Juan Carlos Jaume

The advent of cancer immunotherapy opened a transformative era in oncology, shifting the focus from targeting mutated genes through precision oncology to harnessing the body’s immune system via agnostic therapies. This paradigm has demonstrated that a deeper understanding of the tumor immune microenvironment (TIME) can transcend the challenges posed by cancer’s genetic diversity and evolutionary dynamics. In the case of thyroid cancer, progress in immunotherapy has been comparatively slow. Much of the current research still centers on the genetic landscape of thyroid tumors rather than on comprehensive exploration of their TIME. The TIME, composed of immune cells such as macrophages, lymphocytes, natural killer cells, and mast cells, along with a network of signaling molecules, evolves alongside tumor growth and metastasis. It both influences and is influenced by genetic alterations, metabolic conditions, and therapeutic interventions. This dynamic crosstalk defines the clinical and biological heterogeneity of thyroid cancers; from the aggressive anaplastic thyroid carcinoma (ATC) to the more indolent papillary thyroid carcinoma (PTC). Mapping the spatial and temporal changes within the TIME offers the opportunity to design therapies that counter immune evasion and enhance treatment response. As understanding of the tumor microenvironment deepens, thyroid cancer therapy is undergoing a major shift; from strategies aimed merely at genetic mutations to integrated, combinational approaches incorporating personalized immunotherapy. Building on recent findings, which detail immune cell composition and therapeutic implications in thyroid malignancies, this review expands on the molecular and cellular mechanisms shaping the microenvironment. We highlight how oncogenic signaling, stromal remodeling, and metabolic reprogramming coordinate to influence tumor immunity, and we explore emerging strategies that aim to reengineer the tumor microenvironment for improved therapeutic outcomes.

Introduction: Thyroglobulin antibodies (Tg-Abs) are often thought to be associated with thyroid autoimmunity, and as such, a link with thyroid cancer has been found in some, but not all, studies. Tg-Abs are also found in non-autoimmune thyroid-follicular destruction. Given these contradictory results, we designed the present study. Methods: We reviewed data from patients undergoing thyroidectomy for different indications in multiple centers across Greece and the US over 10 years. We compared the incidence of thyroid cancer and its features of tumor aggressiveness among patients with positive (≥30 IU/mL) and negative (p < 0.05. Tumor size was larger, and capsular invasion and lymph node involvement were significantly more common in Tg-Abs+ subjects. Mean Tg-Abs were higher in subjects with tumors with extrathyroidal extension, capsular invasion, and lymph node involvement. On regression, Tg-Abs positivity was not associated with thyroid cancer incidence or aggressiveness, though, with the important exception of lymph node involvement (p < 0.001). Conclusions: Elevated preoperative thyroglobulin-antibody titers do not seem to affect the likelihood of developing thyroid cancer, even though they seem to be a surrogate for lymph node metastasis (as opposed to thyroid peroxidase antibodies, TPO-Abs). Further work is needed to clarify the interplay of this immune response on thyroid cancer metastatic behavior.

Introduction: Vitamin D deficiency [25(OH)D < 30 ng/mL] is widely prevalent globally and the efforts to tackle it have been rather unsuccessful to date. Despite different cutoffs used to define it, many clinicians adhere to the 2011 Endocrine Society definition. We present a special treat-to-target protocol aiming to restore and maintain vitamin D sufficiency. Methods: We reviewed the efficacy and safety of our vitamin D supplementation protocol over 5 years, and compared it to a group of patients who self-reported never taking vitamin D supplements. We recorded the baseline, 2-month, and annual 25(OH)D (D) measurements, along with subjects’ age, sex, BMI, history of osteoporosis, nephrolithiasis, nephrocalcinosis, and renal colics. According to our supplementation protocol, replenishment of vitamin D involves cholecalciferol dosing in two steps: a loading dose (LD) for 2 months and a maintenance dose (MD) thereafter. Please refer to the main text for loading and maintenance dose titration. Results: Of 8329 cases with vitamin D measurements, 2248 had adequate follow up data of 3524.5 patient-years and were included in the study: a total of 1575 intervention subjects and 673 controls, with an average follow-up of 18.8 months. Baseline vitamin D concentrations of 22.6 ng/mL (controls) did not change significantly (2 months: 22.2; 1 year: 21.7; 2 years: 22.0; 3 years: 23.8; 4 years: 21.8; and 5 years: 22.1 ng/mL), while concentrations of 21.9 ng/mL (intervention group) reached and remained 40 ng/mL (2 months: 41.0; 1 year: 39.4; 2 years: 39.0; 3 years: 39.3; 4 years: 40.4; and 5 years: 39.4 ng/mL). Vitamin D adequacy was achieved in 91.6% of patients in the intervention arm compared to only 16.9% in controls (p < 0.0001). Mean D and rates of adequacy were significantly higher over time in the intervention arm (p < 0.0001). The incidence of renal adverse events or hypervitaminosis did not differ between groups (p > 0.05). Conclusions: Our intervention protocol appears highly efficient in achieving and maintaining vitamin D adequacy over 5 years, with no increase in adverse events compared with controls, presenting it as an effective long-term strategy.

