cytokines did not differ among the treatment groups. Conclusions: The study reports a mouse model of thyroiditis induced by PD-1 blockade and, comparing it to the anti-CTLA-4 model, uncovers distinctive histopathological, sonographic, hormonal, and immunological features, offering biomarkers, such as serum IL-6, that could be used in the clinical setting.

Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies yet remains controversial. Some studies, in fact, have suggested a protective effect of thyroiditis while others have not. We generated a mouse model where PTC and thyroiditis develop in a predictable manner, combining the oncogenic drive of the BRAFv600E mutation (inducible by tamoxifen) to the thyroiditis susceptibility of the NOD.H2h4 strain (inducible by iodine). A total of 113 NOD.H2h4&#95;TPO-CRE-ER&#95;BRAFV600E mice (50 followed throughout lifetime and 63 sacrificed at 16 weeks post tamoxifen) were used to determine whether the PTC phenotype differs when thyroiditis precedes or coincides with the onset of PTC. Mice with pre-existing thyroiditis lived longer (median survival of 28.2 weeks post tamoxifen) than those with concomitant (25.6 weeks) or no (24.5 weeks) thyroiditis (P < 0.01 by Laplace regression). PTC developed less frequently (33%) in the pre-existing thyroiditis group than the concomitant (100%) or no (100%) thyroiditis groups (P < 0.001 by chi-squared) and showed less aggressive histopathological features. The intratumoral mononuclear cell infiltration was more prominent in mice with pre-existing thyroiditis (P = 0.002 vs the other groups) and sustained by a significant expansion of effector memory CD8 + T cells and CD19 + B cells. These findings shed light on the controversial PTC-thyroiditis association and emphasize the contribution of intratumoral T and B lymphocytes to the evolution of PTC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The uninjured murine heart contains a heterogeneous population of macrophages with disparate ontogenies and functions. These macrophages are often associated with blood vessels and can be subclassified based on the expression of CC chemokine receptor 2 (CCR2) and major histocompatibility complex class II (MHC-II). The biological cues that modulate these macrophage pool subpopulations have not been completely identified. It has been recently shown that a sub-population of circulating naïve B cells adheres to the myocardial microvasculature. We hypothesized that B cells might modulate the phenotype of myocardial macrophages. To test this hypothesis, we analyzed both the relative location of B cells and macrophages in myocardial histological section and the prevalence of myocardial macrophage subsets in hearts from B cell-deficient mice (μMT) and mice depleted of B cells through administration of an anti-CD20 antibody. We found that B cells pause in the microvasculature in proximity of macrophages and modulate the number of myocardial CCR2 - MHC-II high cells. Through in vitro studies we found that this is likely the result of a paracrine effect of B cells on the expression of MHC-II in CCR2 - cells. These results reveal an unexpected relationship between B cells and resident macrophages and, highlighting a direct intramyocardial effect of circulating B cells, challenge the currently held belief that naïve recirculating B lymphocytes merely shuttle between lymphoid stations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. Methods: To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). Results: The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. Conclusions: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

The synthesis, and spectroscopic and structural characterization of bridged dicationic derivatives of benzo-2,1,3-selenadiazoles are reported. The chloride salt of [H 4 C 6 NSeN-CH 2 -CH 2 -NSeNC 6 H 4 ] 2+ crystallizes forming a macrocyclic structure in which two cations are bridged by SeCl chalcogen bonds (ChBs), with a third chloride at the centre of the macrocycle. The structure of [1,2-(H 4 C 6 NSeN) 2 -C 6 H 10 ]Cl 2 consists of two selenadiazolium cations linked by a chiral cyclohexane and capped by SeCl ChBs. Tetrafluoroborate salts of a xylene bridge crystallize in two pseudopolymorphs in which the cations form SeF ChBs in an anti- or syn-conformation. The triflate salt of ethylene-bridged cations dimerizes through the formation of the [Se-N] 2 supramolecular synthon with SeO ChBs capping the second selenium atom. In contrast, [H 4 C 6 NSeN-CH 2 -CH 2 -CH 2 -NSeNC 6 H 4 ](CF 3 SO 3 ) 2 only forms SeO ChBs.

