Differentiated and anaplastic thyroid carcinoma: Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE This is a review of the major changes in the American Joint Committee on Cancer staging manual, eighth edition, for differentiated and anaplastic thyroid carcinoma. All patients younger than 55 years have stage I disease unless they have distant metastases, in which case, their disease is stage II. In patients aged 55 years or older, the presence of distant metastases confers stage IVB, while cases without distant metastases are further categorized based on the presence/absence of gross extrathyroidal extension, tumor size, and lymph node status. Patients aged 55 years or older whose tumor measures 4 cm or smaller (T1-T2) and is confined to the thyroid (N0, NX) have stage I disease, and those whose tumor measures greater than 4 cm and is confined to the thyroid (T3a) have stage II disease regardless of lymph node status. Patients aged 55 years or older whose tumor is confined to the thyroid and measures 4 cm or smaller (T1-T2) with any lymph node metastases present (N1a or N1b) have stage II disease. In patients who demonstrate gross extrathyroidal extension, the disease is considered stage II if only the strap muscles are grossly invaded (T3b); stage III if there is gross invasion of the subcutaneous tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve (T4a); or stage IVA if there is gross invasion of the prevertebral fascia or tumor encasing the carotid artery or internal jugular vein (T4b). The same T definitions will be used for both differentiated and anaplastic thyroid cancer, but the basic premise of the anatomic stage groups will remain the same. CA Cancer J Clin 2018;68:55-63. © 2017 American Cancer Society.

Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women.

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, ptrend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, ptrend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, ptrend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.

Effects of a mobile health intervention based on a multitheoretical model of health behavior change on anxiety and depression, fear of cancer progression, and quality of life in patients with differentiated thyroid cancer: A randomized controlled trial.

BACKGROUND: Despite the high cure rate of differentiated thyroid cancer (DTC), patients endure side effects from treatment and psychological distress, impacting their quality of life. The potential of mobile health (mHealth) interventions to address these issues remains unexplored. The purpose of this study is to develop an mHealth intervention based on the Multi-Theoretical Model of Health Behavior Change (MTM) and evaluate its impact on reducing anxiety, depression, fear of cancer progression, and enhancing quality of life in DTC patients. METHODS: A single-blind, single-center, prospective, randomized controlled trial was conducted. One hundred and eleven consecutive DTC patients from Harbin Medical University's Fourth Hospital were enrolled from March 2023 to March 2024. Participants were randomized into a control group and an intervention group that received a 3-month mHealth intervention based on MTM theory. Outcomes were assessed using web-based questionnaires at baseline and conclusion. RESULTS: One hundred four patients with DTC completed the study, with 7 lost to follow-up (6.3%). The intervention group experienced a significant drop in PHQ-4 scores post-MTM-mHealth intervention (P < .026), with no change in the control group, demonstrating a significant difference. The intervention group also had significantly lower anxiety (P < .015) and depression (P < .032) scores compared to controls. All PHQ-4 scores improved in the intervention group except for "Little interest or pleasure in doing things." Anxiety levels were significantly lower in the intervention group (P < .026) but remained unchanged in controls. The control group exhibited a significant increase in FCR-4 scores at follow-up, differing from the intervention group (P < 0.001). Quality of life scores did not differ at baseline but saw a significant improvement in the intervention group, while the control group experienced no significant change. The intervention group had higher VAS scores (P < .030) and greater health education satisfaction across all dimensions (P < .019). CONCLUSIONS: The MTM-based mHealth intervention significantly benefits DTC patients by reducing anxiety, fear of cancer recurrence, and improving quality of life, though its effect on depression requires further investigation. TRIAL REGISTRATION: China Clinical Trial Registry ChiCTR2200064321.

Tyrosine kinase inhibitors for radioiodine refractory differentiated thyroid cancer: A systematic review and meta-analysis.