Background and Objectives: To identify clinical, ultrasound (US) and real-time elastography (RTE) characteristics indicative of malignancy in small thyroid lesions. Materials and Methods: 141 consecutive patients with incidentally discovered solid thyroid nodules (diameter ≤ 10 mm) by neck US were assessed, and RTE was performed. The nodules were classified per American (ACR-TIRADS) and European (EU-TIRADS) criteria; US-guided FNA was conducted on EU-TIRADS 5 nodules. The US and RTE features of nodules classified as benign (Bethesda II) or malignant (Bethesda V and VI) were compared. Results: 41 nodules were classified as EU-TIRADS 5. Their Fine Needle Aspiration (FNA) cytology was Bethesda II (n = 11), III-IV (n = 3), V (n = 10) or VI (n = 17). Bethesda V–VI patients had a higher rate of autoimmune thyroiditis (p = 0.015) and higher ACR-scoring points (p < 0.001) compared with Bethesda II. The elastography ratio was equal between the groups (p = 0.584). In logistic regression analysis, ACR-scoring points predicted FNA results, with an area under the curve (AUC) of 0.993 (sensitivity 92.6% and specificity of 100%). The clinical model (age, body mass index, sex, autoimmunity, L-thyroxine treatment, nodule diameter, elastography ratio) achieved an AUC of 0.744. A “mixed” model, combining clinical characteristics with the ACR scoring points, achieved perfect performance (AUC = 1.000), predicting FNA results with 100% sensitivity and specificity. Conclusions: The proposed “mixed model” can predict Bethesda V–VI in thyroid nodules <10 mm, allowing for the selection of those needing further evaluation.

Background/Objectives: Thyroid nodules are commonly found through sensitive imaging methods like ultrasonography. While most nodules are benign and asymptomatic, certain characteristics may indicate malignancy, prompting fine needle aspiration biopsy. Factors like age and gender affect cancer risk, complicating ultrasound-based risk systems. We aimed to determine whether the cytological malignancy rate of thyroid nodules could be adjusted for several clinical parameters. Methods: Data from patients aged 18 and above with thyroid nodules assessed via fine needle aspiration (FNA) were retrospectively reviewed. Malignancy classification was based on cytopathology and histopathology results. The study examined how various clinical parameters, adjusted for the ACR TI-RADS category, affected thyroid nodule malignancy rates, including age, sex, Body Mass Index (BMI), nodule size, presence of autoimmunity, and thyroxine therapy. Additionally, we analyzed the performance of ACR TI-RADS in predicting malignant cytology across different age subgroups of thyroid nodules. Results: The study included 1128 thyroid nodules from 1001 adult patients, with a median age of 48 years and predominantly female (76.68%). Malignancy rates varied across ACR TI-RADS categories, with higher rates associated with larger nodules and younger age groups. Age emerged as a significant predictor of malignancy, with a consistent decrease in the odds ratio for malignant cytology with advancing age across all ACR TI-RADS categories, indicating its potential utility in risk assessment alongside nodule size and sex. Conclusions: Raising the size threshold for recommending FNA of TR3-3 nodules and incorporating patients’ age and gender into the evaluation process could enhance the system’s accuracy in assessing thyroid nodules and guiding clinical management decisions.

In thyroid cancer, the tumor immune microenvironment (TIME) plays a crucial role in cancer development, progression and response to treatment. Like many other cancers, thyroid cancer creates a complex network of interactions with immune cells directly (cell-to-cell) and via humoral mediators (i.e., cytokines). This dynamic microenvironment undergoes constant modification, which can lead to changes in the immunophenotype that might explain cancer progression, dedifferentiation and resistance to treatment. According to the cancer immunoediting hypothesis, cancerous tumors can shape their immune microenvironment to create an immunosuppressive milieu that allows them to evade classic immune surveillance. One mechanism by which this occurs is through the reprogramming of immune cells, often shifting their phenotypes from cytotoxic to regulatory. Recent research has shed light on cellular components and molecular interactions within the thyroid cancer TIME. Immune cells such as Tumor-Associated Lymphocytes (TALs), myeloid-derived suppressor cells (MDSCs), Tumor-Associated Macrophages (TAMs) and Double-Negative (DN) T cells seem to play key roles in shaping the immune response to thyroid cancer. Additionally, cytokines, chemokines and other signaling molecules contribute to the communication and regulation of immune cells within that microenvironment. By studying these interactions, researchers aim to uncover not just potential therapeutic targets but also biomarkers of thyroid cancer that could provide clues on severity and progression. Based on that knowledge, strategies such as the use of immune checkpoint inhibitors, antigen-specific targeted immunotherapies, and immunomodulatory agents are being explored to enhance the anti-tumor immune response and overcome cancer immunosuppressive mechanisms. In this review, we analyze the available literature and provide our own experience to unravel the complexity of the thyroid immune microenvironment. Continued research in this area holds promise for improving outcomes through the identification of immune markers of severity/progression of thyroid cancer and the development of innovative immunotherapeutic approaches.