Lenvatinib is a tyrosine kinase inhibitor (TKI) with antiproliferative and antiangiogenic effects indicated for the treatment of progressive, locally advanced or metastatic progressive thyroid carcinoma, refractory to radioactive iodine therapy. Antiangiogenic therapies induce ischemic necrosis of tumor tissue, with increased risk of hemorrhagic complications. The management of hemorrhagic risk is based on precautionary measures and for any surgical procedure, it is advised to interrupt the treatment in order to avoid complications. 'Flare-up' of tumor activity may follow TKI interruption. However, it is not known if continuing TKIs during minimally invasive interventions is safe. We report here the first case in which an embolization of metastasis is performed without interrupting lenvatinib treatment. The procedure was successful and free of complications.

The relationship between the three-dimensional (3D) nuclear telomere architecture and specific genetic alterations in papillary thyroid carcinoma (PTC), in particular in cancer stem-like cells (CSLCs), has not yet been investigated. We isolated thyrospheres containing CSLCs from B-CPAP, K1, and TPC-1 PTC-derived cell lines, representative of tumors with different genetic backgrounds within the newly identified BRAF V600E -like PTC subgroup, and used immortalized normal human thyrocytes (Nthy-ori 3.1) as control. We performed quantitative fluorescence in situ hybridization, 3D imaging, and 3D telomere analysis using TeloView software to examine telomere dysfunction in both parental and thyrosphere cells. Among the 3D telomere profile, a wide heterogeneity was observed, except for telomere intensity. Our findings indicate that CSLCs of each cell line had longer telomeres than parental cells, according to telomere intensity values, which correlate with telomere length. Indeed, the thyrosphere cells had lower numbers of lower-intensity telomeres (≤5,000 arbitrary fluorescent units, a.u.), compared with parental cancer cells, as well as parental control cells, (p < 0.0001). The B-CPAP thyrospheres showed a decreased number of higher intensity telomeres (>17,000 a.u.) than K1 and TPC-1 cells, as well as control cells (p < 0.0001). By selecting PTC-derived cell lines with different genetic backgrounds characteristic of BRAF V600E -like PTC subgroups, we demonstrate that thyrosphere cells with BRAF V600E and TP53 mutations show shorter telomeres than those harboring RET/PTC or BRAF V600E and wild-type TP53. Hence, our data reveal a trend towards a decrease in telomere shortening in CSLCs, representing the early cancer-promoting subpopulation, as opposed to parental cells representing the tumor bulk cells., (© 2018 Wiley Periodicals, Inc.)

