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Purpose Typically formulated by investigators from “world centres of excellence,” differentiated thyroid carcinoma (DTC) management guidelines may have more limited applicability in settings of less expert care and fewer resources. Arguably the world’s leading DTC guidelines are those of the American Thyroid Association, revised in 2009 (“ATA 2009”) and 2015 (“ATA 2015”). To further explore the issue of “real-world applicability” of DTC guidelines, we retrospectively compared indications for ablation using ATA 2015 versus ATA 2009 in a two-centre cohort of ablated T1–2, M0 DTC patients ( N  = 336). Based on TNM status and histology, these patients were low–intermediate risk, but many ultimately had other characteristics suggesting elevated or uncertain risk. Methods Working by consensus, two experienced nuclear medicine physicians considered patient and treatment characteristics to classify each case as having “no indication,” a “possible indication,” or a “clear indication” for ablation according to ATA 2009 or ATA 2015. The physicians also identified reasons for classification changes between ATA 2015 versus ATA 2009. Classification was unblinded, but the physicians had cared for only 138/336 patients, and the charts encompassed September 2010–October 2013, several years before the classification was performed. Results One hundred of 336 patients (29.8 %) changed classification regarding indication for ablation using ATA 2015 versus ATA 2009. Most reclassified patients (70/100) moved from “no indication” or “clear indication” to “possible indication.” Reflecting this phenomenon, “possible indication” became the largest category according to the ATA 2015 classification (141/336, 42.0 %, versus 96/336, 28.6 %, according to ATA 2009). Many reclassifications were attributable to multiple clinicopathological characteristics, most commonly, stimulated thyroglobulin or anti-thyroglobulin antibody levels, multifocality, bilateral involvement, or capsular/nodal invasion. Conclusions Regarding indications for ablation, ATA 2015 appears to better “acknowledge grey areas,” i.e., patients with ambiguous or unavailable data requiring individualised, nuanced decision-making, than does ATA 2009.

A hallmark of cancer is the ability of tumor cells to avoid immune destruction. Activated immune cells in tumor microenvironment (TME) secrete proinflammatory cytokines and chemokines which foster the proliferation of tumor cells. Specific antigens expressed by cancer cells are recognized by the main actors of immune response that are involved in their elimination (immunosurveillance). By the recruitment of immunosuppressive cells, decreasing the tumor immunogenicity, or through other immunosuppressive mechanisms, tumors can impair the host immune cells within the TME and escape their surveillance. Within the TME, cells of the innate (e.g., macrophages, mast cells, neutrophils) and the adaptive (e.g., lymphocytes) immune responses are interconnected with epithelial cancer cells, fibroblasts, and endothelial cells via cytokines, chemokines, and adipocytokines. The molecular pattern of cytokines and chemokines has a key role and could explain the involvement of the immune system in tumor initiation and progression. Thyroid cancer-related inflammation is an important target for diagnostic procedures and novel therapeutic strategies. Anticancer immunotherapy, especially immune checkpoint inhibitors, unleashes the immune system and activates cytotoxic lymphocytes to kill cancer cells. A better knowledge of the molecular and immunological characteristics of TME will allow novel and more effective immunotherapeutic strategies in advanced thyroid cancer.

Context: Little is known about prostate-specific membrane antigen (PSMA) expression in patients with cervical involvement of differentiated thyroid cancer (DTC). Objective: We investigated PSMA expression in neck persistent/recurrent disease (PRD) using immunohistochemistry and the association with radioiodine (RAI) or 18-fluorodeoxyglucose ([.sup.18]FDG) uptake, and patient outcome. Design, Setting, and Patients: Data from 44 consecutive DTC patients who underwent neck reoperation from 2006 to 2018 in a comprehensive cancer center. Main Outcome Measure(s): Immunostaining was performed with vascular endothelial marker CD31 and PSMA. PSMA expression was quantified using the immunoreactive score (IRS). RAI and [.sup.18]FDG uptake were assessed before surgery using posttherapeutic RAI scintigraphy and [.sup.18]FDG positron emission tomography with computed tomography. Mean follow-up after reintervention was 6.5 [+ or -] 3.7 years. Results: Thirty patients (68%) showed at least 1 PSMA-positive lesion (IRS [greater than or equal to] 2) with similar proportions in RAI-positive and RAI-negative patients (75% vs 66%). In RAI-negative patients, however, the proportion of PSMA-positive disease (79% vs 25%, P < 0.01) and the mean IRS (4.0 vs 1.0, P = 0.01) were higher in [.sup.18]FDG-positive than in [.sup.18]FDG-negative patients. Furthermore, mean IRS was higher in patients [greater than or equal to] 55 years, large primary tumors (>40 mm) or aggressive subtypes, and was correlated with structural disease at last follow-up. Strong PSMA expression (IRS [greater than or equal to] 9) was associated with shorter progression-free survival (PFS). Conclusions: Our findings show that PSMA expression was present in two-thirds of patients with neck PRD, that it was related to poor prognostic factors and that very high expression was associated with poorer PFS. This preliminary study may offer new perspectives for the management of RAI-refractory DTC. Key Words: prostate-specific membrane antigen, differentiated thyroid cancer, poorly differentiated thyroid cancer, immunohistochemistry, PSMA staining, radioiodine-refractory