BACKGROUND: The poor overall prognosis of radioiodine refractory thyroid cancer is an inevitable challenge in managing this disease. A series of trials have demonstrated the antitumor activity of tyrosine kinase inhibitors (TKIs) in radioiodine refractory differentiated thyroid cancer (RAIR-DTC). However, the available evidence cannot determine the optimal choice of TKI in RAIR-DTC. METHODS: This study searched PubMed, EMBASE, Cochrane databases, and the ClinicalTrials website. The Cochrane bias risk tool was used to assess the risk of bias, and to evaluate randomized clinical trials (RCT) of RAIR-DTC patients treated with the TKI system. Outcomes, including progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were reported. RESULTS: Seven studies involving 1310 patients with RAIR-DTC was conducted to compare the PFS and OS of various TKI monotherapies with placebo. The results showed that all TKI monotherapies had a statistically significant benefit in terms of PFS compared with placebo, with lenvatinib demonstrating the greatest benefit (hazard ratio [HR] 0.19, 95% credible interval [CrI] 0.14-0.25). In terms of OS, only apatinib (HR 0.42, 95% CrI 0.18-0.97) and anlotinib (HR 0.36, 95% CrI 0.18-0.73) showed statistically significant benefits compared with placebo. TKIs also had a higher incidence of AEs of grade 3 or higher compared with placebo. The findings suggest that lenvatinib may be the preferred TKI for the treatment of RAIR-DTC, although its high incidence of AEs should be considered. The results also indicate that TKI treatment may be similarly effective in RAIR-DTC patients with BRAF or RAS mutations and in those with papillary or follicular subtypes of the disease, regardless of prior TKI treatment. CONCLUSIONS: The results of this meta-analysis suggest that targeted therapy with TKIs may be beneficial for patients with radioiodine-refractory advanced or metastatic differentiated thyroid cancer. Among the TKIs analyzed, lenvatinib appeared to be the most effective at improving PFS, although it also had the highest incidence of AEs. Further research through direct randomized controlled trials is needed to determine the optimal choice of TKI for treating patients with RAIR-DTC. This study is beneficial for formulating patients' treatment plans and guides clinicians' decision-making.

[68Ga]Ga-LNC1007 versus 2-[18F]FDG in the evaluation of patients with metastatic differentiated thyroid cancer: a head-to-head comparative study.

PURPOSE: This head-to-head comparison study aimed to compare the performance of [68Ga]Ga-FAPI-RGD (LNC1007) and 2-[18F]FDG PET/CT in the evaluation of patients with metastatic differentiated thyroid cancer (mDTC). METHODS: Ten unexplained hyperthyroglobulinemia (UHTg) patients and 20 patients with definite metastatic lesions of thyroid cancer (DmDTC) were enrolled in the study. All patients underwent both [68Ga]Ga-LNC1007 and 2-[18F]FDG PET/CT within 1 week. The final diagnosis was based on histopathological results and a comprehensive evaluation of laboratory tests and multimodal imaging characteristics. RESULTS: In patients with UHTg, [68Ga]Ga-LNC1007 PET/CT detected more metastatic lymph nodes (LNs) (17 vs. 15, P = 0.317) and lung lesions (2 vs. 0) than 2-[18F]FDG. In patients with DmDTC, [68Ga]Ga-LNC1007 PET/CT also detected more true positive lesions than 2-[18F]FDG (Total: 133 vs. 103, LN: 20 vs. 15, lung: 18 vs. 10, bone: 87 vs.73). [68Ga]Ga-LNC1007 PET/CT demonstrated significantly higher SUVmax (Total: 6.30 vs. 3.84, LN: 8.28 vs. 4.82, Lung: 3.31 vs. 1.49, Bone: 5.73 vs. 3.87, all P < 0.05) and TBR (Total: 6.92 vs. 4.93, LN: 6.48 vs. 4.16, Lung: 5.16 vs. 2.57, Bone: 7.22 vs. 5.41, all P < 0.05) in true positive lesions compared to 2-[18F]FDG. Specifically, the sensitivity of [68Ga]Ga-LNC1007 PET/CT was higher than that of 2-[18F]FDG in detecting lung and bone metastases (94.7% vs. 52.6% and 100% vs. 83.9%, all P < 0.05). [68Ga]Ga-LNC1007 PET/CT exhibited better specificity and accuracy in diagnosing LNs (96.9% vs. 66.7% and 96.3% vs. 68.5%, all P < 0.05). However, the specificity of [68Ga]Ga-LNC1007 for bone metastasis was inferior to 2-[18F]FDG (15.4% vs. 88.5%, P < 0.05). CONCLUSION: Compared with 2-[18F]FDG, [68Ga]Ga-LNC1007 PET/CT could detect more metastatic lesions, with higher SUVmax and TBR, in patients with mDTC. [68Ga]Ga-LNC1007 had better accuracy in the diagnosis of LN and lung metastasis. Trial registration ClinicalTrials.gov NCT05515783. Registered 01 May 2022. URL of registry https://classic. CLINICALTRIALS: gov/ct2/show/NCT05515783.