Background: The impact of free triiodothyronine (FT 3 )/free thyroxine (FT 4 ) ratio on survival in hospitalized geriatric patients was recently described. Up today, there are no data regarding the prognostic role of FT 3 /FT 4 ratio in patients with advanced cancer. We evaluated the impact of FT 3 /FT 4 ratio on survival in patients with refractory colorectal cancer (CRC) treated with regorafenib., Methods: Patients with metastatic CRC treated with regorafenib with available clinical data and baseline measurement of FT 3 , FT 4 , and thyroid-stimulating hormone (TSH) were considered eligible. Exploratory analyses included subjects treated at Istituto Oncologico Veneto. A confirmatory analysis was planned based on FT 3 /FT 4 ratio tertile results, and a validation cohort was built on data retrieved from University of Cagliari., Results: In an exploratory cohort, the median overall survival in patients with low, intermediate, and high FT 3 /FT 4 ratios, according to tertiles' value, was 4.8, 5.0, and 7.6 months, respectively (P = .003). The differences were significant in the multivariate model (hazard ratio, 0.43; 95% confidence interval, 0.28-0.68; P = .0003). Confirmatory results were obtained in a validation cohort, both in univariate (P = .0002) and in multivariate (hazard ratio, 0.56; 95% confidence interval, 0.36-0.88; P = .0118) models., Conclusions: High baseline FT 3 /FT 4 ratio is strongly associated to better outcome in patients with progressive metastatic CRC treated with regorafenib. Further investigations are ongoing to draw definitive conclusions regarding a potential predictive effect., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Walter E. Dandy (1886-1946) was an outstanding neurosurgeon who spent his entire career at the Johns Hopkins Hospital. After graduating from medical school in 1910, he completed a research fellowship in the Hunterian laboratory with Harvey Cushing and then joined the Department of Surgery as resident, rising to the rank professor in 1931. Dandy made several contributions that helped building the neurosurgical specialty, most famously the introduction of pneumo-ventriculography to image brain lesions for which he received a Nobel prize nomination. He also performed many pituitary surgeries, although his role in this area is less known and overshadowed by that of Cushing's., Purpose: This retrospective cohort study was designed to unveil Dandy's pituitary work and place it in the context of the overall pituitary surgeries performed at the Johns Hopkins Hospital., Methods: Pituitary surgery data were obtained by screening the paper and electronic surgical pathology records of the Department of Pathology, as well as the general operating room log books of the Johns Hopkins Hospital housed in the Chesney Medical Archives., Results: A total of 3211 pituitary surgeries associated with a pathological specimen were performed between February 1902 and July 2017 in 2847 patients. Most of the surgeries (2875 of 3211 89%) were done by 21 neurosurgeons. Dandy ranks 4th as number of surgeries, with 287 pituitary operations in 35 years of activity. He averaged 8 pituitary surgeries per year, a rate that positions him 6th among all Hopkins neurosurgeons. With the exception of his first operation done in July 1912 while Cushing was still at Hopkins, Dandy approached the pituitary gland transcranially, rather than transphenoidally. The majority of Dandy's pituitary patients had a pathological diagnosis of pituitary adenomas, followed by craniopharyngiomas and sellar cysts. In the decades Dandy operated, pituitary surgeries represented 0.56% of the total Johns Hopkins surgeries, a percentage significantly greater (p < 0.001) than the 0.1% observed in modern days. Dandy's pituitary clinical work was matched by important experimental studies done in the early stages of his career., Conclusions: This study highlights the role of Dandy as an important contributor to advance our understanding of pathophysiology and treatment of pituitary diseases.

The aim of this study was to carry out genetic screening of the MEN1, CDKN1B and AIP genes, both by direct sequencing of the coding region and multiplex ligation-dependent probe amplification (MLPA) assay in the largest monocentric series of Italian patients with Multiple Endocrine Neoplasia type 1 syndrome (MEN1) and Familial Isolated Hyperparathyroidism (FIHP). The study also aimed to describe and compare the clinical features of MEN1 mutation-negative and mutation-positive patients during long-term follow-up and to correlate the specific types and locations of MEN1 gene mutations with onset and aggressiveness of the main MEN1 manifestations. A total of 69 index cases followed at the Endocrinology Unit in Pisa over a period of 19 years, including 54 MEN1 and 15 FIHP kindreds were enrolled. Seven index cases with MEN1 but MEN1 mutation-negative, followed at the University Hospital of Cagliari, were also investigated. FIHP were also tested for CDC73 and CaSR gene alterations. MEN1 germline mutations were identified in 90% of the index cases of familial MEN1 (F-MEN1) and in 23% of sporadic cases (S-MEN1). MEN1 and CDC73 mutations accounted for 13% and 7% of the FIHP cohort, respectively. A CDKN1B mutation was identified in one F-MEN1. Two AIP variants of unknown significance were detected in two MEN1-negative S-MEN1. A MEN1 positive test best predicted the onset of all three major MEN1-related manifestations or parathyroid and gastro-entero-pancreatic tumors during follow-up. A comparison between the clinical characteristics of F and S-MEN1 showed a higher prevalence of a single parathyroid disease and pituitary tumors in sporadic compared to familial MEN1 patients. No significant correlation was found between the type and location of MEN1 mutations and the clinical phenotype. Since all MEN1 mutation-positive sporadic patients had a phenotype resembling that of familial MEN1 (multiglandular parathyroid hyperplasia, a prevalence of gastro-entero-pancreatic tumors and/or the classic triad) we might hypothesize that a subset of the sporadic MEN1 mutation-negative patients could represent an incidental coexistence of sporadic primary hyperparathyroidism and pituitary tumors or a MEN1 phenocopy, in our cohort, as in most cases described in the literature.