Zoupas I, et al. J Endocr Surg. 2024 Sep;24(3):61-71. https://doi.org/10.16956/jes.2024.24.3.61

Background: Vitamin D testing (VDT) and supplement use (VDS) are on the rise, but most patients remain deficient (3000 IU/day)), intake duration (short-term (2; never users: n = 5553 (80.3%), former users: n = 533 (7.7%), current users: n = 826 (12.0%). Current use of VDS was higher in females. VDT rose from 42.1% in 2014 to 92.7% in 2022, and VDA rose from 14.8% to 25.5% for the same time. VDA was found overall in n = 1511 (21.9%); Never users: n = 864 (15.6%), Former users: n = 123 (23.2%); and Current users: n = 370 (44.8%). The maximal VDA (67.9%) was found in subjects using high-dose VDS in the long term. Conclusions: Despite the significant rise in VDT and VDS use, VDA was found in a minority of patients. Prolonged use of high-dose supplements produces modest improvements in VDA.

Disclosure: R.D. Paparodis: None. D. Bantouna: None. E. Karvounis: None. S. Livadas: None. N.G. Angelopoulos: None. I. Zoupas: None. S. Imam: None. J.C. Jaume: None. Introduction: Vitamin D testing and use of supplements (VDS) has been rising constantly worldwide in the past years. Despite the ample use of resources, clinical observations suggest that the vast majority of the population remains in the deficiency range (VDD). We designed the present real world data study, to assess this paradox. Methods: We reviewed data from all patients attending our clinics between Mar-2014 and Dec-2022. We recorded the patients' gender, age, history of VDS use, duration and dose, and vitamin D measurements within 2 months from the clinic visit, when available. We assessed the percentage of patients reaching vitamin D adequacy (>30ng/ml) (VDA) by year and month of testing, by the use of VDS: in low dose (≤1200IU daily) (LD), medium dose (1201-3000IU daily) (MD) and high dose (>3000IU daily) (HD), by duration of use: short use (Results: We reviewed the charts of 10,102 consecutive patients, age 44.3±17.0 years, n=7691 females (76.1%) and n=2411 males (23.9%). Data on VDS use were available in n=8605 patients (85.2%): NU n=7212 (71.4%), FU n=5.6% and CU n=827 (8.2%). Vitamin D measurements were available in n=6912 patients (68.4%); NU n=5644 (81.7%), FU n=507 (7.3%) and CU n=761 (11.0%). Vitamin D testing was available in 42.1% of patients in 2014 and rose to 86.8% of patients in 2022, p80% during the remaining months of the year, pConclusions: Despite a continuous, significant rise in vitamin D testing, and VDS use, the majority of patients remain deficient. The only strategy that appears somewhat effective in reducing VDD is the prolonged use of VDS, and even in that scenario, it loses efficacy a few months after VDS discontinuation. New strategies are required if we are to solve this world health issue. Presentation: Thursday, June 15, 2023

Context: For some, chronic lymphocytic thyroiditis (Hashimoto thyroiditis) is an important risk factor for differentiated thyroid cancer (DTC). Surgical cohort studies even suggested a potential role for thyroid peroxidase antibodies (TPO-Abs) on that risk. Objective: Our clinical observations argued against that possibility. We designed the present study to evaluate the relationship of TPO-Abs and DTC in a large patient population. Methods: We recruited individuals who underwent thyroidectomies at 4 different clinical sites (USA: 1 clinic, 2000-2013, and Greece: 3 clinics, 2007-2021). We gathered data on TPO-Abs titers measured with commercially available chemiluminescence immunoassays, and reviewed patients’ data including surgical pathology. TPO-Abs of 34 IU/mL or greater was deemed positive (TPO+) and TPO-Abs less than 34 IU/mL was deemed negative (TPO–). Odds ratios (OR) for DTC were calculated with the Fisher exact test and P less than .05 was deemed significant. Results: We reviewed data from 8461 consecutive thyroid surgery cases. TPO-Abs titers were available for 1635 individuals: DTC n = 716 (43.8%), benign pathology n = 919 (56.2%), TPO+ n = 540 (33.0%), and TPO− n = 1095 (67.0%). DTC was found at a lower frequency in TPO+ (198/540, 36.7%) compared to TPO− (518/1095, 47.3%) patients, OR 0.64 (0.52-0.80; P < .0001). Rising TPO-Abs titers conferred protection against DTC in a linear fashion: TPO-Abs less than 10 IU/mL: 59.3%, TPO-Abs less than 34 IU/mL: 47.4%, TPO-Abs 34 to 100 IU/mL: 42.6%, TPO-Abs 100 to 500 IU/mL: 32.0%, TPO-Abs greater than 1000 IU/mL: 19.4%; P less than .0001. Conclusion: Higher TPO-Ab titers appear protective against DTC in our large multicenter cohort of patients who underwent thyroidectomies. Rising preoperative TPO-Abs titers conferred linearly increasing protection against DTC.