Dynamic risk assessment in patients with differentiated thyroid cancer.

The current approach for patients with differentiated thyroid carcinoma should be individualized according to the risk of recurrence, and this stratification could be used to identify the risk of persistent/recurrent disease in three scenarios: preoperatively, immediately postoperatively, and during long-term follow-up. The initial risk of recurrence will tailor the management of the patient in the preoperative and immediate postoperative settings, while the dynamic risk, which considers the responses to treatment, could guide the decision-making process for remnant ablation and long-term management.This review provides a summary of the existing information regarding the dynamic risk of recurrence and recommended management for patients with differentiated thyroid cancer. The application of this approach is essential to avoid unnecessary treatments for most patients who will have a favorable prognosis. On the other hand, it allows specific therapeutic interventions for those patients at high risk of recurrence. In the future, analysis of tumor biology and prospective studies will surely improve the accuracy of recurrence risk prediction.

Current practice in intermediate risk differentiated thyroid cancer - a review.

Although the overall prognosis for differentiated thyroid cancer (DTC) is excellent, a subset of patients will experience disease recurrence or may not respond to standard treatments. In recent years, DTC management has become more personalized in order to enhance treatment efficacy and avoid unnecessary interventions.In this context, major guidelines recommend post-surgery staging to assess the risk of disease persistence, recurrence, and mortality. Consequently, risk stratification becomes pivotal in determining the necessity of postoperative adjuvant therapy, which may include radioiodine therapy (RIT), the degree of TSH suppression, additional imaging studies, and the frequency of follow-up.However, the intermediate risk of recurrence is a highly heterogeneous category that encompasses various risk criteria, often combined, resulting in varying degrees of aggressiveness and a recurrence risk ranging from 5 to 20%. Furthermore, there is not enough long-term prognosis data for these patients. Unlike low- and high-risk DTC, the available literature is contradictory, and there is no consensus regarding adjuvant therapy.We aim to provide an overview of intermediate-risk differentiated thyroid cancer, focusing on criteria to consider when deciding on adjuvant therapy in the current context of personalized approach, including molecular analysis to enhance the accuracy of patient management.

Influencing Factors of Urinary Iodine Concentration Before and After Radioiodine Therapy for Differentiated Thyroid Cancer: An Initial Exploration of the Relationship With Therapeutic Efficacy.

OBJECTIVE: To investigate the impact of urinary iodine concentration (UIC) and post-stimulatory thyroglobulin (ps-Tg) levels on the therapeutic efficacy of differentiated thyroid cancer (DTC) patients after initial radioiodine therapy, and to analyze the validity of these indicators as prognostic factors. METHODS: A total of 213 DTC patients received initial radioiodine therapy from June 2022 to September 2023. Demographic data and UIC were collected before and after therapy. Thyrotropin, thyroglobulin (Tg), and thyroglobulin antibody levels were assessed. Iodine uptake rate was measured, and therapeutic efficacy was evaluated 6 months post-therapy. Statistical tests were used for data comparison, and logistic regression analysis for response factors. RESULTS: Post-therapy UIC and pre-post UIC difference were significantly correlated with Tg levels but not with reaching excellent response (ER) indicated by suppression of Tg levels below 0.2 ug/L. Ps-Tg levels related to therapeutic efficacy, while UIC did not correlate with outcomes. ROC curve analysis found optimal ps-Tg cut-off points for the low-intermediate and high-risk groups classified by primary tumor size, invasion, metastasis, and pathological type. CONCLUSION: Post-treatment UIC and pre-post UIC difference correlate with ps-Tg levels. Ps-Tg levels are an associated factor for DTC, but UIC changes, despite correlation with ps-Tg, are not significantly related to outcomes and cannot be used as a prognostic factor.