Sorafenib, a tyrosine kinase inhibitor, is approved for the treatment of advanced differentiated thyroid carcinoma (DTC). Resistance to sorafenib may appear under treatment and may be associated with increased aggressiveness of the neoplasia. The present study reports the case of a 65-year-old male who underwent total thyroidectomy for a follicular thyroid carcinoma, Hürthle cell variant, in February 2005. Until January 2010, the patient received four consecutive 131 I doses (total dose, 612 mCi) for increased serum thyroglobulin (Tg) and initial faint lung uptake (which eventually became undetectable). Subsequently, the patient developed several sequential bone (humerus, rib and skull), adrenal and lung metastases, the majority of which were surgically removed. Histological examination in all cases revealed evidence of DTC metastases that were strongly positive for Tg, as revealed by immunohistochemistry. In March 2014, sorafenib therapy was initiated, but it was discontinued 10 months later to allow an undelayable prostatectomy. Immediately upon surgery, the patient developed a large metastatic lesion in the right gluteal muscle, whose biopsy revealed undifferentiated neoplasia of epithelial origin, and the patient succumbed shortly afterwards. An extensive comparative search for biochemical and molecular markers was performed on all available tissues (primary tumor, and differentiated and undifferentiated metastases). The primary tumor and all the available metastases exhibited the same molecular oncogenic markers (namely, the RAS mutation p.Q61R and the telomerase promoter mutation C228T). In addition, the undifferentiated metastasis exhibited a p53 mutation. The present study reports a case of a sudden acceleration of DTC metastatic progression following sorafenib discontinuation, which could have been due to the emergence of sorafenib-resistant undifferentiated p53-positive tumor cell clones.

The association between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) has been originally suggested by retrospective pathological studies and has recently been re-evaluated and proposed on the basis of several fine-needle aspiration cytology (FNAC) studies. In FNAC studies, the association between HT and PTC is based on the comparison of anti-thyroid autoantibodies (ATA) (anti-thyroperoxidase [TPOAb] and anti-thyroglobulin [TgAb]), thyroid function (TSH), and cytology with histology of thyroid nodules and lymphocytic thyroid infiltration (LTI) of operated thyroid glands. Most of the pathological studies found a high prevalence rate of PTC in HT. In most FNAC studies, the risk ratio of PTC in HT patients was evaluated using multivariate statistical analysis: increased TSH levels represented the main and common independent risk factor of malignancy, although it resulted not consistently related to HT. On the other hand, several studies provided a positive relationship between ATA and PTC, particularly with TgAb. Two recent FNAC studies from the same referral center clearly demonstrated an independent risk for thyroid malignancy conferred by both TPOAb and TgAb, confirming the role of increased TSH levels, and found a significant association between PTC and ATA and diffuse LTI at histology. These studies are consistent with the hypothesis that autoimmune thyroid inflammation and increased serum TSH concentration may be involved in thyroid tumor growth. The complex relationship between HT and PTC, which involves immunological/hormonal pathogenic links, needs to be further investigated with prospective studies.