Telomerase reverse transcriptase promoter ( TERT p) mutations are associated with non-radioiodine avidity. However, the role of these mutations in the clinical outcomes of patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) remains unknown. Herein, we aim to analyze gene mutations and clinical manifestations to verify TERT p’s role in driving disease progression to RAIR-DTC and clinical outcomes. Next-generation sequencing data and clinical data were obtained from 243 patients with DTC. Of the 25 patients with TERT p mutations, 80% (20/25) had RAIR-DTC. RAIR-DTC was significantly less prevalent in patients with BRAF V600E (9/143, 6.3%) than those with both BRAF V600E and TERT p mutations (14/17, 82.4%). Patients with RAIR-DTC harboring both BRAF V600E and TERT p mutations were more likely to have > 3 distant metastatic sites (85.7%, 12/14) than those with BRAF V600E alone (33.3%, 3/9). Only one patient with both BRAF V600E and TERT p mutations had non-RAIR-DTC. The time from initial radioactive iodine therapy to RAIR-DTC diagnosis was significantly shorter in patients with TERT p mutations than in those without. Patients with BRAF V600E and TERT p mutations progressed faster to RAIR-DTC than those with BRAF V600E alone ( p  < 0.01). Our findings suggest that molecular testing for TERT p and other mutations like BRAF V600E may inform early diagnosis, prognosis, and treatment strategies before progression to RAIR-DTC.

Papillary thyroid cancer (PTC) and poorly differentiated thyroid cancer (PDTC) are treated with radioiodine to reduce recurrence and to treat the spread of disease. Adequate iodine accumulation in cancer tissue, iodine avidity, is important for treatment effect. This study investigated which clinical and histological tumour characteristics correlate with avidity. To quantify avidity in cancer tissue, tracer amounts of iodine-131 were given to 45 patients with cytologically confirmed thyroid cancer. At pathology grossing, representative samples of tumour and lymph nodes were taken and subjected to radioactivity quantification ex vivo to determine avidity. Afterwards, samples underwent extended pathology work-up and analysis. We found that tumoural Tg expression and Ki-67 index were correlated with avidity, whereas tumour size and pT stage were not. The histological variant of thyroid cancer was also correlated with iodine avidity. Variants associated with worse clinical prognoses displayed lower avidity than variants with better prognoses. This work provides new information on which tumours have low iodine avidity. Lower avidity in aggressive histological PTC variants may explain their overall poorer prognoses. Our findings also suggest that radioiodine dosage could be adapted to Tg expression, Ki-67 index or histological variant instead of pT stage, potentially improving the efficacy of radioiodine therapy.

INTRODUCTION: Radioiodine-refractory differentiated thyroid cancer (RAIR DTC), although rare, constitutes a real clinical challenge due to its prognosis despite a growing number of available treatment modalities. This study aimed to analyze the real-world efficacy and toxicity of lenvatinib therapy in a group of Polish patients with advanced RAIR DTC. MATERIAL AND METHODS: A group of 27 patients was eligible for lenvatinib therapy due to measurable, progressive, RAIR DTC, of whom 21 ultimately received the treatment. Treatment outcomes were assessed in terms of Response Evaluation Criteria in Solid Tumors (RECIST) as well as Kaplan-Meier estimates of overall survival and progression-free survival (PFS) for the whole cohort and for subgroups receiving lenvatinib as the first or subsequent line of targeted therapy. PFS was reported using both intention-to-treat (ITT) and per-protocol (PP) definitions, depending on whether treatment discontinuation was treated as censoring. Treatment toxicity was evaluated according toCommon Terminology Criteria for Adverse Events (CTCAE). RESULTS: Median overall survival (OS) in the whole group was 38.9 months [95% confidence interval (CI): 23.8– not reached (NR)], while one-year and two-year survival rates were 0.85 (95% CI: 0.72–1.00) and 0.63 (95% CI 0.45–0.89), respectively. ITT-PFS was 21.3 months (95% CI: 12.2–NR). One-year ITT-PFS was 0.75 (95% CI: 0.57– .00), while 2-year ITT-PFS was 0.44 (95% CI: 0.22–0.76). Similar estimates were obtained using the PP-PFS definition. All patients reported treatment-related side effects, the most common being proteinuria, weight loss, hypertension, and mucositis. CONCLUSION: This retrospective analysis of a Polish RAIR thyroid cancer cohort demonstrated very good efficacy of lenvatinib in the first-line setting, while its activity in the second-line setting, although still present, was reduced. Based on these results, we suggest that lenvatinib should again be available for the treatment of RAIR thyroid cancer in Poland.