ObjectiveTo investigate the impact of urinary iodine concentration (UIC) and post-stimulatory thyroglobulin (ps-Tg) levels on the therapeutic efficacy of differentiated thyroid cancer (DTC) patients after initial radioiodine therapy, and to analyze the validity of these indicators as prognostic factors.Methods213 DTC patients received initial radioiodine therapy from June 2022 to September 2023. Demographic data and UIC were collected before and after therapy. Thyrotropin, thyroglobulin, and thyroglobulin antibody levels were assessed. Iodine uptake rate was measured, and therapeutic efficacy evaluated 6 months post-therapy. Statistical tests were used for data comparison and logistic regression analysis for response factors.ResultsPost-therapy UIC and pre-post UIC difference were significantly correlated with thyroglobulin levels but not with reaching excellent response (ER) where suppression of Tg levels below 0.2ug/l. Ps-Tg levels related to therapeutic efficacy, while UIC did not correlate with outcomes. ROC curve analysis found optimal ps-Tg cut-off points for low-intermediate and high-risk groupsclassified by primary tumor size, invasion, metastasis, and pathological type.ConclusionPost-treatment UIC and pre-post UIC difference correlate with ps-Tg levels. Ps-Tg levels are an associated factor for DTC, but UIC changes, despite correlation with ps-Tg, are not significantly related to outcomes and cannot be used as a prognostic factor.

Surgical management of rare tumors (Part 1).

With an annual cumulative occurrence of approximately 15,000 in North America, all childhood cancers are rare. Very rare cancers as defined by both the European Cooperative Study Group for Rare Pediatric Cancers and the Children's Oncology Group fall into two principal categories: those so uncommon (fewer than 2 cases/million) that their study is challenging even through cooperative group efforts (e.g., pleuropulmonary blastoma and desmoplastic small round cell tumor) and those that are far more common in adults and therefore rarely studied in children (e.g., thyroid, melanoma, and gastrointestinal stromal tumor). Treatment strategies for these latter tumors are typically based on adult guidelines, although the pediatric variants of these tumors may harbor different genetic signatures and demonstrate different behavior. If melanoma and differentiated thyroid cancer are excluded, other rare cancer types account for only 2% of the cancers in children aged 0 to 14. This article highlights several of the most common rare tumor types.

Salvage radiofrequency ablation followed by external beam radiotherapy for inoperable recurrent differentiated thyroid cancer.

PURPOSE: The treatment of recurrent thyroid cancer with critical organ invasion is challenging. The combination of radiofrequency ablation (RFA) and external beam radiation therapy (EBRT) has been proposed as an effective option. This study evaluates outcomes for inoperable residual/recurrent differentiated thyroid cancer (rDTC) patients treated with RFA followed by EBRT. MATERIALS AND METHODS: Patients with rDTC treated with RFA followed by EBRT were retrospectively studied. RFA was performed using a free-hand, 'moving-shot' technique under US or CT guidance. For lesions invading critical structures intolerant to 'en bloc' high-temperature RFA, limited-field EBRT using 6- or 10-MV photons was used for adjuvant treatment at a dose of 66 Gy in 33 daily fractions. Toxicities and outcomes were reviewed. RESULTS: Between April 2020 and January 2022, 11 patients with 14 rDTC lesions underwent RFA followed by EBRT. Five patients had metastatic lesions at rDTC diagnosis. With a median follow-up period of 33.7 months, all patients maintained locoregional control, while achieving a 2-year survival rate of 90.9%. This combined treatment achieved a volume reduction ratio of 92.1% ± 5.1%. The mean nadir thyroglobulin level in patients without initial distant metastases after treatment was 1.40 ± 0.81 ng/ml. Regarding treatment-related complications, one patient (9%) experienced temporary hoarseness after RFA, grade 2 radiation dermatitis occurred in 3 patients (27.2%), and grade 2 dysphagia was noted in 4 patients (36.4%). No grade 3 or greater toxicities occurred. CONCLUSIONS: Salvage RFA followed by EBRT is feasible, effective and safe for patients with rDTC.

Ablation Rates and Long-Term Outcome Following Low-Dose Radioiodine for Differentiated Thyroid Cancer in the West of Scotland: A Retrospective Analysis.