Objective: Thyroid dysfunction has been reported during Regorafenib (Reg) administration, but no detailed study is presently available., Design: Prospective, observational cohort study. Patients with documented metastatic colorectal cancer and progression of disease during or within 3 months after the last standard therapy, with no evidence and history of previous thyroid disease were enrolled., Methods: Twenty-five consecutive patients were evaluated before and 8-50 weeks after initiating Reg therapy by monthly clinical, ultrasound and laboratory (thyrotropin (TSH), free thyroxine (fT4), antithyroglobulin (TgAb) and antithyroid peroxidase (TPOAb)) evaluation., Results: Thirteen/25 patients (52%) became hypothyroid (TSH: 12.5 ± 4.01 IU/L, range: 4.6-22.0) within 5 months of therapy. TPOAb became detectable (99-155 IU/mL) in 2/25 (8%) patients. Thyroid volume progressively decreased (from 8.6  ±  2.2 mL to 4.9 ± 2.4 mL after 5 months of Reg therapy, P  < 0.0001). The progression-free survival (PFS) was longer in patients developing hypothyroidism (43 weeks) than in those remaining euthyroid (17 weeks, P  < 0.01). Fatigue (the most common general serious Reg adverse event) was associated with hypothyroidism severity and reversed after levothyroxine therapy (L-T4)., Conclusions: Reg rapidly causes hypothyroidism in about 50% of patients and in a minority of them also triggers thyroid autoimmunity. Reg-induced hypothyroidism was strictly related to fatigue, easily reversed by L-T4 administration and associated to longer survival. These results suggest that prompt recognition of hypothyroidism in patients with severe fatigue may prevent unnecessary Reg dose reduction or withdrawal., (© 2017 European Society of Endocrinology.)

Human thyroid cancer derived cell lines are widely used to study the mechanisms involved in thyroid carcinogenesis. However, there is limited availability of non-cross-contaminated cancer cell lines derived from papillary thyroid carcinoma (PTC), and the B-CPAP cell line is one of the few such lines. B-CPAP cells have been genetically and cytogenetically well-characterized, but details of their stemness features remain uncertain. Considering that this cell line is extensively used for in vitro studies on thyroid tumorigenesis, we broaden its functional and molecular profiles as well as the tumorigenic capacity. We used functional assays (sphere-forming capacity and efficiency), assessed self-renewal and propagation efficiency and tested in vivo tumorigenicity in Hsd:Athymic Nude-Foxn1 nu mice. Expression of markers of stemness, differentiation, and epithelial-mesenchymal transition were estimated at RNA and protein levels in adherent parental cells and sphere-forming cells. Functional aspects and stemness features were compared with normal thyrocytes. Protein expression of xenograft tumors was evaluated by immunohistochemistry. B-CPAP sphere-forming cells were able to form thyrospheres theoretically indefinitely in an appropriate serum-free medium, reverting to the adherent parental cell phenotype when cultured in differentiation medium. Different expression of ALDH1-A1 and CD44 stemness markers and TTF-1 and CK19 differentiation markers allowed discrimination between isolated sphere-forming cells and adherent parental cells, indicating that sphere-forming cells retained stem-like features. In keeping with these observations, tumorigenicity assays confirmed that, relative to parental adherent cells, thyrospheres had enhanced capacity to initiate xenograft tumors. Thyrospheres from normal cell line retained very low functional capacity, as well as different stemness markers expression compared to tumor thyrospheres. Our findings may constitute a useful background to develop an in vitro model for assessing the origin and progression of papillary thyroid carcinoma bearing BRAF V600E and TERT promoter mutations., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Regorafenib is an orally administered multikinase inhibitor indicated for the treatment of heavily pretreated metastatic colorectal cancer patients with good performance status, albeit less than 50% treated patients achieve disease stabilisation or better at the first radiological evaluation. In addition to that a particularly broad spectrum of toxicities (experienced as G3 or more NCI CTCAE graded by 50% of patients treated) have led to reconsider its widespread use in the majority of patients. We retrospectively collected data about the magnitude of off-target effects experienced during the first 8-weeks of regorafenib monotherapy and analysed their correlation with overall survival, progression free survival and disease control rate. Our findings suggest that skin rash (Exp (B): 0.52, p = 0.0133) or hypothyroidism (Exp (B): 0.11, p = 0.0349) were significantly correlated with improved overall survival at multivariate regression analysis. It was also demonstrated a statistically significant role of diarrhea as predictor of improved survival but its independent prognostic role was lost at multivariate analysis (Exp (B): 0.63, p = 0.162). This is the first analysis showing a potential correlation between the onset of these forms of side effects and regorafenib efficacy, however sample size limitations and the retrospective nature of our analysis prevent us from drawing definitive conclusions.