Theranostics define diagnostic evaluations directing patient-specific therapeutic decisions. Molecular theranostics involves genomic, transcriptomic, proteomic, metabolomic and finally phenonic definitions thyroid cancer differentiation. It is the functional differentiation that determines the sensitivity and accuracy of RAI imaging as well as the effectiveness of RAI treatment. Total thyroidectomy is performed to empower an anticipated RAI treatment. A preoperative determination of the genomic and transcriptomic profile of the tumor is a strong predictor of response to therapeutic interventions. This article discusses the oncopathophysiologic basis of the theranostic risk stratification approach.

Background In the phase 2 double‐blind Study 211, a starting dose of lenvatinib 18 mg/day was compared with the approved starting dose of 24 mg/day in patients with radioiodine‐refractory differentiated thyroid cancer (RR‐DTC). Predefined criteria for noninferiority for efficacy in the 18 mg arm were not met; safety was similar in both arms. Impact of lenvatinib treatment on health‐related quality‐of‐life (HRQoL) was a secondary endpoint of Study 211. Methods Patients with RR‐DTC were randomly assigned to a blinded starting dose of lenvatinib 18 mg/day or 24 mg/day. HRQoL was assessed at baseline, every 8 weeks until Week 24, then every 16 weeks, and at the off‐treatment visit, using the EQ‐5D‐3L and FACT‐G instruments. Completion and compliance rates, mean change from baseline, and times to first and definitive deterioration were evaluated. Results Baseline EQ‐5D and FACT‐G scores, and overall changes from baseline, were comparable between patients in the lenvatinib 18 mg/day (n = 77) and 24 mg/day arms (n = 75). For the 18 mg versus 24 mg arms, least squares mean differences were −0.42 (95% CI −4.88, 4.03) for EQ‐5D‐VAS and 0.47 (95% CI −3.45, 4.39) for FACT‐G total. Time to first deterioration did not significantly favor either arm; EQ‐5D‐VAS HR [18 mg/24 mg] 0.93 (95% CI 0.61–1.40), EQ‐5D‐HUI HR [18 mg/24 mg] 0.68 (95% CI 0.44–1.05), FACT‐G total HR [18 mg/24 mg] 0.73 (95% CI 0.48–1.12). Time to definitive deterioration did not significantly favor either arm, though EQ‐5D‐VAS showed a trend in favor of the 24 mg arm (HR [18 mg/24 mg] 1.72; 95% CI 0.99–3.01); EQ‐5D‐HUI HR [18 mg/24 mg] was 0.96 (95% CI 0.57–1.63), FACT‐G total HR [18 mg/24 mg] was 0.72 (95% CI 0.43–1.21). Conclusions In Study 211, HRQoL for patients in the lenvatinib 18 mg/day arm was not statistically different from that of patients in the 24 mg/day arm. These data further support the use of the approved lenvatinib starting dose of 24 mg/day in patients with RR‐DTC. ClinicalTrials.gov Number NCT02702388. Evaluation of the impact of lenvatinib treatment on health‐related quality‐of‐life was a secondary objective of the phase 2 double‐blinded Study 211. This study compared a starting dose of lenvatinib 18 mg/day with the approved starting dose of 24 mg/day in patients with radioiodine‐refractory differentiated thyroid cancer. Health‐related quality‐of‐life of patients in the 18 mg/day arm was not statistically different from that of patients in the 24 mg/day arm. These data, combined with results from the primary analysis (where the lenvatinib starting dose of 18 mg/day did not demonstrate noninferiority to the approved starting dose of lenvatinib 24 mg/day), support the use of the approved lenvatinib starting dose of 24 mg/day in patients with radioiodine‐refractory differentiated thyroid cancer.

Thyroid cancer (TC) is the most common endocrine malignancy worldwide, with differentiated thyroid cancer (DTC) comprising the majority of cases. Surgical treatment of locally advanced DTC can be challenging, prompting the exploration of tyrosine kinase inhibitors (TKIs) to downstage the disease burden before surgery. Sorafenib and Lenvatinib have shown promising response rates in managing refractory DTC. This study aimed to assess the efficacy and safety profile of Sorafenib and Lenvatinib in the Indian population for locally advanced DTCs. A retrospective multicentric study across three Indian Endocrine surgery centres evaluated the efficacy and safety of Sorafenib and Lenvatinib in locally advanced DTC. Data from 45 patients with DTC, including demographics, treatment details, adverse effects, and outcomes, were analysed. Sorafenib and Lenvatinib demonstrated substantial efficacy, with 70.8% and 42.9% of patients achieving a partial response, respectively ( p  = 0.226). Median progression-free survival (PFS) was 30.15 months for Sorafenib and 35.54 months for Lenvatinib ( p  = 0.868). Overall survival (OS) was 28.23 months for Sorafenib and 34 months for Lenvatinib ( p  < 0.722). Adverse events (AEs) were common, with Sorafenib associated with higher AE rates (72% vs. 35.7% for Lenvatinib) and hand-foot syndrome being the most prevalent ( p  = 0.027). However, AEs did not significantly differ in causing drug discontinuation or dose reduction between the two TKIs. Sorafenib and Lenvatinib show promising results in managing advanced DTCs, with substantial efficacy and manageable AEs. Further research, including prospective studies with larger cohorts, is needed to validate these findings and optimize treatment strategies for advanced DTCs.