OBJECTIVE: Low-dose radioiodine is an accepted means of remnant ablation in patients with low- to intermediate-risk differentiated thyroid cancer (DTC) based on the results of several phase III trials. We evaluated the rate of ablation success and long-term recurrence outcomes in the first 3 years of implementing this practice at our institution. METHODS: Patients who received 1.1 to 1.2 gigabecquerel (30 millicurie) were identified retrospectively from the radionuclide database, January 1, 2012, to December 31, 2014, inclusive. Successful ablation was defined as Iodine-131uptake <0.1% on diagnostic scan and Tg level <2.0 ng/mL at 6 to 8 months after treatment. Follow-up was conducted annually for 10 years and relapse rates were determined based on the available clinical, radiological, and biochemical information. RESULTS: We identified 114 patients, 109 of whom had dual response assessment. The median age was 43 years (range, 14 to 80 years). Almost 70% had T1 or T2 tumors, with T3 and T4 tumors recorded in 27% and 2.5% of patients, respectively. Nodal staging was performed in just over 30% and involved lymph nodes were detected in 21% (N1a 8% and N1b 13%). Ablation success based on diagnostic scan alone was 94.7% (108/114), Tg alone 94.7% (108/114), and on both modalities was 90.4% (103/114). CONCLUSION: Remnant ablation was achieved in >90%, and the corresponding clinical recurrence rate was only 1.8% despite the inclusion of patients with locally advanced disease. Low-dose radioiodine is effective and may be suitable for a proportion of patients with higher-risk DTC.

One-year Thyroglobulin Levels as a Predictive Measure for Recurrence and Need for Continued Surveillance in Treated Differentiated Thyroid Cancer.

PURPOSE: Patients with differentiated thyroid cancer (DTC) undergo posttreatment surveillance for several years. We aim to better define an excellent response to therapy using thyroglobulin (TG) and thyroglobulin antibody (TGab) levels at 1-year to tailor appropriate length of surveillance. METHODS: Patients with DTC who underwent surgical treatment with or without adjuvant radioiodine therapy were followed with standard American Thyroid Association surveillance. TG and TGab levels at 1-year posttreatment were used to define 3 cohorts: undetectable TG (<0.5 ng/mL), detectable TG (≥0.5 ng/mL), and positive TGab (>1 IU/mL). The rates of structural recurrence and the trends of TG and TGab were compared. RESULTS: Of the 268 study patients at 1-year, 210 (78%) had undetectable TG, 29 (11%) had detectable TG, and 29 (11%) had positive TGab. The overall structural recurrence rate was 18/268 (7%): undetectable TG at 1 year, 3/210 (1%), detectable TG at 1-year, 11/29 (38%), and positive TGab at 1-year, 4/29 (13%). At the last follow-up, 196/210 (93%) patients with undetectable TG at 1-year continued to have undetectable TG levels. Regarding patients with detectable TG at 1-year, in 11/29 (38%), detectable TG was converted to undetectable TG at the last follow-up without additional treatments. Of those with positive TGab at 1 year, 6/29 (21%) had resolution of TGab and undetectable TG levels at the last follow-up without additional treatments. CONCLUSION: One year after treatment of DTC, TG levels <0.5 ng/mL, in the absence of TGab, are associated with an exceedingly low risk of recurrence suggesting that further surveillance may not be warranted.

Effect of Thyroid-Stimulating Hormone Suppression Therapy on Cardiac Structure and Function in Patients With Differentiated Thyroid Cancer After Thyroidectomy: A Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppression therapy on cardiac structure and function in patients with differentiated thyroid cancer (DTC) following thyroidectomy. METHODS: Two investigators independently searched the PubMed, Embase, Cochrane Library, and Web of Science databases for relevant studies published from inception to January 6, 2023, without any restrictions on language. Standard mean differences and 95% confidence intervals were calculated using fixed or random effects models. Thirteen clinical outcomes were analyzed, mainly evaluating cardiac morphology, systolic function, and diastolic function. RESULTS: Thirteen studies were included in the quantitative analysis. Compared to healthy controls, left ventricular mass index, left ventricular posterior wall thickness, interventricular septal thickness, and isovolumic relaxation time values increased; the ratio of E-wave velocity to A-wave velocity and E-wave velocity values decreased. The left ventricular ejection fraction and cardiac output did not change in patients with DTC who underwent long-term TSH suppression therapy. Interventricular septal thickness values were significantly correlated with the duration of TSH suppression therapy. CONCLUSION: Long-term TSH suppression therapy leads to cardiac hypertrophy and impaired cardiac diastolic function in patients with DTC. These changes may be related to the duration of TSH suppression therapy. Large prospective studies with long follow-up periods are needed to validate these findings.

Early Structural, Biochemical, and Metabolic Responses to Anlotinib in Patients With Progressive Radioactive Iodine Refractory Differentiated Thyroid Cancer.

OBJECTIVE: We aimed to assess the early efficacy of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer at the structural, biochemical, and metabolic levels. METHODS: Ten eligible patients were prospectively enrolled to receive anlotinib. Their responses were assessed at 6 weeks. Apart from the structural response according to Response Evaluation Criteria in Solid Tumors version 1.1, the biochemical response was assessed by serum thyroglobulin (Tg), and the metabolic response was assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) according to the European Organization for Research and Treatment of Cancer criteria. A safety profile was recorded. RESULTS: Structurally controlled disease (20% partial response + 80% stable disease) was observed in all patients. The median longest diameter of target lesions shrank from 20.8 mm (IQR, 14.9-27.5) to 17.0 mm (IQR, 14.1-23.7) (P < .001), and the average shrinkage rate was -15.1 ± 14.1%. Sharp serum Tg reduction by 72.8 ± 16.4% was observed in 8 measurable patients. The 18F-FDG PET/CT-mapped glucose metabolic response was not quite comparable to the structural response, with 90% of the patients having controlled disease (30% partial metabolic response + 60% stable metabolic disease), whereas 10% presented progressive metabolic disease. The most common treatment-emergent adverse events (AEs) were hypertension (100%) and proteinuria (70%). Most AEs were grade 1 or 2, whereas grade 3 AEs occurred only in hypertension. CONCLUSION: Anlotinib is generally well tolerated and can bring early disease control within the initial 6 weeks of treatment. The sharp biochemical response suggests Tg to be an early sensitive biomarker to anlotinib, whereas the heterogeneous metabolic response might play a complementary role.

Development and validation of survival nomograms for patients with differentiated thyroid cancer with distant metastases: a SEER Program-based study.

BACKGROUND: We aimed to develop a nomogram model of overall survival (OS) and cancer-specific survival (CSS) in patients with differentiated thyroid cancer with distant metastases, and to evaluate and validate the nomogram. Also, its prognostic value was compared with that of the 8th edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8SS). METHODS: Patients with distant metastatic differentiated thyroid cancer (DMDTC) from 2004 to 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) Program to extract the clinical variables used for analysis. A total of 906 patients were divided into a training set (n = 634) and validation set (n = 272). OS and CSS were selected as the primary end point and secondary end point. LASSO regression analysis and multivariate Cox regression analysis were applied to screen variables for constructing OS and CSS nomograms for survival probability at 3, 5, and 10 years. Nomograms were evaluated and validated using the consistency index (C-index), time-dependent receiver operator characteristic (ROC) curves, area under the ROC curve, calibration curves, and decision curve analysis (DCA). The predictive survival of the nomogram was compared with that of AJCC8SS. Kaplan-Meier curves and log-rank tests were used to evaluate the risk-stratification ability OS and CSS nomograms. RESULTS: CS and CSS nomograms included six independent predictors: age, marital status, type of surgical procedure, lymphadenectomy, radiotherapy, and T stage. The C-index for the OS nomogram was 0.7474 (95% CI = 0.7199-0.775), and that for the CSS nomogram was 0.7572 (0.7281-0.7862). The nomogram showed good agreement with the "ideal" calibration curve in the training set and validation sets. DCA confirmed that the survival probability predicted by the nomogram had high clinical predictive value. The nomogram could stratify patients more accurately, and showed more robust accuracy and predictive power, than AJCC8SS. CONCLUSIONS: We established and validated prognostic nomograms for patients with DMDTC, which had significant clinical value compared with AJCC8SS.

Germline polymorphisms of the NOD2 pathway may predict the effectiveness of radioiodine in differentiated thyroid cancer treatment.

PURPOSE: Differentiated thyroid cancer (DTC) presents a complex clinical challenge, especially in patients with distant metastases and resistance to standard treatments. This study aimed to investigate the influence of specific genes and their germline single nucleotide polymorphisms (SNPs) linked to both inflammatory processes and other neoplasms on the clinical and pathological characteristics of DTC, particularly their potential impact on radioiodine (RAI) treatment efficacy. METHODS: This retrospective analysis involved a cohort of 646 patients diagnosed with DTC after thyroidectomy. Study covering 1998-2014, updated in 2023, included 567 women and 79 men (median age: 49; range: 7-83). SNP selection targeted functional significance, while mutational status was assessed by pyrosequencing for comprehensive characterization. Patient genetic profiles were assessed for associations with disease characteristics, RAI response, and cancer pathology. RESULTS: Significant correlations emerged between certain SNPs and DTC features. Notably, the NOD2 c.802 T > C variant (rs2066842) was identified as a marker distinguishing between papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Moreover, the c.802 T allele was associated with an enhanced response to RAI treatment, indicating a more substantial decrease in posttreatment stimulated thyroglobulin (sTg) concentrations. The NFKB1A allele c.126A (rs696) exhibited connections with lower FTC stages and a reduced probability of multifocality. CONCLUSION: This study explored the molecular mechanisms of particular SNPs, highlighting the role of NOD2 in innate immunity and the stress response, and its potential impact on RAI efficacy. This research underscores the clinical promise of SNP analysis and contributes to personalized treatment strategies for DTC, emphasizing the relevance of genetic factors in cancer progression and treatment outcomes.

Clinical impact of a dose-escalation strategy for lenvatinib in differentiated thyroid cancer.

BACKGROUND:  Treatment options for patients with differentiated thyroid cancer (DTC) who experience disease progression on lenvatinib treatment are limited. Although dose escalation of treatment with tyrosine kinase inhibitors at disease progression has been reported across cancer types, clinical significance in patients with DTC has not been investigated. METHODS: We retrospectively reviewed patients with DTC who experienced disease progression on lenvatinib treatment from September 2011 to June 2022. We compared subjects who received dose-escalation treatment with standard treatment of termination at the time of initial disease progression. The escalated dose was decided by referencing to the previous effective and tolerated dose. RESULTS: Thirty-three patients were identified, 15 with dose escalation and 18 with lenvatinib termination. In both groups, the starting dose of lenvatinib was 24 mg/day, and the median dose at initial disease progression was 10 mg/day. In the former, the median dose escalation was 6 mg/day (range: 4-12). Objective response rate, clinical benefit rate by escalation, and median treatment duration of the dose-escalation phase were 13.3%, 73.3%, and 9.9 months (95% confidence interval [CI] 5.71-27.6), respectively. Median overall survival from initial disease progression was significantly longer in the dose-escalation group (median OS: 20.4 months [95% CI 7.0-NA] vs. 3.9 months [95% CI 1.7-7.9], log-rank p-value; 0.0004, hazard ratio; 0.22 [95% CI 0.09-0.55]). There were no grade 5 adverse events, and one patient discontinued due to a grade 3 lung abscess. CONCLUSION: The dose-escalation strategy appears to be a safe and effective treatment option after disease progression in patients treated with lenvatinib for DTC.

Clinical impact of proteinuria on renal function and treatment outcomes in patients with radioiodine-refractory thyroid cancer treated with lenvatinib.

Proteinuria has been described as a major on-target adverse event of lenvatinib, although its long-term impact on renal function and clinical outcomes remains unclear. We conducted a retrospective observational study to assess renal function and prognosis in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) receiving lenvatinib. Overall, 70 patients with RR-DTC treated with lenvatinib were enrolled. When proteinuria was observed, the dose and schedule of lenvatinib were adjusted to achieve a urine protein-to-creatinine ratio (UPCR) of less than 3.5 g/gCre according to the study protocols of recent pivotal trials. In total, 50 (71%) and 25 (36%) patients presented with any-grade and grade 3 proteinuria, respectively. Multivariate analysis revealed that age [>65; odds ratio (OR) 8.24, 95% confidence interval (CI) 1.74-39.00, p < 0.01], history of diabetes mellitus (OR 7.79, 95% CI 1.31-46.20, p = 0.02), and hypertension (OR 4.07, 95% CI 1.22-13.60, p = 0.02) were significantly associated with the development of grade 3 proteinuria. Overall, the median estimating glomerular filtration rate (eGFR) gradually decreased every 3 months during treatment. However, no significant deterioration in eGFR was observed in patients with grade 3 proteinuria compared with patients with grades 0-2 proteinuria until 48 months. Patients who developed proteinuria had better survival outcomes than those without proteinuria. In conclusion, the proteinuria grade was not significantly associated with decreased eGFR under UPCR monitoring in our study. Therefore, lenvatinib can carefully be continued targeting UPCR of less than 3.5 g/gCre.

Radioiodine therapy in advanced differentiated thyroid cancer: Resistance and overcoming strategy.

Thyroid cancer is the most prevalent endocrine tumor and its incidence is fast-growing worldwide in recent years. Differentiated thyroid cancer (DTC) is the most common pathological subtype which is typically curable with surgery and Radioactive iodine (RAI) therapy (approximately 85%). Radioactive iodine is the first-line treatment for patients with metastatic Papillary Thyroid Cancer (PTC). However, 60% of patients with aggressive metastasis DTC developed resistance to RAI treatment and had a poor overall prognosis. The molecular mechanisms of RAI resistance include gene mutation and fusion, failure to transport RAI into the DTC cells, and interference with the tumor microenvironment (TME). However, it is unclear whether the above are the main drivers of the inability of patients with DTC to benefit from iodine therapy. With the development of new biological technologies, strategies that bolster RAI function include TKI-targeted therapy, DTC cell redifferentiation, and improved drug delivery via extracellular vesicles (EVs) have emerged. Despite some promising data and early success, overall survival was not prolonged in the majority of patients, and the disease continued to progress. It is still necessary to understand the genetic landscape and signaling pathways leading to iodine resistance and enhance the effectiveness and safety of the RAI sensitization approach. This review will summarize the mechanisms of RAI resistance, predictive biomarkers of RAI resistance, and the current RAI sensitization strategies.

Impact of lateral cervical lymph node metastasis on lung metastasis in pediatric thyroid cancer: A correlation study.

BACKGROUND: Thyroid cancer (TC) frequently manifests with lung metastases in the pediatric population, occurring at a significant rate of 30 %. This study aims to evaluate the impact of regional patterns of cervical lymph node metastases on lung metastases in pediatric TC. METHODS: Retrospective analysis was conducted on data from pediatric TC patients spanning the years 2000 to 2018. We compared the rates of lymph node metastasis (LNR), the number of lymph node metastases, and the number of dissected lymph nodes in the central and lateral cervical regions between patients with and without lung metastases. Statistical methods were employed to adjust for confounders during hypothesis testing. RESULTS: A total of 227 pediatric patients, with a median age of 15.12 ± 2.84 years, were included in the study. Of these, 202 (89 %) exhibited LN metastasis, with 40(17.62 %) patients presenting with lung metastasis. Patients with lung metastases were found to be younger (13.40 ± 3.11 vs. 15.50 ± 2.64, p < 0.001), had larger primary tumor diameters (3.49 ± 1.98 vs. 2.31 ± 1.45, p < 0.001), and exhibited a higher number of lymph node metastases (23.40 ± 10.75 vs. 14.65 ± 13.16, p < 0.001). Notably, in patients with LN metastases, the presence of >12 lateral cervical lymph node metastases emerged as a significant risk factor for lung metastases. Among children with metachronous lung metastases, the median time to detection of lung metastases was 43 (12-132) months, and they appeared to receive a greater proportion of radioactive iodine (RAI) treatment compared to those with synchronous lung metastases. CONCLUSION: Lateral cervical lymph node metastasis independently predicts the likelihood of lung metastases in pediatric TC. Furthermore, our findings emphasize the importance of thorough examination of the lungs during follow-up, particularly when the number of metastatic lateral cervical lymph nodes exceeds 12.